Relapsed Medulloblastoma in Pre-Irradiated Patients: Current Practice for Diagnostics and Treatment

Relapsed medulloblastoma (rMB) accounts for a considerable, and disproportionate amount of childhood cancer deaths. Recent advances have gone someway to characterising disease biology at relapse including second malignancies that often cannot be distinguished from relapse on imaging alone. Furthermore, there are now multiple international early-phase trials exploring drug–target matches across a range of high-risk/relapsed paediatric tumours. Despite these advances, treatment at relapse in pre-irradiated patients is typically non-curative and focuses on providing life-prolonging and symptom-modifying care that is tailored to the needs and wishes of the individual and their family. Here, we describe the current understanding of prognostic factors at disease relapse such as principal molecular group, adverse molecular biology, and timing of relapse. We provide an overview of the clinical diagnostic process including signs and symptoms, staging investigations, and molecular pathology, followed by a summary of treatment modalities and considerations. Finally, we summarise future directions to progress understanding of treatment resistance and the biological mechanisms underpinning early therapy-refractory and relapsed disease. These initiatives include development of comprehensive and collaborative molecular profiling approaches at relapse, liquid biopsies such as cerebrospinal fluid (CSF) as a biomarker of minimal residual disease (MRD), modelling strategies, and the use of primary tumour material for real-time drug screening approaches.

Sacubitril/valsartan reduces indications for arrhythmic primary prevention in heart failure with reduced ejection fraction: insights from DISCOVER-ARNI, a multicenter Italian register

Background This sub-study deriving from a multicenter Italian register (DISCOVER-ARNI) investigated whether sacubitril/valsartan in adjunction of optimal medical therapy(OMT) could reduce the rate of implantable cardioverter-defibrillator(ICD) indications for primary prevention in heart failure with reduced ejection fraction(HFrEF) according to European guidelines indications, and its potential predictors. Methods In this observational study, consecutive patients with HFrEF eligible for sacubitril/valsartan from 13 Italian centers were included. Lack of follow-up or speckle tracking data represented exclusion criteria. Demographic, clinical, biochemical and echocardiographic data were collected at baseline and after 6 months from sacubitril/valsartan initiation. Results Of 351 patients, 225(64%) were ICD carriers and 126(36%) were not ICD carriers (of whom 13 had not indication) at baseline. After 6 months of sacubitril/valsartan, among 113 non-ICD carriers despite having baseline left ventricular (LV)EF≤35% and New York Heart Asscociation(NYHA) class=II-III, 69(60%) did not show ICD indications; 44(40%) still fulfilled ICD criteria. Age, atrial fibrillation, mitral regurgitation>moderate, left atrial volume index(LAVi), and LV global longitudinal strain(GLS) significantly varied between the groups. With ROC curves, age≥75 years, LAVi≥42ml/m2 and LV GLS≥-8.3% were associated with ICD indications persistence (AUC=0.65,=0.68,=0.68 respectively). With univariate and multivariate analysis, only LV GLS emerged as significant predictor of ICD indications at follow-up in different predictive models. Conclusions Sacubitril/valsartan may provide early improvement of NYHA class and LVEF, reducing the possible number of implanted ICD for primary prevention in HFrEF. Baseline reduced LV GLS was a strong marker of ICD indication despite OMT. Early therapy with sacubitril/valsartan may save infective/hemorrhagic risks and unnecessary costs deriving from ICDs.

Utilizing CT soft-tissue markers as a screening tool for acute invasive fungal sinusitis

Objectives: Acute invasive fungal sinusitis (AIFS) is a rapidly progressive disease, whose delayed identification results in poor outcomes, especially in immunocompromised individuals. A surge in of AIFS in the wake of the COVID-19 pandemic, has lent additional morbidity and mortality to an already precarious clinical scenario. Early detection of AIFS in individuals who are symptomatic/ at risk can allow early therapy, enabling better patient outcomes. Our study aims to determine optimal soft-tissue markers on CT for the early detection of AIFS. Methods: In this case-control study, 142 patients with equal distribution of subjects were chosen based on histopathological diagnosis of AIFS; and their non-contrast CT scans were retrospectively assessed to determine the diagnostic utility of specific soft-tissue markers that would enable diagnosis of AIFS. Results: A total of 9 markers with adequate sensitivity and specificity were identified, including pterygopalatine and sphenopalatine fossae, inferior orbital fissure and nasolacrimal duct involvement, premaxillary thickening, retro-antral and orbital stranding, and infratemporal muscle edema. It was determined that the combined occurrence of any 3 out of 9 markers was 91.5% sensitive and 95.9% specific for diagnosis of AIFS (p < 0.005). Conclusion: Early, accurate detection of AIFS in predisposed individuals is possible with identification of soft-tissue markers on NECT, enabling early intervention. Advances in knowledge: Being the aggressive disease that it is, AIFS may be managed early if the index of suspicion is held high via CT imaging; which our diagnostic checklist aims at enabling.

Translational research approaches to study pediatric polycystic kidney disease

Polycystic kidney diseases (PKD) are severe forms of genetic kidney disorders. The two main types of PKD are autosomal recessive and autosomal dominant PKD (ARPKD, ADPKD). While ARPKD typically is a disorder of early childhood, patients with ADPKD often remain pauci-symptomatic until adulthood even though formation of cysts in the kidney already begins in children. There is clinical and genetic overlap between both entities with very variable clinical courses. Subgroups of very early onset ADPKD may for example clinically resemble ARPKD. The basis of the clinical variability in both forms of PKD is not well understood and there are also limited prediction markers for disease progression for daily clinical life or surrogate endpoints for clinical trials in ARPKD or early ADPKD.As targeted therapeutic approaches to slow disease progression in PKD are emerging, it is becoming more important to reliably identify patients at risk for rapid progression as they might benefit from early therapy. Over the past years regional, national and international data collections to jointly analyze the clinical courses of PKD patients have been set up. The clinical observations are complemented by genetic studies and biorepositories as well as basic science approaches to elucidate the underlying molecular mechanisms in the PKD field. These approaches may serve as a basis for the development of novel therapeutic interventions in specific subgroups of patients. In this article we summarize some of the recent developments in the field with a focus on kidney involvement in PKD during childhood and adolescence and findings obtained in pediatric cohorts.

Factors affecting rehabilitation of infants with Central Coordination Disorders during a three-month-long observation

Background Central coordination disorders (CCD) encompass various abnormalities observed in infants but early therapy may have an impact on their condition. The aim was to seek factors that may affect the early results of therapy of infants with CCD. Methods We analyzed the outcomes of a three-month period of rehabilitation of infants living with CCD. Children were treated at Non-public Specialist Healthcare Institution Medi-Reh in Kalisz in the period from 1 Jan 2014 to 31 Nov 2019. In our retrospective study results of three-month therapy of infants, aged 1 to 6 months, with CCD were analysed regards to the effectiveness and the potential impact of different factors. Therapy and assessment of children were conducted with the use of the Vojta method, which was performed during the first visit (WW) and the follow-up visit (after 3 months- 1WK). The analysis of the influence of various factors on the effect of therapy included: mother's age at the time of delivery, duration of breastfeeding, child APGAR, gestational age in which the child was born, sex of the child, birth weight, age of the child at WW, type of delivery, craniosacral therapy as an additive treatment. Results Based on the examination results from 66 medical records it was demonstrated that after active period of the therapy, improvement was observed in 54 (81.81%) (p=0.48) children (condition during WW versus 1WK among the group). The sole factor impacting improvement after 3 months was the age of the child at WW, when the child started therapy. This factor significantly (p=0.002) increased the chance of achieving improvement - by 3.2 times (OR= 3,2; CI= 95). No statistically significant differences were shown for the other studied factors. Conclusions Prompt implementation of rehabilitation in children with CCD provides a better chance of improving their motor function. The rehabilitation should be started as soon as possible after the diagnosis is constituted.

279 Medical treatment with ARNI may reduce indications for primary prevention of sudden cardiac death in heart failure with reduced ejection fraction: insights from discover-ARNI, a multicentre Italian register

Aims This sub-study deriving from a multicentre Italian register (DISCOVER-ARNI) investigated whether sacubitril/valsartan in adjunction of optimal medical therapy (OMT) could reduce the rate of implantable cardioverter-defibrillator(ICD) indications for primary prevention in heart failure with reduced ejection fraction (HFrEF) according to European guidelines indications, and its potential predictors. Methods and results In this observational study, consecutive patients with HFrEF eligible for sacubitril/valsartan from 13 Italian centres were included. Lack of follow-up or speckle tracking data represented exclusion criteria. Demographic, clinical, biochemical and echocardiographic data were collected at baseline and after 6 months of therapy. Of 351 patients, 225 (64%) were ICD carriers and 126 (36%) were not ICD carriers (of whom 13 had not indication) at baseline. After 6 months of sacubitril/valsartan, among 113 non-ICD carriers despite having baseline left ventricular (LV)EF ≤ 35% and New York Heart Association (NYHA) class = II–III, 69(60%) did not show ICD indications; 44(40%) still fulfilled ICD criteria (Figure 1). Age, atrial fibrillation, mitral regurgitation&gt;moderate, left atrial volume index (LAVi), and LV global longitudinal strain (GLS) significantly varied between the groups. With ROC curves, age ≥ 75 years, LAVi ≥ 42 ml/m2 and LV GLS ≥ −8.3% were associated with ICD indications persistence (AUC = 0.65, 0.68, and 0.68, respectively). With univariate and multivariate analysis, age and LV GLS emerged as the only significant predictors of ICD indications at follow-up. Conclusions Sacubitril/valsartan provided early improvement of NYHA class and LVEF, reducing the possible number of implanted ICD for primary prevention in HFrEF. Baseline advanced age and reduced LV GLS were markers of ICD indication despite OMT. Early therapy with sacubitril/valsartan may save infective/haemorrhagic risks and unnecessary costs deriving from ICDs.

Molecular and Biochemical Pathways Encompassing Diabetes Mellitus and Dementia

: Diabetes mellitus is a major metabolic disorder that has now emerged as an epidemic, and it affects the brain through an array of pathways. Diabetes mellitus patients can develop pathological changes in the brain, which eventually take the shape of mild cognitive impairment progressing to Alzheimer’s Disease. A number of preclinical and clinical studies demonstrate this fact, and it comes out to be those molecular pathways such as amyloidogenesis, oxidative stress, inflammation, and impaired insulin signaling are identical in diabetes mellitus and dementia. However, the critical player involved in the vicious cycle of diabetes mellitus and dementia is insulin, whose signaling, when impaired in diabetes mellitus (both type 1 and 2), leads to a decline in cognition, although other pathways are also essential contributors. Moreover, it is not only that diabetes mellitus patients indicate cognitive decline at a later stage; many Alzheimer’s Disease patients also reflect symptoms of diabetes mellitus, thus creating a vicious cycle inculcating a web of complex molecular mechanisms and hence categorizing Alzheimer’s Disease as ‘brain diabetes’. Thus, it is practical to suggest that anti-diabetic drugs are beneficial in Alzheimer’s Disease; but only smaller trials, not the larger ones, have showcased positive outcomes mainly because of the late onset of therapy. Therefore, it is extremely important to develop more of such molecules that target insulin in dementia patients along with such methods that diagnose impaired insulin signaling and the associated cognitive decline so that early therapy may be initiated and the progression of the disease be prevented.

P093 Algodystrophy in children: a case report

Background Algodystrophy is an entity very often unrecognized by pediatricians. The evolution is readily dragging and disabling in the absence of early and coordinated care. The Objective: Based on a case observed in a 10-year-old boy, the authors recall the main characteristics of the syndrome, guiding the practitioner to make the diagnosis, and implement appropriate and early therapy. Observation A 10-year-old boy with no previous medical history, presenting with neuropathic-like pain in the wrist and the hand that started a month ago without any triggers. Clinical exam noted functional impotence, a whole limb tremor, hyperesthesia as well as allodynia. The patient's hand is swollen and warm with a claw-like appearance. The rest of the body exam is normal. The laboratory markers and x-rays of the whole limb are normal. Bone scintigraphy confirms the diagnosis of wrist algodystrophy. The treatment combining corticosteroids, functional rehabilitation, and psychotherapy allowed a favorable outcome with no sequelae. Conclusion The diagnosis of algodystrophy remains too often unrecognized, and its management is sometimes inadequate. Early diagnosis and treatment improve the prognosis.

P.107 Response to the Ketogenic Diet in refractory epileptic spasms at BC Children’s Hospital

Background: Epileptic spasms (ES) are a devastating seizure type with poor neurodevelopmental outcome; 1/3 are resistant to treatment with first line therapies. Recently attention has been drawn to the ketogenic diet (KD) as a potentially effective therapy, though data regarding optimal time of initiation, and its sustained effectiveness, are lacking. Methods: Retrospective chart review of all patients with ES treated with KD at BC Children’s Hospital between 2002 and 2020 (n=28) with comparison of spasm response based on age of initiation of KD in two groups: < 12 months (n=11) and ≥ 12 months (n=17). Results: Comparing the <12 months and ≥ 12 months groups showed: unknown etiology in 9% vs 25%; spasm freedom for 3 months on KD in 18% vs 41%; median time to spasm freedom was 2 vs 6 weeks; relapse after a period of spasm freedom occurred in 66% vs 70%. Conclusions: Although more effective in children ≥ 12 months of age in the first 3 months, spasm freedom in either group was not sustained with KD. KD is recommended as early therapy for refractory ES, but this study suggests clinicians be aware the KD has limited efficacy in long-term control of ES and must be used with other therapies.