Home mechanical ventilation for children with severe neurological impairment: Parents' perspectives on clinician counselling.

AIM: To retrospectively explore the perspectives of parents of children with severe neurological impairment (SNI), such as those with severe cerebral palsy, epilepsy syndromes, and structural brain differences, on clinician counseling regarding home mechanical ventilation (HMV). METHOD: Inductive thematic analysis was performed on data from telephone interviews with parents who chose for and against HMV for their child with SNI at three academic children's hospitals across the USA. RESULTS: Twenty-six parents/legal guardians of 24 children were interviewed. Fourteen children had static encephalopathy, 11 received HMV, and 20 were alive at the time of parent interviews. Themes included how HMV related to the child's prognosis, risk of death, and integration with goals of care. Although clinicians voiced uncertainty about how HMV would impact their child, parents felt this was coupled with prescriptive/intimidating examples about the child's end of life and judgments about the child's quality of life. INTERPRETATION: While prognositc uncertainty exists, this study suggests that parents of children with SNI seek clinician counseling about HMV that considers their goals of care and views on their child's quality of life.

4-Hydroxy-7-oxo-5-heptenoic Acid Lactone Is a Potent Inducer of the Complement Pathway in Human Retinal Pigmented Epithelial Cells.

We previously discovered that oxidative cleavage of docosahexaenoate (DHA), which is especially abundant in the retinal photoreceptor rod outer segments and retinal pigmented endothelial (RPE) cells, generates 4-hydroxy-7-oxo-5-heptenoate (HOHA) lactone, and that HOHA lactone can enter RPE cells that metabolize it through conjugation with glutathione (GSH). The consequent depletion of GSH results in oxidative stress. We now find that HOHA lactone induces upregulation of the antioxidant transcription factor Nrf2 in ARPE-19 cells. This leads to expression of GCLM, HO1, and NQO1, three known Nrf2-responsive antioxidant genes. Besides this protective response, HOHA lactone also triggers a countervailing inflammatory activation of innate immunity. Evidence for a contribution of the complement pathway to age-related macular degeneration (AMD) pathology includes the presence of complement proteins in drusen and Bruch's membrane from AMD donor eyes, and the identification of genetic susceptibility loci for AMD in the complement pathway. In eye tissues from a mouse model of AMD, accumulation of complement protein in Bruch's membrane below the RPE suggested that the complement pathway targets this interface, where lesions occur in the RPE and photoreceptor rod outer segments. In animal models of AMD, intravenous injection of NaIO3 to induce oxidative injury selectively destroys the RPE and causes secretion of factor C3 from the RPE into areas directly adjacent to sites of RPE damage. However, a molecular-level link between oxidative injury and complement activation remained elusive. We now find that sub-micromolar concentrations of HOHA lactone foster expression of C3, CFB, and C5 in ARPE-19 cells and induce a countervailing upregulation of CD55, an inhibitor of C3 convertase production and complement cascade amplification. Ultimately, HOHA lactone causes membrane attack complex formation on the plasma membrane. Thus, HOHA lactone provides a molecular-level connection between free-radical-induced oxidative cleavage of DHA and activation of the complement pathway in AMD pathology.

Postradiation platinum-etoposide in adult medulloblastomas: retrospective analysis of hematological toxicity.

Aim: Adult medulloblastomas (MB) are rare, and optimal post-craniospinal irradiation (CSI) chemotherapy is not yet defined. We investigated hematological toxicity in patients treated with platinum-etoposide (EP) post-CSI. Methods: Retrospective, single-institution study to determine hematological toxicity in adult MB patients treated with EP (1995-2022). Results: Thirteen patients with a median follow-up of 50 months (range, 10-233) were analyzed. Four discontinued treatment due to toxicity, one after 1, 3 after 3 cycles. Hematological toxicities included grade 3 (5 patients) and grade 4 (6 patients). Two patients experienced post-treatment progression and died 16 and 37 months from diagnosis. Conclusion: Post-CSI EP demonstrates acceptable hematological toxicity in adult MB. However, the small cohort precludes definitive survival outcome conclusions. Prospective studies for comprehensive comparisons with other regimens are needed in this context.

Our study aimed to understand the effect of a chemotherapy combination (platinum and etoposide) on blood counts in adult patients with medulloblastoma after craniospinal radiation. Medulloblastoma is a rare brain cancer in adults. We analyzed data from 13 adult patients with medulloblastoma. The results show that the treatment leads to significant blood count-related side effects. Four of the patients discontinued their treatment early. Blood counts improved again after completion of treatment. Two patients had the tumor grow back after treatment and died later. Overall, the effect from this chemotherapy combination on blood counts was felt to be acceptable. The number of patients in this study was small, and more research is needed to determine the overall effectiveness of this treatment.

A Pilot Study Omitting Radiation in the Treatment of Children with Newly Diagnosed Wnt-Activated Medulloblastoma.

PURPOSE: Treatment of wingless (WNT)-activated medulloblastoma (WNT+MB) with surgery, irradiation (XRT), and chemotherapy results in excellent outcomes. We studied the efficacy of therapy de-intensification by omitting XRT entirely in children with WNT+MB. PATIENTS AND METHODS: Tumors were molecularly screened to confirm the diagnosis of WNT+MB. Eligible children were treated within 31 days following surgery with nine cycles of adjuvant chemotherapy per ACNS0331. No XRT was planned. The primary endpoint was the occurrence of relapse, progression, or death in the absence of XRT within the first two years after study enrollment. Four events in the first 10 evaluable patients would result in early study closure. RESULTS: Fourteen children were prescreened, and nine met the protocol definition of WNT+MB. Six of the nine eligible patients consented to protocol therapy, and five completed planned protocol therapy. The first two children enrolled relapsed shortly after therapy completion with local and leptomeningeal recurrences. The study was closed early due to safety concerns. Both children are surviving after XRT and additional chemotherapy. A third child relapsed at completion of therapy but died of progressive disease 35 months from diagnosis. Two children finished treatment but immediately received post-treatment XRT to guard against early relapse. The final child's treatment was aborted in favor of a high-dose therapy/stem cell rescue approach. Although OS at 5 years is 83%, no child received only planned protocol therapy, with all receiving eventual XRT and/or alternative therapy. CONCLUSIONS: Radiotherapy is required to effectively treat children with WNT-altered medulloblastoma. See related commentary by Gottardo and Gajjar, p. 4996.

BRAF V600E-Mutant Glioblastoma with Extracranial Metastases Responsive to Combined BRAF and MEK Targeted Inhibition: A Case Report.

Recent advancements in understanding the biology of glioblastomas (GBM) and increasing adoption of genomic sequencing in oncology practice have led to the discovery of several targetable mutations in these cancers. Among them, the BRAF V600E mutation can be found in approximately 3% of GBM. Despite the aggressive nature of GBM, metastatic disease is rarely observed. While there are growing data utilizing BRAF-targeting strategies in patients with GBM, data examining their efficacy in cases of metastatic GBM are lacking. We present the case of a 46-year-old female with GBM, isocitrate dehydrogenase (IDH)-wildtype and O6-methylguanine-DNA methyltransferase promoter (MGMT) unmethylated, BRAF V600E-mutant, and MYC amplified with extra-central nervous system spread to the spine and lung. Four months after completion of treatment with standard chemoradiation and temozolomide, the patient developed severe back pain, leading to the eventual discovery of her metastatic disease. Based on the presence of the BRAF V600E mutation, the patient was treated with and achieved an intracranial and systemic response to combination BRAF-MEK targeted inhibition for 9 months before evidence of progression.

Factors associated with a change in disposition for mental health patients boarding in an urban Paediatric emergency department.

AIM: Paediatric emergency departments (ED) nationwide experience a shared burden of boarding mental health patients. Whilst boarding, some patients have a change in disposition from hospitalization to discharge home. This phenomenon raises concern because EDs often have scarce resources for mental health patients. We sought to understand which patient and clinical factors are associated with a change in disposition outcome. METHODS: A nested age-sex-race frequency-matched case-control study was conducted including paediatric patients who presented to an urban PED for mental healthcare over a 36-month period. Control patients included patients admitted to an inpatient psychiatric facility, whilst case patients were those discharged home. Descriptive statistics and multivariable logistic regression analyses were performed to compare groups. RESULTS: Case patients were more likely to receive intramuscular Haloperidol (OR 2.2 [CI 1.1-4.4]) for agitation and a psychiatric consult (OR 2.3 [1.4-3.9]) whilst boarding. Case patients were also more likely to present with behavioural concerns (OR 1.8 [CI 1.1-3.1]) and have additional complexities such as medical comorbidities (OR 1.8 [CI 1.1-2.9]) or suicidal ideation/attempt (OR 2.6 [CI 1.1-6.1]). Amongst the most common themes for disposition change was improved patient status (58.8%). CONCLUSION: These findings suggest that boarding mental health patients have different disposition outcomes and thus may benefit from patient-specific treatment interventions. Given that patients' statuses may change during the boarding period prompting discharge to home, more focus should be directed to developing brief evidence-based practises that may be implemented in the ED and effectively bridge the gap to outpatient mental health services.