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BACKGROUND There is limited data on the longitudinal trajectories of psychiatric disorders in children with cancer and risk factors for their persistence. The current study aimed to longitudinally assess the trajectories and risk factors for anxiety and depressive symptoms and disorders in children and adolescents with cancer. METHODS Children and adolescents with cancer and their parents completed the Patient‐Reported Outcomes Measurement Information System (PROMIS) Depression and Anxiety Module and were interviewed by the semi‐structured Affective and Anxiety Modules of the Kiddie Schedule for Affective Disorders and Schizophrenia for School‐Age Children (K‐SADS), at 4 time points, 1, 4, 7, and 12 months following the diagnosis of cancer. RESULTS Of the 99 patients enrolled, 48% met criteria for anxiety and/or depressive disorders at least once during the follow‐up period. There was a significant decrease in PROMIS pediatric and parent anxiety and depression scores (all p's < 0.01) and in the rate of depressive disorders over time (p = 0.02), while rates of anxiety disorders remained stable. Anxiety PROMIS pediatric and parent scores at baseline, having brain tumors and being in the acute treatment phase significantly predicted the presences of anxiety disorders at endpoint. CONCLUSIONS Our results highlight the importance of screening for anxiety and disorders in children with cancer, especially among those with brain tumors and at the acute phase of treatment. This study aimed to longitudinally assess the trajectories and risk factors for anxiety and depressive symptoms in children and adolescents with cancer. We used a unique model of assessment combining the K‐SADS structured psychiatric interview along with the short PROMIS self and parent report at four time points during one year. Our results highlight the importance of screening for anxiety and disorders in children with cancer, especially among those with brain tumors and at the acute phase of treatment.

Background Kaposiform lymphangiomatosis (KLA) is a complex lymphatic anomaly involving most commonly the mediastinum, lung, skin and bones with few effective treatments. In recent years, RAS-MAPK pathway mutations were shown to underlie the pathogenesis of several complex lymphatic anomalies. Specifically, an activating NRAS mutation (p.Q61R) was found in the majority of KLA patients. Recent reports demonstrated promising results of treatment with the MEK inhibitor, Trametinib, in patients with complex lymphatic anomalies harboring gain of function mutations in ARAF and SOS1, as well as loss of function mutation in the CBL gene, a negative regulator of the RAS-MAPK pathway. We present a 9-year-old child with a severe case of KLA harboring the typical NRAS (p.Q61R) mutation detected by plasma-derived cell free DNA, responsive to trametinib therapy. Methods The NRAS somatic mutation was detected from plasma cfDNA using droplet digital PCR. Concurrent in-vitro studies of trametinib activity on mutant NRAS affected lymphatic endothelial cells were performed using a three-dimensional spheroid sprouting assay. Results Trametinib treatment lead to resolution of lifelong thrombocytopenia, improvement of pulmonary function tests and wellbeing, as well as weaning from prolonged systemic steroid treatment. Concurrent studies of mutant NRAS-expressing cells showed enhanced lymphangiogenic capacity along with over activation of the RAS-MAPK and PI3K-AKT-mTOR pathways, both reversed by trametinib. Conclusions Trametinib treatment can substantially change the prognosis of patients with RAS pathway associated lymphatic anomalies. Impact This is the first description of successful trametinib treatment of a patient with KLA harboring the most characteristic NRAS p.Q61R mutation. Treatment can significantly change the prognosis of patients with RAS pathway-associated lymphatic anomalies. We devised an in vitro model of KLA enabling a reproducible method for the continued study of disease pathogenesis. Mutated NRAS p.Q61R cells demonstrated increased lymphangiogenic capacity.

Physicians and paramedics in the Israel Defense Forces are trained to perform advanced medical procedures using standardized training modalities, such as manikins. We studied the association of experience using these training modalities with self-reported confidence in procedure performance. Providers were sent a questionnaire regarding their experience with and self-confidence levels for performing endotracheal intubation, cricothyroidotomy, needle chest decompression, tube thoracostomy, and intraosseous infusion. Provider level (physician or paramedic) and gender were associated with reported self-confidence levels. Manikin and supervised and unsupervised patient experience exhibited positive associations with self-confidence, but (animal) model experience did not. For many procedure-training modality pairs, we identified a plateau level above which additional experience was minimally associated with an increase in self-confidence. Among military advanced life support providers, self-confidence levels in procedure performance are positively associated with experience gained from manikins and supervised and unsupervised patient application. We were not able to demonstrate a clear benefit of an animal model in increasing self-confidence. A plateau was generally identified, indicating decreased benefit from the use of a particular training modality for a particular procedure. Modifying training regimens in light of these findings may help maximize the self-confidence of advanced life support providers more efficiently.

Background Encephalopathy following Ifosfamide treatment is a well-described phenomenon that is typically treated with Methylene Blue (MB). Chloroacetaldehyde, a potentially neurotoxic metabolite of Ifosfamide is hypothesized to cause this encephalopathy. Current guidelines for treatment is to stop Ifosfamide and provide supportive care. MB acts to inhibit Chloroacetaldehyde formation and has been described as a therapy and prophylaxis for Ifosfamide-encephalopathy. MB is effective within 30 min and lasts up to 3 days. Prolonged encephalopathy and MB therapy has not been described in the literature as lasting longer than 30 days following treatment. Case presentation We present the case of an 11-year-old female with autistic spectrum disorder and recurrent episodes of severe somnolence for 7 months following Ifosfamide therapy for her Non-Germinomatous Germ Cell Tumor (GCT). Periods of somnolence occurred prior to receiving cranial RT. Administration of MB gave immediate but limited response, with resolution of somnolence lasting 1-2 days between administrations. The somnolence could not be explained by neuroimaging or laboratory evaluation, but EEG indicated persistent encephalopathy. Conclusion A literature review determines that neurotoxicity is a side effect of Ifosfamide, but this effect has not been described persisting longer than 30 days. Our case continued to require treatment with MB for 7 months following cessation of therapy. We report these novel clinical findings, and hypothesize that there could be a genetic/metabolic component linking this reaction to Ifosfamide with the case patient’s pre-existing autism. This possible association may also correlate to the already-established link between autism and the development of GCTs. This hypothesis leads to further discussion on the suitable usage of Ifosfamide in children with co-morbidities and the necessity of screening prior to its usage.

Purpose Current standard of care for ameloblastoma (conventional/unicystic - mural type) usually mandates extensive bone resection that frequently necessitates immediate reconstruction with serious sequelae, especially among young patients. BRAF -mutated ameloblastomas can be targeted by BRAF inhibitors to markedly reduce their size, enabling conservative removal of residual tumor. We aimed to characterize the effect of post-treatment histomorphologic changes. Methods Study included 14 patients, 11 mandibular and three maxillary tumors. Cases with very minimal residual tumor were defined as near-complete response, while those with mostly vital residual tumor as partial response. The epithelium component was scored for architectural and cellular changes, stroma - for fibrosis, inflammation and new bone formation, on a 3-tired score system: 0–no, 1–focal and 3–frequent changes. The mean scores of each parameter, total epithelium and total stroma were calculated and related to duration of treatment. Differences in the mean scores were investigated for mandibular tumors with near-complete response ( n  = 3) and partial response ( n  = 8). Results There were no significant differences in mean epithelium or stroma scores between tumors with near-complete and those with partial response (2.22  ±  0.68 versus 2.08  ±  0.43, p  = 0.55; 1.41  ±  1.04 versus 1.43  ±  0.44, p  = 0.27), suggesting that ameloblastomas have potential to undergo complete response to targeted treatment. This is probably dependent upon tumor/patient/treatment-related factors. Response to treatment appears to be predictable with neoplastic epithelium being first, while the stromal response increases during treatment, the entire process expanding over weeks-to-months. Conclusion Albeit preliminary, these are the first comprehensive histomorphologic findings on BRAF-treated ameloblastomas. Analyzing the suggested parameters in tumors with partial response, should highlight which tumor component has responded/failed to respond. This could serve as a basis for decision-taking toward subsequent steps in adjuvant treatment (e.g., follow-up, conservative surgery, modifications/changes in treatment regimen, combinations of approaches), with a prime aim of jaw preservation and minimal risk of sequelae.