Leveraging Rapid Genome Sequencing to Alter Care Plans for Pediatric Patients in a Community Hospital Setting in the United States.

Rapid genome sequencing impacted real-time diagnostic and therapeutic management for patients in a nonacademic community hospital. A retrospective chart review of 24 patients identified that more than 60% had a change in medical management as a result of rapid genome sequencing.

A subset analysis of a phase II trial evaluating the use of DFMO as maintenance therapy for high-risk neuroblastoma.

Neuroblastoma is a sympathetic nervous system tumor, primarily presenting in children under 6 years of age. The long-term prognosis for patients with high-risk neuroblastoma (HRNB) remains poor despite aggressive multimodal therapy. This report provides an update to a phase II trial evaluating DFMO as maintenance therapy in HRNB. Event-free survival (EFS) and overall survival (OS) of 81 subjects with HRNB treated with standard COG induction, consolidation and immunotherapy followed by 2 years of DFMO on the NMTRC003/003b Phase II trial were compared to a historical cohort of 76 HRNB patients treated at Beat Childhood Cancer Research Consortium (BCC) hospitals who were disease-free after completion of standard upfront therapy and did not receive DFMO. The 2- and 5-year EFS were 86.4% [95% confidence interval (CI) 79.3%-94.2%] and 85.2% [77.8%-93.3%] for the NMTRC003/003b subset vs 78.3% [69.5%-88.3%] and 65.6% [55.5%-77.5%] for the historical control group. The 2- and 5-year OS were 98.8% [96.4-100%] and 95.1% [90.5%-99.9%] vs 94.4% [89.3%-99.9%] and 81.6% [73.0%-91.2%], respectively. DFMO maintenance for HRNB after completion of standard of care therapy was associated with improved EFS and OS relative to historical controls treated at the same institutions. These results support additional investigations into the potential role of DFMO in preventing relapse in HRNB.

Radiation-induced osteosarcoma of the hand: case report.

Radiation-associated sarcomas represent less than 5% of all sarcomas and can arise from previously irradiated bone or soft tissue. We report a case of radiation-associated osteosarcoma that developed in the hand of a patient who had previously been treated for synovial sarcoma. Despite aggressive, multimodality treatment, the disease progressed rapidly. This case highlights the need for patients and treating physicians to be aware of this potential complication of radiotherapy to the hand.

Heterogeneity of tethered agonist signaling in adhesion G protein-coupled receptors.

Adhesion G protein-coupled receptor (aGPCR) signaling influences development and homeostasis in a wide range of tissues. In the current model for aGPCR signaling, ligand binding liberates a conserved sequence that acts as an intramolecular, tethered agonist (TA), yet this model has not been evaluated systematically for all aGPCRs. Here, we assessed the TA-dependent activities of all 33 aGPCRs in a suite of transcriptional reporter, G protein activation, and ß-arrestin recruitment assays using a new fusion protein platform. Strikingly, only ∼50% of aGPCRs exhibited robust TA-dependent activation, and unlike other GPCR families, aGPCRs showed a notable preference for G12/13 signaling. AlphaFold2 predictions assessing TA engagement in the predicted intramolecular binding pocket aligned with the TA dependence of the cellular responses. This dataset provides a comprehensive resource to inform the investigation of all human aGPCRs and for targeting aGPCRs therapeutically.

Effects of oxymetazoline nasal spray on the nasal cycle assessed by long-term rhinoflowmetry.

BACKGROUND: Long-term rhinoflowmetry assesses bilateral nasal flow over 24 hours. In the present study, we evaluated the effects of a standard dose of oxymetazoline topical nasal spray, a widely used over-the-counter drug, on the nasal cycle, since the exact long-term effects, such as the duration of the decongestive effect, are not yet reported. METHODOLOGY/PRINCIPAL: Thirty healthy volunteers received a portable long-term rhinoflowmetry device and applied 22.5 µg oxymetazoline in each nostril. RESULTS: In 90 % of the probands, effects of the nasal spray application could be seen as changes in nasal flow. A decongestive effect could be seen after 18 minutes on average. We found a mean duration of the maximal decongestive effect of four hours. However, it took more than six hours on average until the nasal cycle resumed its normal condition. We did not find significant differences of the effect between probands with a 'classic,' 'in concert' or impaired nasal cycle. In contrast to a substantial interindividual variability, repeated measurements showed that intraindividual variability of the effect of decongestive nasal spray seems to be rather small. CONCLUSION: Long-term rhinoflowmetry, yielding reliable results, is a valuable tool in the assessment of the effects of nasal drugs on the nasal cycle.

Maintenance DFMO Increases Survival in High Risk Neuroblastoma.

High risk neuroblastoma (HRNB) accounts for 15% of all pediatric cancer deaths. Despite aggressive therapy approximately half of patients will relapse, typically with only transient responses to second-line therapy. This study evaluated the ornithine decarboxylase inhibitor difluoromethylornithine (DFMO) as maintenance therapy to prevent relapse following completion of standard therapy (Stratum 1) or after salvage therapy for relapsed/refractory disease (Stratum 2). This Phase II single agent, single arm multicenter study enrolled from June 2012 to February 2016. Subjects received 2 years of oral DFMO (750 ± 250 mg/m2 twice daily). Event free survival (EFS) and overall survival (OS) were determined on an intention-to-treat (ITT) basis. 101 subjects enrolled on Stratum 1 and 100 were eligible for ITT analysis; two-year EFS was 84% (±4%) and OS 97% (±2%). 39 subjects enrolled on Stratum 2, with a two-year EFS of 54% (±8%) and OS 84% (±6%). DFMO was well tolerated. The median survival time is not yet defined for either stratum. DFMO maintenance therapy for HRNB in remission is safe and associated with high EFS and OS. Targeting ODC represents a novel therapeutic mechanism that may provide a new strategy for preventing relapse in children with HRNB.

Tolcapone induces oxidative stress leading to apoptosis and inhibition of tumor growth in Neuroblastoma.

Catechol-O-methyltransferase (COMT) is an enzyme that inactivates dopamine and other catecholamines by O-methylation. Tolcapone, a drug commonly used in the treatment of Parkinson's disease, is a potent inhibitor of COMT and previous studies indicate that Tolcapone increases the bioavailability of dopamine in cells. In this study, we demonstrate that Tolcapone kills neuroblastoma (NB) cells in preclinical models by inhibition of COMT. Treating four established NB cells lines (SMS-KCNR, SH-SY5Y, BE(2)-C, CHLA-90) and two primary NB cell lines with Tolcapone for 48 h decreased cell viability in a dose-dependent manner, with IncuCyte imaging and Western blotting indicating that cell death was due to caspase-3-mediated apoptosis. Tolcapone also increased ROS while simultaneously decreasing ATP-per-cell in NB cells. Additionally, COMT was inhibited by siRNA in NB cells and showed similar increases in apoptotic markers compared to Tolcapone. In vivo xenograft models displayed inhibition of tumor growth and a significant decrease in time-to-event in mice treated with Tolcapone compared to untreated mice. These results indicate that Tolcapone is cytotoxic to neuroblastoma cells and invite further studies into Tolcapone as a promising novel therapy for the treatment of neuroblastoma.

Molecular Guided Therapy Provides Sustained Clinical Response in Refractory Choroid Plexus Carcinoma.

Choroid plexus carcinomas (CPCs) are rare, aggressive pediatric brain tumors with no established curative therapy for relapsed disease, and poor survival rates. TP53 Mutation or dysfunction correlates with poor or no survival outcome in CPCs. Here, we report the case of a 4 month-old female who presented with disseminated CPC. After initial response to tumor resection and adjuvant-chemotherapy, the tumor recurred and metastasized with no response to aggressive relapse therapy suggesting genetic predisposition. This patient was then enrolled to a Molecular Guided Therapy Clinical Trial. Genomic profiling of patient tumor and normal sample identified a TP53 germline mutation with loss of heterozygosity, somatic mutations including IDH2, and aberrant activation of biological pathways. The mutations were not targetable for therapy. However, targeting the altered biological pathways (mTOR, PDGFRB, FGF2, HDAC) guided identification of possibly beneficial treatment with a combination of sirolimus, thalidomide, sunitinib, and vorinostat. This therapy led to 92% reduction in tumor size with no serious adverse events, excellent quality of life and long term survival.

Targeting ornithine decarboxylase reverses the LIN28/Let-7 axis and inhibits glycolytic metabolism in neuroblastoma.

LIN28 has emerged as an oncogenic driver in a number of cancers, including neuroblastoma (NB). Overexpression of LIN28 correlates with poor outcome in NB, therefore drugs that impact the LIN28/Let-7 pathway could be beneficial in treating NB patients. The LIN28/Let-7 pathway affects many cellular processes including the regulation of cancer stem cells and glycolytic metabolism. Polyamines, regulated by ornithine decarboxylase (ODC) modulate eIF-5A which is a direct regulator of the LIN28/Let-7 axis. We propose that therapy inhibiting ODC will restore balance to the LIN28/Let-7 axis, suppress glycolytic metabolism, and decrease MYCN protein expression in NB. Difluoromethylornithine (DFMO) is an inhibitor of ODC in clinical trials for children with NB. In vitro experiments using NB cell lines, BE(2)-C, SMS-KCNR, and CHLA90 show that DFMO treatment reduced LIN28B and MYCN protein levels and increased Let-7 miRNA and decreased neurosphere formation. Glycolytic metabolic activity decreased with DFMO treatment in vivo. Additionally, sensitivity to DFMO treatment correlated with LIN28B overexpression (BE(2)-C>SMS-KCNR>CHLA90). This is the first study to demonstrate that DFMO treatment restores balance to the LIN28/Let-7 axis and inhibits glycolytic metabolism and neurosphere formation in NB and that PET scans may be a meaningful imaging tool to evaluate the therapeutic effects of DFMO treatment.

Correlation of three variables describing nasal patency (HD, MCA, NOSE score) in healthy subjects.

UNLABELLED: Rhinoresistometry and acoustic rhinometry are two established apparative methods to objectify the respiratory function of the nose. Both methods use different variables to describe nasal patency: "hydraulic diameter", HD, in rhinoresistometry, and "minimal cross-sectional area", MCA1 (nasal isthmus) and MCA2 (head of the inferior turbinate and cavernous body of the nasal septum), in acoustic rhinometry. OBJECTIVE: This study analyzes the mutual correlation of HD and MCA as a pilot study in patients without nasal pathologies. Additionally, we investigated if these objective variables correlate with the NOSE score, a validated tool to measure subjective perception of nasal patency. METHOD: Planned data collection in a collective of 24 healthy subjects without nasal pathologies. RESULTS: Statistically significant, weak to moderate correlations were found between HD and MCA2 before decongestion. A moderate correlation was found between both HD and MCA2 and the NOSE score on the narrower side. CONCLUSION: In the assessment of nasal patency, it seems advisable to determine HD, MCA1 and MCA2, but also a subjective variable such as the NOSE score, which all seem to be not fully redundant variables. In further studies, the correlation of the variables should be assessed in patients with nasal pathologies.

Correlação de três variáveis na descrição da permeabilidade nasal (HD, MCA, escala NOSE) de pacientes saudáveis / Correlation of three variables describing nasal patency (HD, MCA, NOSE score) in healthy subjects

Rinoresistometria e rinometria acústica são dois métodos utilizados na avaliação da função respiratória nasal. Ambos utilizam variáveis diferentes para descrever a permeabilidade nasal: o diâmetro hidráulico, HD, na rinoresistometria; e as áreas mínimas da seção transversal, MCA1 (istmo nasal) e MCA2 (cabeça do corneto inferior e corpo cavernoso do septo nasal), na rinometria acústica. OBJETIVO: Analisar a relação entre HD e MCA em pacientes sem afecções nasais e identificar se tais variáveis objetivas apresentam correlação com a escala NOSE, uma ferramenta validada para avaliar a percepção subjetiva de permeabilidade nasal. MÉTODO: Coleta estruturada dos dados de 24 indivíduos saudáveis sem afecções nasais. RESULTADOS: Correlações estatisticamente significativas de fracas a moderadas foram identificadas entre HD e MCA2 antes do descongestionamento. Foi identificada correlação moderada entre HD, MCA2 e escala NOSE no lado mais estreito. CONCLUSÃO: Na avaliação de permeabilidade nasal, parece ser recomendável determinar HD, MCA1 e MCA2, bem como uma variável subjetiva como a escala NOSE, que não aparentam ser variáveis completamente redundantes. Estudos futuros devem avaliar a correlação destas variáveis em pacientes com afecções nasais.

Rhinoresistometry and acoustic rhinometry are two established apparative methods to objectify the respiratory function of the nose. Both methods use different variables to describe nasal patency: "hydraulic diameter", HD, in rhinoresistometry, and "minimal cross-sectional area", MCA1 (nasal isthmus) and MCA2 (head of the inferior turbinate and cavernous body of the nasal septum), in acoustic rhinometry. OBJECTIVE: This study analyzes the mutual correlation of HD and MCA as a pilot study in patients without nasal pathologies. Additionally, we investigated if these objective variables correlate with the NOSE score, a validated tool to measure subjective perception of nasal patency. METHOD: Planned data collection in a collective of 24 healthy subjects without nasal pathologies. RESULTS: Statistically significant, weak to moderate correlations were found between HD and MCA2 before decongestion. A moderate correlation was found between both HD and MCA2 and the NOSE score on the narrower side. CONCLUSION: In the assessment of nasal patency, it seems advisable to determine HD, MCA1 and MCA2, but also a subjective variable such as the NOSE score, which all seem to be not fully redundant variables. In further studies, the correlation of the variables should be assessed in patients with nasal pathologies.