10018
Background: Tumor sequencing has the potential to inform diagnosis, prognosis, and treatment of childhood cancer patients. Prospective data are needed to evaluate the clinical utility of these ...tests. Methods: Patients less than 18 years of age with extracranial solid tumors (ST), central nervous system tumors (CNS), lymphomas and histiocytic disorders (L/H) were enrolled in the Texas KidsCanSeq clinical genomics study at six Texas institutions. Available tumor samples from a subset of patients designated as high risk (based on poor prognosis at diagnosis or tumor recurrence) were sequenced using pediatric cancer-focused targeted DNA (initially 124 genes; expanded to 169 genes) and RNA (81 genes) panels developed at Texas Children’s Hospital. DNA variants (single nucleotide variants, insertion/deletions, splice site variants, copy number alterations) and fusion genes detected by RNA testing were analyzed. Tumor alterations were classified by molecular pathologists and oncologists as carrying strong (Tier 1) or potential (Tier 2) clinical significance following consensus guidelines from the Association for Molecular Pathology, American Society of Clinical Oncology, and College of American Pathologists. Results: A total of 626 patients were enrolled between 2018 and 2021, of whom 380 were designated as high risk. Tumor samples adequate for molecular testing were available from 342 of the 380 (90%) high risk patients (196 ST 57%, 132 CNS 39% and 14 L/H 4%). Clinically significant alterations were identified in 246 of 342 (72%) tumors: 165 (48%) from DNA testing only, 34 (10%) from RNA testing only, and 47 (14%) from both modalities. The frequency of clinically significant alterations was similar across tumor cohorts (74% ST, 68% CNS, 71% L/H). Alterations relevant to therapy-choice were reported in 127 of 342 (37%) tumors (35% ST, 26% CNS, 57% L/H); 87 of these 127 (69%) were not known from prior clinical testing. The most frequently altered therapeutic gene alterations (Table) involved BRAF (n=25), CDKN2A/B (n=20), SMARCB1 (n=17), FGFR1/2/3/4 (n=14), NF1 (n=13), PIK3CA (n=11), ALK (n=10), CDK4 (n=9), and RET (n=7). One hypermutated tumor was identified: a high-grade glioma (tumor mutation burden >190 mut/Mb) in a patient with Lynch syndrome due to a germline MSH6 variant. Conclusions: Tumor alterations of clinical significance according to consensus guidelines were reported in a large proportion of children with diverse high risk or recurrent cancer diagnoses, the majority of which were not detected by other standard pathologic analysis. These data further support broader adoption of tumor molecular profiling for these patients. Table: see text
BackgroundAssessment of the seriousness, expectedness and causality are necessary for any adverse event (AE) in a clinical trial. In addition, assessing AE severity helps determine the importance of ...the AE in the clinical setting. Standardisation of AE severity criteria could make safety information more reliable and comparable across trials. Although standardised AE severity scales have been developed in other research fields, they are not suitable for use in neonates. The development of an AE severity scale to facilitate the conduct and interpretation of neonatal clinical trials is therefore urgently needed.MethodsA stepwise consensus process was undertaken within the International Neonatal Consortium (INC) with input from all relevant stakeholders. The consensus process included several rounds of surveys (based on a Delphi approach), face-to-face meetings and a pilot validation.ResultsNeonatal AE severity was classified by five grades (mild, moderate, severe, life threatening or death). AE severity in neonates was defined by the effect of the AE on age appropriate behaviour, basal physiological functions and care changes in response to the AE. Pilot validation of the generic criteria revealed κ=0.23 and guided further refinement. This generic scale was applied to 35 typical and common neonatal AEs resulting in the INC neonatal AE severity scale (NAESS) V.1.0, which is now publicly available.DiscussionThe INC NAESS is an ongoing effort that will be continuously updated. Future perspectives include further validation and the development of a training module for users.
Abstract
The cosmic-ray ionization rate (CRIR) is a key parameter in understanding the physical and chemical processes in the interstellar medium. Cosmic rays are a significant source of energy in ...star formation regions, impacting the physical and chemical processes that drive the formation of stars. Previous studies of the circum-molecular zone of the starburst galaxy NGC 253 have found evidence for a high CRIR value: 10
3
–10
6
times the average CRIR within the Milky Way. This is a broad constraint, and one goal of this study is to determine this value with much higher precision. We exploit ALMA observations toward the central molecular zone of NGC 253 to measure the CRIR. We first demonstrate that the abundance ratio of H
3
O
+
and SO is strongly sensitive to the CRIR. We then combine chemical and radiative transfer models with nested sampling to infer the gas properties and CRIR of several star-forming regions in NGC 253 from emission from their transitions. We find that each of the four regions modeled has a CRIR in the range (1–80) × 10
−14
s
−1
and that this result adequately fits the abundances of other species that are believed to be sensitive to cosmic rays, including C
2
H, HCO
+
, HOC
+
, and CO. From shock and photon-dominated/X-ray dominated region models, we further find that neither UV-/X-ray-driven nor shock-dominated chemistry is a viable single alternative as none of these processes can adequately fit the abundances of all of these species.
Context.
HNCO and SiO are well-known shock tracers and have been observed in nearby galaxies, including the nearby (
D
= 3.5 Mpc) starburst galaxy NGC 253. The simultaneous detection of these two ...species in regions where the star-formation rate is high may be used to study the shock history of the gas.
Aims.
We perform a multi-line molecular study of NGC 253 using the shock tracers SiO and HNCO and aim to characterize its gas properties. We also explore the possibility of reconstructing the shock history in the central molecular zone (CMZ) of the galaxy.
Methods.
Six SiO transitions and eleven HNCO transitions were imaged at high resolution 1
.
″
6 (28 pc) with the Atacama Large Millimeter/submillimeter Array (ALMA) as part of the ALCHEMI Large Programme. Both non local thermaldynamic equilibrium (non-LTE) radiative transfer analysis and chemical modeling were performed in order to characterize the gas properties and investigate the chemical origin of the emission.
Results.
The nonLTE radiative transfer analysis coupled with Bayesian inference shows clear evidence that the gas traced by SiO has different densities and temperatures than that traced by HNCO, with an indication that shocks are needed to produce both species. Chemical modeling further confirms such a scenario and suggests that fast and slow shocks are responsible for SiO and HNCO production, respectively, in most GMCs. We are also able to infer the physical characteristics of the shocks traced by SiO and HNCO for each GMC.
Conclusions.
Radiative transfer and chemical analysis of the SiO and HNCO in the CMZ of NGC 253 reveal a complex picture whereby most of the GMCs are subjected to shocks. We speculate on the possible shock scenarios responsible for the observed emission and provide potential history and timescales for each shock scenario. Observations of higher spatial resolution for these two species are required in order to quantitatively differentiate between the possible scenarios.
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Abstract
BACKGROUND
Tumor and germline alterations detected by sequencing have the potential to inform management of children with CNS tumors. Comparative clinical utility data for available ...molecular sequencing modalities are needed to optimize testing strategies.
METHODS
Cancer patients less than 18 years of age were eligible to enroll in the Texas KidsCanSeq (KCS) clinical genomics study at six Texas institutions. Blood testing was performed on all patients using a pediatric solid tumor targeted DNA panel (124 genes), which included 35 genes associated with known cancer predisposition syndromes. Tumor testing was conducted on high-risk or recurrent tumors using the same DNA panel as well as an 81-gene RNA fusion panel. Tumor variants were classified as being of strong (Tier 1) or potential (Tier 2) clinical significance following AMP/ASCO/CAP guidelines. Germline pathogenic (P) or likely pathogenic (LP) variants per ACMG/AMP guidelines were considered clinically relevant.
RESULTS
A total of 224 children with CNS tumors were enrolled, including 146 patients with high-risk or recurrent tumors. Tissues were sufficient for analysis from 132 tumors and 211 germline samples. Clinically relevant alterations were identified in 90 of 132 (68%) tumors tested. Of 50 with therapeutic implications, 21 (42%) were not known from prior clinical testing. Therapeutically relevant tumor variants most frequently involved BRAF (n=20), CDKN2A/B (n=16), SMARCB1 (n=9), PIK3CA (n=8), and NF1 (n=7). One high grade glioma (in a patient with Lynch syndrome) was found to be hypermutated (tumor mutation burden >190 mut/Mb). Germline analysis detected P/LP variants in cancer predisposition genes in 25 of 211 (12%) patients tested, including 12 of 135 (9%) with high-risk/recurrent tumors.
CONCLUSION
Combined tumor and germline panel testing revealed alterations of clinical relevance according to consensus guidelines in approximately 70% of children with high-risk or recurrent CNS tumors.
Extreme preterm birth (<32 weeks gestational age) results in arrested development of the lung characterized by abnormal alveologenesis and pulmonary vasculogenesis causing obstructive lung disease ...that persists into adulthood. We have recently shown that adults with a history of extreme preterm birth (PRE) have reduced aerobic exercise capacity relative to full term controls (CONT) that is not explained by pulmonary gas exchange inefficiency during exercise. These PRE subjects also have significant exercise‐induced flow limitation (EIFL), which has been suggested to be associated with a reduction in exercise capacity in healthy humans and in COPD subjects. Therefore, we hypothesized that reducing EIFL by breathing heliox (21% O2, 79% He) would improve exercise performance. Both PRE (n = 4) and CONT (n = 4) subjects performed two cycle ergometer exercise tests to exhaustion at 80% of their maximum power output; one breathing room air and one breathing heliox. Measurements breathing heliox were compared to those breathing room air at iso‐time. Flow‐volume loops were measured at rest and during both exercise tests to quantify EIFL. EIFL significantly decreased in PRE from room air (57% of tidal volume; VT) to heliox (9% VT), while CONT did not exhibit EIFL in either condition. Time to exhaustion significantly increased in PRE (38%), but not CONT (9%), breathing heliox compared to room air. These data suggest that excessive EIFL, may lead to an excessive work of breathing and/or mechanical constraints to increasing tidal volume during exercise, thereby significantly limiting exercise performance in PRE subjects.
Grant Funding Source: Supported by AHA Scientist Development Grant and OHSU Early Clinical Investigator Grant
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
New Findings
What is the central question of this study?
Do individuals with chronic obstructive pulmonary disease have blood flow through intrapulmonary arteriovenous anastomoses at rest or during ...exercise?
What is the main finding and its importance?
Individuals with chronic obstructive pulmonary disease have a greater prevalence of blood flow through intrapulmonary arteriovenous anastomoses at rest than age‐matched control subjects. Given that the intrapulmonary arteriovenous anastomoses are large enough to permit venous emboli to pass into the arterial circulation, patients with chronic obstructive pulmonary disease and an elevated risk of thrombus formation may be at risk of intrapulmonary arteriovenous anastomosis‐facilitated embolic injury (e.g. stroke or transient ischaemic attack).
The pulmonary capillaries prevent stroke by filtering venous emboli from the circulation. Intrapulmonary arteriovenous anastomoses are large‐diameter (≥50 μm) vascular connections in the lung that may compromise the integrity of the pulmonary capillary filter and have recently been linked to cryptogenic stroke and transient ischaemic attack. Prothrombotic populations, such as individuals with chronic obstructive pulmonary disease (COPD), may be at increased risk of stroke and transient ischaemic attack facilitated by intrapulmonary arteriovenous anastomoses, but the prevalence and degree of blood flow through intrapulmonary arteriovenous anastomoses in this population has not been fully examined and compared with age‐matched healthy control subjects. We used saline contrast echocardiography to assess blood flow through intrapulmonary arteriovenous anastomoses at rest (n = 29 COPD and 19 control subjects) and during exercise (n = 10 COPD and 10 control subjects) in subjects with COPD and age‐matched healthy control subjects. Blood flow through intrapulmonary arteriovenous anastomoses was detected in 23% of subjects with COPD at rest and was significantly higher compared with age‐matched healthy control subjects. Blood flow through intrapulmonary arteriovenous anastomoses at rest was reduced or eliminated in subjects with COPD after breathing hyperoxic gas. Sixty per cent of subjects with COPD who did not have blood flow through the intrapulmonary arteriovenous anastomoses at rest had blood flow through them during exercise. The combination of blood flow through intrapulmonary arteriovenous anastomoses and potential for thrombus formation in individuals with COPD may permit venous emboli to pass into the arterial circulation and cause stroke and transient ischaemic attack. Breathing supplemental oxygen may reduce this risk in COPD. The link between blood flow through intrapulmonary arteriovenous anastomoses, stroke and transient ischaemic attack is worthy of future investigation in COPD and other populations.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
Abstract
BACKGROUND
DNA and RNA-based tumor sequencing tests have the potential to guide the clinical management of children with CNS tumors. However, data describing the utility of these tests are ...limited.
METHODS
Children with high-risk or recurrent CNS tumors are included in the diverse cohort of patients enrolling in the KidsCanSeq study from six Texas sites. DNA and RNA from FFPE tumor is subjected to targeted sequencing using a 124-gene mutation panel and an 81-gene fusion panel. Tumor capture transcriptome sequencing, exome sequencing, and copy number array (as well as germline panel and exome testing) are also performed. Tumor variants are classified using AMP/ASCO/CAP consensus guidelines.
RESULTS
A total of 74 children with high-risk/recurrent CNS tumors enrolled as of 1/28/20. Targeted tumor DNA and RNA panel testing was completed for 57 patients with varied diagnoses. At least one tumor variant with strong or potential clinical significance was identified in 43 of 57 (75%) tumors, with therapeutic significance in 20 of 57 (35%) tumors. The 38 therapeutically-relevant variants most frequently affected MAPK signaling (BRAF x9, EGFR x3, FGFR2, FGFR3, KRAS, NF1, NTRK2) and the AKT/mTOR pathway (PIK3CA x3, PTEN x2, mTOR, TSC1, PIK3R1). Most had not been detected by prior targeted diagnostic testing (27/38, 71%).
CONCLUSION
Integrated DNA and RNA-based panel testing identified variants with potential to impact clinical decision-making in a majority of children with high-risk/recurrent CNS tumors. The comparative yield of panel testing vs. exome/transcriptome/array will be evaluated in the KidsCanSeq study cohort.
Extreme preterm birth results in abnormal alveologenesis and pulmonary vasculogenesis. Abnormal pulmonary vasculature may be unable to accommodate increased cardiac output during exercise, thereby ...resulting in an abnormally increased pulmonary artery systolic pressure (PASP) and exercise‐induced pulmonary hemorrhage (EIPH) in adult with a history of extreme preterm birth (PRE). We hypothesized that 1) PRE would have increased PASP during exercise thereby causing EIPH and 2) oral sildenafil would reduce PASP thereby preventing EIPH. PRE (n = 2) performed exercise at 80% of max power output to exhaustion on a cycle ergometer 60 mins after 100 mg sildenafil (p.o.) and, on a separate day, without sildenafil. Age and sex matched full term controls (CON; n = 2) exercised at the same workload and for the same time as PRE. PASP was measured via ultrasonography at rest and within the last minute of exercise. Induced sputum samples were collected post‐exercise and analyzed for cellular constituents. PASP was not different at rest between groups. During exercise, PASP was greater in PRE (54 Torr) vs CONT (48 Torr) without drug, and was unchanged in PRE (59 Torr) but decreased in CONT (41 Torr), with sildenafil. There was no evidence of EIPH in either group. These data suggest that excessive PASP during exercise in PRE may be the result of abnormal pulmonary vascular architecture, which cannot be ameliorated by oral sildenafil.
Grant Funding Source: Supported by AHA Scientist Development Grant and OHSU Early Clinical Investigator Grant
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
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