Does the Primary Tumor Site Drive Biology for Patients With Synovial Sarcoma?

OBJECTIVE: We evaluated survival outcomes by primary tumor site in synovial sarcoma (SS) patients with localized and metastatic disease at diagnosis. METHODS: We conducted a retrospective review of 504 SS patients diagnosed from 1974 to 2020. Kaplan-Meier method, log-rank test, and Cox-proportional hazards regression were used. RESULTS: Among 504 patients, 401 (79.6%) presented with localized disease, and 103 (20.4%) with metastases. For patients with localized disease, (1) 5-year OS by tumor site was as follows: 80% (95% CI, 67%-89%) for head/neck, 30% (95% CI, 18%-42%) for intrathoracic, 51% (95% CI, 35%-65%) for abdomen/pelvis, 71% (95% CI, 62%-79%) for proximal-extremity, and 83% (71%, 91%) for distal-extremity. (2) On multivariable analysis, tumor site (compared with proximal-extremity: intrathoracic tumors [HR: 1.95; 95% CI, 1.22-3.16]; hand/foot [HR: 0.52; 95% CI, 0.28-0.97]), tumor size (compared with <5 cm, 5-10 cm [HR: 1.80; 95% CI, 1.14-2.85]; ≥10 cm [HR: 4.37; 95% CI, 2.69-7.11]), and use of neo/adjuvant radiation (HR: 0.54; 95% CI, 0.37-0.79) remained significantly associated with OS. For patients with metastatic disease, (1) 5-year OS was 12% (95% CI, 6%-21%) and (2) the only factor that remained significantly associated with OS on multivariable analysis was surgical resection for the primary tumor (HR: 0.14; 95% CI, 0.08-0.26). CONCLUSIONS: The primary tumor location plays a significant role in predicting outcomes for patients with localized SS. Even though patients present with metastatic disease, surgical resection of the primary tumor improves their survival. These findings are critical for patient counseling and designing a personalized treatment plan that reflects the corresponding outcomes.

Kmt2c restricts G-CSF-driven HSC mobilization and granulocyte production in a methyltransferase-independent manner.

Granulocyte colony-stimulating factor (G-CSF) is widely used to enhance myeloid recovery after chemotherapy and to mobilize hematopoietic stem cells (HSCs) for transplantation. Unfortunately, through the course of chemotherapy, cancer patients can acquire leukemogenic mutations that cause therapy-related myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML). This raises the question of whether therapeutic G-CSF might potentiate therapy-related MDS/AML by disproportionately stimulating mutant HSCs and other myeloid progenitors. A common mutation in therapy-related MDS/AML involves chromosome 7 deletions that inactivate many tumor suppressor genes, including KMT2C. Here, we show that Kmt2c deletions hypersensitize murine HSCs and myeloid progenitors to G-CSF, as evidenced by increased HSC mobilization and enhanced granulocyte production from granulocyte-monocyte progenitors (GMPs). Furthermore, Kmt2c attenuates the G-CSF response independently from its SET methyltransferase function. Altogether, the data raise concerns that monosomy 7 can hypersensitize progenitors to G-CSF, such that clinical use of G-CSF may amplify the risk of therapy-related MDS/AML.

Epidemiological trends of synovial sarcoma by primary tumor sites in the US from 2000 to 2020.

BACKGROUND: Synovial sarcoma (SS) is a rare soft-tissue cancer. Existing literature encompasses Surveillance, Epidemiology, and End Results (SEER) data-based research on SS explaining the incidence-prevalence in general, by subtypes, and by age at diagnosis. Therefore, this study aimed to fill in the gap of knowledge about measures of disease occurrence and burden of SS by tumor site using the SEER database. METHODS: In this cross-sectional study, primary SS patients were selected from SEER 17 Registries, Nov. 2021 (2000-2020) using ICD-O-3 codes 9040, 9041, 9042, and 9043. Patients with additional cancers were excluded. The primary tumor site was categorized into (1) head/neck, (2) internal thorax, (3) abdomen/pelvis, (4) upper extremity, and (5) lower extremity using ICD-10CM codes. Five outcomes were analyzed: age-adjusted incidence rate, 5-year limited-duration prevalence rate, incidence-based mortality, case-fatality rate, and overall survival. RESULTS: From 2000-2020, the overall age-adjusted incidence rate was 0.15 per 100,000; the 5-year limited duration prevalence rate was 0.56 per 100,000; and the incidence-based mortality rate was 0.06 per 100,000 people. The case-fatality and 5-year OS rates were 39.2 % and 62.9 %, respectively. Lower extremity had the highest incidence of 0.07 (estimated 1166 cases), prevalence of 0.36 (estimated 224 cases), and mortality rate of 0.025 (estimated 429 deaths) per 100,000. The other four locations had much closer rates with each other. Intrathoracic SS had the highest case-fatality rate of 71.5 % (148/207) and lowest 5-year OS of 26.0 % (95 % CI: 19.6 %, 32.9 %) than other sites. CONCLUSION: Based on the measures of disease frequency, the most common primary tumor site is the lower extremity, followed by the upper extremity, abdomen/pelvis, internal thorax, and head/neck. The least favorable primary location is the internal thorax. Those with a primary location of the upper extremity have the longest overall survival, followed by the head/neck, lower extremity, abdomen/pelvis, and internal thorax.

Sacituzumab Govitecan Versus Docetaxel for Previously Treated Advanced or Metastatic Non-Small Cell Lung Cancer: The Randomized, Open-Label Phase III EVOKE-01 Study.

PURPOSE: The open-label, phase III EVOKE-01 study evaluated sacituzumab govitecan (SG) versus standard-of-care docetaxel in metastatic non-small cell lung cancer (mNSCLC) with progression on/after platinum-based chemotherapy, anti-PD-(L)1, and targeted treatment for actionable genomic alterations (AGAs). Primary analysis is reported. METHODS: Patients were randomly assigned 1:1 (stratified by histology, best response to last anti-PD-(L)1-containing regimen, and AGA treatment received or not) to SG (one 10 mg/kg intravenous infusion on days 1 and 8) or docetaxel (one 75 mg/m2 intravenous infusion on day 1) in 21-day cycles. Primary end point was overall survival (OS). Key secondary end points were investigator-assessed progression-free survival (PFS), objective response rate, patient-reported symptom assessment, and safety. RESULTS: In the intention-to-treat population (SG, n = 299; docetaxel, n = 304), 55.4% had one previous line of therapy. Median follow-up was 12.7 months (range, 6.0-24.0). The primary end point was not met. There was a numerical OS improvement for SG versus docetaxel (median, 11.1 v 9.8 months; hazard ratio [HR], 0.84 [95% CI, 0.68 to 1.04]; one-sided P = .0534), consistent across squamous and nonsquamous histologies. Median PFS was 4.1 versus 3.9 months (HR, 0.92 [95% CI, 0.77 to 1.11]). An OS benefit was observed for SG (n = 192) versus docetaxel (n = 191) in mNSCLC nonresponsive to last anti-PD-(L)1-containing regimen (3.5-month median OS increase; HR, 0.75 [95% CI, 0.58 to 0.97]); this was consistent across histologies. Among patients receiving SG and docetaxel, 6.8% and 14.2% discontinued because of treatment-related adverse events (TRAEs), respectively; 1.4% and 1.0%, respectively, had TRAEs leading to death. CONCLUSION: Although statistical significance was not met, OS numerically improved with SG versus docetaxel, which was consistent across histologies. Clinically meaningful improvement in OS was noted in mNSCLC nonresponsive to last anti-PD-(L)1-containing regimen. SG was better tolerated than docetaxel and consistent with its known safety profile, with no new safety signals.

Cleaning Tasks and Products and Asthma Among Health Care Professionals.

OBJECTIVE: Health care workers are at risk for work-related asthma, which may be affected by changes in cleaning practices. We examined associations of cleaning tasks and products with work-related asthma in health care workers in 2016, comparing them with prior results from 2003. METHODS: We estimated asthma prevalence by professional group and explored associations of self-reported asthma with job-exposure matrix-based cleaning tasks/products in a representative Texas sample of 9914 physicians, nurses, respiratory/occupational therapists, and nurse aides. RESULTS: Response rate was 34.8% (n = 2421). The weighted prevalence rates of physician-diagnosed (15.3%), work-exacerbated (4.1%), and new-onset asthma (6.7%) and bronchial hyperresponsiveness symptoms (31.1%) were similar to 2003. New-onset asthma was associated with building surface cleaning (odds ratio [OR], 1.91; 95% confidence interval [CI], 1.10-3.33), use of ortho-phthalaldehyde (OR, 1.77; 95% CI, 1.15-2.72), bleach/quaternary compounds (OR, 1.91; 95% CI, 1.10-3.33), and sprays (OR, 1.97; 95% CI, 1.12-3.47). CONCLUSION: Prevalence of asthma/bronchial hyperresponsiveness seems unchanged, whereas associations of new-onset asthma with exposures to surface cleaning remained, and decreased for instrument cleaning.

Acquired hyperexcitable peripheral nerve disorders: Clinical and laboratory features, therapeutic responses, and long-term follow-up.

INTRODUCTION/AIMS: Hyperexcitable peripheral nerve disorders (HPNDs) are rare. Although their clinical and laboratory features have been well studied, information on treatment and follow-up is limited. The aim of this study is to explore the long-term clinical, investigative, and therapeutic profile of patients with acquired HPNDs. METHODS: This study retrospectively analyzed patients from a single tertiary care center with HPND (January 2012 to January 2022). Patients were recruited according to published inclusion and exclusion criteria. Details of clinical features, diagnostic tests, therapeutic interventions, and follow-up were recorded. This study included patients with follow-up of 2 or more years. RESULTS: A total of 32 patients (M = 26, F = 6) were studied. The common clinical features included myokymia, neuropathic or shock-like pain, cramps, sleep disturbances, encephalopathy, cerebellar ataxia, and seizures. A total of 81.25% of patients responded favorably to corticosteroids and membrane stabilizers. Among the nonresponders, five received intravenous immunoglobulin (IVIG), and one received plasma exchange (PLEX). Two patients required rituximab due to poor responses to the above treatments. The mean duration of response was 6 weeks (4-24 weeks) from the initiation of treatment. All patients had favorable outcomes, reaching clinical remission within 1-5 years from the initiation of treatment. Only two patients had relapses. Immunotherapy could be stopped in 78% of patients within 3 years and 100% by 5 years. DISCUSSION: Chronic immunosuppression starting with corticosteroids is required for satisfactory outcomes of HPNDs. These disorders usually run a monophasic course, and relapses are uncommon.

Immunoassay Urine Drug Testing among Patients Receiving Opioids at a Safety-Net Palliative Medicine Clinic.

BACKGROUND: Few studies have examined the use of immunoassay urine drug testing of cancer patients in palliative care clinics. OBJECTIVES: We examined the frequency of immunoassay urine drug test (UDT) abnormalities and the factors associated with aberrancy at a safety-net hospital palliative medicine clinic. METHODS: A retrospective review of the electronic medical records of consecutive eligible patients seen at the outpatient palliative medicine clinic in a resource-limited safety-net hospital system was conducted between 1 September 2015 and 31 December 2020. We collected longitudinal data on patient demographics, UDT findings, and potential predictors of aberrant results. RESULTS: Of the 913 patients in the study, 500 (55%) underwent UDT testing, with 455 (50%) having the testing within the first three visits. Among those tested within the first three visits, 125 (27%) had aberrant UDT results; 44 (35%) of these 125 patients were positive for cocaine. In a multivariable regression model analysis of predictors for aberrant UDT within the first three visits, non-Hispanic White race (odds ratio (OR) = 2.13; 95% confidence interval (CI): 1.03-4.38; p = 0.04), history of illicit drug use (OR = 3.57; CI: 1.78-7.13; p < 0.001), and history of marijuana use (OR = 7.05; CI: 3.85-12.91; p < 0.001) were independent predictors of an aberrant UDT finding. CONCLUSION: Despite limitations of immunoassay UDT, it was able to detect aberrant drug-taking behaviors in a significant number of patients seen at a safety-net hospital palliative care clinic, including cocaine use. These findings support universal UDT monitoring and utility of immunoassay-based UDT in resource-limited settings.

Comparison of Effectiveness of Hiora SG Gel With Triamcinolone Acetonide Gel in Recurrent Aphthous Stomatitis.

Background The oral condition known as recurrent aphthous ulceration (RAU) or recurrent aphthous stomatitis (RAS) is very prevalent. Its etiopathogenesis is unknown; hence, symptomatic therapy is all that can be offered if it manifests clinically. Lesion care aims to minimize discomfort and the frequency of relapses by bringing active illness under local control in the affected area. The current treatment options that may have negative side effects include the use of topical and systemic steroids, antibiotics, cauterization, and laser therapy. Objectives and Importance This study aimed to compare the efficiency of HiOra SG gel with triamcinolone acetonide gel in the management of RAS. Materials and Methods Fifty individuals with RAS were recruited for the trial and randomly assigned to either group I (HiOra SG gel) or group II (0.1% triamcinolone acetonide ointment; Oraways). After each meal for a total of 10 days, those with mouth ulcers were instructed to topically administer the drugs. The clinical data were analyzed by comparing the ulcer severity scores from the first, fifth, and 10th days. Results There was a statistically significant (p = 0.001) reduction in reported pain, pain duration, and overall ulcer severity across all groups. After therapy, however, neither the HiOra gel group nor the triamcinolone group showed any discernible improvement over the other. Conclusion The present study's findings corroborate the efficacy of HiOra SG gel in the treatment of RAS when compared to triamcinolone acetonide gel (0.1%). In this trial, no patients had any negative reactions to HiOra SG gel. In the future, further studies are needed with larger samples to prove its benefits.

Predicting inpatient mortality in pediatric traumatic brain injury: insights from a national database.

PURPOSE: The purpose of this study was to determine factors significantly associated with mortality and length of stay (LOS) in admissions to the pediatric intensive care unit (PICU) for traumatic brain injury (TBI). METHODS: A cross-sectional, retrospective cohort study that identified PICU admissions with TBI from forty-nine hospitals in the USA using the Pediatric Health Information System database from 2016 to 2021. Univariable analyses comparing those who did and did not experience mortality were performed. The following regression analyses were conducted: logistic regression with mortality as dependent variable; linear regression with LOS as the dependent variable; logistic regression with mortality as the dependent variable but only included patients with cerebral edema; and linear regression with LOS as the dependent variable but only included patients who survived. From the regression analysis for mortality in all TBI patients was utilized to develop a mortality risk score. RESULTS: A total of 3041 admissions were included. Those with inpatient mortality (18.5%) tended to be significantly younger (54 vs. 92 months, p < 0.01), have < 9 pediatric Glasgow Coma Scale on admission (100% vs. 52.9%, p < 0.01) and more likely to experience acute renal, hepatic and respiratory failure, acidosis, central diabetes insipidus, hyperkalemia, and hypocalcemia. Regression analysis identified that pediatric Glasgow Coma Scale, alkalosis and cardiac arrest significantly increased risks of mortality. The TBI mortality risk score had an area under the curve of 0.89 to identify those with mortality; a score of 6 ≤ was associated with 88% mortality. CONCLUSION: Patients admitted to the PICU with TBI have 18.5% risk of inpatient mortality with most occurring the first 48 h and these are characterized with greater multisystem organ dysfunction, received medical and mechanical support. TBI mortality risk score suggested is a practical tool to identify patients with an increase likelihood to die.

Adherence to Opioid Patient Prescriber Agreements at a Safety Net Hospital.

Patient prescriber agreements, also known as opioid contracts or opioid treatment agreements, have been recommended as a strategy for mitigating non-medical opioid use (NMOU). The purpose of our study was to characterize the proportion of patients with PPAs, the rate of non-adherence, and clinical predictors for PPA completion and non-adherence. This retrospective study covered consecutive cancer patients seen at a palliative care clinic at a safety net hospital between 1 September 2015 and 31 December 2019. We included patients 18 years or older with cancer diagnoses who received opioids. We collected patient characteristics at consultation and information regarding PPA. The primary purpose was to determine the frequency and predictors of patients with a PPA and non-adherence to PPAs. Descriptive statistics and multivariable logistic regression models were used for the analysis. The survey covered 905 patients having a mean age of 55 (range 18-93), of whom 474 (52%) were female, 423 (47%) were Hispanic, 603 (67%) were single, and 814 (90%) had advanced cancer. Of patients surveyed, 484 (54%) had a PPA, and 50 (10%) of these did not adhere to their PPA. In multivariable analysis, PPAs were associated with younger age (odds ratio [OR] 1.44; p = 0.02) and alcohol use (OR 1.72; p = 0.01). Non-adherence was associated with males (OR 3.66; p = 0.007), being single (OR 12.23; p = 0.003), tobacco (OR 3.34; p = 0.03) and alcohol use (OR 0.29; p = 0.02), contact with persons involved in criminal activity (OR 9.87; p < 0.001), use for non-malignant pain (OR 7.45; p = 0.006), and higher pain score (OR 1.2; p = 0.01). In summary, we found that PPA non-adherence occurred in a substantial minority of patients and was more likely in patients with known NMOU risk factors. These findings underscore the potential role of universal PPAs and systematic screening of NMOU risk factors to streamline care.

The Impact of Trimethylamine N-Oxide and Coronary Microcirculatory Dysfunction on Outcomes following ST-Elevation Myocardial Infarction.

INTRODUCTION: Persistent coronary microcirculatory dysfunction (CMD) and elevated trimethylamine N-oxide (TMAO) levels after ST-elevation myocardial infarction (STEMI) may drive negative structural and electrical cardiac remodeling, resulting in new-onset atrial fibrillation (AF) and a decrease in left ventricular ejection fraction (LVEF). AIMS: TMAO and CMD are investigated as potential predictors of new-onset AF and left ventricular remodeling following STEMI. METHODS: This prospective study included STEMI patients who had primary percutaneous coronary intervention (PCI) followed by staged PCI three months later. Cardiac ultrasound images were obtained at baseline and after 12 months to assess LVEF. Coronary flow reserve (CFR), and index of microvascular resistance (IMR) were assessed using the coronary pressure wire during the staged PCI. Microcirculatory dysfunction was defined as having an IMR value ≥25 U and CFR value <2.5 U. RESULTS: A total of 200 patients were included in the study. Patients were categorized according to whether or not they had CMD. Neither group differed from the other with regards to known risk factors. Despite making up only 40.5% of the study population, females represented 67.4% of the CMD group p < 0.001. Similarly, CMD patients had a much higher prevalence of diabetes than those without CMD (45.7% vs. 18.2%; p < 0.001). At the one-year follow-up, the LVEF in the CMD group had decreased to significantly lower levels than those in the non-CMD group (40% vs. 50%; p < 0.001), whereas it had been higher in the CMD group at baseline (45% vs. 40%; p = 0.019). Similarly, during the follow-up, the CMD group had a greater incidence of AF (32.6% vs. 4.5%; p < 0.001). In the adjusted multivariable analysis, the IMR and TMAO were associated with increased odds of AF development (OR: 1.066, 95% CI: 1.018-1.117, p = 0.007), and (OR: 1.290, 95% CI: 1.002-1.660, p = 0.048), respectively. Similarly, elevated levels of IMR and TMAO were linked with decreased odds of LVEF improvement, while higher CFR values are related to a greater likelihood of LVEF improvement. CONCLUSIONS: CMD and elevated TMAO levels were highly prevalent three months after STEMI. Patients with CMD had an increased incidence of AF and a lower LVEF 12 months after STEMI.

First mitogenome phylogeny of the sun bear Helarctos malayanus reveals a deep split between Indochinese and Sundaic lineages.

The sun bear Helarctos malayanus is one of the most endangered ursids, and to date classification of sun bear populations has been based almost exclusively on geographic distribution and morphology. The very few molecular studies focussing on this species were limited in geographic scope. Using archival and non-invasively collected sample material, we have added a substantial number of complete or near-complete mitochondrial genome sequences from sun bears of several range countries of the species' distribution. We here report 32 new mitogenome sequences representing sun bears from Cambodia, Thailand, Peninsular Malaysia, Sumatra, and Borneo. Reconstruction of phylogenetic relationships revealed two matrilines that diverged ~295 thousand years ago: one restricted to portions of mainland Indochina (China, Cambodia, Thailand; "Mainland clade"), and one comprising bears from Borneo, Sumatra, Peninsular Malaysia but also Thailand ("Sunda clade"). Generally recent coalescence times in the mitochondrial phylogeny suggest that recent or historical demographic processes have resulted in a loss of mtDNA variation. Additionally, analysis of our data in conjunction with shorter mtDNA sequences revealed that the Bornean sun bear, classified as a distinct subspecies (H. m. euryspilus), does not harbor a distinctive matriline. Further molecular studies of H. malayanus are needed, which should ideally include data from nuclear loci.

Basal type I interferon signaling has only modest effects on neonatal and juvenile hematopoiesis.

Type I interferon (IFN-1) regulates gene expression and hematopoiesis both during development and in response to inflammatory stress. We previously showed that during development in mice, hematopoietic stem cells (HSCs) and multipotent progenitors (MPPs) induce IFN-1 target genes shortly before birth. This coincides with the onset of a transition to adult hematopoiesis, and it drives the expression of genes associated with antigen presentation. However, it is not clear whether perinatal IFN-1 modulates hematopoietic output, as has been observed in contexts of inflammation. We have characterized hematopoiesis at several different stages of blood formation, from HSCs to mature blood cells, and found that loss of the IFN-1 receptor (IFNAR1) leads to depletion of several phenotypic HSC and MPP subpopulations in neonatal and juvenile mice. Committed lymphoid and myeloid progenitor populations expand simultaneously. These changes had a surprisingly little effect on the production of more differentiated blood cells. Cellular indexing of transcriptomes and epitopes by sequencing resolved the discrepancy between the extensive changes in progenitor numbers and modest changes in hematopoiesis, revealing stability in most MPP populations in Ifnar1-deficient neonates when the populations were identified based on gene expression rather than surface marker phenotype. Thus, basal IFN-1 signaling has only modest effects on hematopoiesis. Discordance between transcriptionally and phenotypically defined MPP populations may affect interpretations of how IFN-1 shapes hematopoiesis in other contexts, such as aging or inflammation.

Effect of Carnitine Supplementation in Pediatric Patients with Left Ventricular Dysfunction.

Carnitine is an essential amino acid involved in transporting fatty acids across the mitochondrial membrane. Fatty acids are a primary source of energy for the myocardium. Studies in adults demonstrated decreased carnitine levels in the ischemic myocardium, but subsequent exogenous carnitine supplementation showed improvement of myocardial metabolism and left ventricular function. However, only limited data regarding carnitine are available in pediatrics. A single-center retrospective, paired data study was conducted. Patients < 18 years, left ventricular ejection fraction (LVEF) < 55% by echocardiography, and had received at least 7 days of oral or intravenous carnitine supplementation between January 2018 and March 2021 are included in the study. Several endpoints and covariates were collected for each patient: before, one week after, one month after, and 6 months after carnitine supplementation. Univariate analysis consisted of an analysis of variance (ANOVA), followed by an analysis of covariance (ANCOVA) to model LVEF while adjusting for other variables. 44 patients included in the final analyses. LVEF significantly improved from 50.5 to 56.6% (p < 0.01). When LVEF was adjusted for other interventions (mechanical ventilation, afterload reduction, diuretic therapy, spironolactone), the estimated means demonstrated a significant increase from 45.7 to 58.0% (p < 0.01). Free carnitine level increased significantly (p = 0.03), and N-terminal-pro-brain natriuretic peptide (p = 0.03), creatinine (p < 0.01), and lactate (p < 0.01) all significantly decreased over the study period. Carnitine supplementation in pediatric patients with left ventricular systolic dysfunction may be associated with an increase in LVEF and improvement in laboratory markers of myocardial stress and cardiac output.

FLT3ITD drives context-specific changes in cell identity and variable interferon dependence during AML initiation.

Acute myeloid leukemia (AML) initiation requires multiple rate-limiting mutations to cooperatively reprogram progenitor cell identity. For example, FLT3 internal tandem duplication (FLT3ITD) mutations cooperate with a variety of different initiating mutations to reprogram myeloid progenitor fate. These initiating mutations often skew toward either pediatric or adult AML patient populations, though FLT3ITD itself occurs at similar frequencies in both age groups. This raises the question of whether FLT3ITD might induce distinct transcriptional programs and unmask distinct therapeutic vulnerabilities when paired with pediatric, as opposed to adult AML-initiating mutations. To explore this possibility, we compared AML evolution in mice that carried Flt3ITD/NUP98-HOXD13 (NHD13) or Flt3ITD/Runx1DEL mutation pairs, which are respectively most common in pediatric and adult AML. Single-cell analyses and epigenome profiling revealed distinct interactions between Flt3ITD and its cooperating mutations. Whereas Flt3ITD and Flt3ITD/Runx1DEL caused aberrant expansion of myeloid progenitors, Flt3ITD/NHD13 drove the emergence of a pre-AML population that did not resemble normal hematopoietic progenitors. Differences between Flt3ITD/Runx1DEL and Flt3ITD/NHD13 cooperative target gene expression extended to fully transformed AML as well. Flt3ITD/NHD13 cooperative target genes were enriched in human NUP98-translocated AML. Flt3ITD/NHD13 selectively hijacked type I interferon signaling to drive expansion of the pre-AML population. Blocking interferon signaling delayed AML initiation and extended survival. Thus, common AML driver mutations, such as FLT3ITD, can coopt different mechanisms of transformation in different genetic contexts. Furthermore, pediatric-biased NUP98 fusions convey actionable interferon dependence.

Randomized Controlled Trials in Pediatric Cardiology: A Power Struggle?

Sample size and statistical power are often limited in pediatric cardiology studies due to the relative infrequency of specific congenital malformations of the heart and specific circulatory physiologies. The primary aim of this study was to determine what proportion of pediatric cardiology randomized controlled trials achieve an 80% statistical power. Secondary aims included characterizing reporting habits in these studies. A systematic review was performed to identify pertinent pediatric cardiology randomized controlled trials. The following data were collected: publication year, journal, if "power" or "sample size" were mentioned if a discrete, primary endpoint was identified. Power analyses were conducted to assess if the sample size was adequate to demonstrate results at 80% power with a p-value of less than 0.05. A total of 83 pediatric cardiology randomized controlled trials were included. Of these studies, 48% mentioned "power" or "sample size" in the methods, 49% mentioned either in the results, 12% mentioned either in the discussion, and 66% mentioned either at any point in the manuscript. 63% defined a discrete, primary endpoint. 38 studies (45%) had an adequate sample size to demonstrate differences with 80% power at a p-value of less than 0.05. A majority of these are not powered to reach the conventionally accepted 80% power target. Adequately powered studies were found to be more likely to report "power" or "sample size" and have a discrete, primary endpoint.

The Development and Validation of a Mobile Application for Guidance for Management of Severe Diabetic Ketoacidosis.

OBJECTIVE: To develop and validate a mobile application-based tool for the management guidance of children and adolescents with diabetic ketoacidosis (DKA). METHODS: The study involved the development of a mobile application-based tool for DKA management in accordance with the International Society of Pediatric and Adolescent Diabetes (ISAPD) guidelines, 2018. The impact of the mobile application in preventing protocol deviation and resultant complications was assessed. Case records of 70 children and adolescents [39 boys, 8.9 (4.1) y of age] with severe DKA managed in the authors' intensive care unit were examined. The application guidance and real-time management were compared to the standard protocol. RESULTS: Protocol deviations were observed in 58 (82.9%), with two or more errors in 28 (40%). These included lack of initial fluid bolus (4, 5.7%), excessive fluid supplementation (8, 11.4%), inadequate initial fluid (25, 35.7%) and potassium supplementation (13, 18.6%), delayed response to fall in potassium (15, 21.4%) and glucose levels (24, 34.3%), and erroneous insulin administration (19, 27.1%). These errors contributed to 42.1% of severe hypokalemia and 56% of significant hypoglycemia episodes. The mobile application guidance was in accordance with the protocol in all the case scenario. CONCLUSION: Deviation from the management protocol is common in DKA and associated with adverse outcomes. Mobile application guidance is expected to reduce the protocol deviation with a potential of improving outcomes.