Can We Just Play? Internal Validity of Assessing Physiological State With a Semistandardized Kicking Drill in Professional Australian Football.

PURPOSE: To examine associations between exercise heart rate (HRex) during a continuous-fixed submaximal fitness test (CF-SMFT) and an intermittent-variable protocol (semistandardized kicking drill [SSD]) in Australian Football athletes, controlling for external intensities, within-session scheduling, and environmental conditions. METHODS: Forty-four professional male Australian Football athletes (22.8 [8.0] y) were monitored over 10 sessions involving a 3-minute CF-SMFT (12 km·h-1) as the first activity and a SSD administered 35.7 (8.0) minutes after the CF-SMFT. Initial heart rate and HRex were collected, with external intensities measured as average velocity (in meters per minute) and average acceleration-deceleration (in meters per second squared). Environmental conditions were sampled. A penalized hierarchical linear mixed model was tuned for a Bayesian information criterion minima using a 10-fold cross-validation, with out-of-sample prediction accuracy assessed via root-mean-squared error. RESULTS: SSD average acceleration-deceleration, initial heart rate, temperature, and ground hardness were significant moderators in the tuned model. When model covariates were held constant, a 1%-point change in SSD HRex associated with a 0.4%-point change in CF-SMFT HRex (95% CI, 0.3-0.5). The tuned model predicted CF-SMFT HRex with an average root-mean-squared error of 2.64 (0.57) over the 10-fold cross-validation, with 74% and 86% of out-of-sample predictions falling within 2.7%-points and 3.7%-points, respectively, from observed values, representing the lower and upper limits for detecting meaningful changes in HRex according to the documented typical error. CONCLUSIONS: Our findings support the use of an SSD to monitor physiological state in Australian Football athletes, despite varied scheduling within session. Model predictions of CF-SMFT HRex from SSD HRex closely aligned with observed values, considering measurement imprecision.

Long-term outcomes and patterns of relapse in patients with bilateral Wilms tumor or bilaterally predisposed unilateral Wilms tumor, a report from the COG AREN0534 study.

The objective of this study is to report the long-term timing and patterns of relapse for children enrolled in Children's Oncology Group AREN0534, a multicenter phase III clinical trial conducted from 2009 to 2015. Participants included children with bilateral Wilms tumor (BWT) or unilateral WT with genetic predisposition to develop BWT followed for up to 10 years. Smoothed hazard (risk) functions for event-free survival (EFS) were plotted so that the timing of events could be visualized, both overall and within pre-specified groups. Two hundred and twenty-two children (190 BWT and 32 unilateral WT with BWT predisposition) were followed for a median of 8.6 years. Fifty events were reported, of which 48 were relapse/progression. The overall 8-year EFS was 75% (95% confidence interval: 69%-83%). The highest risk for an EFS event was immediately after diagnosis with a declining rate over 2 years. A second peak of events was observed around 4 years after diagnosis, and a small number of events were reported until the end of the follow-up period. In subset analyses, later increases in risk were more commonly observed in patients with female sex, anaplastic histology, negative lymph nodes or margins, and favorable histology Wilms tumor patients with post-chemotherapy intermediate risk. Among relapses that occurred after 2 years, most were to the kidney. These patterns suggest that late events may be second primary tumors occurring more commonly in females, although more investigation is required. Clinicians may consider observation of patients with BWT beyond 4 years from diagnosis.

Development of an enhanced recovery after surgery program for pediatric solid tumors.

Introduction: Enhanced recovery after surgery (ERAS) is an evidence-based, multi-modal approach to decrease surgical stress, expedite recovery, and improve postoperative outcomes. ERAS is increasingly being utilized in pediatric surgery. Its applicability to pediatric patients undergoing abdominal tumor resections remains unknown. Methods and Analysis: A group of key stakeholders adopted ERAS principles and developed a protocol suitable for the variable complexity of pediatric abdominal solid tumor resections. A multi-center, prospective, propensity-matched case control study was then developed to evaluate the feasibility of the protocol. A pilot-phase was utilized prior to enrollment of all patients older than one month of age undergoing any abdominal, retroperitoneal, or pelvic tumor resections. The primary outcome was 90-day complications per patient. Additional secondary outcomes included: ERAS protocol adherence, length of stay, time to administration of adjuvant chemotherapy, readmissions, reoperations, emergency room visits, pain scores, opioid usage, and differences in Quality of Recovery 9 scores. Ethics and Dissemination: Institutional review board approval was obtained at all participating centers. Informed consent was obtained from each participating patient. The results of this study will be presented at pertinent society meetings and published in peer-reviewed journals. We expect the results will inform peri-operative care for pediatric surgical oncology patients and provide guidance on initiation of ERAS programs. We anticipate this study will take four years to meet accrual targets and complete follow-up. Trial Registration Number: NCT04344899.

The role of activator protein-1 (AP-1) complex in diabetes associated atherosclerosis: Insights from single cell RNA sequencing.

Despite advances in the treatment of atherosclerotic cardiovascular disease, it remains the leading cause of death in patients with diabetes. Even when risk factors are mitigated, the disease progresses, and thus newer targets need to be identified that directly inhibit the underlying pathobiology of atherosclerosis in diabetes. A single cell sequencing approach was utilised to distinguish the proatherogenic transcriptional profile in aortic cells in diabetes using a streptozotocin induced-diabetic Apoe-/- mouse model. Human carotid endarterectomy specimens from individuals with and without diabetes were also evaluated via immunohistochemical analysis. Further mechanistic studies were performed in human aortic endothelial cells and human THP-1 derived macrophages. We then performed a preclinical study using an AP-1 inhibitor in a diabetic Apoe-/- mouse model. Single cell RNA sequencing analysis identified the AP-1 complex as a novel target in diabetes-associated atherosclerosis. AP-1 levels were elevated in carotid endarterectomy specimens from diabetic when compared to non-diabetic individuals. AP-1 was validated as a mechanosensitive transcription factor via immunofluorescence staining for regional heterogeneity of endothelial cells of the aortic region exposed to turbulent blood flow and by performing microfluidics experiments in HAECs. AP-1 inhibition with T-5224 blunted endothelial cell activation as assessed by a monocyte adhesion assay and expression of genes relevant to endothelial function. Furthermore, AP-1 inhibition attenuated foam cell formation. Critically, treatment with T-5224 attenuated atherosclerosis development in diabetic Apoe-/- mice. This study has identified the AP-1 complex as a novel target, inhibition of which treats the underlying pathobiology of atherosclerosis in diabetes.

Health systems developments and predictors of bystander CPR in Ireland.

Aims: To explore predictors of bystander CPR (i.e. any CPR performed prior to EMS arrival) in Ireland over the period 2012-2020. To examine the relationship between bystander CPR and key health system developments during this period. Methods: National level out-of-hospital cardiac arrest (OHCA) registry data relating to unwitnessed, and bystander witnessed OHCA were interrogated. Logistic regression models were built, then refined by fitting predictors, performing stepwise variable selection and by adding pairwise interactions that improved fit. Missing data sensitivity analyses were conducted using multiple imputation. Results: The data included 18,177 OHCA resuscitation attempts of whom 77% had bystander CPR. The final model included ten variables. Four variables (aetiology, incident location, time of day, and who witnessed collapse) were involved in interactions. The COVID-19 period was associated with reduced adjusted odds of bystander CPR (OR 0.77, 95% CI 0.65, 0.92), as were increasing age in years (OR 0.992, 95% CI 0.989, 0.994) and urban location (OR 0.52, 95% CI 0.47, 0.57). Increasing year over time (OR 1.23, 95% CI 1.16, 1.29), and an increased call response interval in minutes (OR 1.017, 95% CI 1.012, 1.022) were associated with increased adjusted odds of bystander CPR. Conclusions: Bystander CPR increased over the study period, and it is likely that health system developments contributed to the yearly increases observed. However, COVID-19 appeared to disrupt this positive trend. Urban OHCA location was associated with markedly decreased odds of bystander CPR compared to rural location. Given its importance bystander CPR in urban areas should be an immediate target for intervention.

The context-dependent epigenetic and organogenesis programs determine 3D vs. 2D cellular fitness of MYC-driven cancer.

3D cellular-specific epigenetic and transcriptomic reprogramming is critical to organogenesis and tumorigenesis. Here we dissect the distinct cell fitness in 2D (normoxia vs. chronic hypoxia) vs 3D (normoxia) culture conditions. We identify over 600 shared essential genes and additional context-specific fitness genes and pathways. Knockout of the VHL-HIF1 pathway results in incompatible fitness defects under normoxia vs. 1% oxygen or 3D culture conditions. Moreover, deletion of each of the mitochondrial respiratory electron transport chain complex has distinct fitness outcomes. Notably, multicellular organogenesis signaling pathways including TGFß-SMAD specifically constrict the uncontrolled cell proliferation in 3D while inactivation of epigenetic modifiers (Bcor, Kmt2d, Mettl3 and Mettl14) has opposite outcomes in 2D vs. 3D. We further identify a 3D-dependent synthetic lethality with partial loss of Prmt5 due to a reduction of Mtap expression resulting from 3D-specific epigenetic reprogramming. Our study highlights unique epigenetic, metabolic and organogenesis signaling dependencies under different cellular settings.

Prevalence and risk factors for milk allergy overdiagnosis in the BEEP trial cohort.

BACKGROUND: Cow's milk allergy (CMA) overdiagnosis in young children appears to be increasing and has not been well characterised. We used a clinical trial population to characterise CMA overdiagnosis and identify individual-level and primary care practice-level risk factors. METHODS: We analysed data from 1394 children born in England in 2014-2016 (BEEP trial, ISRCTN21528841). Participants underwent formal CMA diagnosis at ≤2 years. CMA overdiagnosis was defined in three separate ways: parent-reported milk reaction; primary care record of milk hypersensitivity symptoms; and primary care record of low-allergy formula prescription. RESULTS: CMA was formally diagnosed in 19 (1.4%) participants. CMA overdiagnosis was common: 16.1% had parent-reported cow's milk hypersensitivity, 11.3% primary care recorded milk hypersensitivity and 8.7% had low-allergy formula prescription. Symptoms attributed to cow's milk hypersensitivity in participants without CMA were commonly gastrointestinal and reported from a median age of 49 days. Low-allergy formula prescriptions in participants without CMA lasted a median of 10 months (interquartile range 1, 16); the estimated volume consumed was a median of 272 litres (26, 448). Risk factors for CMA overdiagnosis were high practice-based low-allergy formula prescribing in the previous year and maternal report of antibiotic prescription during pregnancy. Exclusive formula feeding from birth was associated with increased low-allergy formula prescription. There was no evidence that practice prescribing of paediatric adrenaline auto-injectors or anti-reflux medications, or maternal features such as anxiety, age, parity and socioeconomic status were associated with CMA overdiagnosis. CONCLUSION: CMA overdiagnosis is common in early infancy. Risk factors include high primary care practice-based low-allergy formula prescribing and maternal report of antibiotic prescription during pregnancy.

Exploring health professionals' knowledge, practices and attitudes regarding gestational diabetes: A cross-sectional Irish national survey.

AIM: Gestational diabetes confers short- and long-term risk of mother and offspring health complications. Healthcare professionals such as endocrinologists, diabetes nurses, dietitians, midwives and general practitioners provide gestational diabetes care. We sought to explore healthcare professionals' perspectives on gestational diabetes care during pregnancy and postpartum. METHODS: Healthcare professionals in the Republic of Ireland, whose role included gestational diabetes care were invited to complete an online 20-item survey between June and September 2022. Social media, professional organisations and personal networks were used for recruitment. Questions included guideline use, postpartum diabetes screening and advice practices. Analyses were performed using SPSS statistical software and free text was coded using NVivo. RESULTS: Seventeen healthcare professions across primary and secondary care settings participated (n = 127). No differences were noted between groups (medical, nursing/midwifery, allied health/other); therefore, findings were reported as a single group. Healthcare professionals reported using multiple different guidelines to support gestational diabetes management (n = 14). The most cited were 'Health Service Executive guidelines' (24.5%), 'local guidelines' (13.2%) and National Institute for Clinical Excellence guidelines (11.3%); 12.3% cited uncertainty, and 27.5% reported not to follow any named guidelines. For postpartum follow-up, 39% felt clear guidelines were available to support practice, 37% felt appropriate systems were in place and 29% reported effective communication between primary and secondary care services. Qualitative findings emphasised a desire for improved communication between systems, participants and providers, clear interdisciplinary guidelines, and adequate resourcing for gestational diabetes management and postpartum diabetes prevention, including comprehensive support and follow-up. CONCLUSION: System-level challenges and ineffective communication across settings are barriers to optimum postpartum care. Nationally agreed guidelines for best practice gestational diabetes management including postpartum diabetes prevention are needed.

A distinct, high-affinity, alkaline phosphatase facilitates occupation of P-depleted environments by marine picocyanobacteria.

Marine picocyanobacteria of the genera Prochlorococcus and Synechococcus, the two most abundant phototrophs on Earth, thrive in oligotrophic oceanic regions. While it is well known that specific lineages are exquisitely adapted to prevailing in situ light and temperature regimes, much less is known of the molecular machinery required to facilitate occupancy of these low-nutrient environments. Here, we describe a hitherto unknown alkaline phosphatase, Psip1, that has a substantially higher affinity for phosphomonoesters than other well-known phosphatases like PhoA, PhoX, or PhoD and is restricted to clade III Synechococcus and a subset of high light I-adapted Prochlorococcus strains, suggesting niche specificity. We demonstrate that Psip1 has undergone convergent evolution with PhoX, requiring both iron and calcium for activity and likely possessing identical key residues around the active site, despite generally very low sequence homology. Interrogation of metagenomes and transcriptomes from TARA oceans and an Atlantic Meridional transect shows that psip1 is abundant and highly expressed in picocyanobacterial populations from the Mediterranean Sea and north Atlantic gyre, regions well recognized to be phosphorus (P)-deplete. Together, this identifies psip1 as an important oligotrophy-specific gene for P recycling in these organisms. Furthermore, psip1 is not restricted to picocyanobacteria and is abundant and highly transcribed in some α-proteobacteria and eukaryotic algae, suggesting that such a high-affinity phosphatase is important across the microbial taxonomic world to occupy low-P environments.

Current surgical approaches to pediatric renal tumors.

Pediatric renal tumors are among the most common pediatric solid malignancies. Surgical resection is a key component in the multidisciplinary therapy for children with kidney tumors. Therefore, it is imperative that surgeons caring for children with renal tumors fully understand the current standards of care in order to provide appropriate surgical expertise within this multimodal framework. Fortunately, the last 60 years of international, multidisciplinary pediatric cancer cooperative group studies have enabled high rates of cure for these patients. This review will highlight the international surgical approaches to pediatric patients with kidney cancer to help surgeons understand the key differences and similarities between the European (International Society of Pediatric Oncology) and North American (Children's Oncology Group) recommendations.

Move for Life an intervention for inactive adults aged 50 years and older: a cluster randomised feasibility trial.

Background: Move for Life (MFL) is a theory-informed intervention that was developed to augment established physical activity (PA) programmes and enable inactive adults aged 50 years and older to be more active. This study examined the feasibility of MFL and sought to provide evidence of its potential for improving PA and associated health outcomes. Methods: A 3-arm cluster randomised feasibility trial compared MFL intervention, usual provision (UP) and control (CON) groups at baseline (T0), post-intervention (T1, at 8, 10 or 12- weeks) and 6-month follow up (T2). We used purposive sampling strategies to recruit participants according to characteristics of interest. Feasibility outcomes assessed recruitment, fidelity, adherence, retention and data completion rates based on pre-set criteria. Primary outcomes were accelerometer-based moderate-to-vigorous intensity PA (MVPA) and self-reported compliance with physical activity guidelines (PAGL). Secondary outcomes included light intensity PA (LiPA), standing time, sedentary time, body composition (adiposity), physical function and psychological well-being. We used linear mixed models (continuous outcomes) or generalized estimated equations (categorical outcomes) to estimate group differences over time in the study outcomes. Results: Progression criteria for feasibility outcomes were met, and 733 individuals were recruited. Considering a 6-month period (T0-T2), while self-reported compliance with PAGL increased in MFL relative to UP and CON and in UP relative to CON, standing time decreased in MFL relative to CON and sedentary time increased in the latter compared to UP. Waist circumference decreased in MFL relative to UP and CON. MFL outperformed UP in the Timed Up and Go Test while MFL and UP increased the distance covered in the Six-Minute Walk Test compared to CON. Psychological well-being increased in MFL relative to CON (all p < 0.05). Conclusion: Findings show that MFL is feasible, while data are promising with regards to the potential of improving community PA programmes for adults aged 50 or more years. Clinical trial registration: https://www.isrctn.com/Registration#ISRCTN11235176.

Conditional c-MYC activation in catecholaminergic cells drives distinct neuroendocrine tumors: neuroblastoma vs somatostatinoma.

The MYC proto-oncogenes (c-MYC, MYCN , MYCL ) are among the most deregulated oncogenic drivers in human malignancies including high-risk neuroblastoma, 50% of which are MYCN -amplified. Genetically engineered mouse models (GEMMs) based on the MYCN transgene have greatly expanded the understanding of neuroblastoma biology and are powerful tools for testing new therapies. However, a lack of c-MYC-driven GEMMs has hampered the ability to better understand mechanisms of neuroblastoma oncogenesis and therapy development given that c-MYC is also an important driver of many high-risk neuroblastomas. In this study, we report two transgenic murine neuroendocrine models driven by conditional c-MYC induction in tyrosine hydroxylase (Th) and dopamine ß-hydroxylase (Dbh)-expressing cells. c-MYC induction in Th-expressing cells leads to a preponderance of Pdx1 + somatostatinomas, a type of pancreatic neuroendocrine tumor (PNET), resembling human somatostatinoma with highly expressed gene signatures of δ cells and potassium channels. In contrast, c-MYC induction in Dbh-expressing cells leads to onset of neuroblastomas, showing a better transforming capacity than MYCN in a comparable C57BL/6 genetic background. The c-MYC murine neuroblastoma tumors recapitulate the pathologic and genetic features of human neuroblastoma, express GD2, and respond to anti-GD2 immunotherapy. This model also responds to DFMO, an FDA-approved inhibitor targeting ODC1, which is a known MYC transcriptional target. Thus, establishing c-MYC-overexpressing GEMMs resulted in different but related tumor types depending on the targeted cell and provide useful tools for testing immunotherapies and targeted therapies for these diseases.

A lipid atlas of human and mouse immune cells provides insights into ferroptosis susceptibility.

The cellular lipidome comprises thousands of unique lipid species. Here, using mass spectrometry-based targeted lipidomics, we characterize the lipid landscape of human and mouse immune cells ( www.cellularlipidatlas.com ). Using this resource, we show that immune cells have unique lipidomic signatures and that processes such as activation, maturation and development impact immune cell lipid composition. To demonstrate the potential of this resource to provide insights into immune cell biology, we determine how a cell-specific lipid trait-differences in the abundance of polyunsaturated fatty acid-containing glycerophospholipids (PUFA-PLs)-influences immune cell biology. First, we show that differences in PUFA-PL content underpin the differential susceptibility of immune cells to ferroptosis. Second, we show that low PUFA-PL content promotes resistance to ferroptosis in activated neutrophils. In summary, we show that the lipid landscape is a defining feature of immune cell identity and that cell-specific lipid phenotypes underpin aspects of immune cell physiology.

Resuscitation for out-of-hospital cardiac arrest in Ireland 2012-2020: Modelling national temporal developments and survival predictors.

Aim: To explore potential predictors of national out-of-hospital cardiac arrest (OHCA) survival, including health system developments and the COVID pandemic in Ireland. Methods: National level OHCA registry data from 2012 through to 2020, relating to unwitnessed, and bystander witnessed OHCA were interrogated. Logistic regression models were built by including predictors through stepwise variable selection and enhancing the models by adding pairwise interactions that improved fit. Missing data sensitivity analyses were conducted using multiple imputation. Results: The data included 18,177 cases. The final model included seventeen variables. Of these nine variables were involved in pairwise interactions. The COVID-19 period was associated with reduced survival (OR 0.61, 95%CI 0.43, 0.87), as were increasing age in years (OR 0.96, 95% CI 0.96, 0.97) and call response interval in minutes (OR 0.97, 95% CI 0.96, 0.99). Amiodarone administration (OR 3.91, 95% CI 2.80, 5.48), urban location (OR 1.40, 95% CI 1.12, 1.77), and chronological year over time (OR 1.14, 95% CI 1.08, 1.20) were associated with increased survival. Conclusions: National survival from OHCA has significantly increased incrementally over time in Ireland. The COVID-19 pandemic was associated with decreased survival even after accounting for potential disruption to key elements of bystander and EMS care. Further research is needed to understand and address the discrepancy between urban and rural OHCA survival. Information concerning pre-event patient health status and inpatient care process may yield important additional insights in future.

Targeting TRIP13 in favorable histology Wilms tumor with nuclear export inhibitors synergizes with doxorubicin.

Wilms tumor (WT) is the most common renal malignancy of childhood. Despite improvements in the overall survival, relapse occurs in ~15% of patients with favorable histology WT (FHWT). Half of these patients will succumb to their disease. Identifying novel targeted therapies remains challenging in part due to the lack of faithful preclinical in vitro models. Here we establish twelve patient-derived WT cell lines and demonstrate that these models faithfully recapitulate WT biology using genomic and transcriptomic techniques. We then perform loss-of-function screens to identify the nuclear export gene, XPO1, as a vulnerability. We find that the FDA approved XPO1 inhibitor, KPT-330, suppresses TRIP13 expression, which is required for survival. We further identify synergy between KPT-330 and doxorubicin, a chemotherapy used in high-risk FHWT. Taken together, we identify XPO1 inhibition with KPT-330 as a potential therapeutic option to treat FHWTs and in combination with doxorubicin, leads to durable remissions in vivo.

Dose-Response Modelling of Resistance Exercise Across Outcome Domains in Strength and Conditioning: A Meta-analysis.

BACKGROUND: Resistance exercise is the most common training modality included within strength and conditioning (S&C) practice. Understanding dose-response relationships between resistance training and a range of outcomes relevant to physical and sporting performance is of primary importance for quality S&C prescription. OBJECTIVES: The aim of this meta-analysis was to use contemporary modelling techniques to investigate resistance-only and resistance-dominant training interventions, and explore relationships between training variables (frequency, volume, intensity), participant characteristics (training status, sex), and improvements across a range of outcome domains including maximum strength, power, vertical jump, change of direction, and sprinting performance. METHODS: Data were obtained from a database of training studies conducted between 1962 and 2018, which comprised healthy trained or untrained adults engaged in resistance-only or resistance-dominant interventions. Studies were not required to include a control group. Standardized mean difference effect sizes were calculated and interventions categorized according to a range of training variables describing frequency (number of sessions per week), volume (number of sets and repetitions performed), overall intensity (intensity of effort and load, categorised as low, medium or high), and intensity of load (represented as % of one-repetition maximum [1RM] prescribed). Contemporary modelling techniques including Bayesian mixed-effects meta-analytic models were fitted to investigate linear and non-linear dose-responses with models compared based on predictive accuracy. RESULTS: Data from a total of 295 studies comprising 535 groups and 6,710 participants were included with analyses conducted on time points ≤ 26 weeks. The best performing model included: duration from baseline, average number of sets, and the main and interaction effects between outcome domain and intensity of load (% 1RM) expressed non-linearly. Model performance was not improved by the inclusion of participant training status or sex. CONCLUSIONS: The current meta-analysis represents the most comprehensive investigation of dose-response relationships across a range of outcome domains commonly targeted within strength and conditioning to date. Results demonstrate the magnitude of improvements is predominantly influenced by training intensity of load and the outcome measured. When considering the effects of intensity as a % 1RM, profiles differ across outcome domains with maximum strength likely to be maximised with the heaviest loads, vertical jump performance likely to be maximised with relatively light loads (~ 30% 1RM), and power likely to be maximised with low to moderate loads (40-70% 1RM).

Management of undifferentiated embryonal sarcoma of the liver: A Pediatric Surgical Oncology Research Collaborative study.

BACKGROUND: Undifferentiated embryonal sarcoma of the liver (UESL) is a rare tumor for which there are few evidence-based guidelines. The aim of this study was to define current management strategies and outcomes for these patients using a multi-institutional dataset curated by the Pediatric Surgical Oncology Research Collaborative. METHODS: Data were collected retrospectively for patients with UESL treated across 17 children's hospitals in North America from 1989 to 2019. Factors analyzed included patient and tumor characteristics, PRETEXT group, operative details, and neoadjuvant/adjuvant regimens. Event-free and overall survival (EFS, OS) were the primary and secondary outcomes, respectively. RESULTS: Seventy-eight patients were identified with a median age of 9.9 years [interquartile range [IQR): 7-12]. Twenty-seven patients underwent resection at diagnosis, and 47 patients underwent delayed resection, including eight liver transplants. Neoadjuvant chemotherapy led to a median change in maximum tumor diameter of 1.6 cm [IQR: 0.0-4.4] and greater than 90% tumor necrosis in 79% of the patients undergoing delayed resection. R0 resections were accomplished in 63 patients (81%). Univariate analysis found that metastatic disease impacted OS, and completeness of resection impacted both EFS and OS, while multivariate analysis revealed that R0 resection was associated with decreased expected hazards of experiencing an event [hazard ratio (HR): 0.14, 95% confidence interval (CI): 0.04-0.6]. At a median follow-up of 4 years [IQR: 2-8], the EFS was 70.0% [95% CI: 60%-82%] and OS was 83% [95% CI: 75%-93%]. CONCLUSION: Complete resection is associated with improved survival for patients with UESL. Neoadjuvant chemotherapy causes minimal radiographic response, but significant tumor necrosis.

Bilateral Wilms tumor with anaplasia: A report from the Children's Oncology Group Study AREN0534.

INTRODUCTION: The purpose of this study is to examine the outcomes in children with anaplastic bilateral Wilms tumor (BWT) from study AREN0534 in order to define potential prognostic factors and areas to target in future clinical trials. METHODS: Demographic and clinical data from AREN0534 study patients with anaplasia (focal anaplasia [FA], or diffuse anaplasia [DA]) were compared. Event-free survival (EFS) and overall survival (OS) were reported using Kaplan-Meier estimation with 95% confidence bands, and differences in outcomes between FA and DA compared using log-rank tests. The impact of margin status was analyzed. RESULTS: Twenty-seven children who enrolled on AREN0534 had evidence of anaplasia (17 DA, 10 FA) in at least one kidney and were included in this analysis. Twenty-six (96%) had BWT. Nineteen percent had anaplastic histology in both kidneys (four of 17 DA, and one of 10 FA). Forty-six percent with BWT had bilateral nephron-sparing surgery (NSS); one child who went off protocol therapy, eventually required bilateral completion nephrectomies. Median follow-up for EFS and OS was 8.6 and 8.7 years from enrollment. Four- and 8-year EFS was 53% [95% confidence interval (CI): 34%-83%] for DA; 4-year EFS was 80% [95% CI: 59%-100%], and 8-year EFS 70% [95% CI: 47%-100%] for FA. Three out of 10 children with FA and eight out of 17 children with DA had events. EFS did not differ statistically by margin status (p = .79; HR = 0.88). Among the six children who died (five DA, one FA), all experienced prior relapse or progression within 18 months. CONCLUSION: Events in children with DA/FA in the setting of BWT occurred early. Caution should be taken about interpreting the impact of margin status outcomes in the context of contemporary multimodal therapy. Future targeted investigations in children with BWT and DA/FA are needed.

Response of bilateral wilms tumor to chemotherapy suggests histologic subtype and guides treatment.

OBJECTIVES: Patients with bilateral Wilms tumor (BWT) initially receive neoadjuvant chemotherapy to shrink the tumors and increase the likelihood of successful nephron-sparing surgery. Biopsy of poorly responding tumors is often done to better understand therapy resistance. The purpose of this retrospective, single-institution study was to determine whether initial chemotherapy response is associated with tumor histology, potentially obviating the need for biopsy or change in chemotherapy. METHODS: Patients with synchronous BWT who underwent surgery at St Jude Children's Research Hospital from January 2000 to March 2022 were considered for this study. A mixed-effects logistic regression model was used to evaluate the likelihood of the tumor being stromal predominant, as predicted by tumor response to neoadjuvant chemotherapy. RESULTS: Sixty-eight patients were eligible for this study. Tumors that increased in size had an odds ratio of 19.5 (95% CI: 2.46-155.03) for being stromal-predominant vs any other histologic subtype. Age at diagnosis was youngest in patients with stromal-predominant tumors, with a mean age of 18.8 months (SD = 14.1 months), compared to all other histologic subtypes (χ2=7.05, p = .07). The predictive value of a tumor growing, combined with patient age less than 18 months, for confirming stromal-predominant histology was 85.7% (95% CI: 57.18%-93.5%). CONCLUSIONS: Tumors that increased in size during neoadjuvant chemotherapy were most frequently stromal-predominant BWT, especially in younger patients. Therefore, nephron-sparing surgery, rather than biopsy, or extension or intensification of neoadjuvant chemotherapy, should be considered for bilateral BWT that increase in volume during neoadjuvant chemotherapy, particularly in patients younger than 18 months of age.