Search

OBJECTIVE: Clinical observations suggest a role for the fetus in the maternal manifestations of preeclampsia, but the possible signaling mechanisms remain unclear. This study compares the fetal plasma concentrations of adenosine from normal pregnancies with those from preeclampsia. STUDY DESIGN: This secondary data analysis included normal pregnancies (n = 27) and patients with preeclampsia (n = 39). Patients with preeclampsia were subclassified into patients with (n = 25) and without (n = 14) abnormal uterine artery Doppler velocimetry (UADV). RESULTS: Fetal plasma concentrations of adenosine were significantly higher in patients with preeclampsia (1.35 ± 0.09 [mu]mol/L) than in normal pregnancies (0.52 ± 0.06 [mu]mol/L; P < .0001). Fetal plasma concentrations of adenosine in patients with preeclampsia with abnormal UADV (1.78 ± 0.15 [mu]mol/L), but not with normal UADV (0.58 ± 0.14 [mu]mol/L), were significantly higher than in normal pregnancies (P < .0001). CONCLUSION: Patients with preeclampsia with sonographic evidence of chronic uteroplacental ischemia have high fetal plasma concentrations of adenosine. [ABSTRACT FROM AUTHOR]

Background: Patients with hepatoblastoma (HB) have a higher risk of congenital heart defects (CHD). There is limited literature on the management and outcomes of these patients. The purpose of this study was to identify demographics and outcomes of these patients in a single tertiary referral center., Methods: An Institutional Review Board (IRB)-approved retrospective chart review of patients with newly diagnosed HB from October 2004 to January 2021 was performed. CHD was defined as the presence of a septal defect, patent ductus arteriosus, pulmonary atresia, or bicuspid aortic valve. Chi-square and t-test were utilized for statistical analyses., Results: Of the 151 patients diagnosed with HB during the study timeframe, 29 patients were found to have CHD. Five-year overall survival (OS) for non-CHD HB patients was 81.9% compared to 68.9% in the CHD cohort (p = .12). The 5-year OS for patients without surgically intervened CHD was 63.6% compared to 70.5% for those with surgically repaired CHD (p = .88). Pre-treatment extent of tumor IV was present more often in patients with HB and CHD who passed away (6/9, 66.7%) compared to those who survived (3/16,18.8%, p = .01)., Conclusions: Patients with HB and CHD have similar survival compared to those without CHD. Our data support that patients with HB and CHD should be treated with curative intent including cardiac surgical intervention, medical oncology therapy, and oncological surgery for their HB., (© 2024 Wiley Periodicals LLC.)

Background: Image-defined risk factors (IDRFs) were promulgated for predicting the feasibility and safety of complete primary tumor resection in children with neuroblastoma (NB). There is limited understanding of the impact of individual IDRFs on resectability of the primary tumor or patient outcomes. A multicenter database of patients with high-risk NB was interrogated to answer this question., Design/methods: Patients with high-risk NB (age <20 years) were eligible if cross-sectional imaging was performed at least twice prior to resection. IDRFs and primary tumor measurements were recorded for each imaging study. Extent of resection was determined from operative reports., Results: There were 211 of 229 patients with IDRFs at diagnosis, and 171 patients with IDRFs present pre-surgery. A ≥90% resection was significantly more likely in the absence of tumor invading or encasing the porta hepatis, hepatoduodenal ligament, superior mesenteric artery (SMA), renal pedicles, abdominal aorta/inferior vena cava (IVC), iliac vessels, and/or diaphragm at diagnosis or an overlapping subset of IDRFs (except diaphragm) at pre-surgery. There were no significant differences in event-free survival (EFS) and overall survival (OS) when patients were stratified by the presence versus absence of any IDRF either at diagnosis or pre-surgery., Conclusion: Two distinct but overlapping subsets of IDRFs present either at diagnosis or after induction chemotherapy significantly influence the probability of a complete resection in children with high-risk NB. The presence of IDRFs was not associated with significant differences in OS or EFS in this cohort., (© 2024 Wiley Periodicals LLC.)

Background: The pathology and management of breast masses in pediatric patients is markedly different than in adults. The vast majority of lesions in children and adolescents are benign, but the rare malignant breast masses require prompt recognition and treatment. Pediatric surgeons navigating clinical evaluation of these masses must balance preservation of the developing breast with appropriate diagnosis and surgical management., Methods: The current English language literature was queried for pediatric and adolescent breast masses. Identified manuscripts were reviewed and classified by level of evidence. Based on these results, as well as expert consensus, an algorithm regarding clinical workup and management was established., Results: Evaluation of pediatric breast masses begins with a thorough history and physical exam. Palpable masses should then be further characterized using an ultrasound-guided algorithm. In select cases, observation without surgical resection is appropriate. Surgical management of presumed benign lesions, when performed, should prioritize conserving developing breast tissue and the nipple areolar complex. Excisional biopsy is preferable to core needle biopsy when technically feasible. Surgical management of malignant lesions varies depending on the type of malignancy., Conclusion: Pediatric surgeons are often the first point of contact after identification of a breast mass in a pediatric or adolescent patient, and therefore play a critical role in management. Based on literature review and expert consensus, we propose an algorithm to guide pediatric surgeons in the diagnosis and treatment of these predominantly benign lesions. For the rare malignant lesions, a multi-disciplinary team approach is recommended to optimize patient care., (Copyright © 2024. Published by Elsevier Inc.)

Introduction: Synovial sarcoma is one of the most common soft tissue sarcomas in children. Guidelines regarding the adequate extent of resection margins and the role of re-resection are lacking. We sought to evaluate the adequate resection margin and the role of re-resection in predicting outcomes in children with synovial sarcomas., Methods: A cohort of 36 patients less than 18 years of age at diagnosis who were treated for localized synovial sarcoma at three tertiary pediatric hospitals between January 2004 and December 2020 were included in this study. Patient and tumor demographics, treatment information, and margin status after surgical resection were collected from the medical record. Clinical, treatment, and surgical characteristics, as well as outcomes including hazard ratios (HRs), event-free survival (EFS), and overall survival (OS) were compared by resection margins group and re-resection status., Results: Patients in the R1 resection group were significantly more likely to relapse or die compared to patients in the R0 resection group. However, there was no significant difference in EFS (HR 0.52, p = 0.54) or OS (HR 1.56, p = 0.719) in R0 patients with less than 5 mm margins compared to R0 patients with more than 5 mm margins. Patients with R1 on initial or re-resection had significantly worse OS than patients who had R0 resection on initial or re-resection (HR = 10.12, p = 0.005)., Conclusion: This study re-affirms that R0 resection is an independent prognostic predictor of better OS/EFS in pediatric synovial sarcoma. Second, our study extends this finding to report negative margins on initial resection or re-resection is associated with better OS/EFS than positive margins on initial resection or re-resection. Lastly, we found that there is no difference in outcomes associated with re-resection or <5 mm margins for R0 patients, indicating that re-resection and <5 mm margins are acceptable if microscopic disease is removed., (© 2024 The Author(s). Cancer Medicine published by John Wiley & Sons Ltd.)

Background: Hepatoblastoma and HCC are the most common malignant hepatocellular tumors seen in children. The aim of this study was to develop a liquid biopsy test for circulating tumor cells (CTCs) for these tumors that would be less invasive and provide real-time information about tumor response to therapy., Methods: For this test, we utilized indocyanine green (ICG), a far-red fluorescent dye used clinically to identify malignant liver cells during surgery. We assessed ICG accumulation in cell lines using fluorescence microscopy and flow cytometry. For our CTC test, we developed a panel of liver tumor-specific markers, including ICG, Glypican-3, and DAPI, and tested it with cell lines and noncancer control blood samples. We then used this panel to analyze whole-blood samples for CTC burden with a cohort of 15 patients with hepatoblastoma and HCC and correlated with patient characteristics and outcomes., Results: We showed that ICG accumulation is specific to liver cancer cells, compared to nonmalignant liver cells, non-liver solid tumor cells, and other nonmalignant cells, and can be used to identify liver tumor cells in a mixed population of cells. Experiments with the ICG/Glypican-3/DAPI panel showed that it specifically tagged malignant liver cells. Using patient samples, we found that CTC burden from sequential blood samples from the same patients mirrored the patients' responses to therapy., Conclusions: Our novel ICG-based liquid biopsy test for CTCs can be used to specifically detect and quantify CTCs in the blood of pediatric patients with liver cancer., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Association for the Study of Liver Diseases.)

Background & Aims: Patients with metastatic, treatment-refractory, and relapsed hepatoblastoma (HB) have survival rates of less than 50% due to limited treatment options. To develop new therapeutic strategies for these patients, our laboratory has developed a preclinical testing pipeline. Given that histone deacetylase (HDAC) inhibition has been proposed for HB, we hypothesized that we could find an effective combination treatment strategy utilizing HDAC inhibition., Methods: RNA sequencing, microarray, NanoString, and immunohistochemistry data of patient HB samples were analyzed for HDAC class expression. Patient-derived spheroids (PDSp) were used to screen combination chemotherapy with an HDAC inhibitor, panobinostat. Patient-derived xenograft (PDX) mouse models were developed and treated with the combination therapy that showed the highest efficacy in the PDSp drug screen., Results: HDAC RNA and protein expression were elevated in HB tumors compared to normal livers. Panobinostat (IC 50 of 0.013-0.059 μM) showed strong in vitro effects and was associated with lower cell viability than other HDAC inhibitors. PDSp demonstrated the highest level of cell death with combination treatment of vincristine/irinotecan/panobinostat (VIP). All four models responded to VIP therapy with a decrease in tumor size compared to placebo. After 6 weeks of treatment, two models demonstrated necrotic cell death, with lower Ki67 expression, decreased serum alpha fetoprotein and reduced tumor burden compared to paired VI- and placebo-treated groups., Conclusions: Utilizing a preclinical HB pipeline, we demonstrate that panobinostat in combination with VI chemotherapy can induce an effective tumor response in models developed from patients with high-risk, relapsed, and treatment-refractory HB., Impact and Implications: Patients with treatment-refractory hepatoblastoma have limited treatment options with survival rates of less than 50%. Our manuscript demonstrates that combination therapy with vincristine, irinotecan, and panobinostat reduces the size of high-risk, relapsed, and treatment-refractory tumors. With this work we provide preclinical evidence to support utilizing this combination therapy as an arm in future clinical trials., (Copyright © 2024 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.)

Advances in targeted therapies for pediatric hepatocellular tumors have been limited due to a paucity of clinically relevant models. Establishment and validation of intrahepatic patient-derived xenograft (PDX) models would help bridging this gap. The aim of this study is to compare the histomorphologic and immunophenotypic fidelity of patient tumors and their corresponding intrahepatic PDX models. Murine PDX models were established by intrahepatic implantation of patient tumors. Pathology slides from both patients and their corresponding PDX models were reviewed and quantitatively assessed for various histologic components and immunophenotypic markers. Ten PDX models were successfully established from nine patients with pre- (n=3) and post- (n=6) chemotherapy samples; diagnosed of hepatoblastoma (n=8) and hepatocellular neoplasm, not otherwise specified (n=1). Two of nine (22.2%) patients showed ≥75% fetal component; however, the corresponding PDX models did not maintain this fetal differentiation. High grade histology was seen in three patients (33.3%) and overrepresented in six PDX models (60%). Within the subset of three PDXs that were further characterized, significant IHC concordance was seen in all 3 models for CK7, CK19, Ki-67, and p53; and 2 of 3 models for Sox9 and Beta-catenin. GPC-3 and GS showed variable to moderate concordance, while Hepar was the least concordant. Our study shows that in general, the PDX models appear to represent the higher-grade component of the original tumor and show significant concordance for Ki-67, making them appropriate tools for testing new therapies for the most aggressive, therapy-resistant tumors., Competing Interests: Declaration of Competing Interest There is no conflict of interest., (Copyright © 2024 Elsevier GmbH. All rights reserved.)

Hepatoblastoma is characterized by driver mutations in CTNNB1 , making it an attractive biomarker for a liquid biopsy approach utilizing circulating tumor DNA (ctDNA). This prospective observational study sought to ascertain the feasibility of ctDNA detection in patients with hepatoblastoma and explore its associations with established clinical indicators and biomarkers, including serum Alpha-fetoprotein (AFP). We obtained 38 plasma samples and 17 tumor samples from 20 patients with hepatoblastoma. These samples were collected at various stages: 10 at initial diagnosis, 17 during neoadjuvant chemotherapy, 6 post-operatively, and 5 at disease recurrence. Utilizing a bespoke sequencing assay we developed called QUENCH, we identified single nucleotide variants and deletions in CTNNB1 ctDNA. Our study demonstrated the capability to quantitate ctDNA down to a variant allele frequency of 0.3%, achieving a sensitivity of 90% for patients at initial diagnosis, and a specificity of 100% at the patient level. Notably, ctDNA positivity correlated with tumor burden, and ctDNA levels exhibited associations with macroscopic residual disease and treatment response. Our findings provide evidence for the utility of quantitative ctDNA detection in hepatoblastoma management. Given the distinct detection targets, ctDNA and AFP-based stratification and monitoring approaches could synergize to enhance clinical decision-making. Further research is needed to elucidate the interplay between ctDNA and AFP and determine the optimal clinical applications for both methods in risk stratification and residual disease detection.

Objective: Hepatoblastoma (HB) is the most common primary hepatic malignancy in childhood. Relapse occurs in more than 50% of high-risk patients with a high mortality due to ineffective salvage therapies. The purpose of this study is to identify risk factors for relapsed HB and predictors of survival in a single tertiary referral center., Methods: A retrospective chart review showed 129 surgically treated HB patients from October 2004 to July 2020. Of the cohort, 22 patients presented with relapsed HB. Relapse was defined as re-appearance of malignancy after 4 weeks of normalized AFP and disappearance of all tumors on imaging., Results: Patients with relapsed HB had a 5-year overall survival (OS) of 45.4% compared to 93.1% in those without relapse (p = 0.001). When comparing PRETEXT IV, microvascular invasion, metastatic disease, and age on multivariate logistic regression, only PRETEXT IV was an independent risk factor for relapsed HB with an OR of 2.39 (95% CI: 1.16-4.96; p = 0.019). Mixed epithelial and mesenchymal HB (12/19, 63.2%) was the most common histology of primary tumors while pure epithelial HB (13/15, 86.6%) was the most common relapsed histology. Combination of surgical and medical therapy for relapsed disease was predictive of survival with an HR of 16.3 (95% CI: 1.783-149.091; p = 0.013) compared to only chemotherapy., Conclusions: This study demonstrates that PRETEXT IV staging is an independent predictor of relapsed disease. The most common relapsed histology was epithelial, suggesting a potential selection or resistance of this component. Surgical resection is a critical component of multimodal therapy for relapsed HB., (© 2023 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

Background: Intercostal nerve cryoablation with the Nuss procedure has been shown to decrease opioid requirements and hospital length of stay; however, few studies have evaluated the impact on complications and hospital costs., Methods: A retrospective cohort study was performed for all Nuss procedures at our institution from 2016 through 2020. Outcomes were compared across 4 pain modalities: cryoablation with standardized pain regimen (n = 98), patient-controlled analgesia (PCA; n = 96), epidural (n = 36), and PCA with peripheral nerve block (PNB; n = 35). Outcomes collected included length of stay, opioid use, variable direct costs, and postoperative complications. Univariate and multivariate hierarchical regression analysis was used to compare outcomes between the pain modalities., Results: Cryoablation was associated with increased total hospital cost compared with PCA (cryoablation, $11 145; PCA, $8975; P < .01), but not when compared with epidural ($9678) or PCA with PNB ($10 303). The primary driver for increased costs was operating room supplies (PCA, $2741; epidural, $2767; PCA with PNB, $3157; and cryoablation, $5938; P < .01). With multivariate analysis, cryoablation was associated with decreased length of stay (-1.94; 95% CI, -2.30 to -1.57), opioid use during hospitalization (-3.54; 95% CI, -4.81 to -2.28), and urinary retention (0.13; 95% CI, 0.05-0.35)., Conclusions: Cryoablation significantly reduces opioid requirements and length of stay relative to alternative modalities, but it was associated with an increase in total hospital costs relative to PCA, but not epidural or PCA with PNB. Cryoablation was not associated with allodynia or slipped bars requiring reoperation., (Copyright © 2023 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.)

Current understanding and classification of pediatric hepatocellular adenomas (HCA) are largely based on adult data. HCAs are rare in children and, unlike in adults, are often seen in the context of syndromes or abnormal background liver. Attempts to apply the adult classification to pediatric tumors have led to several "unclassifiable" lesions. Although typically considered benign, few can show atypical features and those with beta-catenin mutations have a risk for malignant transformation. Small lesions can be monitored while larger (>5.0 cm) lesions are excised due to symptoms or risk of bleeding/rupture, etc. Management depends on gender, age, underlying liver disease, multifocality, size of lesion, histologic subtype and presence of mutation, if any. In this review, we summarize the data on pediatric HCAs and highlight our experience with their diagnosis and management.

Objective: To compare the outcomes of patients with multifocal hepatoblastoma (HB) treated at our institution with either orthotopic liver transplant (OLTx) or hepatic resection to determine outcomes and risk factors for recurrence., Background: Multifocality in HB has been shown to be a significant prognostic factor for recurrence and worse outcome. The surgical management of this type of disease is complex and primarily involves OLTx to avoid leaving behind microscopic foci of disease in the remnant liver., Methods: We performed a retrospective chart review on all patients <18 years of age with multifocal HB treated at our institution between 2000 and 2021. Patient demographics, operative procedure, post-operative course, pathological data, laboratory values, short- and long-term outcomes were analyzed., Results: A total of 41 patients were identified as having complete radiologic and pathologic inclusion criteria. Twenty-three (56.1%) underwent OLTx and 18 (43.9%) underwent partial hepatectomy. Median length of follow-up across all patients was 3.1 years (IQR 1.1-6.6 years). Cohorts were similar in rates of PRETEXT designation status identified on standardized imaging re-review (p = .22). Three-year overall survival (OS) estimate was 76.8% (95% CI: 60.0%-87.3%). There was no difference in rates of recurrence or overall survival in patients who underwent either resection or OLTx (p = .54 and p = .92 respectively). Older patients (>72 months), patients with a positive porta hepatis margin, and patients with associated tumor thrombus experienced worse recurrence rates and survival. Histopathology demonstrating pleomorphic features independently associated with worse rates of recurrence., Conclusions: Through proper patient selection, multifocal HB was adequately treated with either partial hepatectomy or OLTx with comparable outcome results. HB with pleomorphic features, increased patient age at diagnosis, involved porta hepatis margin on pathology, and the presence of associated tumor thrombus may be associated with worse outcomes regardless of the local control surgery offered., Level of Evidence: III., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Liver cancer is one of the leading causes of cancer-related deaths, with a significant increase in incidence worldwide. Novel therapies are needed to address this unmet clinical need. Indocyanine green (ICG) is a broadly used fluorescence-guided surgery (FGS) agent for liver tumor resection and has significant potential for conversion to a targeted therapy. Here, we report the design, synthesis, and investigation of a series of iodinated ICG analogs (I-ICG), which can be used to develop ICG-based targeted radiopharmaceutical therapy. We applied a CRISPR-based screen to identify the solute carrier transporter, OATP1B3, as a likely mechanism for ICG uptake. Our lead I-ICG compound specifically localizes to tumors in mice bearing liver cancer xenografts. This study introduces the chemistry needed to incorporate iodine onto the ICG scaffold and defines the impact of these modifications on key properties, including targeting liver cancer in vitro and in vivo ., Competing Interests: The authors declare no competing financial interest., (© 2023 American Chemical Society.)

Background: Hepatoblastoma (HB) is the most common primary liver cancer in children with emerging evidence that incidence is increasing globally. While overall survival for low risk hepatoblastoma is >90%, children with metastatic disease have worse survival. As identifying factors associated with high-risk disease is critical for improving outcomes for these children, a need for a further understanding of the epidemiology of hepatoblastoma is warranted. Therefore, we conducted a population-based epidemiologic study of hepatoblastoma in Texas, a large state characterized by ethnic and geographic diversity., Methods: Information on children diagnosed with hepatoblastoma at 0-19 years of age for the period of 1995-2018 was obtained from the Texas Cancer Registry (TCR). Demographic and clinical variables including sex, race/ethnicity, age at diagnosis, urban-rural status, and residence along the Texas-Mexico border were evaluated. Multivariable Poisson regression was used to calculate adjusted incidence rate ratios (aIRRs) and 95% confidence intervals (CIs) for each variable of interest. Joinpoint regression analysis was used to determine the trend in incidence of hepatoblastoma, overall and by ethnicity., Results: Overall, 309 children diagnosed with hepatoblastoma in Texas for the period of 1995-2018. Joinpoint regression analysis showed no joinpoints in the overall or the ethnic-specific analyses. Over this period, the incidence increased at 4.59% annually; with the annual percent change higher among Latinos (5.12%) compared to non-Latinos (3.15%). Among these children, 57 (18%) had metastatic disease at diagnosis. Factors associated with hepatoblastoma included male sex (aIRR = 1.5, 95% CI: 1.2-1.8, p = 0.002); infancy (aIRR = 7.6, 95% CI: 6.0-9.7, p < 0.001); and Latino ethnicity (aIRR = 1.3, 95% CI: 1.0-1.7, p = 0.04). Additionally, children living in rural areas were less likely to develop hepatoblastoma (aIRR = 0.6, 95% CI: 0.4-1.0, p = 0.03). While residence on the Texas-Mexico border association with hepatoblastoma approached statistical significance ( p = 0.06) in unadjusted models, this finding did not remain significant after adjusting for Latino ethnicity. The two factors associated with being diagnosed with metastatic hepatoblastoma included Latino ethnicity (aIRR = 2.1, 95% CI: 1.1-3.8, p = 0.02) and male sex (aIRR = 2.4, 95% CI: 1.3-4.3, p = 0.003)., Conclusions: In this large population-based study of hepatoblastoma, we found several factors associated with hepatoblastoma and metastatic disease. The reasons for a higher burden of hepatoblastoma among Latino children is unclear but could be due to differences in geographic genetic ancestry, environmental exposures, or other unmeasured factors. Additionally, it is notable that Latino children were also more likely to be diagnosed with metastatic hepatoblastoma compared to non-Latino white children. To our knowledge, this has not been previously reported and warrants further study to delineate the causes of this disparity and identify interventions to improve outcomes., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Espinoza, Scheurer, Chambers, Vasudevan and Lupo.)

Introduction: The aim of the study was to characterize the changes in fetal lung volume following fetoscopic endoluminal tracheal occlusion (FETO) that are associated with infant survival and need for extracorporeal membrane oxygenation (ECMO) in congenital diaphragmatic hernia (CDH)., Methods: Fetuses with CDH who underwent FETO at a single institution were included. CDH cases were reclassified by MRI metrics [observed-to-expected total lung volume (O/E TLV) and percent liver herniation]. The percent changes of MRI metrics after FETO were calculated. ROC-derived cutoffs of these changes were derived to predict infant survival to discharge. Regression analyses were done to determine the association between these cutoffs with infant survival and ECMO need, adjusted for site of CDH, gestational age at delivery, fetal sex, and CDH severity., Results: Thirty CDH cases were included. ROC analysis demonstrated that post-FETO increases in O/E TLV had an area under the curve of 0.74 (p = 0.035) for the prediction of survival to hospital discharge; a cutoff of less than 10% was selected. Fetuses with a <10% post-FETO increase in O/E TLV had lower survival to hospital discharge [44.8% vs. 91.7%; p = 0.018] and higher ECMO use [61.1% vs. 16.7%; p = 0.026] compared to those with an O/E TLV increase ≥10%. Similar results were observed when the analyses were restricted to left-sided CDH cases. A post-FETO <10% increase in O/E TLV was independently associated with lower survival at hospital discharge (aOR: 0.073, 95% CI: 0.008-0.689; p = 0.022) and at 12 months of age (aOR: 0.091, 95% CI: 0.01-0.825; p = 0.036) as well as with higher ECMO use (aOR: 7.88, 95% CI: 1.31-47.04; p = 0.024)., Conclusion: Fetuses with less than 10% increase in O/E TLV following the FETO procedure are at increased risk for requiring ECMO and for death in the postnatal period when adjusted for gestational age at delivery, CDH severity, and other confounders., (© 2023 S. Karger AG, Basel.)

Objective: To study the role of fetal endoscopic tracheal occlusion (FETO) on resolution of pulmonary hypertension (PH) in fetuses with isolated moderate left-sided diaphragmatic hernia (CDH)., Methods: This retrospective study included fetuses with CDH evaluated between February 2004 and July 2017. Using the tracheal occlusion to accelerate lung growth (TOTAL) trial definition, we classified fetuses into moderate left CDH if O/E-LHR (observed/expected-lung head ratio) was 25-34.9% regardless of liver position or O/E-LHR of 35-44.9% if liver was in the chest. Postnatal echocardiograms were used to diagnose PH. Logistic regression analyses were performed to determine the relationship of FETO with study outcomes., Results: Of 184 cases with no other major anomalies, 30 (16%) met criteria. There were nine FETO and 21 non-FETO cases. By hospital discharge, a higher proportion of infants in the FETO group had resolution of PH (87.5 (7/8) vs. 40% (8/20); p =.013). FETO was associated with adjusted odds ratio of 17.3 (95% CI: 1.75-171; p =.015) to resolve PH by hospital discharge. No significant differences were noted in need for ECMO or survival to discharge between groups., Conclusions: Infants with moderate left-sided CDH according to O/E-LHR, FETO is associated with resolution of PH by the time of hospital discharge.

Hepatoblastoma (HB) is the most common pediatric primary liver malignancy, and survival for high-risk disease approaches 50%. Mouse models of HB fail to recapitulate hallmarks of high-risk disease. The aim of this work was to generate murine models that show high-risk features including multifocal tumors, vascular invasion, metastasis, and circulating tumor cells (CTCs). HepT1 cells were injected into the livers or tail veins of mice, and tumor growth was monitored with magnetic resonance and bioluminescent imaging. Blood was analyzed with fluorescence-activated cell sorting to identify CTCs. Intra- and extra-hepatic tumor samples were harvested for immunohistochemistry and RNA and DNA sequencing. Cell lines were grown from tumor samples and profiled with RNA sequencing. With intrahepatic injection of HepT1 cells, 100% of animals grew liver tumors and showed vascular invasion, metastasis, and CTCs. Mutation profiling revealed genetic alterations in seven cancer-related genes, while transcriptomic analyses showed changes in gene expression with cells that invade vessels. Tail vein injection of HepT1 cells resulted in multifocal, metastatic disease. These unique models will facilitate further meaningful studies of high-risk HB. This article has an associated First Person interview with the first author of the paper., Competing Interests: Competing interests The authors declare no competing or financial interests., (© 2022. Published by The Company of Biologists Ltd.)

Introduction:  The Nuss procedure is the most common and preferred operative correction of pectus excavatum. Surgeon preference and patient factors can result in variations in Nuss procedure technique. We hypothesize that certain techniques are associated with increased risk of complications., Materials and Methods:  We performed a single-center retrospective review of Nuss operations from 2016 to 2020. Variations in intraoperative techniques included sternal elevator (SE) use, number of bars placed, and usage of bilateral stabilizing sutures. Patient demographics, intraoperative data, and postoperative outcomes were reported as median with interquartile ranges or percentages. Statistical significance ( p  < 0.05) was determined with Wilcoxon's rank-sum and chi-square tests. Multivariate analysis was performed to control for introduction of intercostal nerve cryoablation and surgeon volume, and reported as odds ratio with 95% confidence interval., Results:  Two hundred and sixty-five patients were identified. Patients repaired with two bars were older with a larger Haller index (HI). Patient demographics were not significantly different for SE or stabilizing suture use. Placement of two bars was associated with significantly increased risk of readmission. Similarly, SE use was associated with increased risk of pleural effusion and readmission. Finally, the use of bilateral stabilizing sutures resulted in less frequent slipped bars without statistical significance., Conclusion:  Older patients with a larger HI were more likely to need two bars placed to repair pectus excavatum. Placement of multiple bars and SE use are associated with significantly higher odds of certain complications., Competing Interests: None declared., (Thieme. All rights reserved.)

Background: Recent studies have shown intercostal cryoablation(IC) during the Nuss procedure decreases hospital length of stay(LOS) and opioid administration. However, few studies have also evaluated the risk of postoperative complications related to IC., Methods: We performed a single center retrospective analysis of all patients who underwent Nuss procedure by one surgeon from 2/2016 to 2/2020, comparing intraoperative IC to other pain management modalities(non-IC). Primary outcomes were postoperative complications, hospital LOS, and opioid administration. Multivariate analysis was performed with outcomes reported as regression coefficients(RC) or odds ratios(OR) with 95% confidence interval., Results: IC was associated with decreased hospital LOS (RC -1.91[-2.29 to -1.54], less hospital opioid administration (RC -4.28[-5.13 to -3.43]), and less discharge opioid administration (RC -3.82[-5.23 to -2.41]). With respect to postoperative complications, IC decreased the odds of urinary retention (OR 0.16[0.06 to 0.44]); however, increased the odds of slipped bars requiring reoperation (OR 36.65[5.04-266.39])., Conclusions: Our single surgeon experience controls for surgeon variability and demonstrates intraoperative IC for the Nuss procedure is an effective pain management modality that decreases hospital LOS and opioid use during hospitalization and at discharge; however, it is associated with increased odds of slipped bars requiring reoperation., Level of Evidence: III., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Objective: To evaluate the association of laser photocoagulation of placental anastomoses (LPA) prior to 18 weeks' gestation (early LPA) with very preterm delivery and neonatal survival in pregnancies with twin-twin transfusion syndrome (TTTS)., Methods: This was a retrospective cohort study of monochorionic diamniotic twin pregnancies with TTTS undergoing LPA between 2002 and 2018 at two institutions. The rates of delivery < 28, < 30 and < 32 weeks' gestation, preterm prelabor rupture of membranes (PPROM) and 30-day survival of one or both infants were compared between pregnancies undergoing early LPA and those undergoing LPA ≥ 18 weeks' gestation. Regression analysis was performed to determine the association of early LPA with very preterm delivery and 30-day survival, adjusted for Quintero stage, study phase, selective fetal growth restriction, gestational age at delivery, maternal age ≥ 35 years, body mass index > 35 kg/m 2 , placental location, use of Seldinger method to place the operative trocar, size of the trocar, participating center, use of Solomon technique, cerclage and PPROM. Survival analysis using the Cox proportional hazard model was applied to examine the LPA-to-delivery interval according to the timing of surgery, adjusted for confounding variables., Results: A total of 414 TTTS pregnancies were included in the study, of which 68 (16.4%) underwent early LPA. In the total cohort, the incidence of delivery at < 28, < 30 and < 32 weeks' gestation was 22.7%, 39.6% and 53.4%, respectively. Survival of both twins and survival of at least one twin at 30 days were 67.5% and 90.8%, respectively. No significant difference was noted between pregnancies that underwent early LPA and those that had LPA ≥ 18 weeks in the rate of delivery < 28 weeks (19.1% vs 23.4%; P = 0.4), < 30 weeks (38.2% vs 39.9%; P = 0.8) and < 32 weeks (44.1% vs 55.2%; P = 0.1) and PPROM (29.0% vs 24.1%; P = 0.4), or in the incidence of double-twin survival (63.9% vs 68.1%; P = 0.5) and survival of at least one infant (91.8% vs 90.6%; P = 0.7) at 30 days. Early LPA was not associated with very preterm delivery or neonatal survival in the regression analyses. Early LPA was associated with a longer LPA-to-delivery interval compared with LPA performed ≥ 18 weeks (median, 106.9 days (range, 2-164 days) vs median, 69.3 days (range, 0-146 days); P < 0.001) when adjusted for confounding variables (hazard ratio, 2.56 (95% CI, 1.76-3.73); P < 0.001)., Conclusion: Laser surgery before 18 weeks is not associated with an increased rate of very preterm delivery and PPROM or with reduced neonatal survival when compared with LPA after 18 weeks. © 2020 International Society of Ultrasound in Obstetrics and Gynecology., (© 2020 International Society of Ultrasound in Obstetrics and Gynecology.)

Objectives: To evaluate the association of intertwin differences in umbilical artery pulsatility index (DUAPI) and infant survival in twin-to-twin transfusion syndrome (TTTS)., Methods: Absolute DUAPI was calculated prior to laser surgery. Receiver-operating characteristics (ROC) curve analysis provided an intertwin DUAPI cutoff of 0.4 for the prediction of double twin survival to 30 days of life. Infant survival was compared between women with an intertwin DUAPI <0.4 and ≥0.4 in the whole cohort, in TTTS cases with Quintero stages I/II and in those with Quintero stages III/IV. Regression analyses were performed to evaluate the association of intertwin DUAPI <0.4 and infant survival adjusted for confounders., Results: In total, 349 TTTS cases were included. Double twin survival to 30 days was observed in 67% (234/349) of cases. Significant differences in double twin survival was seen between intertwin DUAPI groups in the whole cohort (76.8 vs. 52.2%; p<0.001), in women with TTTS Quintero stage I or II (77.8 vs. 58.5%; p=0.015) as well as in women with TTTS Quintero stage III or IV (75 vs. 49.5%; p=0.001). Intertwin DUAPI <0.4 conferred a threefold increased chance for double twin survival., Conclusions: Small intertwin DUAPI is associated with increased double infant survival in early and advanced TTTS stages., (© 2021 Walter de Gruyter GmbH, Berlin/Boston.)

Unpublished randomized controlled trial (RCT) frequency, correlates, and financial impact are not well understood. We sought to characterize the nonpublication of peer-reviewed manuscripts among interventional, therapeutic, multi-arm, phase 3 oncology RCTs. Trials were identified by searching ClinicalTrials.gov, while publications and abstracts were identified through PubMed and Google Scholar. Trial data were extracted from ClinicalTrials.gov and individual publications. Publication was defined as a peer-reviewed manuscript addressing the primary endpoint. Patient accrual cost was extrapolated from experimental data; investigators/sponsors were contacted to determine nonpublication reasons. Six hundred eighty-four completed RCTs met inclusion criteria, which accrued 434,610 patients from 1994 to 2015; 638 were published (93.3%) and 46 were unpublished (6.7%). Among the unpublished trials, the time difference from primary endpoint maturity to data abstraction was a median of 6 years (interquartile range, 4 to 8 years). On multiple binary logistic regression analysis, factors associated with unpublished trials included lack of cooperative group sponsorship (odds ratio, 5.91, 95% CI, 1.35 to 25.97; P=.019) and supportive care investigation (odds ratio, 2.90; 95% CI, 1.13 to 7.41; P=.027). The estimated inflation-adjusted average cost of patient accrual for all unpublished trials was $113,937,849 (range, $41,136,883 to $320,201,063). Direct contact with sponsors/investigators led to a 50.0% response rate (n=23 of 46); manuscript in preparation and/or in submission (n=10 of 23) was the most commonly cited reason for nonpublication. In conclusion, approximately 1 in 15 clinical oncology RCTs are unpublished and this has a profound impact on the research enterprise. The cooperative group infrastructure may serve as a blueprint to reduce nonpublication., (Copyright © 2020 Mayo Foundation for Medical Education and Research. Published by Elsevier Inc. All rights reserved.)

Objectives: To evaluate the association of abnormal Doppler velocimetric patterns in the umbilical arteries (UAs) and right ventricular outflow tract abnormalities (RVOTAs) in twin- twin transfusion syndrome (TTTS) cases., Methods: This retrospective study involved women who had laser surgery for TTTS between January 2012 and May 2018 at a single institution. The prevalence of an RVOTA in either twin was compared among TTTS cases in which both twins had positive end-diastolic flow (EDF) in the UA and those in which either twin had intermittent or persistent absent/reversed UA EDF. Nonparametric tests were used for comparisons. Logistic regression was performed to identify variables associated with an RVOTA in either twin, adjusted for moderate or severe tricuspid regurgitation, right ventricular hypertrophy, right ventricular systolic or diastolic dysfunction, the Quintero stage, and other confounders. P < .05 was considered significant., Results: A total of 126 consecutive TTTS cases were included. Right ventricular outflow tract abnormalities were seen in 8.7% (11of 126) of cases, all in recipient twins. Significant differences in the rate of RVOTAs in the recipient twin were seen between TTTS cases with intermittent absent/reversed UA EDF and those with positive UA EDF (26.9% [7 of 26] versus 3.7% [3 of 82]; P = .002]. However, no significant differences were noted among the other study groups. Intermittent absent/reversed UA EDF was associated with a significantly increased risk for an RVOTA (adjusted odds ratio, 20.6 [95% confidence interval, 3.1-138]; P = .002) after adjusting for confounders., Conclusions: Intermittent changes in vascular impedance to UA flow may contribute to the pathogenesis of acquired right-sided cardiac lesions in the recipient twin affected with TTTS., (© 2020 American Institute of Ultrasound in Medicine.)

Background: The use of professional medical writers (PMWs) has been historically low, but contemporary data regarding PMW usage are scarce. In this study, we sought to quantify PMW use in oncologic phase III randomized controlled trials (RCTs)., Methods: We performed a database query through ClinicalTrials.gov to identify cancer-specific phase III RCTs; we then identified whether a PMW was involved in writing the associated trial manuscript reporting primary endpoint results., Results: Two-hundred sixty trials of 600 (43.3%) used a PMW. Industry-funded trials used PMWs more often than nonindustry trials (54.9% vs. 3.0%, p < .001). Increased PMW usage was further noted among trials meeting their primary endpoint (53.4% vs. 32.9%, p < .001) and trials that led to subsequent Food and Drug Administration approval (63.1% vs. 36.3%, p < .001). By treatment interventions, PMW use was highest among systemic therapy trials (50.2%). Lastly, the use of PMWs increased significantly over time (odds ratio: 1.11/year, p = .001)., Conclusion: PMW use rates are high among industry-funded trials. We urge continued and increased transparency in reporting the funding and use of PMWs., (© 2020 The Authors. The Oncologist published by Wiley Periodicals LLC on behalf of AlphaMed Press.)

Background: Patients with good performance status (PS) tend to be favored in randomized clinical trials (RCTs), possibly limiting the generalizability of trial findings. We aimed to characterize trial-related factors associated with the use of PS eligibility criteria and analyze patient accrual breakdown by PS., Methods: Adult, therapeutic, multiarm phase III cancer-specific RCTs were identified through ClinicalTrials.gov. PS data were extracted from articles. Trials with a PS restriction ECOG score ≤1 were identified. Factors associated with PS restriction were determined, and the use of PS restrictions was analyzed over time., Results: In total, 600 trials were included and 238,213 patients had PS data. Of those trials, 527 studies (87.8%) specified a PS restriction cutoff, with 237 (39.5%) having a strict inclusion criterion (ECOG PS ≤1). Enrollment criteria restrictions based on PS (ECOG PS ≤1) were more common among industry-supported trials (P<.001) and lung cancer trials (P<.001). Nearly half of trials that led to FDA approval included strict PS restrictions. Most patients enrolled across all trials had an ECOG PS of 0 to 1 (96.3%). Even among trials that allowed patients with ECOG PS ≥2, only 8.1% of those enrolled had a poor PS. Trials of lung, breast, gastrointestinal, and genitourinary cancers all included <5% of patients with poor PS. Finally, only 4.7% of patients enrolled in trials that led to subsequent FDA approval had poor PS., Conclusions: Use of PS restrictions in oncologic RCTs is pervasive, and exceedingly few patients with poor PS are enrolled. The selective accrual of healthier patients has the potential to severely limit and bias trial results. Future trials should consider a wider cancer population with close toxicity monitoring to ensure the generalizability of results while maintaining patient safety.

The pace of clinical trial data generation and publication is an area of interest within clinical oncology; however, little is known about the dynamics and covariates of time to reporting (TTR) of trial results. To assess these, ClinicalTrials.gov was queried for phase three clinical trials for patients with metastatic solid tumors, and the factors associated with TTR from enrollment completion to publication were analyzed. Based on the 319 included trials, cooperative-group-sponsored trials were reported at a slower rate than non-cooperative-group trials (median 37.5 vs. 31.0 months; p < 0.001), while industry-funded studies were reported at a faster rate than non-industry-supported trials (31.0 vs. 40.0 months; p = 0.005). Furthermore, successful trials (those meeting their primary endpoint) were reported at a faster rate than unsuccessful studies (27.5 vs. 36.0 months; p < 0.001). Multivariable analysis confirmed that industry funding was independently associated with a shorter TTR ( p = 0.006), while cooperative group sponsorship was not associated with a statistically significant difference in TTR ( p = 0.18). These data underscore an opportunity to improve cooperative group trial efficiency by reducing TTR.

Background: The use of overall survival (OS) as the gold standard primary end-point (PEP) in metastatic oncologic randomised controlled trials (RCTs) has declined in favour of progression-free survival (PFS) without a complete understanding of the degree to which PFS reliably predicts for OS., Methods: Using ClinicalTrials.gov, we identified 1239 phase III oncologic RCTs, 260 of which were metastatic solid tumour trials with a superiority-design investigating a therapeutic intervention by using either a PFS or OS PEP. Each individual trial was reviewed to quantify RCT design factors and disease-related outcomes., Results: A total of 172,133 patients were enrolled from the year 1999 to 2015 in RCTs that used PFS (56.2%, 146/260) or OS (43.8%, 114/260) as the PEP. PFS trials were more likely to restrict patient eligibility by using molecular criteria (15.1% versus 4.4%, p = 0.005) use targeted therapy (80.1% versus 67.5%, p = 0.048), accrue fewer patients (median 495 versus 619, p = 0.03), and successfully meet the trial PEP (66.9% versus 33.3%, p < 0.0001). On multiple binary logistic regression analysis, factors that predicted for PFS or OS PEP trial success included choice of PFS PEP (p < 0.0001), molecular profile restriction (p = 0.02) and single agent therapy (p = 0.02). Notably, there was only a 38% (31/82) conversion rate of positive PFS-to-OS benefit; lack of industry sponsorship predicted for PFS-to-OS signal conversion (80.0% without industry sponsorship versus 35.1% with industry sponsorship, p = 0.045)., Conclusions: A PFS PEP has suboptimal positive predictive value for OS among phase III metastatic solid tumour RCTs. Regulatory agency decisions should be judicious in using PFS results as the primary basis for approval., Competing Interests: Conflict of interest statement The authors report no financial disclosures or conflicts of interests related to this work. Dr. Jagsi reports stock ownership and an advisory role in Equity Quotient; personal fees from Amgen and Vizient; grants from the National Institutes of Health, the Doris Duke Foundation, the Greenwall Foundation, and Blue Cross Blue Shield of Michigan. Dr. Das reports personal fees from Adlai Nortye. Dr. Fuller reports honoraria from the University of Texas Health Science Center San Antonio and Elekta AB; royalties from Demos Medical Publishing; travel expenses/accommodations from Oregon Health & Science University, Great Baltimore Medical Center, University of Illinois Chicago, Elekta AB, the Translational Research Institute of Australia; grants from the National Science Foundation and National Institutes of Health. Dr. Thomas reports receiving a stipend as deputy editor of JAMA Oncology. Dr. V. Subbiah reports funding for clinical trials from Roche/Genentech, Novartis, Bayer, GlaxoSmithKline, Nanocarrier, Vegenics, Celgene, Northwest Biotherapeutics, Berghealth, Incyte, Fujifilm, Pharmamar, D3, Pfizer, Multivir, Amgen, Abbvie, Alfa-sigma, Agensys, Boston Biomedical, Idera Pharma, Inhibrx, Exelixis, Blueprint medicines, Loxo Oncology, Medimmune, Altum, Dragonfly Therapeutics, Takeda, National Comprehensive Cancer Network, NCI-CTEP and UT MD Anderson Cancer Center, Turning point therapeutics, Boston Pharmaceuticals; for travel from Novartis, Pharmamar, ASCO, ESMO, Helsinn, Incyte; for consultancy from Helsinn, LOXO Oncology/Eli Lilly, R-Pharma US, INCYTE, QED pharma, Medimmune, Novartis; and for other duties from Medscape., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Although improving representation of racial and ethnic groups in United States clinical trials has been a focus of federal initiatives for nearly 3 decades, the status of racial and ethnic minority enrollment on cancer trials is largely unknown. We used a broad collection of phase 3 cancer trials derived from ClinicalTrials.gov to evaluate racial and ethnic enrollment among US cancer trials. The difference in incidence by race and ethnicity was the median absolute difference between trial and corresponding Surveillance, Epidemiology, and End Results data. All statistical tests were 2-sided. Using a cohort of 168 eligible trials, median difference in incidence by race and ethnicity was +6.8% for Whites (interquartile range [IQR] = +1.8% to +10.1%; P < .001 by Wilcoxon signed-rank test comparing median difference in incidence by race and ethnicity to a value of 0), -2.6% for Blacks (IQR = -5.1% to +1.2%; P = .004), -4.7% for Hispanics (IQR = -7.5% to -0.3%; P < .001), and -4.7% for Asians (IQR = -5.7% to -3.3%; P < .001). These data demonstrate overrepresentation of Whites, with continued underrepresentation of racial and ethnic minority subgroups., (© The Author(s) 2020. Published by Oxford University Press.)

Patient-reported outcome measures (PROMs) are increasingly incorporated as endpoints in oncology clinical trials but are often only validated in English. ClinicalTrials.gov was queried for cancer-specific randomized control trials (RCTs) addressing a therapeutic intervention and enrolling primarily in the USA. Peer-reviewed validation of Spanish and Chinese versions of each PROM was assessed. Of 103 eligible trials, a PROM was used as a primary endpoint in 25 RCTs (24.3%) and as a secondary endpoint in 78 RCTs (75.7%). A total of 61 of the 103 eligible trials (59.2%) and 17 of the 25 trials with a PROM primary endpoint (68.0%) used a PROM with either no Spanish or Chinese validation. The absence of validated PROM translations may diminish the voices of non-English language speaking trial participants. With an increasingly diverse US population, validation of non-English PROM translations may decrease disparities in trial participation and improve generalizability of study results.

Male breast cancer treatment regimens are often extrapolated from female-based studies because of a paucity of literature analyzing male breast cancer. Using ClinicalTrials.gov, we analyzed breast cancer randomized clinical trials (RCTs) to determine which factors were associated with male-gender inclusion. Of 131 breast cancer RCTs identified, male patients represented 0.087% of the total study population, which is significantly less than the proportion of male patients with breast cancer in the U.S. (0.95%; p < .001). Twenty-seven trials included male patients (20.6%). Lower rates of male inclusion were seen in trials that randomized or mandated hormone therapy as part of the trial protocol compared with trials that did not randomize or mandate endocrine therapy (2.5% vs. 28.6% male inclusion; p < .001). It is imperative for breast cancer clinical trials to include men when allowable in order to improve generalizability and treatment decisions in male patients with breast cancer., (© AlphaMed Press 2020.)

Objective: To evaluate infant survival according to the Doppler pattern of impedance to blood flow in the umbilical arteries (UAs) prior to laser surgery, in pregnancies with twin-to-twin transfusion syndrome (TTTS)., Methods: This was a retrospective study of women with a monochorionic diamniotic twin pregnancy who underwent laser surgery for TTTS between January 2012 and May 2018 at a single institution. Absolute intertwin difference in UA pulsatility index (DUAPI) was measured within 48 h prior to laser surgery. Twins with intermittent or persistent absent/reversed end-diastolic flow (EDF) in the UA (UA-EDF) were analyzed separately. Survival of both or at least one infant at birth and at 30 days postpartum was compared between pregnancies with an intertwin DUAPI of ≥ 0.4 and those with an intertwin DUAPI of < 0.4, as well as between fetuses with intermittent and those with persistent absent/reversed UA-EDF. Parametric and non-parametric tests were used for analysis. Regression analysis was performed to determine if intertwin DUAPI and intermittent or persistent absent/reversed UA-EDF were associated independently with infant survival, while controlling for gestational age at delivery, Quintero stage and other important confounding variables., Results: Of 231 TTTS pregnancies that underwent laser surgery during the study period, UA Doppler information could be retrieved for 206 and delivery information was available for 184, which comprised the study population. Rates of double-twin survival at birth were significantly higher in pregnancies with an intertwin DUAPI of < 0.4 than in those with an intertwin DUAPI of ≥ 0.4 (83.9% (78/93) vs 50.0% (12/24); P < 0.001). Double-infant survival at birth was higher in pregnancies with intermittent compared to those with persistent absent/reversed UA-EDF (73.0% (27/37) vs 36.7% (11/30); P = 0.003). Regression analysis demonstrated that an intertwin DUAPI of < 0.4 was associated with increased survival of both twins at delivery (P < 0.001) and at 30 days postpartum (P = 0.002), as well as increased survival of at least one twin at delivery (P = 0.009). Similarly, intermittent absent/reversed UA-EDF was associated with increased survival of both twins at delivery (P = 0.007) and at 30 days after birth (P = 0.015)., Conclusions: Evaluation of intertwin differences in UA impedance to blood flow as well as identification of intermittent or persistent absent or reversed UA-EDF prior to laser surgery could help in the prediction of double-infant survival at birth and to 30 days in twin pregnancies with TTTS. Copyright © 2019 ISUOG. Published by John Wiley & Sons Ltd., (Copyright © 2019 ISUOG. Published by John Wiley & Sons Ltd.)

Background: Age disparities among cancer clinical trial participants are pervasive and worsening over time. Identification of factors associated with age disparities is critical to improve enrollment of older patients on trials. The incidence and impact of trial eligibility criteria that exclude patients on the basis of age remains opaque., Methods: ClinicalTrials.gov was queried for completed oncologic randomized controlled trials (RCTs). Phase 3 RCTs assessing a therapeutic intervention among adult cancer patients were included. Trial eligibility criteria were assessed using the ClinicalTrials.gov website as well as trial publications and protocol documentation., Results: Seven hundred and forty-two trials met inclusion criteria, with a total combined enrollment of 449,720 patients. Upper age restriction enrollment criteria were identified for 10.1% of RCTs; the median age cutoff for restricted trials was 72 years (interquartile range 70-80 years). Linear regression modeling revealed decreasing incidence of age restriction criteria over time, at a rate of -1.1% annually (p = .03); trials initiating enrollment in 2002-2005, for example, had a 16.1% rate of age-restrictive eligibility criteria, compared with 7.6% for trials initiating enrollment in 2010-2014., Conclusion: Use of eligibility criteria that explicitly exclude patients on the basis of age appears to be decreasing with time. Future efforts should aim to better characterize the relationship between eligibility criteria (such as those that exclude patients on the basis of specific organ function) and their association with age disparities among enrolled patients., Competing Interests: Declaration of Competing Interest No portion of this work has been presented or published previously. This work was supported by the Breast Cancer Research Foundation (Arti Hurria Award in Geriatric Oncology). The authors are grateful for their generous support of this work., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Importance: Seminal investigation 2 decades ago alerted the oncology community to age disparities in participation in cooperative group trials; less is known about whether these disparities persist in industry-funded research., Objective: To characterize the age disparities among trial enrollees on randomized clinical trials (RCTs) of common cancers in clinical oncology and identify factors associated with wider age imbalances., Data Sources: Phase 3 clinical oncology RCTs were identified through ClinicalTrials.gov., Study Selection: Multiarm RCTs assessing a therapeutic intervention for patients with breast, prostate, colorectal, or lung cancer (the 4 most common cancer disease sites) were included., Data Extraction and Synthesis: Trial data were extracted from ClinicalTrials.gov. Trial screening and parameter identification were independently performed by 2 individuals. Data were analyzed in 2018., Main Outcomes and Measures: The difference in median age (DMA) between the trial participant median age and the population-based disease-site-specific median age was determined for each trial., Results: Three hundred two trials met inclusion criteria. The trials collectively enrolled 262 354 participants; 249 trials (82.5%) were industry-funded. For all trials, the trial median age of trial participants was a mean of 6.49 years younger than the population median age (95% CI, -7.17 to -5.81 years; P < .001). Age disparities were heightened among industry-funded trials compared with non-industry-funded trials (mean DMA, -6.84 vs -4.72 years; P = .002). Enrollment criteria restrictions based on performance status or age cutoffs were associated with age disparities; however, industry-funded trials were not more likely to use these enrollment restrictions than non-industry-funded trials. Age disparities were also larger among trials that evaluated a targeted systemic therapy and among lung cancer trials. Linear regression modeling revealed a widening gap between trial and population median ages over time at a rate of -0.19 years annually (95% CI, -0.37 to -0.01 years; P = .04)., Conclusions and Relevance: Age disparities between trial participants and the incident disease population are pervasive across trials and appear to be increasing over time. Industry sponsorship of trials is associated with heightened age imbalances among trial participants. With an increasing role of industry funding among cancer trials, efforts to understand and address age disparities are necessary to ensure generalizability of trial results as well as equity in trial access.

Two decades following the creation of the Office of Cancer Complementary and Alternative Medicine at the National Cancer Institute, the status of complementary and alternative medicine (CAM) research within oncology remains opaque. To better understand the landscape of CAM studies in oncology, we identified CAM-related phase III randomized controlled trials (RCTs) through ClinicalTrials.gov and compared these CAM trials to all non-CAM oncologic RCTs. Pearson χ2 testing was used to compare proportions across groups; all tests were two-sided. Comparing the 25 identified CAM RCTs with 739 non-CAM RCTs, CAM studies were more likely to be sponsored by a cooperative group (64.0% vs 28.6%, P < .001) and less likely to be industry funded (8.0% vs 76.5%, P < .001). CAM trials disproportionately excluded disease-related outcomes as endpoints (8.0% vs 84.6%, P < .001), were unsupported by prior early-phase data (55.0% vs 96.1%, P < .001), and did not meet the primary endpoint (8.7% vs 53.0%, P < .001). Given the observed relationship between encouraging pilot data and subsequent phase III trial success, we contend that future CAM RCTs may yield more promising findings if better supported by appropriately designed and well-characterized early-phase signals., (© The Author(s) 2019. Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Objectives: The association of an abnormal fetal heart rate (FHR) and chromosomal anomalies in the first trimester of pregnancy remains unclear, probably because of the lack of control for known confounding factors. This study was designed to determine whether an increased FHR is an independent risk factor for chromosomal anomalies between 11 and 14 weeks' gestation., Methods: This cohort study included women who underwent first-trimester genetic screening between 2011 and 2014 at a single institution. A multivariable logistic regression analysis was performed to determine whether an FHR of 170 beats per minute (bpm) or higher, derived from a receiver operating characteristic curve, is an independent risk factor for all chromosomal anomalies while controlling for known confounding factors. P < .05 was considered significant., Results: An FHR of 170 bpm or higher was observed in 7% (228 of 3254), and chromosomal anomalies were present in 1.0% (31 of 3254) of the population. A higher proportion of fetuses with an FHR of 170 bpm or higher had chromosomal anomalies compared to those with an FHR lower than 170 bpm. An FHR of 170 bpm or higher was an independent risk factor for chromosomal anomalies after controlling for known confounding factors. Of note, in the group of fetuses with a nuchal translucency above the 95th percentile, the frequency of chromosomal anomalies was significantly higher among fetuses with an FHR of 170 bpm or higher compared to those with an FHR lower than 170 bpm., Conclusions: Fetal tachycardia is a risk factor for chromosomal anomalies during first-trimester genetic screening, independent of increased nuchal translucency, nuchal septations, and maternal age., (© 2018 by the American Institute of Ultrasound in Medicine.)

Clinical and experimental evidence indicates that angiogenic imbalances may participate in the mechanisms of disease of several pregnancy complications, some of which may be life threatening. This article reviews current evidence in support of this view and the possibility that the fetus may play a central role in these imbalances; it also reviews recent experimental observations that modulation of angiogenic imbalances during pregnancy may have prophylactic and/or therapeutic value., (Copyright (c) 2010 Mosby, Inc. All rights reserved.)