A role for abdominal ultrasound in discriminating suspected necrotizing enterocolitis in congenital heart disease patients.

PURPOSE: We evaluated the diagnostic utility of abdominal ultrasound (AUS), an adjunct to abdominal X-ray (AXR), for necrotizing enterocolitis (NEC) in congenital heart disease (CHD) patients. METHODS: 86 patients with suspected NEC from 2009 to 2018 were classified as with CHD (n = 18) if they required cardiac intervention versus without CHD (n = 68). Clinical and radiological data were collected, including AXR and AUS concordance. Wilcoxon rank-sum test and Fisher's exact test were performed. RESULTS: CHD patients had higher birth weights (p < 0.001) and gestational ages (p < 0.001) than non-CHD patients. CHD patients presented more frequently with hypotension (p = 0.041) and less frequently with bilious emesis (p < 0.001). Overall, CHD patients were less likely to have AUS findings of pneumatosis (33.3 vs. 72.1%; p = 0.005) and decreased mural flow (0 vs. 20.6%; p = 0.035) compared to non-CHD patients. On concordance analysis, CHD patients had 3.9-fold more discordant studies with pneumatosis on AXR but not on AUS (33.3 vs. 8.8%; p = 0.016) compared to non-CHD patients. Urgent surgery was required in 5.6% of CHD patients versus 16.2% of non-CHD patients. CONCLUSION: CHD patients with suspected NEC represent a distinct clinical population. AUS has particular utility in assessing findings of bowel viability in the CHD NEC population, reflecting reduced rates of surgical NEC.

Abdominal ultrasound findings contribute to a multivariable predictive risk score for surgical necrotizing enterocolitis: A pilot study.

BACKGROUND: Abdominal ultrasound (AUS) is a promising adjunct to abdominal x-ray (AXR) for evaluating necrotizing enterocolitis (NEC). We developed a multivariable risk score incorporating AUS to predict surgical NEC. METHODS: 83 patients were evaluated by AXR and AUS for suspected NEC. A subset had surgical NEC. Multivariate logistic regression determined predictors of surgical NEC, which were incorporated into a risk score. RESULTS: 14/83 patients (16.9%) had surgical NEC. 10/83 (12.0%) patients required acute intervention, while 4/83 (4.8%) patients only required delayed surgery. Four predictors of surgical NEC were identified: abdominal wall erythema (OR: 8.2, p = 0.048), portal venous gas on AXR (OR: 29.8, p = 0.014), and echogenic free fluid (OR: 17.2, p = 0.027) and bowel wall thickening (OR: 12.5, p = 0.030) on AUS. A multivariable risk score incorporating these predictors had excellent area-under-the-curve of 0.937 (95% CI: 0.879-0.994). CONCLUSIONS: AUS, as an adjunct to physical exam and AXR, has utility for predicting surgical NEC.

Transamniotic Stem Cell Therapy for Experimental Congenital Diaphragmatic Hernia: Structural, Transcriptional, and Cell Kinetics Analyses in the Nitrofen Model.

PURPOSE: We examined select pulmonary effects and donor cell kinetics after transamniotic stem cell therapy (TRASCET) in a model of congenital diaphragmatic hernia (CDH). METHODS: Pregnant dams (n = 58) received nitrofen on gestational day 9.5 (E9) to induce fetal CDH. Fetuses (n = 681) were divided into 4 groups: untreated (n = 99) and 3 groups receiving volume-matched intra-amniotic injections on E17 of either saline (n = 142), luciferase-labeled amniotic fluid-derived mesenchymal stem cells (afMSCs; n = 299), or acellular recombinant luciferase (n = 141). Pulmonary morphometry, quantitative gene expression of pulmonary vascular tone mediators, or screening for labeled afMSCs were performed at term (E22). Statistical comparisons were by Mann-Whitney U-test, nested ANOVA, and Wald test. RESULTS: TRASCET led to significant downregulation of endothelial nitric oxide synthase and endothelin receptor-A expressions compared to both untreated and saline groups (both p < 0.001). TRASCET also led to a significant decrease in arteriole wall thickness compared to the untreated group (p < 0.001) but not the saline group (p = 0.180). Donor afMSCs were identified in the bone marrow and umbilical cord (p = 0.035 and 0.015, respectively, vs. plain luciferase controls). CONCLUSIONS: The effects of TRASCET in experimental CDH appear to be centered on the pulmonary vasculature and to derive from circulating donor cells.

Enhancement of transamniotic stem cell therapy for spina bifida by genetic engineering of donor mesenchymal stem cells with an Fgf2 transgene.

BACKGROUND/PURPOSE: We examined whether engineered overexpression of fibroblast growth factor-2 (Fgf2) in donor mesenchymal stem cells (MSCs) could enhance spina bifida coverage induced by transamniotic stem cell therapy (TRASCET). METHODS: Pregnant Sprague-Dawley dams (n = 24) exposed to retinoic acid for induction of fetal spina bifida were divided in three groups. An untreated group had no further manipulations. Two groups received volume-matched intra-amniotic injections into all fetuses (n = 157) of either amniotic fluid-derived MSCs (afMSC; n = 85) or afMSCs transduced with an Fgf2 transgene (Fgf2-afMSC; n = 72) on gestational day 17 (term=21-22 days). Defect coverage was categorized at term by histology and pan-cytokeratin immunohistochemistry. Statistical coverage comparisons were by logistic regression. RESULTS: Among 84 survivors with isolated spina bifida, 71 had definitive histology. Defect coverage rates in both the afMSC (38.5%) and Fgf2-afMSC (73.3%) groups were statistically significantly higher than in the untreated group (10%; p<0.001 for both). There was a significantly higher coverage rate in the Fgf2-afMSC group compared with the afMSC group (p = 0.025). CONCLUSIONS: Fgf2 overexpression in donor mesenchymal stem cells increases defect coverage rates in a rodent model of transamniotic stem cell therapy for spina bifida. Genetic engineering of donor cells is a promising strategy for the enhancement of this emerging therapy.

Fetal hematogenous routing of a donor hematopoietic stem cell line in a healthy syngeneic model of transamniotic stem cell therapy.

BACKGROUND/PURPOSE: In utero administration of hematopoietic stem cells (HSCs) has a variety of actual or potential clinical applications but is hindered by invasive, morbid administration techniques. We sought to determine whether donor HSCs could reach the fetal circulation after simple intra-amniotic delivery in a syngeneic rat model of transamniotic stem cell therapy (TRASCET). METHODS: Pregnant Lewis rat dams underwent volume-matched intra-amniotic injections in all fetuses (n = 90) on gestational day 17 (E17; term=E21-22) of a suspension of commercially available syngeneic Lewis rat HSCs labeled with luciferase (n = 37 fetuses) or an acellular suspension of recombinant luciferase (n = 53). HSC phenotype was confirmed by flow cytometry. Fetuses were euthanized at term for screening of luciferase activity at select anatomical sites. Statistical comparisons were by Fisher's exact test. RESULTS: Among survivors (47/90; 52.2%), donor HSCs were identified selectively in the placenta (p = 0.003), umbilical cord (p < 0.001), bone marrow (p < 0.001), thymus (p = 0.009), bowel (p = 0.003), kidney (p = 0.022), and skin (p < 0.001) when compared with acellular luciferase controls. CONCLUSIONS: Donor hematopoietic stem cells undergo hematogenous routing and can reach the fetal bone marrow after simple intra-amniotic delivery in a syngeneic rat model. Transamniotic stem cell therapy may become a practicable, minimally invasive strategy for the prenatal administration of these cells.

Prenatal Imaging Diagnosis of Suprarenal Lesions.

INTRODUCTION: Prenatal suprarenal lesions represent diverse pathologies. This study investigated prenatal imaging features and regression patterns associated with specific lesion diagnoses. METHODS: This is a multicenter retrospective review of fetuses with prenatally diagnosed suprarenal lesions between 2001 and 2019. Prenatal ultrasound and MRI characteristics, postnatal imaging, and clinical course were reviewed. Prenatal imaging findings were compared by the most common diagnoses and regression patterns. RESULTS: Forty-four fetuses were prenatally diagnosed with suprarenal lesions. Diagnoses included pulmonary sequestration (n = 12; 27.3%), adrenal hemorrhage (n = 12; 27.3%), upper quadrant cyst (including 2 duplication cysts, 1 splenic cyst, and 3 indeterminate cysts), neuroblastoma (n = 4), adrenal hyperplasia (n = 3), bilateral adrenal calcifications (n = 1), and indeterminate lesions (n = 6). Sequestrations were uniformly left-sided (100 vs. 50%; p = 0.014) and diagnosed earlier in gestation than adrenal hemorrhages (p = 0.025). Sequestrations were also significantly more likely to have a prenatal feeding vessel (p = 0.005), low T1 MRI signal (p = 0.015), and no MRI blood products (p = 0.018) compared to adrenal hemorrhages. When comparing all 44 patients, a prenatal feeding vessel and low T1 signal on prenatal MRI were significantly associated with lesion persistence (p = 0.003; p = 0.044). DISCUSSION/CONCLUSION: Imaging findings on prenatal ultrasound and MRI aid in the diagnosis of suprarenal lesions, including differentiating pulmonary sequestrations and adrenal hemorrhages.

A novel two-component, expandable bioadhesive for exposed defect coverage: Applicability to prenatal procedures.

BACKGROUND/PURPOSE: We sought to test select properties of a novel, expandable bioadhesive composite that allows for enhanced adhesion control in liquid environments. METHODS: Rabbit fetuses (n = 23) underwent surgical creation of spina bifida on gestational day 22-25 (term 32-33 days). Defects were immediately covered with a two-component tough adhesive consisting of a hydrogel made of a double network of ionically crosslinked alginate and covalently crosslinked polyacrylamide linked to a bridging chitosan polymer adhesive. Animals were euthanized prior to term for different analyses, including hydraulic pressure testing. RESULTS: Hydrogels remained adherent in 70% (16/23) of the recovered fetuses and in all of the last 14 fetuses as the procedure was optimized. Adherent hydrogels showed a median two-fold (IQR: 1.7-2.4) increase in area at euthanasia, with defect coverage confirmed by ultrasound and histology. The median maximum pressure to repair failure was 15 mmHg (IQR: 7.8-55.3), exceeding reported neonatal cerebrospinal fluid pressures. CONCLUSIONS: This novel bioadhesive composite allows for selective, stable attachment of an alginate-polyacrylamide hydrogel to specific areas of the spina bifida defect in a fetal rabbit model, while the hydrogel expands with the defect over time. It could become a valuable alternative for the prenatal repair of spina bifida and possibly other congenital anomalies. TYPE OF STUDY: N/A (animal and laboratory study). LEVEL OF EVIDENCE: N/A (animal and laboratory study).

Initial Mechanistic Screening of Transamniotic Stem Cell Therapy in the Rodent Model of Spina Bifida: Host Bone Marrow and Paracrine Activity.

PURPOSE: Transamniotic stem cell therapy (TRASCET) with mesenchymal stem cells (MSCs) can induce spina bifida coverage with neoskin. We initiated a mechanistic analysis of this host response. METHODS: Pregnant dams (n = 28) exposed to retinoic acid to induce fetal spina bifida were divided into an untreated group and 2 groups receiving intra-amniotic injections on gestational day 17 (E17; term = E21-22) of either amniotic fluid-derived MSCs (afMSCs; n = 105) or saline (n = 107). Gene expressions of multiple paracrine and cell clonality markers were quantified at term by RT-qPCR at the defect and fetal bone marrow. Defects were examined histologically for neoskin coverage. Comparisons were by Mann-Whitney U tests and logistic regression. RESULTS: Defect coverage was associated with significant downregulation of both epidermal growth factor (Egf; p = 0.031) and fibroblast growth factor-2 (Fgf-2; p = 0.042) expressions at the defect and with significant downregulation of transforming growth factor-beta-1 (Tgfb-1; p = 0.021) and CD45 (p = 0.028) expressions at the fetal bone marrow. CONCLUSIONS: Coverage of experimental spina bifida is associated with local and bone marrow negative feedback of select paracrine factors, as well as increased relative mesenchymal stem cell activity in the bone marrow. Further analyses informed by these findings may lead to strategies of nonsurgical induction of prenatal coverage of spina bifida.

A matched-pair analysis of clinical outcomes after intracavitary cesium-131 brachytherapy versus stereotactic radiosurgery for resected brain metastases.

OBJECTIVE: Adjuvant radiation therapy (RT), such as cesium-131 (Cs-131) brachytherapy or stereotactic radiosurgery (SRS), reduces local recurrence (LR) of brain metastases (BM). However, SRS is less efficacious for large cavities, and the delay between surgery and SRS may permit tumor repopulation. Cs-131 has demonstrated improved local control, with reduced radiation necrosis (RN) compared to SRS. This study represents the first comparison of outcomes between Cs-131 brachytherapy and SRS for resected BM. METHODS: Patients with BM treated with Cs-131 and SRS following gross-total resection were retrospectively identified. Thirty patients who underwent Cs-131 brachytherapy were compared to 60 controls who received SRS. Controls were selected from a larger cohort to match the patients treated with Cs-131 in a 2:1 ratio according to tumor size, histology, performance status, and recursive partitioning analysis class. Overall survival (OS), LR, regional recurrence, distant recurrence (DR), and RN were compared. RESULTS: With a median follow-up of 17.5 months for Cs-131-treated and 13.0 months for SRS-treated patients, the LR rate was significantly lower with brachytherapy; 10% for the Cs-131 cohort compared to 28.3% for SRS patients (OR 0.281, 95% CI 0.082-0.949; p = 0.049). Rates of regional recurrence, DR, and OS did not differ significantly between the two cohorts. Kaplan-Meier analysis with log-rank testing showed a significantly higher likelihood of freedom from LR (p = 0.027) as well as DR (p = 0.018) after Cs-131 compared to SRS treatment (p = 0.027), but no difference in likelihood of OS (p = 0.093). Six (10.0%) patients who underwent SRS experienced RN compared to 1 (3.3%) patient who received Cs-131 (p = 0.417). CONCLUSIONS: Postresection patients with BM treated with Cs-131 brachytherapy were more likely to achieve local control compared to SRS-treated patients. This study provides preliminary evidence of the potential of Cs-131 to reduce LR following gross-total resection of single BM, with minimal toxicity, and suggests the need for a prospective study to address this question.

Predictors of index admission mortality and morbidity in contemporary esophageal atresia patients.

BACKGROUND/PURPOSE: The Spitz classification for esophageal atresia with/without tracheoesophageal fistula (EA/TEF) predicts mortality. This study evaluates the contemporary relevance of the Spitz classification and investigates predictors of morbidity. METHODS: EA/TEF patients born between 1995 and 2018 at two centers were retrospectively reviewed. Clinical variables including sex, prenatal diagnosis, birth weight, prematurity, major congenital heart disease (MCHD), and pre-operative mechanical ventilation (POMV) were collected. Index admission composite morbidity was considered positive if: length-of-stay >90th percentile (139 days), ventilation days >90th percentile (24 days), and/or gastrostomy was used for long-term feeding. Multivariable regression determined predictors of index admission mortality and composite morbidity. A composite morbidity predictive algorithm was created. ROC curves evaluated model discrimination. RESULTS: Of 253 patients, 13 (5.1%) experienced index admission mortality. Of the patients not suffering mortality, 74 (31.6%) experienced composite morbidity. Only MCHD predicted mortality (p = 0.001); birth weight did not (p = 0.173). There was no difference between the Spitz classification and MCHD alone in predicting mortality risk (p = 0.198); both demonstrated very good discrimination. Prenatal diagnosis, POMV, prematurity, and male sex predicted composite morbidity risk (p < 0.001; p = 0.008; p = 0.009; p = 0.05). An algorithm incorporating these predictors demonstrated good discrimination (AUC = 0.784; 95% CI: 0.724, 0.844). CONCLUSIONS: The Spitz classification maintains contemporary relevance for mortality risk, though birth weight can be de-emphasized. A new morbidity risk algorithm is proposed for early postnatal counseling. TYPE OF STUDY: Prognosis study. LEVEL OF EVIDENCE: Level IV.

Postnatal fate of donor mesenchymal stem cells after transamniotic stem cell therapy in a healthy model.

PURPOSE: We sought to examine donor mesenchymal stem cell (MSC) fate after birth following transamniotic stem cell therapy (TRASCET) in a healthy model. METHODS: Lewis rat fetuses (n = 91) were divided into two groups based on the content of volume-matched intraamniotic injections performed on gestational day 17 (term = 21-22 days): either a suspension of amniotic fluid-derived MSCs (afMSCs) labeled with luciferase (n = 38) or acellular luciferase only (n = 53). Infused afMSCs consisted of syngeneic Lewis rat cells phenotyped by flow cytometry. Samples from 14 anatomical sites (heart, lung, brain, liver, spleen, pancreas, bowel, kidney, thyroid, skin, skeletal muscle, thymus, peripheral blood and bone marrow) from survivors were screened for luciferase activity 16 days after birth. Statistical analysis was by logistic regression and the Wald test (p < 0.05). RESULTS: Overall survival was 32% (29/91). When controlled by the acellular luciferase injections, donor afMSCs were not identified at any anatomical site in any neonate as measured by relative light units (all p > 0.05). Donor afMSC viability was confirmed in term placentas. CONCLUSIONS: Donor mesenchymal stem cells are not detectable in the neonate after intraamniotic injection in a normal syngeneic rodent model. This finding suggests that clinical trials of transamniotic stem cell therapy may be amenable to regulatory approval. LEVEL OF EVIDENCE: N/A (animal and laboratory study).

Is Abdominal Sonography a Useful Adjunct to Abdominal Radiography in Evaluating Neonates with Suspected Necrotizing Enterocolitis?

BACKGROUND: Abdominal sonography (AUS) is emerging as a potentially valuable adjunct to conventional abdominal radiography (AXR) in the setting of suspected necrotizing enterocolitis (NEC). We sought to evaluate concordance between AUS and AXR for signs of NEC to better understand the potential advantages and disadvantages of AUS. As a secondary aim, we characterized AUS-specific findings and evaluated the association of imaging results with clinical outcomes. STUDY DESIGN: Hospitalized infants with clinical concern for NEC from 2009 to 2018 were included in this multicenter retrospective review. All infant patients had at least 1 paired AXR followed by an AUS within 24 hours. Findings were abstracted from written radiology reports. Cohen's κ, nonparametric Mann-Whitney U test, and quantile regression were used to evaluate chance-corrected levels of agreement for concordance analyses and associations with clinical outcomes. RESULTS: In total, 66 patients and 96 paired studies were evaluated. Agreement between the 2 imaging modalities was 61 of 96 (63.5%) for pneumatosis (κ = 0.29; 95% CI, 0.10 to 0.48), 79 of 96 (82.3%) for portal venous gas (κ = 0.07; 95% CI, 0.00 to 0.47), and 91 of 96 (94.8%) for pneumoperitoneum (κ = 0.52; 95% CI, 0.11 to 0.93). Each finding was present more frequently on AUS than AXR. On AUS, pneumatosis and focal fluid collection were independently associated with a longer antibiotic course (4.1 days longer; p = 0.03 and 21.3 days longer; p < 0.001, respectively). CONCLUSIONS: AUS holds promise as a useful adjunct to radiography for neonates with possible NEC. It might be more sensitive for the presence or absence of bowel ischemia and can reveal findings not detectable by radiography, which can aid provider decision-making.

The structural and motivational role of the unique lip-flip movement in the gelada (Theropithecus gelada) facial display repertoire.

OBJECTIVES: Human language represents an extreme form of communicative complexity. Primate facial display complexity, which depends upon facial mobility, can be used as a model for the study of the evolution of communicative complexity. The gelada (Theropithecus gelada) is the only primate that can produce a lip-flip eversion. This study investigates the role of the lip-flip relative to the bared-teeth display to understand its role in generating communicative complexity. MATERIALS AND METHODS: We reviewed videos of gelada social interactions. We utilized the facial action coding system (FACS) to define structural component action units (AUs) of each display. We inferred display motivation from the behaviors of the display sender. RESULTS: The lip-flip was used only in combination with the essential AUs of the bared-teeth display, serving as an optional structural element added to produce a structural variant. Both the bared-teeth display with and without a lip-flip occurred most frequently with nonaggressive, submissive behaviors. The lip-flip was more frequently preceded by approach than the bared-teeth display, especially in males. The lip-flip was also present in the majority of structurally blended facial displays though the motivation of the non-lip-flip parent display often dominated. DISCUSSION: The lip-flip may potentially function as an indicator of benign intent after an approach or as an intensifying component of nonaggressive intent. Adaptations to increase facial mobility in geladas via facilitating the lip-flip may promote increased communicative complexity through increased conspicuousness and motivational signaling specification or intensification.

A comparison between placental and amniotic mesenchymal stem cells in transamniotic stem cell therapy for experimental gastroschisis.

PURPOSE: We compared placental and amniotic fluid-derived mesenchymal stem cells (pMSCs and afMSCs, respectively) in transamniotic stem cell therapy for experimental gastroschisis. METHODS: Gastroschisis was surgically created in 126 rat fetuses at gestational day 18 (term = 22 days), immediately followed by volume-matched intraamniotic injections of suspensions of afMSCs (n = 32), pMSCs (n = 33), or normal saline (NS) (n = 33). Untreated fetuses served as controls (n = 28). Blinded observers performed computerized measurements of total and segmental (serosa, muscularis, and mucosa) intestinal wall thickness on the herniated bowel at term. Statistical analysis included ANOVA, the Wald test, and Levene's test (p < 0.05). RESULTS: Among survivors, there were statistically significant decreases in segmental and total bowel wall thicknesses in both the afMSC and pMSC groups vs. the untreated (p < 0.001 to 0.003) and saline (p < 0.001 to 0.011) groups. There were significant differences between the afMSC and pMSC groups favoring the former in both therapeutic impact and its variability (p < 0.001 to 0.031). Labeled cells were comparably identified within the intestinal wall in the afMSC and pMSC groups. CONCLUSIONS: Both placental and amniotic mesenchymal stem cells can mitigate bowel damage in experimental gastroschisis as agents of transamniotic stem cell therapy. However, amniotic cells lead to improved and more consistent outcomes. LEVEL OF EVIDENCE: N/A (animal and laboratory study).

Transamniotic Stem Cell Therapy.

Transamniotic stem cell therapy (TRASCET) is a novel prenatal therapeutic alternative for the treatment of congenital anomalies. It is based upon the principle of augmenting the pre-existing biological role of select populations of fetal stem cells for targeted therapeutic benefit. For example, amniotic fluid-derived mesenchymal stem cells (afMSCs) play an integral role in fetal tissue repair, validating the use of afMSCs in regenerative strategies. The simple intra-amniotic delivery of these cells in expanded numbers via TRASCET has been shown to promote the repair of and/or significantly ameliorate the effects associated with major congenital anomalies such as neural tube and abdominal wall defects. For example, TRASCET can induce partial or complete coverage of experimental spina bifida through the formation of a host-derived rudimentary neoskin, thus protecting the spinal cord from further damage secondary to amniotic fluid exposure. Furthermore, TRASCET can significantly reduce the bowel inflammation associated with gastroschisis, a common major abdominal wall defect. After intra-amniotic injection, donor stem cells home to the placenta and the fetal bone marrow in the spina bifida model, suggesting a role for hematogenous cell routing rather than direct defect seeding. Therefore, the expansion of TRASCET to congenital diseases without amniotic fluid exposure, such as congenital diaphragmatic hernia, as well as to maternal diseases, is currently under investigation in this emerging and evolving field of fetal stem cell therapy.

Congenital diaphragmatic hernia as a potential target for transamniotic stem cell therapy.

PURPOSE: We sought to determine whether TRASCET could impact congenital diaphragmatic hernia (CDH). METHODS: Twelve pregnant dams received Nitrofen on gestational day 9.5 (E9; term = 22 days) to induce fetal CDH. Fetuses were divided into three groups: untreated (n = 31) and two groups receiving volume-matched intraamniotic injections of either saline (n = 37) or a suspension of 2 × 106 cells/mL of amniotic fluid-derived mesenchymal stem cells (afMSCs; n = 65) on E17. Animals were euthanized at term. Expression of fibroblast growth factor-10 (FGF-10), vascular endothelial growth factor-A (VEGF-A), and surfactant protein-C (SPC) was quantified by qRT-PCR. Statistical analysis was by the Mann-Whitney U test with Bonferroni adjusted criterion (p ≤ 0.01). RESULTS: Among survivors with CDH (n = 27/133), the TRASCET group showed significant downregulation of FGF-10 and VEGF-A gene expressions compared to the untreated (p < 0.001 for both) and saline groups (p = 0.005 and p = 0.004, respectively). SPC expression was higher in the TRASCET group compared to the untreated group (p = 0.01), but not the saline group (p = 0.043). Lung laterality had minimal impact on these comparisons. CONCLUSIONS: Transamniotic stem cell therapy affects select processes of lung development in experimental congenital diaphragmatic hernia. Further scrutiny into this novel therapy as a potential component of the prenatal management of this disease is warranted. LEVEL OF EVIDENCE: N/A (animal and laboratory study).

Comparison of breast-conserving therapy vs mastectomy in women under age 40: National trends and potential survival implications.

INTRODUCTION: Despite initial increased rates of breast-conserving therapy compared to mastectomy after 1990, mastectomy rates have increased in women under age 40 since 2000. Our study explores the demographic and survival implications of this trend. METHODS: The National Cancer Database was used to study stage 1 breast cancer diagnosed in women under age 40 between 2004 and 2014. Demographic and clinical data were obtained. Multivariable regression and survival analyses were performed. RESULTS: Of 11 859 patients under age 40, 57.2% underwent mastectomy (39.0% unilateral and 61.0% bilateral) rather than breast-conserving therapy (42.8%). The rate of mastectomy was significantly higher in 2014 compared to 2004 (43.6% in 2004 vs 62.4% in 2014; P < 0.001). The rate of bilateral mastectomy was significantly higher in 2014 compared to 2004 in contrast to unilateral mastectomy (31.7% in 2004 vs 73.0% in 2014; P < 0.001). Non-Hispanic Caucasian ethnicity and private insurance status were predictors of bilateral mastectomy (OR 2.06 [95% CI: 1.84-2.30], P < 0.001; OR 1.39 [95% CI: 1.21-1.59], P < 0.001). Controlling for demographics, tumor grade, and adjuvant therapies, bilateral mastectomy was associated with significantly increased 10-year survival vs unilateral mastectomy (HR 0.75 [0.59-0.96], P = 0.023). Additionally, breast-conserving therapy was associated with significantly increased 10-year survival vs unilateral (HR 2.36 [95% CI: 1.83-3.05]; P < 0.001) and bilateral mastectomy (HR 2.30 [95% CI: 1.61-3.27]; P < 0.001). CONCLUSIONS: The majority of women under age 40 with stage 1 invasive breast cancer underwent mastectomy instead of breast-conserving therapy. This largely reflects increased rates of contralateral prophylactic mastectomy. Bilateral mastectomy and breast-conserving therapy vs unilateral mastectomy were associated with a small but significant increase in survival. This finding warrants further investigation to determine the clinical implications of decision-making in younger women.