Faculty Bibliography

Objective: The literature suggests that lung-head ratio (LHR) and liver position may inconsistently predict outcome for congenital diaphragmatic hernia (CDH). We reviewed our inborn neonates with isolated left-sided CDH to determine whether these variables predicted survival and to estimate the optimal LHR threshold. Methods: Prenatal LHR and liver position were obtained from 2002 to 2009. The primary endpoint was survival. Results: LHR was greater in survivors after adjusting for gestational age (median 1.40 versus 0.81; p < 0.001). LHR demonstrated excellent diagnostic discrimination, with area under receiver operating characteristic (ROC) curve 0.93 (95% CI 0.86-0.99). LHR threshold of 1.0 was 83% sensitive and 91% specific in predicting survival. An optimal LHR threshold of 0.85 predicted survival with 95% sensitivity and 64% specificity, reducing false negatives (survivors with low LHR). LHR > 0.85 predicted survival after adjustment for gestational age (OR = 33.6, 95% CI = 5.4-209.5). Liver position did not predict survival. Conclusions: Prenatal LHR >0.85 predicts survival for infants with isolated left-sided CDH without compromising discrimination of survivors from non-survivors. The diagnostic utility of LHR may be confounded by gestational age at measurement. Stringent LHR threshold may minimize false-negative attribution and improve utility of this measurement as predictor of survival.

ABSTRACT: Vascular endothelial growth factor (VEGF) blockade is an effective therapy for human cancer, yet virtually all neoplasms resume primary tumor growth or metastasize during therapy. Mechanisms of progression have been proposed to include genes that control vascular remodeling and are elicited by hypoperfusion, such as the inducible enzyme cyclooxygenase-2 (COX-2). We have previously shown that COX-2 inhibition by the celecoxib analog SC236 attenuates perivascular stromal cell recruitment and tumor growth. We therefore examined the effect of combined SC236 and VEGF blockade, using the metastasizing orthotopic SKNEP1 model of pediatric cancer. Combined treatment perturbed tumor vessel remodeling and macrophage recruitment, but did not further limit primary tumor growth as compared to VEGF blockade alone. However, combining SC236 and VEGF inhibition significantly reduced the incidence of lung metastasis, suggesting a distinct effect on prometastatic mechanisms. We found that SC236 limited tumor cell viability and migration in vitro, with effects enhanced by hypoxia, but did not change tumor proliferation or matrix metalloproteinase expression in vivo. Gene set expression analysis (GSEA) indicated that the addition of SC236 to VEGF inhibition significantly reduced expression of gene sets linked to macrophage mobilization. Perivascular recruitment of macrophages induced by VEGF blockade was disrupted in tumors treated with combined VEGF- and COX-2-inhibition. Collectively, these findings suggest that during VEGF blockade COX-2 may restrict metastasis by limiting both prometastatic behaviors in individual tumor cells and mobilization of macrophages to the tumor vasculature.

INTRODUCTION: Experience in thoracoscopic congenital diaphragmatic hernia (CDH) repair has expanded, yet efficacy equal to that of open repair has not been demonstrated. In spite of reports suggesting higher recurrent hernia rates after thoracoscopic repair, this approach has widely been adopted into practice. We report a large, single institutional experience with thoracoscopic CDH repair with special attention to recurrent hernia rates. METHODS: We reviewed the records of neonates with unilateral CDH repaired between January 2006 and February 2010 at Morgan Stanley Children's Hospital. Completely thoracoscopic repairs were compared to open repairs of the same period. In addition, successful thoracoscopic repairs were compared with thoracoscopic repairs that developed recurrence. Data were analyzed by Mann-Whitney U and Fisher exact tests. RESULTS: Thirty-five neonates underwent attempted thoracoscopic repair, with 26 completed. Concurrently, 19 initially open CDH repairs were performed. Preoperatively, patients in the open repair group required more ventilatory support than the thoracoscopic group. Recurrence was higher after thoracoscopic repair (23% vs 0%; P = .032). In comparing successful thoracoscopic repairs to those with recurrence, none of the factors analyzed were predictive of recurrence. CONCLUSIONS: Early recurrence of hernia is higher in thoracoscopic CDH repairs than in open repairs. Technical factors and a steep learning curve for thoracoscopy may account for the higher recurrence rates, but not patient severity of illness. In an already-tenuous patient population, performing the repair thoracoscopically with a higher risk of recurrence may not be advantageous.

PURPOSE: Extracorporeal Life Support Organization Registry data confirm that the number of pediatric patients being supported by extracorporeal membrane oxygenation (ECMO) is increasing. To minimize the potential neurologic effects of carotid artery ligation, the common femoral artery (CFA) is frequently being used for arterial cannulation. The cannula has the potential for obstructing flow to the lower limb, thus increasing ischemia and possible limb loss. We present a single institution's experience with CFA cannulation for venoarterial (VA) ECMO and ask whether any precannulation variables correlate with the development of significant limb ischemia. METHODS: We reviewed all pediatric patients who were supported by VA ECMO via CFA cannulation from January 2000 to February 2010. Limb ischemia was the primary variable. The ischemia group was defined as the patients requiring an intervention because of the development of lower extremity ischemia. The patients in the no-ischemia group did not develop significant ischemia. Continuous variables were reported as medians with interquartile ranges and compared using Mann-Whitney U tests. Differences in categorical variables were assessed using chi(2) testing (Fisher's Exact). Statistical significance was assumed at P < .05. RESULTS: Twenty-one patients (age, 2-22 years) were cannulated via the CFA for VA ECMO. Significant ischemia requiring intervention (ischemia group) occurred in 11 (52%) of 21. In comparing the 2 groups (ischemia vs no ischemia), no clinical variables predicted the development of ischemia (Table 1). In the ischemia group, 9 (81%) of 11 had a distal perfusion catheter (DPC) placed. Complications of DPC placement included one case of compartment syndrome requiring a fasciotomy and one patient requiring interval toe amputation. Of the 2 patients in the ischemia group who did not have a DPC placed, 1 required a vascular reconstruction of an injured superficial femoral artery and 1 underwent a below-the-knee amputation. Mortality was lower in the ischemia group (27% vs 60%). CONCLUSIONS: Limb ischemia remains a significant problem, as more than half of our patients developed it. The true incidence may not be known as a 60% mortality in the no-ischemia group could mask subsequent ischemia. Although children are at risk for developing limb ischemia/loss, no variable was predictive of the development of significant limb ischemia in our series. Because of the inability to predict who will develop limb ischemia, early routine placement of a DPC at the time of cannulation may be warranted. However, DPCs do not completely resolve issues around tissue loss and morbidity. Prevention of limb ischemia/loss because of CFA cannulation for VA ECMO continues to be a problem that could benefit from new strategies.

Hepatic pulmonary fusion is extremely rare with only 9 previous cases reported in the literature. In typical cases, the clinician should be alerted to the possibility of hepatic pulmonary fusion if the chest radiograph shows a large opacity on the right side without a contralateral mediastinal shift. The authors present a case of right-sided diaphragmatic hernia and hepatic pulmonary fusion with associated contralateral mediastinal shift discovered beyond the neonatal period. The 9 previous cases were retrospectively reviewed with special attention to mediastinal shift on preoperative chest radiograph, operative procedure, and mortality. Only one previous case demonstrated a contralateral mediastinal shift. The most common procedure performed was partial separation of the hepatic pulmonary fusion and approximation of the diaphragmatic defect. Four of the previous 9 patients died. In our case, reduction of bowel and approximation of the diaphragmatic defect around the fused liver and lung have been successful.

Clear cell sarcoma of the kidney (CCSK) is uncommon pediatric renal tumor and can present a significant therapeutic challenge in those patients whose tumors spread beyond the kidney. Thus, identifying potential novel targets for treatment may be clinically important. Clear cell sarcoma of the kidney is characterized by a unique vascular pattern, in which nests of tumor cells are separated by regularly-spaced, fine fibrovascular septa. This distinctive histopathology raises the possibility that understanding the factors which drive angiogenesis in CCSK tumors may suggest new therapeutic targets. Here, we describe a case of CCSK and present immunohistochemical studies of its vasculature.

Several short and long-term complications of esophageal replacement have been described in the literature. We report the case of a gastric tube-pericardial fistula occurring 20 years after initial repair of long gap esophageal atresia with a reversed gastric tube.

BACKGROUND: Rapamycin can inhibit tumor growth and angiogenesis in various human cancers. Cyclooxygenase 2 (COX-2) is involved in the angiogenic process. We hypothesized that the antiangiogenic effect of rapamycin may be mediated by suppression of COX-2. METHODS: Ewing sarcoma (ES) cells were implanted in athymic mice. Selected animals were treated with rapamycin for 5 weeks. Tumor vascularity was assessed by lectin perfusion angiography and immunohistochemistry. Phosphorylation of mammalian target of rapamycin pathway proteins was determined by Western blot analysis. Staining of COX-2 protein was determined by immunohistochemistry, and expression of COX-2 messenger RNA levels was assessed with quantitative real-time (RT) polymerase chain reaction. RESULTS: Mean tumor weights were significantly reduced in the treated group (5.43 g +/- 1.43 SEM vs 0.49 g +/- 0.15 SEM, P < .003). There was abundant vasculature in the control group and blunted vascularity in the treated xenografts. The phosphorylation of p70s6k and Akt was not inhibited in the rapamycin-treated tumors. Cyclooxygenase 2 was suppressed in the treated xenografts at both the protein and messenger RNA levels. CONCLUSION: Low-dose rapamycin inhibits tumor growth and angiogenesis in human ES without inhibiting the phosphorylation of p70s6k and Akt. Cyclooxygenase 2 levels are inhibited by low-dose treatment of ES with rapamycin. Cyclooxygenase 2 suppression may mediate the antiangiogenic effect of rapamycin in Ewing sarcoma.

PURPOSE: Risk factors that predispose children with congenital diaphragmatic hernia (CDH) to recurrence remain poorly defined. We report a large series of recurrent CDH and ask whether prenatal patient factors or postnatal treatment variables better predict recurrence. METHODS: Two hundred thirty-eight neonates with unilateral CDH underwent repair from 1990 to 2006. Data were assessed by chi(2) and Mann-Whitney U tests. Multivariate regression identified independent predictors of recurrence. Statistical significance was set at P < .05. RESULTS: We identified 24 recurrences (10%). Median time from repair to recurrence diagnosis was 4.9 months. Patients with recurrence were older (P = .02) and more often required abdominal wall patches at initial repair (P = .01) compared to nonrecurrence patients. Postoperative length of stay (LOS) after initial repair (P < .01) and morbidity (P = .01) were greater in recurrence patients. Use of diaphragm patch at initial repair was greater in patients with recurrence but only approached statistical significance (P = .05). Only 2 variables independently predicted recurrence by multivariate regression as follows: abdominal (not diaphragm) wall patch during initial repair (odds ratio [OR] 3.50; P = .04) and postoperative LOS (OR, 1.012; P = .01). CONCLUSION: Neonates at risk for CDH recurrence are better identified by postnatal treatment variables than by prenatal patient factors. Although age at repair and diaphragm patch use are greater in recurrence patients, the only factors to independently predict recurrence were postoperative LOS and abdominal wall patch use. These data can help optimize follow-up regimens.

Femoral cannulation in pediatric patients requiring extracorporeal membrane oxygenation (ECMO) is commonly associated with distal limb ischemia. Authors have previously reported successful lower limb perfusion using various open techniques to cannulate a distal lower extremity artery at the time of initial ECMO cannulation. These procedures include open femoral artery antegrade cannulation and distal posterior tibial artery retrograde cannulation in older children and adults. Such approaches require ample vessel diameters to accommodate an arteriotomy and catheter insertion and, therefore, are of limited use in smaller children. We hypothesized that after femoral artery cannulation for ECMO, a percutaneous technique of distal limb perfusion might offer unique advantages when treating lower extremity ischemia in small pediatric patients. We report a technique for percutaneous antegrade cannulation in a 4-year-old patient shortly after her primary cannulation for venoarterial ECMO via the femoral artery.