Richard D. Glick

Nonoperative management of symptomatic urachal anomalies

INTRODUCTION Symptomatic urachal anomalies are rare disorders that consist of urachal remnants or fistulas with or without an associated cyst. Traditionally, when a urachal anomaly was recognized, operative excision was performed. There has been a shift toward the nonoperative management of urachal anomalies at many centers, although there is little in the literature to support this practice. METHODS A retrospective chart review of patients with urachal anomalies was performed from January 2002 to March 2008. Children with a draining umbilicus and no radiographic or surgical confirmation of a urachal anomaly were excluded. RESULTS Fifteen patients with symptomatic urachal anomalies were identified. The average age was 3.5 years (4 weeks to 14 years). Symptoms included umbilical drainage (n = 10), abdominal pain (n = 6), omphalitis (n = 4), intraabdominal mass (n = 3), dysuria (n = 1), recurrent urinary tract infections (n = 1), and fever (n = 4). The diagnosis was confirmed by ultrasound (n = 13) and/or computed tomographic scan (n = 4). The surgically treated cases included 7 urachal cysts (5 uninfected, 2 infected) and 1 patent urachal fistula. Mean follow-up is 37 months, and there have been no reported recurrences. Those treated without surgical excision included 4 patent urachal fistulas (mean follow-up, 20 months-no recurrences) and 3 infected urachal cysts (percutaneous drainage [n = 2] and laparoscopic drainage [n = 1]-no recurrences on ultrasound at 26 months). CONCLUSION Nonoperative management of urachal anomalies is a reasonable approach and may be extended to infected urachal cysts after initial drainage. Infected cysts that are adequately drained seem to obliterate with time. Modern ultrasonography facilitates thorough follow-up. We propose a treatment algorithm for the management of suspected urachal anomalies.

Laparoscopic inguinal hernia inversion and ligation in female children: a review of 173 consecutive cases at a single institution.

PURPOSE Laparoscopic inguinal hernia inversion and ligation (LIHIL) is a method of hernia repair in which the hernia sac is inverted into the peritoneal cavity and subsequently ligated and excised. Since 2003, 5 surgeons at our institution have been performing LIHIL in girls. METHODS A retrospective review of inguinal hernias in girls from 2003 to 2009 was performed. RESULTS Two hundred forty-one LIHILs were performed on 173 girls. The average age of children undergoing LIHIL was 57 months (range, 1-210 months). Fifteen cases were ex-premature babies (8.7%). Of the unilateral inguinal hernias, 34% were found to have bilateral hernias intraoperatively, and these were repaired at the same operation. There have been no intraoperative complications. Postoperatively, there have been no wound complications and 2 recurrences (0.83%). Both recurrences were repaired using an open technique. CONCLUSIONS Laparoscopic inguinal hernia inversion and ligation is a safe and effective operation in girls with a low recurrence rate. Benefits of this procedure include diagnosis and repair of the contralateral side using the same incisions, diagnosis of androgen insensitivity and other dysgenic situations, and excellent cosmesis. This operation is a straightforward technique that can be performed by most pediatric surgeons with basic laparoscopic skills.

Celecoxib inhibits invasion and metastasis via a cyclooxygenase 2–independent mechanism in an in vitro model of Ewing sarcoma

BACKGROUND/INTRODUCTION Previously, we reported that celecoxib, a cyclooxygenase-2 (COX-2) inhibitor, prevented lung metastases but did not affect tumor growth in a model of Ewing sarcoma. Cyclooxygenase-2 inhibition has been proposed as an antimetastatic strategy. The mechanism of action remains unclear. METHODS Ewing sarcoma cells were suspended in a soluble basement membrane extract (Cultrex; Trevigen, Inc, Gaithersburg, MD) and supplemented with celecoxib or with rofecoxib, a second COX-2 inhibitor, above a filter. Controls received solvent. After 48 hours, the cells that invaded through the basement membrane and filter were stained and counted. The assay was repeated with the addition of 500-nM prostaglandin E2 (PGE(2)). RESULTS Invasion was significantly decreased in the celecoxib groups compared with the control. The addition of PGE(2) did not overcome celecoxib inhibition. Rofecoxib did not significantly affect invasion compared with control either with or without PGE(2). CONCLUSIONS Celecoxib significantly inhibits invasion of Ewing sarcoma cells in vitro. Prostaglandin E2, a downstream product of COX-2, did not reverse in vitro inhibition, suggesting that celecoxib acts through a COX-2-independent mechanism. This is further supported by the failure of rofecoxib to inhibit invasion despite more selectively inhibiting COX-2.

Selective inhibition of cyclooxygenase-2 suppresses metastatic disease without affecting primary tumor growth in a murine model of Ewing sarcoma

BACKGROUND/PURPOSE Mammalian target of rapamycin suppression by rapamycin inhibits tumor growth and neovascularization via cyclooxygenase-2 (COX-2) downregulation with no effect on lung metastases. We hypothesize that combining a selective COX-2 antagonist (celecoxib) with rapamycin would decrease lung metastases. METHODS Ewing sarcoma cells (SK-NEP-1) were surgically implanted into the left kidney of athymic mice (n = 40). The mice were divided into 4 treatment groups (control, rapamycin only, celecoxib only, and combination) and then killed at 6 weeks. Primary tumors were weighed. Vasculature was examined using lectin angiography and immunohistochemistry, and lung metastases were examined using H&E and CD99 immunostaining. Tumor weight and lung metastases were analyzed. RESULTS Mean primary tumor weights were significantly reduced in the rapamycin-treated groups but not in the celecoxib-only group. Lectin angiography and endothelial markers immunostaining showed markedly decreased vascularity in the rapamycin-treated groups but not in the celecoxib-only group. Celecoxib-treated groups showed significantly fewer mice with lung metastases than non-celecoxib-treated groups. CONCLUSION Celecoxib prevents lung metastasis in a murine model of Ewing sarcoma with no effect on tumor size or neovascularization. Cyclooxygenase-2 may represent a future potential target for metastatic disease prevention.

Neonatal esophageal perforation: nonoperative management

BACKGROUND Esophageal perforation is a rare complication of enteric instrumentation in neonates. Enteric tube placement in micro-preemies poses a particular hazard to the narrow lumen and thin wall of the developing esophagus. The complication may be difficult to recognize or misdiagnosed as esophageal atresia, and is associated with considerable mortality. Historically, management of this life-threatening iatrogenic disease was operative, but trends have shifted toward nonoperative treatment. Here, we review neonatal esophageal perforation at our own institution for management techniques, risk factors, and outcomes. MATERIALS AND METHODS Seven neonatal patients with esophageal perforation were identified and charts reviewed for demographics, comorbidities, etiology of perforation, diagnostic modalities, management decisions, complications, and outcomes. RESULTS Mean gestational age was 27.2 ± 4.0 wk, and weight at diagnosis was 892 ± 674 g. All seven patients had esophageal perforation resulting from endotracheal or enterogastric intubation and were managed nonoperatively. Treatment included removal of the offending tube, nil per os, and antibiotics. Five patients required additional interventions: four tube thoracostomies for pneumothoraces and one peritoneal drain for pneumoperitoneum. Three patients died because of sequelae of prematurity (intraventricular hemorrhage, necrotizing enterocolitis, and sepsis). One patient was diagnosed as having esophageal atresia; esophagoscopy before surgical repair established the correct diagnosis. CONCLUSIONS Neonates, particularly those under 1500 g, are at substantial risk for iatrogenic esophageal perforation during enterogastric intubation. Nonoperative management may be a safe initial strategy in the neonatal setting, but more aggressive interventions may ultimately be required. Despite recent improvement in early recognition of this injury, misdiagnosis still occurs.

Cyclooxygenase 2 mediates the antiangiogenic effect of rapamycin in Ewing sarcoma

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.

The Macrophage Inhibitor CNI-1493 Blocks Metastasis in a Mouse Model of Ewing Sarcoma through Inhibition of Extravasation

Metastatic Ewing Sarcoma carries a poor prognosis, and novel therapeutics to prevent and treat metastatic disease are greatly needed. Recent evidence demonstrates that tumor-associated macrophages in Ewing Sarcoma are associated with more advanced disease. While some macrophage phenotypes (M1) exhibit anti-tumor activity, distinct phenotypes (M2) may contribute to malignant progression and metastasis. In this study, we show that M2 macrophages promote Ewing Sarcoma invasion and extravasation, pointing to a potential target of anti-metastatic therapy. CNI-1493 is a selective inhibitor of macrophage function and has shown to be safe in clinical trials as an anti-inflammatory agent. In a xenograft mouse model of metastatic Ewing Sarcoma, CNI-1493 treatment dramatically reduces metastatic tumor burden. Furthermore, metastases in treated animals have a less invasive morphology. We show in vitro that CNI-1493 decreases M2-stimulated Ewing Sarcoma tumor cell invasion and extravasation, offering a functional mechanism through which CNI-1493 attenuates metastasis. These data indicate that CNI-1493 may be a safe and effective adjuvant agent for the prevention and treatment of metastatic Ewing Sarcoma.

Intrathoracic glial implants in a child with gliomatosis peritonei

Glial peritoneal implants, commonly referred to as gliomatosis peritonei, are an occasional feature of ovarian teratomas. They are benign nodules of mature glial tissue and usually do not adversely affect outcome. We present the case of a 12-year-old girl who underwent excision of an immature ovarian teratoma, along with biopsies of multiple glial peritoneal implants. She also had a 2-cm right-sided pleural mass, which turned out to be normal glial tissue that was histologically indistinguishable from the peritoneal glial tissue. Pleural gliomatosis has not been described in the literature. The pathophysiology of gliomatosis peritonei was originally thought to be the direct extrusion or lymphatic spread of glial cells from the associated teratoma, although it has been postulated that the glial implants may instead be the result of pluripotent Mullerian stem cells that undergo metaplasia. This report provides evidence to bolster the metaplastic theory.

Celecoxib inhibits Ewing sarcoma cell migration via actin modulation

BACKGROUND Ewing sarcoma (ES) is an aggressive childhood solid tumor in which 30% of cases are metastatic at presentation, and subsequently carry a poor prognosis. We have previously shown that treatment with celecoxib significantly reduces invasion and metastasis of ES cells in a cyclooxygenase-2-independent fashion. Celecoxib is known to downregulate β-catenin independently of cyclooxygenase-2. Additionally, the actin cytoskeleton is known to play an important role in tumor micrometastasis. We hypothesized that celecoxibs antimetastatic effect in ES acts via modulation of one of these two targets. METHODS ES cells were treated with celecoxib, and the levels of β-catenin and total actin were examined by Western blot and quantitative polymerase chain reaction. Cells were transfected with small interfering RNA targeting β-catenin, and invasion assays were performed. Immunofluorescence staining for β-catenin and F-actin was performed on treated and untreated cells. Additionally, cells were subjected to a wound healing assay to assess migration. RESULTS Celecoxib had no effect on the messenger RNA or protein levels of β-catenin but did significantly decrease the amount of total actin within ES cells. Reduction of β-catenin by small interfering RNA had no effect on invasion, and celecoxib treatment of the β-catenin depleted cells continued to inhibit invasion. Immunofluorescence staining demonstrated no change in β-catenin with treatment but did show a significant reduction in the amount of F-actin, as well as morphologic changes of the cells. Wound healing assays demonstrated that celecoxib significantly inhibited migration. CONCLUSIONS Celecoxib does not exert its antimetastatic effects in ES through alteration of β-catenin but does significantly modulate the actin cytoskeleton.