Belinda Dickie

Efficacy and Safety of Sirolimus in the Treatment of Complicated Vascular Anomalies.

BACKGROUND AND OBJECTIVES: Complicated vascular anomalies have limited therapeutic options and cause significant morbidity and mortality. This Phase II trial enrolled patients with complicated vascular anomalies to determine the efficacy and safety of treatment with sirolimus for 12 courses; each course was defined as 28 days. METHODS: Treatment consisted of a continuous dosing schedule of oral sirolimus starting at 0.8 mg/m2 per dose twice daily, with pharmacokinetic-guided target serum trough levels of 10 to 15 ng/mL. The primary outcomes were responsiveness to sirolimus by the end of course 6 (evaluated according to functional impairment score, quality of life, and radiologic assessment) and the incidence of toxicities and/or infection-related deaths. RESULTS: Sixty-one patients were enrolled; 57 patients were evaluable for efficacy at the end of course 6, and 53 were evaluable at the end of course 12. No patient had a complete response at the end of course 6 or 12 as anticipated. At the end of course 6, a total of 47 patients had a partial response, 3 patients had stable disease, and 7 patients had progressive disease. Two patients were taken off of study medicine secondary to persistent adverse effects. Grade 3 and higher toxicities attributable to sirolimus included blood/bone marrow toxicity in 27% of patients, gastrointestinal toxicity in 3%, and metabolic/laboratory toxicity in 3%. No toxicity-related deaths occurred. CONCLUSIONS: Sirolimus was efficacious and well tolerated in these study patients with complicated vascular anomalies. Clinical activity was reported in the majority of the disorders.

Spectrum of hepatic hemangiomas: management and outcome.

PURPOSE Infants with multiple cutaneous hemangiomas often present with hepatic hemangiomas. They can follow a benign clinical course or require complex management. We reviewed our experience in the management of hepatic hemangiomas. METHODS We performed a retrospective review of patients (1996-2007) with hepatic hemangiomas treated in our institution. RESULTS Twenty-six patients were diagnosed with hepatic hemangiomas as follows: 8 focal, 12 multiple, and 6 diffuse lesions. Nineteen (73%) patients had associated cutaneous hemangiomas. Sixteen patients had multiple and 3 patients had single cutaneous hemangiomas. All patients with multiple or diffuse liver lesions were screened for heart failure and hypothyroidism. Congestive heart failure developed in 4 patients, 3/4 of these patients had diffuse lesions. Two patients required thyroid replacement because of elevated thyroid-stimulating hormone. Because of progression of disease, 9 patients required steroid treatment. Two patients were treated with vincristine and 3 patients received alpha-interferon because of poor response to steroid treatment. Two patients went on to surgical resection for failed response to medical management and worsening heart failure (left lobectomy, liver transplant). Both patients had uncomplicated postoperative courses. Five patients had a previously undescribed constellation of rapidly involuting cutaneous hemangiomas (gone by 3 months, glut-1-negative) with associated liver lesions also resolving at a faster pace (mean resolution of cutaneous hemangiomas, 1.9 vs 7.9 months; P = .001; liver, 5.8 vs 25.3 months; P = .004). All patients in our series survived. CONCLUSION Patients with multiple cutaneous hemangiomas should be screened for hepatic lesions. Patients with diffuse or multifocal liver hemangiomas should be screened for congestive heart failure and hypothyroidism. A subgroup of rapidly involuting cutaneous hemangiomas have a significantly shorter time for involution of hepatic lesions. The status of cutaneous lesions can be used as indicators for the liver hemangiomas.

Activating PIK3CA Alleles and Lymphangiogenic Phenotype of Lymphatic Endothelial Cells Isolated from Lymphatic Malformations

Lymphatic malformations (LMs) are developmental anomalies of the lymphatic system associated with the dysmorphogenesis of vascular channels lined by lymphatic endothelial cells (LECs). Seeking to identify intrinsic defects in affected LECs, cells were isolated from malformation tissue or fluid on the basis of CD31 and podoplanin (PDPN) expression. LECs from five unrelated LM lesions were characterized, including cells derived from one patient previously diagnosed with CLOVES. CLOVES-related LECs carried a known, activating mutation in PIK3CA (p.H1047L), confirmed by direct sequencing. Activating PIK3CA mutations (p.E542K and p.E545A) were identified in lesion-derived cells from the other four patients, also by direct sequencing. The five LM-LEC cultures shared a lymphangiogenic phenotype distinguished by PI3K/AKT activation, enhanced sprouting efficiency, elevated VEGF-C expression and COX2 expression, shorter doubling times and reduced expression of angiopoietin 2 and CXCR4. Nine additional LM-LEC populations and 12 of 15 archived LM tissue samples were shown to bear common PIK3CA variants by allele-specific PCR. The activation of a central growth/survival pathway (PI3K/AKT) represents a feasible target for the non-invasive treatment of LMs bearing in mind that background genetics may individualize lesions and influence treatments.

Evaluation and treatment of the patient with Hirschsprung disease who is not doing well after a pull-through procedure

Ideally, after operative management of Hirschsprung disease, a child should thrive, avoid recurrent episodes of abdominal distention and enterocolitis, and be fecally continent. However, there is a small group of patients that do not do well after their pull-through procedure. The purpose of this article is to describe our algorithm for the work-up and management of the post pull-through patient with Hirschsprung disease who is not doing well. These children can be categorized into 2 distinct groups: (1) those who are soiling, and (2) those who suffer from distention and enterocolitis. Both of these patient types can be systematically treated with a combination of bowel management, dietary changes, and laxatives, and, potentially, a redo operation, with the goal of having a clean, and happy child.

The Hirschsprungs patient who is soiling after what was considered a “successful” pull-through

After surgery for Hirschsprungs disease, most children thrive, have few if any episodes of abdominal distention and enterocolitis, and are fecally continent. However, there exists a small group of patients who do not do well. Either they suffer from persistent distension and enterocolitis or they experience soiling after their pull-through procedure. These patients can be systematically evaluated and successfully treated with a combination of bowel management, dietary changes, and laxatives, and, in certain circumstances, a reoperation.

Response of Blue Rubber Bleb Nevus Syndrome to Sirolimus Treatment.

Blue rubber bleb nevus syndrome (BRBNS) is a rare multifocal venous malformation syndrome involving predominantly the skin and gastrointestinal tract. Traditional treatment modalities include corticosteroids, interferon‐α, sclerotherapy, and aggressive surgical resection. Sirolimus has been used in several single case reports.

Hepatic vascular tumors

The most common hepatic vascular tumor in the pediatric population is the infantile hepatic hemangioma. Although these lesions have a spectrum of presentations, there are three main subtypes that have been described-focal, multifocal, and diffuse. An algorithm on the workup, treatment, and follow-up of these lesions can be based on this categorization. Recent shifts in the management of hemangiomas with beta-blockers (propranolol) have also influenced the treatment of hepatic hemangiomas. This article reviews the current understanding of hepatic hemangiomas and protocols in the management of these patients.

The Usefulness of the Upper Gastrointestinal Series in the Pediatric Patient Before Anti-Reflux Procedure or Gastrostomy Tube Placement

OBJECTIVE Most children undergo an upper gastrointestinal study (UGI) before an anti-reflux (AR) procedure or gastrostomy tube placement (GT). Anatomic abnormalities detected by UGI are uncommon and we hypothesize that the value of routine preoperative use of this test is limited. METHODS Five hundred and seventy-two patients who underwent either an AR or GT over a 10-y period at our institution were reviewed. Data including patient demographics, indications for surgery, preoperative testing, and type of operation were collected. RESULTS Of the 572 cases, an UGI was performed in approximately 71%. The results were interpreted as normal in 63%, and abnormal in 37%. The most common abnormality noted was gastroesophageal reflux in approximately 80%, followed by an anatomic abnormality in 6%, most of which were expected. Of 36 anatomic abnormalities noted, only four were unexpected in the total cohort. In addition to an UGI, half of the subjects received additional evaluations that included pH probes and gastric emptying studies (GES). In these studies, 56% of pH probes and 45% of GES had findings in which reflux was noted. Compared with UGIs, these tests were significantly more likely to identify reflux in patients. CONCLUSION These results suggest that the utility of an UGI before AR or GT procedures is low. Anatomic abnormalities were rare and changed clinical management in a total of four cases. A prospective trial would help to further validate these findings and help identify patients who would benefit from an UGI.

The problematic Soave cuff in Hirschsprung disease: Manifestations and treatment

PURPOSE Following a Soave pull-through for Hirschsprung disease (HD), some children struggle with obstructive symptoms. We hypothesized that these symptoms could result from a functional obstruction of the pull through caused by the Soave cuff, and that cuff resection might improve bowel emptying. METHODS We reviewed patients referred to our center from 2008 to 2012 with obstructive problems following a Soave pull-through for HD (CCHMC IRB # 2011-2019). Only patients with an obstructing Soave cuff were analyzed. Patients with other reasons for obstruction (anastomotic stricture, transition zone, aganglionic segment) were excluded. RESULTS Thirty-six patients underwent reoperation at our center for obstructive symptoms after an initial Soave pull-through. Seventeen of these patients had a Soave cuff only as the potential source of obstruction. Pre-operative symptoms included enterocolitis (10), constipation (6), and failure to thrive (1). Nine patients (53%) required irrigations to manage distension or enterocolitis pre-operatively. 14/17 patients (82%) had a palpable cuff on rectal exam. Eight patients (47%) had radiographic evidence of a cuff demonstrated by distal narrowing (4) or a prominent presacral space (4). Four children (23%) underwent excision of the cuff only. Thirteen (76%) had removal of the cuff and proximally dilated colon [(average length 7.2cm) (12 performed transanally, and five needed laparotomy as well.)] Post-operatively, episodes of enterocolitis were reduced to zero, and need for irrigation to treat distension was reduced by 50%. Nine patients have voluntary bowel movements, and five are clean on enemas. 3/6 patients with pre-operative constipation or impaction now empty without enemas. (Follow up 1-17months, mean 7months.) CONCLUSIONS Recurrent enterocolitis, constipation, or failure to thrive can indicate a functional obstruction due to a Soave cuff when no other pathologic cause exists. Physical exam or contrast enema can identify a problematic cuff. Reoperation with cuff resection can dramatically improve bowel emptying.

Lung nodules in pediatric oncology patients: a prediction rule for when to biopsy

PURPOSE The purpose of the study was to develop a prediction rule regarding the factors that most accurately predict the diagnosis of a malignancy in a lung nodule in the pediatric oncology patient. METHODS A retrospective review of pediatric oncology patients that underwent lung nodule resection between 1998 and 2007 was performed. Multivariable logistic regression was used to create a prediction rule. RESULTS Fifty pediatric oncology patients underwent 21 thoracotomies and 48 thoracoscopies to resect discrete lung nodules seen on computed tomographic scans during workup for metastasis or routine surveillance. The mean nodule size was 10.43 ± 7.08 mm. The most significant predictors of malignancy in a nodule were peripheral location (odds ratio [OR], 9.1); size between 5 and 10 mm (OR, 2.78); location within the right lower lobe (OR, 2.43); and patients with osteosarcoma (OR, 10.8), Ewing sarcoma (OR, 3.05), or hepatocellular carcinoma (OR, 2.38). CONCLUSIONS Lesions that are between 5 and 10 mm in size and peripherally located in patients with osteosarcoma, Ewing sarcoma, or hepatocellular carcinoma are most likely to be malignant. Use of a prediction rule can help guide clinical practice by determining which patients should undergo surgical resection of lung nodules and which patients may be closely observed with continued radiologic studies.