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/m(2) 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.

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.

Risk of incomplete pyloromyotomy and mucosal perforation in open and laparoscopic pyloromyotomy.

BACKGROUND: Despite randomized controlled trials and meta-analyses, it remains unclear whether laparoscopic pyloromyotomy (LP) carries a higher risk of incomplete pyloromyotomy and mucosal perforation compared with open pyloromyotomy (OP). METHODS: Multicenter study of all pyloromyotomies (May 2007-December 2010) at nine high-volume institutions. The effect of laparoscopy on the procedure-related complications of incomplete pyloromyotomy and mucosal perforation was determined using binomial logistic regression adjusting for differences among centers. RESULTS: Data relating to 2830 pyloromyotomies (1802 [64%] LP) were analyzed. There were 24 cases of incomplete pyloromyotomy; 3 in the open group (0.29%) and 21 in the laparoscopic group (1.16%). There were 18 cases of mucosal perforation; 3 in the open group (0.29%) and 15 in the laparoscopic group (0.83%). The regression model demonstrated that LP was a marginally significant predictor of incomplete pyloromyotomy (adjusted difference 0.87% [95% CI 0.006-4.083]; P=0.046) but not of mucosal perforation (adjusted difference 0.56% [95% CI -0.096 to 3.365]; P=0.153). Trainees performed a similar proportion of each procedure (laparoscopic 82.6% vs. open 80.3%; P=0.2) and grade of primary operator did not affect the rate of either complication. CONCLUSIONS: This is one of the largest series of pyloromyotomy ever reported. Although laparoscopy is associated with a statistically significant increase in the risk of incomplete pyloromyotomy, the effect size is small and of questionable clinical relevance. Both OP and LP are associated with low rates of mucosal perforation and incomplete pyloromyotomy in specialist centers, whether trainee or consultant surgeons perform the procedure.

Junctional epidermolysis bullosa incidence and survival: 5-year experience of the Dystrophic Epidermolysis Bullosa Research Association of America (DebRA) nurse educator, 2007 to 2011.

Junctional epidermolysis bullosa (JEB) is a particularly devastating type of epidermolysis bullosa, especially in the newborn period. Data about the number of new cases of JEB in the United States were collected from the records of the Dystrophic Epidermolysis Bullosa Research Association of America (DebRA) nurse educator. Seventy-one children with JEB were reported to have been born in the 5 years between 2007 and 2011, reflecting an incidence of at least 3.59 per million per year, significantly higher than previously estimated (2.04 per million). There was a high prevalence of morbidity and infant mortality of at least 73%, as 52 of the 71 cases proved fatal by June 2012. These data emphasize the need for future research to develop treatment and ultimately a cure for this disorder.

Multicenter study of pectus excavatum, final report: complications, static/exercise pulmonary function, and anatomic outcomes.

BACKGROUND: A multicenter study of pectus excavatum was described previously. This report presents our final results. STUDY DESIGN: Patients treated surgically at 11 centers were followed prospectively. Each underwent a preoperative evaluation with CT scan, pulmonary function tests, and body image survey. Data were collected about associated conditions, complications, and perioperative pain. One year after treatment, patients underwent repeat chest CT scan, pulmonary function tests, and body image survey. A subset of 50 underwent exercise pulmonary function testing. RESULTS: Of 327 patients, 284 underwent Nuss procedure and 43 underwent open procedure without mortality. Of 182 patients with complete follow-up (56%), 18% had late complications, similarly distributed, including substernal bar displacement in 7% and wound infection in 2%. Mean initial CT scan index of 4.4 improved to 3.0 post operation (severe >3.2, normal = 2.5). Computed tomography index improved at the deepest point (xiphoid) and also upper and middle sternum. Pulmonary function tests improved (forced vital capacity from 88% to 93%, forced expiratory volume in 1 second from 87% to 90%, and total lung capacity from 94% to 100% of predicted (p < 0.001 for each). VO2 max during peak exercise increased by 10.1% (p = 0.015) and O2 pulse by 19% (p = 0.007) in 20 subjects who completed both pre- and postoperative exercise tests. CONCLUSIONS: There is significant improvement in lung function at rest and in VO2 max and O2 pulse after surgical correction of pectus excavatum, with CT index >3.2. Operative correction significantly reduces CT index and markedly improves the shape of the entire chest, and can be performed safely in a variety of centers.

Complex vascular anomalies.

The classification system for vascular anomalies now used by experts worldwide comprises two distinct disease entities that differ in their biologic and pathologic features: vascular tumors and vascular malformations. Vascular tumors include infantile and congenital hemangiomas, tufted angiomas, and kaposiform hemangioendotheliomas. Infantile hemangiomas, the most common vascular anomaly, generally have a predetermined life cycle (proliferation and subsequent involution). GLUT-1, a glucose transporter, is a marker for these specific lesions during all phases of development. Vascular malformations are classified according to their vascular tissue of origin and include capillary, venous, arteriovenous, lymphatic, and mixed malformations. Complex lymphatic malformations and complex mixed malformations, which may have most vascular components, are the most difficult vascular malformations to successfully treat. These lesions are present at birth and often expand or grow in response to trauma, infection, or hormonal changes. Imaging advancements have enabled more accurate assessments and improved management of vascular anomalies. In addition, many lesions are now being managed with targeted pharmacologic therapy. Propranolol and steroids are used for complex or disfiguring tumors, and new anti-angiogenesis inhibitors such as sirolimus are selectively used to treat lymphatic and venous lymphatic malformations that are poorly responsive to sclerotherapy, embolization, and surgical excision. Multimodal therapies are often essential for complex lesions and require the combined expertise of an interdisciplinary team.

Upper airway complications of junctional epidermolysis bullosa.

OBJECTIVE: To assess the incidence of upper airway pathology in patients with junctional epidermolysis bullosa (JEB). STUDY DESIGN: We conducted a retrospective chart review of all patients with JEB who came to an interdisciplinary epidermolysis bullosa center at a tertiary care institution between 2004 and 2010. RESULTS: Twenty-five patients with JEB were identified, and 12 patients were seen in the otolaryngology clinic (age range, 2 months-15 years; 8 male, 4 female). Of the 12 patients, 8 underwent rigid laryngoscopy and bronchoscopy for upper respiratory tract symptoms; 7 of these patients displayed laryngeal pathology, and 5 of them underwent surgical intervention with successful resolution of symptoms. Furthermore, none of these patients had any short- or long-term complications from their surgery. A strict protocol and a precise problem-focused cold surgical technique were used in these cases to protect skin and mucus membranes. CONCLUSION: With appropriate precautions, endoscopic laryngeal surgery can be safe and effective in patients with JEB and larygnotracheal disease. Endoscopic laryngeal surgery is feasible when indicated for these patients.

Sirolimus for the treatment of complicated vascular anomalies in children.

BACKGROUND: Vascular anomalies comprise a diverse group of diagnoses. While infantile hemangiomas are common, the majority of these conditions are quite rare and have not been widely studied. Some of these lesions, though benign, can impair vital structures, be deforming, or even become life-threatening. Vascular tumors such as kaposiform hemangioendotheliomas (KHE) and complicated vascular malformations have proven particularly difficult to treat. PROCEDURE: Here we retrospectively evaluate a series of six patients with complicated, life-threatening vascular anomalies who were treated with the mTOR inhibitor sirolimus for compassionate use at two centers after failing multiple other therapies. RESULTS: These patients showed significant improvement in clinical status with tolerable side effects. CONCLUSIONS: Sirolimus appears to be effective and safe in patients with life-threatening vascular anomalies and represents an important tool in treating these diseases. These findings are currently being further evaluated in a Phase II safety and efficacy trial.

Increasing severity of pectus excavatum is associated with reduced pulmonary function.

OBJECTIVE: To determine whether pulmonary function decreases as a function of severity of pectus excavatum, and whether reduced function is restrictive or obstructive in nature in a large multicenter study. STUDY DESIGN: We evaluated preoperative spirometry data in 310 patients and lung volumes in 218 patients aged 6 to 21 years at 11 North American centers. We modeled the impact of the severity of deformity (based on the Haller index) on pulmonary function. RESULTS: The percentages of patients with abnormal forced vital capacity (FVC), forced expiratory volume in 1 second (FEV(1)), forced expiratory flow from 25% exhalation to 75% exhalation, and total lung capacity findings increased with increasing Haller index score. Less than 2% of patients demonstrated an obstructive pattern (FEV(1)/FVC <67%), and 14.5% demonstrated a restrictive pattern (FVC and FEV(1) <80% predicted; FEV(1)/FVC >80%). Patients with a Haller index of 7 are >4 times more likely to have an FVC of ≤80% than those with a Haller index of 4, and are also 4 times more likely to exhibit a restrictive pulmonary pattern. CONCLUSIONS: Among patients presenting for surgical repair of pectus excavatum, those with more severe deformities have a much higher likelihood of decreased pulmonary function with a restrictive pulmonary pattern.

Perioperative care of patients with epidermolysis bullosa: proceedings of the 5th international symposium on epidermolysis bullosa, Santiago Chile, December 4-6, 2008.

Epidermolysis bullosa (EB) has become recognized as a multisystem disorder that poses a number of pre-, intra-, and postoperative challenges. While anesthesiologists have long appreciated the potential difficult intubation in patients with EB, other systems can be affected by this disorder. Hematologic, cardiac, skeletal, gastrointestinal, nutritional, and metabolic deficiencies are foci of preoperative medical care, in addition to the airway concerns. Therefore, multidisciplinary planning for operative care is imperative. A multinational, interdisciplinary panel of experts assembled in Santiagio, Chile to review the best practices for perioperative care of patients with EB. This paper presents guidelines that represent a synthesis of evidence-based approaches and the expert consensus of this panel and are intended to aid physicians new to caring for patients with EB when operative management is indicated. With proper medical optimization and attention to detail in the operating room, patients with EB can have an uneventful perioperative course.

Dilated cardiomyopathy in epidermolysis bullosa: a retrospective, multicenter study.

Dilated cardiomyopathy (DC) has been reported in severe epidermolysis bullosa (EB) subtypes. Poor nutritional status, low carnitine levels, selenium deficiency, chronic iron overload, drugs and viral etiology have been proposed as potential contributors. This was a retrospective, descriptive, multicenter study describing EB patients that developed DC, and determining potential pre-disposing risk factors. Fifteen patients were enrolled in the study; 11 of them were male subjects (73%). Eighty-seven per cent of the participants had dystrophic EB and 13% had junctional EB. Mean age at diagnosis of DC was 12.18 +/- 4.99 years. Chronic anemia was diagnosed in 13 of 15 patients (86.7%). Sixty per cent of patients had prior red blood cell transfusions. At diagnosis, selenium levels were low in 55% of the patients (n = 11) and total carnitine levels were low in 45% of the patients (n = 11). Systolic function was moderately impaired, with a mean shortening fraction of 19.38% (SD = 5.04, n = 8). After a mean follow-up period of 6.3 +/- 4.8 years, six patients were alive without being on any medications (40.0%), two were alive on medications (13.3%) and seven had died (46.7%). Limitations of the study was that it was a retrospective chart review with relatively small sample size. Retrospective chart review, relatively small sample size. This study substantiates the association between DC and EB. Currently, there is no single risk factor identified in EB patients that leads to DC. Further prospective studies are needed.

Epidermolysis bullosa: management of esophageal strictures and enteric access by gastrostomy.

Epidermolysis bullosa (EB) is a spectrum of rare, inherited, blistering skin disorders, primarily affecting the skin and pharyngoesophageal mucosa. EB affects approximately 2 to 4 per 100,000 children each year. Blistering and scarring occur in response to even the most minor trauma. In this article, the authors outline the potential management options for patients with EB complicated by feeding difficulties secondary to esophageal strictures as well as those with nutritional deficiencies requiring a gastrostomy tube for supplemental feeding.

Prevalence of adrenal insufficiency following systemic glucocorticoid therapy in infants with hemangiomas.

OBJECTIVE: To determine the prevalence of adrenal insufficiency in infants with hemangiomas following treatment with systemic glucocorticoids (GCs). DESIGN: Prospective study for 18 months. SETTING: Hemangioma and vascular malformation center at a tertiary care children's hospital. PATIENTS: Sixteen infants with hemangiomas had an adrenal axis evaluation as soon as possible following the completion of GC therapy. Ten healthy control infants were also evaluated for comparison. INTERVENTIONS: Prednisolone at a starting dose of 2 to 3 mg/kg/d for 4 weeks, followed by a tapering period. The mean duration of GC treatment was 7.2 months. MAIN OUTCOME MEASURE: Prevalence of adrenal insufficiency in GC-treated subjects as assessed by a combination low-dose/high-dose corticotropin stimulation test. RESULTS: Subjects underwent corticotropin testing at a mean of 13 days after the completion of therapy. Only 1 of the 16 GC-treated infants (6%) had adrenal insufficiency. This subject was tested 1 day after GC treatment was stopped, and results from retesting 3 months later were normal. All control subjects had normal adrenal function. CONCLUSION: Infants with hemangiomas are at low risk of adrenal insufficiency following the completion of GC therapy, as used in our hemangioma center.

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.

Esophageal atresia repair with thoracotomy: the Cincinnati contemporary experience.

Esophageal atresia/tracheoesophageal fistula (EA/TEF) repair using an open muscle-sparing thoracotomy has been the standard approach used in our institution. Whereas perioperative mortality is now very uncommon, short- and long-term morbidity is very common in these patients. However, the complexity of the esophageal anatomy and significant comorbidities appear to be important contributors to significant complications in these patients. At least 30% of the EA/TEF patients required esophageal dilatations for anastomotic stricture; this increased to 50% for patients with pure EA. Gastroesophageal reflux requiring an antireflux procedure was performed 23% of the time for EA/TEF and 30% for EA patients. In addition, there were a few complications, such as winging of the scapula and scoliosis, that were attributed in part to the utilization of a nonmuscle-sparing thoracotomy. The standard muscle-sparing thoracotomy remains a very versatile and useful approach to repairing esophageal atresia, and it is the standard for repairing more complex anatomical variants. The self-reported long-term quality of life in these patients is very good, except for a few individuals with protracted feeding disorders and severe dysphagia.

Early discharge following laparoscopic appendectomy in children utilizing an evidence-based clinical pathway.

BACKGROUND: The utility of laparoscopic appendectomy (LA) in children remains controversial. The determination of the efficacy of LA in children is complicated by variable postoperative management, duration of antibiotics,and criteria for discharge. The aim of this study was to examine the results of a commitment to LA and the concurrent implementation of an evidence-based clinical pathway (CP) for management appendicitis in a children's hospital. METHODS: With institutional review board approval, all children presenting with appendicitis (n = 72; age =10.6 +/- 0.1 years) were offered LA and management directed by CP. Data were accrued prospectively for 12 consecutive months (May 2006 to April 2007) and analysis performed at 15 months. Data are reported as the mean +/- standard error of the mean. RESULTS: Children were stratified based on the operative findings: group one - acute 41; group two-suppurative=11; and group 3-gangrenous or perforated 20. Duration of hospital stay differed between the groups:group one= 26 +/- 0.3 hours; group 2 =48 +/- 3 hours; group 3= 127 +/- 6 hours (P <0.05). No patients in groups one or two suffered a complication or were readmitted following discharge. Two patients in group 3 (10%)were readmitted and treated with antibiotic therapy alone. Overall, 66% of the children with acute appendicitis(27/41) and 27% with suppurative appendicitis (3/11) were discharged within 24 hours of admission. Discharge by 24 hours in groups 1 and 2 was not influenced by age, gender, or time of operation (before or after 7 PM). CONCLUSIONS: The commitment to LA and use of CP resulted in discharge within 24 hours in 2 of 3 of children with acute appendicitis without readmission or complications being observed. Early discharge was not influenced by age, gender, or time of admission. For advanced appendicitis, length of hospital stay, determined by clinical parameters, resulted in a low rate of complication or readmission.

Surgical repair of pectus excavatum markedly improves body image and perceived ability for physical activity: multicenter study.

OBJECTIVE: This study evaluated changes in both physical and psychosocial quality of life reported by the parent and child after surgical repair of pectus excavatum. METHODS: As part of a multicenter study of pectus excavatum, a previously validated tool called the Pectus Excavatum Evaluation Questionnaire was administered by the research coordinator, via telephone, to parents and patients (8-21 years of age) before and 1 year after surgery. Eleven North American children's hospitals participated. From 2001 to 2006, 264 patients and 291 parents completed the initial questionnaire, and 247 patients and 274 parents completed the postoperative questionnaire. Responses used a Likert-type scale of 1 to 4, reflecting the extent or frequency of a particular experience, with higher values conveying less-desirable experience. RESULTS: Preoperative psychosocial functioning was unrelated to objective pectus excavatum severity (computed tomographic index). Patients and their parents reported significant positive postoperative changes. Improvements occurred in both physical and psychosocial functioning, including less social self-consciousness and a more-favorable body image. For children, the body image component improved from 2.30+/-0.62 (mean+/-SD) to 1.40+/-0.42 after surgery and the physical difficulties component improved from 2.11+/-0.82 to 1.37+/-0.44. For the parent questionnaire, the child's emotional difficulties improved from 1.81+/-0.70 to 1.24+/-0.36, social self-consciousness improved from 2.86+/-1.03 to 1.33+/-0.68, and physical difficulties improved from 2.14+/-0.75 to 1.32+/-0.39. Ninety-seven percent of patients thought that surgery improved how their chest looked. CONCLUSIONS: Surgical repair of pectus excavatum can significantly improve the body image difficulties and limitations on physical activity experienced by patients. These results should prompt physicians to consider the physiologic and psychological implications of pectus excavatum just as they would any other physical deformity known to have such consequences.

Noninterventional treatment of selected head and neck lymphatic malformations.

BACKGROUND: Indications for treatment of lymphatic malformations include disfigurement, symptoms, and infection. Patients with lymphatic malformations often undergo resection or sclerotherapy to prevent possible complications, as it has been thought that lymphatic lesions do not regress. METHODS: A retrospective analysis of all head and neck lymphatic malformations for the past 5 years was performed. RESULTS: Twenty-five patients with lymphatic malformations of the head and neck were treated, all underwent computed tomography or magnetic resonance imaging for evaluation. Fourteen patients had macrocystic lesions; others were considered mixed or microcystic. Seventeen patients underwent intervention. Ten patients underwent surgical resection alone, 4 patients underwent sclerotherapy, and 3 patients had both sclerotherapy and surgical resection. Of 17, 15 patients who underwent intervention had complications, including recurrence and nerve damage. Eight patients with predominantly macrocystic lesions were managed with close observation and were asymptomatic other than a mass. With follow-up of 33.4 months, in 4 of 8 patients, the lesion significantly decreased; 4 of 8 patients continue to be asymptomatic. CONCLUSIONS: Patients who undergo intervention have a high complication and recurrence rate. Selected patients with asymptomatic macrocystic lymphatic malformations of the head and neck can often be managed by observation alone. These patients should be followed closely in a multidiscliplinary clinical setting.