The standard treatment for Langerhans cell histiocytosis (LCH) is chemotherapy, although the failure rates are high. Since MAP-kinase activating mutations are found in most cases, BRAF- and MEK-inhibitors have been used successfully to treat patients with refractory or relapsed disease. However, data on long-term responses in children are limited and there are no data on the use of these inhibitors as first-line therapy. We treated 34 patients (26 with LCH, 2 with juvenile xanthogranuloma, 2 with Rosai-Dorfman disease, and 4 with presumed single site-central nervous system histiocytosis) with dabrafenib and/or trametinib, either as first line or after relapse or failure of chemotherapy. Sixteen patients, aged 1.3-21 years, had disease that was recurrent or refractory to chemotherapy, nine of whom had multisystem LCH with risk-organ involvement. With a median treatment duration of 4.3 years, 15 (94%) patients have sustained favorable responses. Eighteen patients, aged 0.2-45 years, received an inhibitor as first-line treatment. All of these have had sustained favorable responses, with a median treatment duration of 2.5 years. Three patients with presumed isolated central nervous system/pituitary stalk histiocytosis had stabilization or improvement of their disease. Overall, inhibitors were well tolerated. Five patients with single-system LCH discontinued therapy and remain off therapy without recurrence. In contrast, all four patients with multisystem disease who discontinued therapy had to restart treatment. Our data suggest that children suffering from histiocytoses can be treated safely and effectively with dabrafenib or trametinib. Additional studies are, however, needed to determine the long-term safety and optimal duration of therapy.

Comparer les taux de réponse et le coût par patient répondeur d’un traitement par romiplostim ou par rituximab chez le patient adulte atteint de purpura thrombopénique immunologique primaire (PTI), du point de vue de l’Assurance maladie.Un modèle d’analyse décisionnelle a estimé le coût par patient et par patient répondeur au romiplostim ou au rituximab pendant 6 mois. Une revue de la littérature a identifié des essais de phase 3 contrôlés randomisés, permettant de définir le taux de réponse plaquettaire (≥ 50 × 109/L). Les coûts comprenaient les consultations, l’administration du traitement, les soins d’urgence et, pour les non-répondeurs, les coûts de la prise en charge des épisodes hémorragiques.La revue de la littérature a identifié un essai de phase 3 contrôlé randomisé pour le romiplostim avec un taux de réponse de 83 %. En l’absence d’une telle étude pour le rituximab, une analyse systématique des études disponibles a permis de retenir un taux de réponse de 62,5 % pour ce médicament. Le coût des traitements par patient était comparable : 17 456 € (romiplostim) et 17 068 € (rituximab). Le coût du traitement par rituximab par patient répondeur (27 308 €) était supérieur de 30 % à celui par romiplostim (21 031 €). L’utilisation du romiplostim réduisait les coûts d’administration du médicament, d’utilisation des immunoglobulines intraveineuses et des hospitalisations.De par son efficacité permettant une réduction des coûts liés à la prise en charge d’épisodes hémorragiques, le romiplostim représente une utilisation efficiente des ressources pour les adultes atteints de PTI en France.This analysis compared the response rates and cost per responder associated with romiplostim and rituximab in adult immune thrombocytopenia from the French National Health System payer perspective.A decision analytic model was developed to estimate the cost per patient and per responder of treating adult immune thrombocytopenia patients with romiplostim versus rituximab over 6 months. A systematic literature review identified phase 3 randomized controlled trials. Published response rates were extracted (response definition: ≥ 50 × 109 platelets/liter). Resource utilization was based on French and international treatment guidelines, and clinical expert opinion. Unit costs were derived from literature and French reimbursement lists, and included the costs of routine physician visits, treatment administration, and emergency care. Non-responders incurred bleeding-related event costs.The literature review identified a phase 3 randomized controlled trial for romiplostim with a response rate of 83%. Due to a lack of phase 3 randomized controlled trials for rituximab, a systematic review of studies was selected as the best source, reporting a response rate of 62.5%. Romiplostim and rituximab were associated with similar treatment costs, with an estimated cost per patient for romiplostim of € 17,456 and € 17,068 for rituximab. Rituximab resulted in a 30% higher cost per responder (€ 27,308 for rituximab versus € 21,031 for romiplostim). Romiplostim use reduced drug administration, intravenous immunoglobulin, and bleeding-related hospitalization costs compared to rituximab.Due to its high efficacy leading to lower bleeding-related costs, romiplostim represents an efficient use of resources for adult immune thrombocytopenia patients in the French healthcare system.

Purpose Intestinal malrotation is often diagnosed in infancy. The true incidence of malrotation outside of this age is unknown. These patients can present atypically or be asymptomatic and diagnosed incidentally. We evaluate the incidence, clinical presentation, ideal imaging, and intra-operative findings of patients with malrotation over 1 year of age. Methods Retrospective review was conducted in patients older than 1 year, treated for malrotation at a single pediatric tertiary care center from 2000 to 2015. Data analyzed included demographics, presentation, imaging, intraoperative findings, and follow-up. Patients predisposed to malrotation were excluded. Results 246 patients were diagnosed with malrotation, of which 77 patients were older than 1 year of age. The most common presenting symptoms were vomiting (68%) and abdominal pain (57%). The most common method of diagnosis was UGI (61%). In 88%, the UGI revealed malrotation. 73 of 75 were confirmed to have malrotation at surgery. Intra-operatively, 60% were found to have a malrotated intestinal orientation and 33% with a non-rotated orientation. Obstruction was present in 22% with 12% having volvulus. Of those with follow-up, 58% reported alleviation of symptoms. Conclusion Despite age malrotation should be on the differential given a variable clinical presentation. UGI should be conducted to allow for prompt diagnosis and surgical intervention.

Nuclear medicine has a central role in the diagnosis, staging, response assessment and long-term follow-up of neuroblastoma, the most common solid extracranial tumour in children. These EANM guidelines include updated information on 123 I-mIBG, the most common study in nuclear medicine for the evaluation of neuroblastoma, and on PET/CT imaging with 18 F-FDG, 18 F-DOPA and 68 Ga-DOTA peptides. These PET/CT studies are increasingly employed in clinical practice. Indications, advantages and limitations are presented along with recommendations on study protocols, interpretation of findings and reporting results.

BACKGROUND:Children with a symptomatic indirect inguinal hernia have a patent processus vaginalis (PPV). However, the reverse is unknown, as the natural history of PPV is unclear. Currently, there are little data regarding the incidence and time frame for developing a symptomatic hernia with a known asymptomatic PPV. METHODS:A retrospective chart review was conducted in children who were evaluated for a PPV during nonhernia laparoscopic surgery by a single pediatric surgeon (GWH) from 2000 to 2014. Those patients with intraoperative findings of PPV were followed up by chart review and phone inquiry. RESULTS:1548 children underwent a laparoscopic operation, with 308 having an asymptomatic PPV. Phone contact was successful in 125 (43%) of these patients at a median of 8.1years (range 4.8-12.7) after the initial laparoscopic operation. Nineteen (13%) patients returned with a symptomatic hernia at a median age of 17months (range: 5-74) and a median presentation of 9months (range: 1-66) after the initial laparoscopy. Ten hernia repairs were unilateral and 9 bilateral. None of those who were contacted via phone inquiry reported hernia symptoms or hernia repair. CONCLUSIONS:These data suggest that the risk of developing a symptomatic hernia during childhood in the presence of a known PPV is relatively low. LEVEL OF EVIDENCE:Level 3; type of study: retrospective study.

1782 Objectives The current protocol for bone scans performed for back pain at our institution consists of planar whole body images followed by SPECT of the thoracic, lumbar and sacral spine with low dose CT performed only over areas of abnormality identified on SPECT or on prior imaging. Overall camera time is ~45 minutes with ~18 minutes (40%) dedicated to planar scanning and the remainder to SPECT and CT. The purpose of this study was to assess the diagnostic performance of each of the three elements of this examination (planar, SPECT, CT) relative to the gold standard of SPECT plus CT. Methods Imaging records were searched for SPECT/CT examinations performed in patients less than 21 years old for back pain prior to July 15, 2015. Cases related to prior back surgery or systemic disease (e.g. JIA, CRMO, etc.) were excluded. The 100 most recently performed examinations were separated into their components (planar, SPECT, CT), anonymized and randomized and were reviewed by two of four reviewers with Nuclear Medicine specialization. Reviewers were blinded to each other’s interpretations. Two months after review of the individual components, each co-registered SPECT/CT examinations was reviewed by two of four reviewers, also in random, blinded fashion. The diagnosis and affected spinal level given by the two reviewers on the SPECT/CT examination served as the gold standard against which the components of the examination were compared. For SPECT/CT examinations in which both reviewers did not agree on the diagnosis, a third reviewer served as arbiter. Results Both reviewers agreed on the presence or absence of an abnormality for 87% (87/100) of the planar images, 72% (72/100) of the SPECT images and 77% (77/100) of the CT images. For SPECT/CT the two primary reviewers agreed on the presence or absence of any abnormality in 80% (80/100) of cases. The primary reviewers agreed on both the presence of an abnormality and specific diagnosis in 66% (66/100) of cases. Considering SPECT/CT, with arbitration as needed, as the gold standard, SPECT alone was 90% accurate in cases where both reviewers agreed with 88% sensitivity and 95% specificity for the detection of an abnormality. Limited CT was 75% accurate in cases where both reviewers agreed with 70% sensitivity and 87% specificity for the detection of an abnormality. Planar imaging, however, was only 41% accurate in cases where both reviewers agreed with 18% sensitivity and 100% specificity for the detection of an abnormality. Abnormalities outside of the spine potentially requiring further evaluation were identified on planar imaging in 14/100 cases. Conclusions In pediatric and young adult patients with uncomplicated low back pain, whole body planar imaging is only 41% accurate in identifying the presence or absence of potential causes of low back pain. Given the relatively poor diagnostic performance of whole body planar imaging and the fact that planar imaging identifies only a relatively small number of abnormalities outside of the thoracic, lumbar and sacral spine, not performing whole body planar imaging in this group of patients may be reasonable, allowing potential camera time savings of 40%.

Introduction: Despite evidence from prospective trials and meta-analyses supporting laparoscopic pyloromyotomy (LP) over open pyloromyotomy (OP), the open technique is still utilized by some surgeons on the premise that there is minimal clinical benefit to LP over OP. Although the potential cosmetic benefit of LP over OP is often cited in reports, it has never been objectively evaluated. Methods: After internal review board approval, the parents of patients from a previous prospective trial who had undergone LP (n=9) and OP (n=10) were contacted. After consent was obtained, the parents and patients were asked to complete a validated scar scoring questionnaire that was compared between groups. Standardized photos were taken of study subjects and controls with no abdominal procedures. Blinded volunteers were recruited to view the photos, identify if scars were present, and complete questions if a scar(s) was seen. Volunteers were also asked about the degree of satisfaction if their child had similar scars on a four-point scale from happy to unacceptable. Results: Mean age was 7 years in both groups. Parental scar assessment scores were superior in the LP group in every category. Blinded volunteers detected abdominal scars significantly more often in the OP group (98%) vs. the LP group (28%; P<.001). The volunteers detected a scar in 16% of the controls, comparable to the 28% detected in the LP group (P=.17). The degree of satisfaction estimate by volunteers was 1.78 for OP and 1.02 for LP and controls, generating a Cohen's d effect size of 5.1 standard deviation units comparing OP to either LP or controls (very large 1.3). Conclusions: Parents of children scored LP scars superior to OP scars. Surgical scars are almost always identifiable with OP while the surgical scars associated with LP approach invisibility to the observer, appearing similar to patients with no prior abdominal operation.

PURPOSE:The success of prospective randomized trials relies on voluntary participation, which has been perceived as a barrier for successful trials in children who rely on parental permission. We sought to identify the reasons parents decline child participation to understand potential limitations in the consent process.METHODS:A prospective observational study was conducted in 92 patients asked to participate in prospective randomized trials between 2012 and 2015. Parental reasons for refusal were documented.RESULTS:The 92 refusals were distributed between studies investigating the management of circumcision, gastroschisis, pectus excavatum, appendicitis, pyloric stenosis, undescended testicles, abdominal abscess and gastroesophageal reflux. Reasons for refusal included preference of treatment path (37 %), inability to follow up (21 %), unspecified resistance to participate in research (18 %), preference to maintain independent surgeon decision (16 %), and desire for historically standard treatment (8 %). Of the families who opted to pursue a specific treatment arm rather than randomization, 35 % had prior experience with that treatment, 32 % had researched the procedure, 18 % wished to pursue the minimal intervention and 15 % did not specify.CONCLUSIONS:Parental preference of therapy is the most common reason for refusal of study participation. This variable could be influenced with more effective explanation of study rationale and existing equipoise.

Objectives: To investigate the association between time to appendectomy and the risk of surgical site infections (SSIs) in children with appendicitis across multiple NSQIP-Pediatrics institutions.Background: Several recently published single institution retrospective studies have reported conflicting relationships between delaying appendectomy and the risk of increasing surgical site infections (SSI) in both children and adults. This study combines data from NSQIP-Pediatrics with institutional data to perform a multi-institutional analysis to examine the effects of delaying appendectomy on surgical site infections.Methods: Data from NSQIP-Pediatrics between January 2010 and June 2012 for cases of appendectomy for appendicitis at 6 institutions (preoperative characteristics, time of operation, and postoperative occurrences) were combined with data from medical record review (length of symptoms; times of initial presentation, emergency department (ED) triage, and admission; and diagnosis as simple appendicitis (SA, acute) or complicated appendicitis (CA, gangrenous/ruptured)). Cochran-Armitage tests for trend and multivariable logistic regression models were used to evaluate associations between time to appendectomy and SSI.Results: Of the 1338 patients included, 70% had SA and 30% had CA. Postoperative SSIs were more common in CA (5.7% vs 1.2%, P < 0.001). SSI rates did not differ significantly across hospitals (P=0.17). Compared with patients who did not develop an SSI, patients who developed an SSI had similar times between ED triage and appendectomy (median (interquartile range) 11.5 hours (6.4-14.7) versus 9.7 hours (5.8-15.6, P = 0.36), and similar times from admission to appendectomy (5.5 hours (1.9-10.2) versus 4.3 hours (1.4-9.9), P=0.36). Independent risk factors for SSI were CA (Odds Ratio (95% CI): 3.46 (1.48-8.10), P = 0.004), longer symptom duration (OR for a 10 -hour increase: 1.05 (1.01-1.10), P = 0.02), and presence of sepsis/septic shock (2.70 (1.17-6.28), P = 0.02).Conclusions: A 16 -hour delay from ED presentation or a 12 -hour delay from hospital admission to appendectomy was not associated with an increased risk for SSI.

1710 Objectives SPECT/CT can aid in identification and evaluation of primary neuroblastoma lesions and metastases. The objective of this study is to determine if SPECT/CT should be included in the Curie scoring processs to improve the accuracy of clinical studies of neuroblastoma therapy. Methods Each of 29 clinically acquired I-123-MIBG imaging studies in 18 children with neuroblastoma was retrospectively scored by 2 members of a 3 physician panel who were experienced in interpretation of I-123-MIBG scans in neuroblastoma patients. Reviewers were blinded to the clinical interpretation. First, they scored a set of planar images that included anterior and posterior whole body and lateral skull images. Then SPECT images with co-registered low dose CT were reviewed in combination with planar images and a second Curie score was calculated. A single SPECT acquisition with a 39.5 cm z-axis field of view was performed that included chest, abdomen and/or pelvis depending on the location of the primary tumor and patient length. Results Planar image Curie scores were 0 in 4 patient studies, >0 and ≤4 in 7 studies, >4 and ≤20 in 9 studies and >20 in 9 studies. Curie scores increased by an average of 1 point when SPECT/CT was added to planar imaging. When the planar Curie score was 0, SPECT/CT did not identify any missed sites of disease. Nine studies demonstrated no metastatic disease on planar imaging and SPECT/CT did not identify undetected metastases in any of these studies. The only clinically important change occurred in 2 studies with planar Curie scores of 1, where SPECT/CT indicated that the I-123-MIBG uptake in the torso on planar imaging was not due to tumor in both cases. Conclusions Curie scores changed little when SPECT/CT imaging was added to planar imaging for scoring purposes. In the 29 studies, there were no increases in Curie score that would have affected classification of patient prognosis. SPECT/CT prevented a false positive reading in 2 patients with no other disease.

Background Minimally invasive bar repair for pectus patients produces substantial pain which dictates the post-operative hospital course. We have data from 2 randomized trials comparing epidural catheter placement to patient controlled analgesia. The purpose of this study was to compare the outcomes of patients who were enrolled in the trials to those that did not participate in the trials. Methods A retrospective chart review was performed on patients not enrolled in the trials to compare to the prospective datasets from October 2006 to June 2014. Perioperative outcomes were examined. Results There were 135 patients in a study protocol (IS) and 195 patients that were not enrolled in a study (OS). Comparing the entire IS and OS groups, length of stay was less in the IS group, as was time to regular diet. Average pain scores, operative time and complication rates were not significantly different between the groups. Of the IS patients a significantly lower number of patients had epidural failure, requiring substitution of a PCA for pain control. Conclusions There are benefits derived from participating in our randomized trials comparing epidural to patient controlled analgesia after bar placement for pectus excavatum regardless of which arm is utilized.

BACKGROUND: Emerging data suggest instillation of tissue plasminogen activator (tPA) is safe and potentially efficacious in the treatment of intra-abdominal abscess. To date, prospective comparative data are lacking in children. Therefore, we conducted a randomized trial comparing abscess irrigation with tPA and irrigation with saline alone.STUDY DESIGN: After IRB approval, children with an abscess secondary to perforated appendicitis who had a percutaneous drain placed for treatment were randomized to twice-daily instillation of 13 mL 10% tPA or 13 mL normal saline. All patients were treated with once-daily dosing of ceftriaxone and metronidazole throughout their course. The primary end point variable was duration of hospitalization after drain placement. Using a power of 0.8 and an alpha of 0.05, a sample size of 62 patients was calculated.RESULTS: Sixty-two patients were enrolled between January 2009 and February 2013. There were no differences in demographics, abscess size, abscess number, admission WBC, or duration of symptoms. Duration of hospitalization after drainage was considerably longer with the use of tPA. There was no difference in total duration of hospitalization, days of drainage, or days of antibiotics. However, medication charges were higher with tPA.CONCLUSIONS: There are no advantages to routine tPA flushes in the treatment of abdominal abscess secondary to perforated appendicitis in children. (C) 2015 by the American College of Surgeons)

366 Objectives To define the interval between granulocyte colony stimulating factor (G-CSF) administration and FDG PET imaging that limits interference by stimulated marrow. Methods FDG PET scans performed in patients with Ewing sarcoma or rhabdomyosarcoma were retrospectively reviewed by two reviewers blinded to G-CSF administration. Reviewers subjectively scored marrow activity (1-4) with regard to interference with clinical interpretation and measured standardized uptake values in the spine. Results 44 FDG PET exams were reviewed in 22 patients, 18 of whom received pegfilgrastim and 4 of whom received filgrastim. There was substantial agreement in scoring between reviewers (α=0.633). Stimulated marrow was scored as potentially or definitely interfering in 19/44 scans (43.2%). Of the 18 patients treated with pegfilgrastim, the median time between G-CSF administration and imaging was 10 days (range:1-19 days) for scans with potential or definite marrow interference and 19.5 days (range:7-55 days) for scans without marrow interference (score≤2). No scan >10 days after pegfilgrastim administration had marrow activity considered definitely interfering. Of the 4 patients treated with filgrastim, subjective interference by marrow stimulation was present in only 1 scan (1 day after G-CSF). SUVmax in the spine was ≥3 (high enough to interfere) in 17/44 scans (38.6%). Median time between pegfilgrastim administration and imaging in patients with SUVmax ≥3 in the spine was 16 days (range:1-20 days). In patients with SUVmax Conclusions An interval of 19-20 days between pegfilgrastim administration and FDG PET scanning appears sufficient to limit interference by stimulated marrow. In patients treated with filgrastim, shorter intervals may suffice but additional study is needed to confirm this.