Publications by authors named "Jason S Frischer"

41 Publications

Creating a collaborative program for the care of children with colorectal and pelvic problems.

Semin Pediatr Surg 2020 Dec 8;29(6):150985. Epub 2020 Nov 8.

Children's National Hospital, Washington, DC, USA.

The treatment of patients with colorectal disorders and their associated urologic, gynecologic, gastrointestinal, spinal, and orthopedic anomalies requires care from various medical and surgical specialties over the course of their lifetime. This is ideally handled by a collaborative center which facilitates the assessment and development of a long-term patient care plan among multiple specialties which can enhance the quality of care, improve communication among different specialties, and improve patient satisfaction and outcomes. We describe the process, as well as lessons learned in developing such a center.
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http://dx.doi.org/10.1016/j.sempedsurg.2020.150985DOI Listing
December 2020

A child presents with perianal symptoms - how often is this Crohn's disease?

J Pediatr Surg 2020 Nov 20. Epub 2020 Nov 20.

Colorectal Center, Cincinnati Children's Hospital Medical Center, 3333 Burnet Ave, Cincinnati, OH 45229, United States.

Background: The cumulative incidence and predictors of future diagnosis of Crohn's disease (CD) following presentation with perianal symptoms, such as anorectal abscess, fistula or fissure, is unknown.

Methods: A 5-year retrospective review of children presenting with perianal symptoms without prior CD diagnosis was performed. Institutional cumulative incidence of CD was calculated to determine the risk of CD presenting with perianal symptoms.

Results: 1140 children presented for evaluation of an anorectal abscess (n = 232), fistula (n = 49), or fissure (n = 859). Thirty-five were later diagnosed with CD, resulting in an incidence of 3%. Prognostic indicators of future CD diagnosis included increased age per every additional year (RR 1.19, 95% CI: 1.14-1.25, p < 0.001), male sex (RR 2.12, 95% CI 1.07-4.22, p = 0.024), or perianal fistula (RR 4.67, 95% CI 2.26-9.67, p = 0.022). Among those diagnosed with CD, 57% experienced and had a documented history of a CD-associated symptom prior to perianal symptom onset. Absence of symptoms resulted in delayed diagnosis (43 vs 3 days, p < 0.02).

Conclusion: Of children presenting with a perianal symptom, three percent will eventually be diagnosed with CD. At highest risk (35%) were males aged 10 years or older with a perianal fistula; which should prompt expeditious workup.
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http://dx.doi.org/10.1016/j.jpedsurg.2020.11.016DOI Listing
November 2020

Hemorrhage after on-ECMO repair of CDH is equivalent for muscle flap and prosthetic patch.

J Pediatr Surg 2019 Oct 6;54(10):2044-2047. Epub 2019 May 6.

Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA. Electronic address:

Background/purpose: Prosthetic patch (patch) and muscle flap (flap) techniques are utilized for severe congenital diaphragmatic hernia (CDH) repair; however, when performed on extracorporeal membrane oxygenation (ECMO), the risk of hemorrhage increases. We sought to compare bleeding complications between repair types.

Methods: We retrospectively reviewed 2010-2016 on-ECMO CDH repairs.

Results: Twenty-nine patients met criteria: 13 patch (44.8%) and 16 flap (55.2%). Eight patch (61.5%) and 13 flap (81.2%) patients had left-sided defects (p = 0.223). All defects were Type C or D (Type C: patch 53.8%, flap 56.2%, p = 0.596). There was no difference in gestational age at delivery (patch 37.5 ± 0.9 weeks, flap 37.2 ± 1.3 weeks, p = 0.390) or age at repair (patch 7.46 ± 6.6 days, flap 6.00 ± 4.3 days, p = 0.476). Seven patch (53.8%) and 9 flap (56.2%) patients survived to discharge (p = 0.596). Estimated intraoperative blood loss was equivalent (patch 35.3 ± 53.9 mL, flap 24.2 ± 18.4 mL, p = 0.443). One patch patient (7.6%) and two (12.5%) flap patients required reoperation in the first 48 h for bleeding (p = 0.580). 48-h postoperative transfusions were the same for those that required reoperation (patch 282.0 mL/kg, flap 208.5 ± 21.9 mL/kg, p = 0.054) and those that did not (patch 120.7 ± 111.7 mL/kg, flap 118.4 ± 89.9 mL/kg, p = 0.561).

Conclusions: On-ECMO bleeding complications are equivalent for both flap and patch CDH repair.

Level Of Evidence: Type III (retrospective comparative study).
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http://dx.doi.org/10.1016/j.jpedsurg.2019.04.025DOI Listing
October 2019

A comparison of surgical complications after appendicostomy and neoappendicostomy in pediatric patients.

J Pediatr Surg 2019 Aug 12;54(8):1660-1663. Epub 2019 Apr 12.

Colorectal Center at Cincinnati Children's Hospital Medical Center, 3333 Burnet Ave, Cincinnati, OH 45229. Electronic address:

Purpose: There are limited data on neoappendicostomy complications owing to small patient populations. This study compares appendicostomy and neoappendicostomy procedures with an emphasis on major postoperative complications requiring either a surgical or interventional radiology procedure.

Method: A single-institution retrospective review included all patients with complete medical charts in the Cincinnati Children's Colorectal Database who underwent either an appendicostomy or neoappendicostomy from August 2005 through December 2016. Demographics, details of the procedure, and major postoperative complications were evaluated.

Results: 261 patients (appendicostomy n = 208, neoappendicostomy n = 53) with a median follow up time of 2.5 years resulted in 84 patients (appendicostomy n = 60, neoappendicostomy n = 24) experiencing a total of 118 complications requiring surgical or radiologic intervention with a significant difference between the groups (29% vs 45%, RR = 1.79 (95% CI: 1.24-2.60), p < 0.01). Skin level stricture was the most common complication (20% appendicostomies vs 30% neoappendicostomies, p = 0.13).

Conclusions: Appendicostomies and neoappendicostomies can be an effective way to manage fecal incontinence; however, 32% of our patients experienced a complication that required either a surgical or interventional radiology procedure. Patients need to be informed of the possible complications that are associated with appendicostomy and neoappendicostomy construction.

Type Of Study: Single institution retrospective review.

Level Of Evidence: IV.
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http://dx.doi.org/10.1016/j.jpedsurg.2019.04.002DOI Listing
August 2019

Initial development and validation of a fecal incontinence-specific quality of life measure.

J Pediatr Surg 2018 Jun 7;53(6):1148-1153. Epub 2018 Mar 7.

Colorectal Center at Cincinnati Children's, Division of Pediatric General & Thoracic Surgery, Cincinnati, OH. Electronic address:

Background/purpose: Fecal incontinence is a prevalent pediatric condition with psychosocial impacts on both children and their caregivers. We sought to develop and validate the Cincinnati Fecal Incontinence Scale (CINCY-FIS) as a psychometrically valid measure to assess the quality of life and caregiver impacts of pediatric fecal incontinence.

Methods: Items were generated through review of previous measures, expert consensus, and pilot testing with feedback from 8 families. Initial study measures were completed by 222 caregivers. Following item reduction, 18 items were subjected to confirmatory factor analysis. Convergent and criterion validity were assessed using correlation. Reliability was established using internal consistency statistics and test-retest reliability at baseline and 2-week follow-up.

Results: A five factor first-order structure with two higher-order factors demonstrated acceptable fit to the data, was consistent with a priori hypotheses, and was more parsimonious than the alternative model. Convergent validity and criterion-related validity were established for all of the CINCY-FIS scales. Reliability was high and consistent across both measurement occasions.

Conclusions: The CINCY-FIS is a reliable and valid assessment of pediatric fecal incontinence-specific quality of life and parenting stress. The score is highly sensitive to patient changes making it suitable for both clinical and research purposes.

Type Of Study: Prospective observational.

Level Of Evidence: Study of Diagnostic Test Level II.
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http://dx.doi.org/10.1016/j.jpedsurg.2018.02.076DOI Listing
June 2018

Extracorporeal Membrane Oxygenation in a Patient with Biliary Atresia: Case and Review of Extracorporeal Life Support Organization Data.

ASAIO J 2018 Nov/Dec;64(6):e191-e195

From the Division of Pediatric General and Thoracic Surgery, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio.

Biliary atresia is a newborn cholangiopathy that may lead to portopulmonary hypertension and cirrhosis-induced cardiomyopathy while awaiting liver transplantation. Extracorporeal life support and hepatic toxin filtration are life-saving interventions that provide cardiopulmonary support and hepatic dialysis to allow resolution of a child's illness. We utilized a combination of these extreme measures to bridge an infant with biliary atresia to transplantation. We reviewed cases of extracorporeal life support utilization in transplantation recipients in the Extracorporeal Life Support Organization database and determined that ours was the only use of pretransplant extracorporeal life support in biliary atresia.
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http://dx.doi.org/10.1097/MAT.0000000000000749DOI Listing
September 2019

Complications in colorectal surgery.

Semin Pediatr Surg 2016 Dec 31;25(6):380-387. Epub 2016 Oct 31.

Colorectal Center for Children, Division of Pediatric General & Thoracic Surgery, Cincinnati Children׳s Hospital Medical Center, College of Medicine, University of Cincinnati, 3333 Burnet Ave, MLC-2023, Cincinnati, Ohio 45229.

Colorectal pediatric surgery is a diverse field that encompasses many different procedures. The pullthrough for Hirschsprung disease, the posterior sagittal anorectoplasty for anorectal malformations including complex cloaca reconstructions and the ileal pouch anal anastomosis for ulcerative colitis and familial adenomatous polyposis present some of the most technically challenging procedures pediatric surgeons undertake. Many children prevail successfully following these surgical interventions, however, a small number of patients suffer from complications following these procedures. Anticipated postoperative problems are discussed along with medical and surgical strategies for managing these complications.
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http://dx.doi.org/10.1053/j.sempedsurg.2016.10.008DOI Listing
December 2016

Extensive heterotopic gastric mucosa of the small intestine: imaging with Tc-sodium pertechnetate SPECT/CT enterography.

Pediatr Radiol 2016 Dec 29;46(13):1873-1878. Epub 2016 Aug 29.

Department of Radiology and Medical Imaging, Cincinnati Children's Hospital Medical Center, 3333 Burnet Ave., Cincinnati, OH, 45229, USA.

Extensive heterotopic gastric mucosa of the small intestine is a rare, but potentially life-threatening condition characterized by multifocal or long-segment heterotopic gastric mucosa within the bowel lumen that is often associated with other anomalies including malrotation and annular pancreas. Although the imaging findings are characteristic, this entity may be unrecognized due to its unusual imaging appearance and rarity. CT or MR enterography and Tc-sodium pertechnetate scintigraphy can provide complementary information that enables specific diagnosis and accurate assessment of disease extent. We present a case of extensive heterotopic gastric mucosa of the small intestine imaged by simultaneous, combined Tc-sodium pertechnetate single photon-emission computed tomography (SPECT)/CT enterography to both familiarize the reader with the condition and describe an imaging strategy that enables specific diagnosis and assists with treatment planning.
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http://dx.doi.org/10.1007/s00247-016-3687-7DOI Listing
December 2016

Surgical outcomes, bowel habits and quality of life in young patients after ileoanal anastomosis for ulcerative colitis.

J Pediatr Surg 2016 Aug 23;51(8):1246-50. Epub 2016 Mar 23.

Cincinnati Children's Hospital Medical Center, 3333 Burnett Avenue, MLC-2023, Cincinnati, OH 45229, USA. Electronic address:

Purpose: We aim to investigate the postoperative outcomes, bowel habits and quality of life (QoL) of younger pediatric ulcerative colitis (UC) patients following surgical intervention compared to an older pediatric population.

Methods: Medical records of UC patients after colectomy with ileoanal reconstruction (2002-2013) at our institution were reviewed. Patients/parents completed a QoL, bowel habits and disease course questionnaire. Surgical outcomes, bowel habits and QoL were reported comparing the younger (≤11years old, n=26) to older (>11years old, n=38) cohorts.

Results: The mean age at colectomy was 7.04±0.63years vs 14.71±0.32years in the two groups. Patients had a significant (P<0.001) reduction in stooling frequency after surgery in both age groups and had favorable rates of fecal continence. The frequency of pouchitis and postoperative small bowel obstruction was similar in both cohorts. Dehydration was slightly increased in the younger population but not significant. Anastomotic leak and stricture rates were slightly reduced in younger patients. Postoperative QoL was favorable and similar regardless of age at surgery.

Conclusions: Colectomy with ileoanal anastomosis for young children (≤11years old) with UC is without increased complications relative to older patients and maintains a postoperative QoL and stool patterns.
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http://dx.doi.org/10.1016/j.jpedsurg.2016.03.002DOI Listing
August 2016

The association of the severity of anorectal malformations and intestinal malrotation.

J Pediatr Surg 2016 Aug 21;51(8):1241-5. Epub 2016 Apr 21.

Colorectal Center for Children, Pediatric Surgery Division, Cincinnati Children's Hospital Medical Center, 3333 Burnet Avenue, MLC 2023, Cincinnati, OH, 45229, U.S.A.. Electronic address:

Introduction: Intestinal malrotation is a known association of anorectal malformations (ARM). Exact incidence, prognosis and surgical implications related to ARM are unknown. The aim of this study was to identify relevant associations between ARM and the presence of malrotation.

Methods: Records of patients from two referral centers were retrospectively analyzed looking for malrotation associated to ARM and its management, as well as factors for functional prognosis.

Results: 40 patients out of 2572 with ARM (1.6%) were found to have malrotation. Females were more commonly affected, and severe malformations were more frequent (cloaca, covered cloacal exstrophy in females and rectoprostatic and rectobladder neck fistula in males). Factors significantly associated with malrotation included Müllerian or Wolffian duct anomalies (P<0.05), while fecal continence status, presence of constipation, and use of laxatives or enemas were not. Detecting and correcting malrotation early on or at the time of colostomy creation represented a protective factor against additional surgeries for bowel obstruction and volvulus (P<0.001). Removal of the appendix during malrotation treatment required constructing a neoappendicostomy using a cecal flap in 9 out of 14 patients needing antegrade enema administration.

Conclusions: Malrotation presence in patients with ARM has the same frequency as in the general population, but it is more common in severe malformations. Surgeons treating these patients should address the malrotation at the time of colostomy opening if detected. The appendix should be preserved for potential future use as an appendicostomy for antegrade administration of enemas.
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http://dx.doi.org/10.1016/j.jpedsurg.2016.04.008DOI Listing
August 2016

Health-Related Quality of Life and Parental Stress in Children With Fecal Incontinence: A Normative Comparison.

J Pediatr Gastroenterol Nutr 2016 12;63(6):633-636

*Clinical Child Psychology Program, University of Kansas, Lawrence †Colorectal Center ‡Behavioral Medicine and Clinical Psychology, Cincinnati Children's Hospital Medical Center, OH.

Objective: The aim of the present study was to describe the quality of life and parenting stress associated with a child with fecal incontinence (FI).

Methods: Female caregivers (n = 170) of children of 3 to 12 years age with FI completed a broad and general measure of quality of life and a measure of parenting stress. Results were compared with proxy reports for a normative sample of healthy children.

Results: Caregivers of children with FI reported significantly impaired quality of life for their children and increased parenting stress in all of the respective domains relative to healthy controls. Impairments reported by caregivers were large in magnitude. Similarly, rates of parenting stress were at or greater than the 98th percentile for caregivers of children with FI.

Conclusions: Children with fecal incontinence and their families are in need of interventions targeting their quality of life and the stress associated with caregiving. FI appears to be particularly stressful for caregivers who may be in need of support beyond medical management of their child's bowel. Moreover, additional refinements in disease-specific quality of life assessment are needed in this population. Such refinement would allow for more precise measurement of the quality of life processes that are unique to FI.
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http://dx.doi.org/10.1097/MPG.0000000000001201DOI Listing
December 2016

Angiogenesis and Vascular Endothelial Growth Factor-A Expression Associated with Inflammation in Pediatric Crohn's Disease.

J Gastrointest Surg 2016 Mar 3;20(3):624-30. Epub 2015 Nov 3.

Division of Pediatric General & Thoracic Surgery, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.

Background And Aims: Angiogenesis is a component of chronic inflammatory diseases including inflammatory bowel disease. Some studies describe increased angiogenesis associated with acute disease in adult Crohn's disease and ulcerative colitis, while animal models aid investigations of mechanism and pathophysiology of angiogenesis. We aim to explore the role of angiogenesis and its pathways in pediatric Crohn's disease.

Methods: Surgical specimens were obtained from pediatric Crohn's disease (both inflamed and non-inflamed regions of ileum) and control patients. Samples were examined for inflammation, microvessel density, and molecular expression of vascular endothelial growth factor-A, platelet-derived growth factor-β, angiopoietin-1, and angiopoietin-2.

Results: Angiogenesis and inflammation were increased in parallel in Crohn's disease compared to controls. We also discovered increased angiogenesis in Crohn's disease tissue that was relatively free of inflammatory disease. Vascular endothelial growth factor-A gene expression (P = 0.034) was elevated in Crohn's disease over controls, while gene expression of platelet-derived growth factor-β (P = 0.069), angiopoietin-1 (P = 0.206), and angiopoietin-2 (P = 0.082) was not significantly elevated.

Conclusions: We confirm that inflammation-associated angiogenesis is upregulated in pediatric Crohn's disease. This population also exhibits elevated mucosal angiogenesis at the surgical margin with limited inflammation. This suggests that angiogenesis is an additional pathologic characteristic to potentially identify normal mucosa and margins of surgical resection that are uninvolved with disease and, furthermore, may have implications for monitoring complete disease remission. We further identify the vascular endothelial growth factor-A pathway involvement in the disease process, which may serve as a future molecular target for anti-angiogenic therapy in inflammatory bowel disease.
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http://dx.doi.org/10.1007/s11605-015-3002-1DOI Listing
March 2016

Murine colitis treated with multitargeted tyrosine kinase inhibitors.

J Surg Res 2016 Feb 28;200(2):501-7. Epub 2015 Sep 28.

Peña Colorectal Center, Division of Pediatric General & Thoracic Surgery, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio. Electronic address:

Background: Angiogenesis, a known pathogenic component of neoplastic and nonneoplastic diseases, serves as a therapeutic target. Vascular endothelial growth factor (VEGF) and angiogenesis are clinically elevated in inflammatory bowel disease. By targeting vascular endothelial growth factor receptor (VEGFR) and platelet-derived growth factor receptor (PDGFR) with receptor tyrosine kinase inhibitors in a murine model of colitis, we hypothesize that angiogenesis will be suppressed and disease severity improved.

Methods And Methods: Sorafenib, sunitinib, and axitinib were administered by oral gavage in a murine model of dextran sodium sulfate (DSS) colitis. Inflammation score, microvessel density (MVD), and gene expression of VEGF, VEGFR, platelet-derived growth factor, PDGFR, Ang-2, and epidermal growth factor receptor was assessed.

Results: Inflammation and MVD were elevated in groups receiving DSS, but were similar between DSS-only and treatment cohorts. Unexpected weight loss was present in the gavaged groups versus DSS only. In treated groups, VEGFR was significantly decreased (P = 0.002) and VEGF gene expression trended down (P = 0.213) versus DSS only. Neither the platelet-derived growth factor/PDGFR pathway nor the alternative pathways, Ang-2 and epidermal growth factor receptor, were significantly changed from DSS control in treatment cohorts.

Conclusions: This study confirms the association between inflammation and MVD. Antiangiogenic receptor tyrosine kinase inhibitors suppressed the VEGF/VEGFR pathway but the expected decrease in colonic MVD did not follow, suggesting possible involvement of other angiogenic pathway(s). In the DSS model of colitis, vehicle selection and mouse strain can impact disease response.
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http://dx.doi.org/10.1016/j.jss.2015.09.023DOI Listing
February 2016

Mouse strain influences angiogenic response to dextran sodium sulfate-induced colitis.

J Surg Res 2014 Jul 12;190(1):47-54. Epub 2014 Apr 12.

Colorectal Center for Children, Division of Pediatric General & Thoracic Surgery, Cincinnati Children's Hospital Medical Center. Electronic address:

Background: Angiogenesis is a known pathologic factor in chronic inflammatory diseases. Regarding the murine dextran sodium sulfate (DSS) colitis model, different mouse strains produce variable clinical and inflammatory responses. We hypothesize that DSS colitis applied to diverse mouse strains will similarly elevate colonic microvessel density in parallel with inflammation, but will do so with different angiogenic profiles.

Materials And Methods: We induced DSS colitis in 129S2/SvPas, BALB/c, and C57BL/6 mice, then performed histologic and molecular analysis at day 7 to evaluate colonic inflammation and angiogenesis.

Results: Inflammation and microvessel density were similarly increased in DSS groups. The C57BL/6 cohort mounted a more severe colitis with 25% weight loss and greater colonic ulceration. Gene expression of angiogenic factors at baseline and in colitis groups were widely variable among strains. BALB/c mice exhibited higher angiogenic gene expression in control and DSS groups compared with other strains, specifically platelet-derived growth factor, angiopoietin-1, angiopoietin-1 (Ang-2), vascular endothelial growth factor receptor, and PDGF receptor. When evaluating the effect of DSS relative to controls, BALB/c mice were not significantly affected. 129S2/SvPas mice exhibited broad suppression of growth factors, significantly platelet-derived growth factor, Ang-2, and PDGF receptor. In contrast, C57BL/6 mice displayed increased gene expression, especially for angiopoietin-1 and Ang-2.

Conclusions: Genetic heterogeneity influences the angiogenic profile elicited by DSS colitis. We demonstrate that within a model of murine colitis, mouse strain significantly affects inflammation-associated angiogenesis. These results may impact strain selection when using a colitis model focusing on inflammation and angiogenesis. Future studies to further define the angiogenesis pathway and potentially alter the disease course with targeted antiangiogenics are warranted.
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http://dx.doi.org/10.1016/j.jss.2014.04.009DOI Listing
July 2014

The role of a colon resection in combination with a Malone appendicostomy as part of a bowel management program for the treatment of fecal incontinence.

J Pediatr Surg 2013 Nov;48(11):2296-300

Division of Pediatric Surgery, Colorectal Center for Children, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA.

Purpose: Surgical options previously described by us as part of a bowel management program for the treatment of soiling and fecal incontinence include (1) resection of a megarectosigmoid to reduce a patient's laxative requirement or (2) a Malone appendicostomy in patients who require enemas. We have found that some patients may benefit from both procedures.

Methods: We reviewed 18 fecally incontinent patients with structural or functional disorders of the anorectosigmoid (16 ARM, 1 spina bifida, and 1 SCT) who underwent both procedures.

Results: Of 18 patients, the enema regimen prior to resection had an average volume of 681 ml of saline (Range 400-1000 ml) and 60 ml (Range 48-117 ml) of additives (glycerine, castile soap and/or phosphate). Following the colon resection, the average volume of saline and additives was 335 ml (Range 130-650 ml) and 25 ml (Range 0-60 ml), respectively, a 50% reduction for both (P<0.01). The time for enema administration and evacuation was reduced by 25%, and the enemas were more effective, rendering the patients clean in 18 of 18 cases (follow-up was 3 months to 21 years). 2 patients later demonstrated that they could be managed with laxatives alone.

Conclusion: In patients with poor continence potential and a megarectosigmoid, combining a colon resection with a Malone appendicostomy can make the enema more effective. In some rare cases we found the resection may allow for a better response to laxatives.
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http://dx.doi.org/10.1016/j.jpedsurg.2013.03.058DOI Listing
November 2013

Pyloric atresia with epidermolysis bullosa: fetal MRI diagnosis with postnatal correlation.

Pediatr Radiol 2013 Dec 7;43(12):1656-61. Epub 2013 Jul 7.

Department of Radiology, Cincinnati Children's Hospital Medical Center, 3333 Burnet Ave., MLC 5031, Cincinnati, OH, 45229-3026, USA,

Pyloric atresia is an uncommon congenital gastric outlet obstruction, accounting for only 1% of gastrointestinal atresias. Up to 55% of cases have associated anomalies, the most common of which is epidermolysis bullosa. Fetal MRI findings of the epidermolysis bullosa-pyloric atresia association have not been previously reported. We present a case of this association diagnosed by prenatal MRI with corroborative postnatal imaging and surgical findings.
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http://dx.doi.org/10.1007/s00247-013-2737-7DOI Listing
December 2013

Foregut duplication cyst associated with esophageal atresia and tracheoesophageal fistula: a case report and literature review.

J Pediatr Surg 2013 May;48(5):E5-7

Division of Pediatric General and Thoracic Surgery, Cincinnati Children's Hospital Medical Center, 3333 Burnet Avenue, MLC-2023, Cincinnati, Ohio 45229, USA.

A case of esophageal atresia associated with a foregut duplication cyst is reported and the literature reviewed. This is the first documented occurrence in conjunction with Down syndrome and the second case where both anomalies were treated at the initial surgery.
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http://dx.doi.org/10.1016/j.jpedsurg.2013.02.071DOI Listing
May 2013

Vascular endothelial growth factor receptor-2 inhibition in experimental murine colitis.

J Surg Res 2013 Sep 6;184(1):101-7. Epub 2013 May 6.

Division of Pediatric General and Thoracic Surgery, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio 45229, USA.

Background: In the setting of inflammatory bowel disease, inflammation is associated with a simultaneous increase in angiogenesis; moreover, elevated vascular endothelial growth factor (VEGF) levels implicate angiogenesis as a pathologic contributor to disease severity. We hypothesize that selectively inhibiting vascular endothelial growth factor receptor-2 (VEGFR2) in a model of murine colitis will reduce angiogenesis, resulting in decreased inflammation and disease severity, providing mechanistic insight into the role of pathologic angiogenesis in IBD.

Materials And Methods: In a dextran sodium sulfate model of murine colitis, anti-VEGFR2 monoclonal antibody (DC101) or placebo was administered. Clinical assessments followed by histologic and molecular tissue analysis were performed to quantify inflammation, microvessel density (MVD), VEGF and VEGFR2 gene expression, and phosphorylated mitogen-activated protein kinase protein expression.

Results: Weight loss began after d 6 with the treatment group demonstrating a more favorable percent weight change. Inflammation and MVD were similar between cohorts, both increasing in parallel toward a plateau. VEGF and VEGFR2 messenger RNA expression were not significantly different, but phosphorylated mitogen-activated protein kinase was elevated in the DC101 cohort (P = 0.03).

Conclusions: Despite a more favorable weight change profile in the treated group, no difference was observed between cohorts regarding clinical disease severity. However, a parallel rise in inflammation and MVD was observed coinciding with weight loss, suggesting their relationship in IBD. VEGFR2 downstream signaling was significantly elevated in the treated cohort, possibly by VEGF-independent signal transduction. Early and effective inhibition of angiogenesis by limiting downstream VEGF signaling or targeting multiple angiogenic pathways may block angiogenesis, thereby reducing disease severity and provide evidence toward the mechanism and clinical benefit of antiangiogenics in the setting of IBD.
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http://dx.doi.org/10.1016/j.jss.2013.04.026DOI Listing
September 2013

VEGF blockade enables oncolytic cancer virotherapy in part by modulating intratumoral myeloid cells.

Mol Ther 2013 May 12;21(5):1014-23. Epub 2013 Mar 12.

Divison of Oncology, Department of Pediatrics, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA.

Understanding the host response to oncolytic viruses is important to maximize their antitumor efficacy. Despite robust cytotoxicity and high virus production of an oncolytic herpes simplex virus (oHSV) in cultured human sarcoma cells, intratumoral (ITu) virus injection resulted in only mild antitumor effects in some xenograft models, prompting us to characterize the host inflammatory response. Virotherapy induced an acute neutrophilic infiltrate, a relative decrease of ITu macrophages, and a myeloid cell-dependent upregulation of host-derived vascular endothelial growth factor (VEGF). Anti-VEGF antibodies, bevacizumab and r84, the latter of which binds VEGF and selectively inhibits binding to VEGF receptor-2 (VEGFR2) but not VEGFR1, enhanced the antitumor effects of virotherapy, in part due to decreased angiogenesis but not increased virus production. Neither antibody affected neutrophilic infiltration but both partially mitigated virus-induced depletion of macrophages. Enhancement of virotherapy-mediated antitumor effects by anti-VEGF antibodies could largely be recapitulated by systemic depletion of CD11b(+) cells. These data suggest the combined effect of oHSV virotherapy and anti-VEGF antibodies is in part due to modulation of a host inflammatory reaction to virus. Our data provide strong preclinical support for combined oHSV and anti-VEGF antibody therapy and suggest that understanding and counteracting the innate host response may help enable the full antitumor potential of oncolytic virotherapy.
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http://dx.doi.org/10.1038/mt.2013.39DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3666636PMC
May 2013

Pretreatment with anti-VEGF therapy may exacerbate inflammation in experimental acute colitis.

J Pediatr Surg 2012 Feb;47(2):347-54

Division of Pediatric General & Thoracic Surgery, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA.

Aim: Our previous investigations of angiogenesis in inflammatory bowel disease showed that vascular endothelial growth factor (VEGF) blockade reduced colonic neovascularization and inflammation. We hypothesized that pretreatment with bevacizumab, a monoclonal anti-VEGF antibody, would attenuate the severity of angiogenesis and inflammation in a murine model of colitis.

Methods: C57BL/6 mice were treated with intraperitoneal injections of bevacizumab (250 μg/dose) before induction of colitis with dextran sulfate sodium (DSS). The colons were examined at predetermined time points. Colonic inflammation and microvessel density were assessed microscopically.

Results: All mice acutely developed melena and weight loss (18.8% ± 1.1% control vs 20.2% ± 1.1% treated, P = .37) and regained a similar weight percentage after the recovery (26.5% ± 4.0% vs 20.9% ± 4.4%, P = .37). Microvessel density acutely increased in both groups in response to DSS, with a trend toward inhibited angiogenesis in the treated group at the conclusion of the acute phase (194,100 ± 14,240 vs 149,400 ± 17,590 μm(2), P = .11). Bevacizumab-treated mice exhibited significantly increased inflammation after the acute phase (8.3 ± 0.8 vs 13.0 ± 2.0, P = .05), but were similar to control after the recovery (7.3 ± 1.5 vs 5.5 ± 1.0, P = .27).

Conclusions: Preemptive VEGF inhibition does not significantly attenuate angiogenesis and, in fact, worsens inflammation in a model of acute colitis. Preventive VEGF blockade may disrupt healing and exacerbate injury via alternative angiogenic or inflammatory pathways.
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http://dx.doi.org/10.1016/j.jpedsurg.2011.11.028DOI Listing
February 2012

Pediatric hernia repair: 1-stop shopping.

J Pediatr Surg 2012 Jan;47(1):213-6

Division of Pediatric General and Thoracic Surgery, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229-3039, USA.

Purpose: Multiple visits for the evaluation, treatment, and follow-up of straightforward surgical problems are inconvenient, can result in lost work for the parents, and missed school for the child. We hypothesized that with proper previsit screening, patients with select diagnoses can be evaluated in an outpatient clinic setting and undergo operation the same day.

Methods: Criteria were developed to identify straightforward referrals to our surgical practice for umbilical, epigastric, or inguinal hernias. Scripting was created to offer families the option of consultation and, if indicated, surgical treatment on the same day. Data collected included number of patients, cases performed, insurance status, and consultation reimbursement and surgical fees. Families were surveyed postoperatively.

Results: Sixty-one patient candidates participated. The diagnosis and indication for surgery were confirmed in 56 (92%), of which 50 underwent repair the day of their consultation. Seventy-two percent of patients had commercial insurance, whereas 28% had Medicaid. The preoperative consultation fee was reimbursed in 39 (78%) of 50 encounters (57% Medicaid, 86% commercial). All surgical cases were reimbursed. Patient and family satisfaction was high.

Conclusions: We conclude that it is feasible to provide same-day evaluation and service for straightforward pediatric hernias with acceptable financial reimbursement and high parent satisfaction.
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http://dx.doi.org/10.1016/j.jpedsurg.2011.10.047DOI Listing
January 2012

The utility of routine pouchogram before ileostomy reversal in children and adolescents following ileal pouch anal anastomosis.

J Pediatr Surg 2011 Jun;46(6):1222-5

Division of Pediatric Surgery, Department of Surgery, Colorectal Center for Children, Cincinnati Children's Hospital Medical Center, University of Cincinnati, Cincinnati, OH 45229, USA.

Introduction: Pouchograms are used to assess the integrity of the ileal pouch anal anastomosis (IPAA) in patients who have undergone restorative proctocolectomy. Its benefits have been questioned, and there are no data to support the routine use in children.

Methods: We retrospectively reviewed the charts of 26 patients who had an IPAA and pouchogram at our institution between 2001 and 2009. Each patient also underwent an examination under anesthesia to assess the integrity of the IPAA on the day of the ileostomy closure.

Results: The mean age of the patients was 13.8 (± 0.7) years. The pouchogram was performed at a median of 6 weeks after the IPAA (range, 4-20 weeks). The findings were normal in 26 (89.7%) and demonstrated stricture in 2 (6.9%) and leak in 1 (3.4%). History was suggestive and physical examination was confirmatory in these 3 problematic cases.

Conclusions: A contrast enema is not routinely required to evaluate the integrity of the IPAA before ileostomy reversal in pediatric patients. Complications can be detected by history and rectal examination before ileostomy closure. We recommend the use of contrast enema only in symptomatic patients where a leak is suspected, thereby limiting radiation exposure and inconvenience.
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http://dx.doi.org/10.1016/j.jpedsurg.2011.03.055DOI Listing
June 2011

Late gestation fetal magnetic resonance imaging-derived total lung volume predicts postnatal survival and need for extracorporeal membrane oxygenation support in isolated congenital diaphragmatic hernia.

J Pediatr Surg 2011 Jun;46(6):1165-71

The CDH Team, Division of Pediatric General, Thoracic and Fetal Surgery, Cincinnati Children's Hospital, Cincinnati, OH 45229-3039, USA.

Purpose: Magnetic resonance imaging (MRI) has been used as an imaging modality to assess pulmonary hypoplasia in congenital diaphragmatic hernias (CDHs). The objective of this study was to determine if there is a correlation between late gestational fetal MRI-derived total lung volumes (TLVs) and CDH outcomes.

Methods: From 2006 to 2009, 44 patients met criteria of an isolated CDH with a late gestational MRI evaluation. The prenatal TLV (in milliliters) was obtained between 32 and 34 weeks gestation. The measured study outcomes included survival, need for extracorporeal membrane oxygenation (ECMO), and length of stay.

Results: There were 39 left and 5 right CDH patients. The average TLV was significantly lower for nonsurvivors (P = .01), and there was a significant association between lower TLV and the need for ECMO (P = .0001). When stratified by TLV, patients with a TLV of greater than 40 mL had a 90% survival vs 35% survival for a TLV of less than 20 mL. Furthermore, patients with a TLV greater than 40 mL had a lower rate of ECMO use (10%) than patients with a TLV of less than 20 mL (86%). Shorter length of stay was found to correlate with increasing TLV (P = .022).

Conclusion: Late gestation fetal MRI-derived TLV significantly correlates with postnatal survival and need for ECMO. Fetal MRI may be useful for the evaluation of patients who present late in gestation with a CDH.
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http://dx.doi.org/10.1016/j.jpedsurg.2011.03.046DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3870885PMC
June 2011

EGFR inhibition fails to suppress vascular proliferation and tumor growth in a Ewing's sarcoma model.

J Surg Res 2012 Mar 17;173(1):1-9. Epub 2011 May 17.

Department of Pediatric General and Thoracic Surgery, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio 45229-3039, USA.

Background: Expression of epidermal growth factor receptor (EGFR), a potent regulator of cellular homeostasis, is associated with aggressive tumor behavior. The mechanism by which EGFR inhibition functions is unclear, with controversial results demonstrating an effect on the tumor cells, endothelial cells, or pericytes. EGFR activation has been linked to the expression of vascular endothelial growth factor (VEGF), a known mitogen of angiogenesis, but the relationship between these factors and their effect on tumor vessel development is vague. We hypothesized that using an EGFR inhibitor on a human Ewing's sarcoma model would inhibit tumor growth by suppressing vessel proliferation.

Methods: A cell proliferation assay was performed on the Ewing's sarcoma (SK-NEP-1) cell line. Tumor cells were implanted intrarenally in athymic mice. Animals received daily gavage with vehicle or gefitinib 1 wk following implantation. Mice (n = 12/cohort) were euthanized 6 wk following implantation. Remaining mice were maintained without treatment for 2 wk. Vascular changes were assessed by angiography and immunohistochemically. EGFR and vascular endothelial growth factor (VEGF) expression were quantified using quantitative polymerase chain reaction (qPCR).

Results: Gefitinib suppressed in vitro cell growth with an IC(50) = 1.36 μM. Minimal tumor growth suppression was noted at 6 wk (6.01 ± 1.2 g in control versus 4.61 ± 0.9 g treated, P = 0.36). After cessation of gefitinib, tumor growth was increased in both groups (7.37 ± 1.62 g versus 6.77 ± 1.53 g, P = 0.79). Microvessel density was unchanged despite EGFR inhibition (161,000 ± 16,000 pixels versus 135,000 ± 18,000 pixels, P = 0.31). At 6 wk, the vascular maturity index was similar in both groups (3.63 ± 1.12 versus 4.09 ± 1.71, P = 0.83). A downward trend in EGFR expression (49% of control) and an upward trend in VEGF levels (50% of control) occurred in the treated group.

Conclusions: EGFR expression was suppressed in cultured cells and xenograft tumors. Despite a cytotoxic effect on cell lines, gefitinib had little effect on tumor growth. No effects on the tumor vasculature were noted in the setting of EGFR suppression, suggesting that angiogenesis induced by SK-NEP-1 cells is refractory to EGFR inhibition. Interestingly, the resulting increase in VEGF expression following EGFR blockade, provides an alternative pro-angiogenic pathway promoting tumor survival.
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http://dx.doi.org/10.1016/j.jss.2011.04.041DOI Listing
March 2012

Cancer screening by systemic administration of a gene delivery vector encoding tumor-selective secretable biomarker expression.

PLoS One 2011 May 11;6(5):e19530. Epub 2011 May 11.

Division of Oncology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, United States of America.

Cancer biomarkers facilitate screening and early detection but are known for only a few cancer types. We demonstrated the principle of inducing tumors to secrete a serum biomarker using a systemically administered gene delivery vector that targets tumors for selective expression of an engineered cassette. We exploited tumor-selective replication of a conditionally replicative Herpes simplex virus (HSV) combined with a replication-dependent late viral promoter to achieve tumor-selective biomarker expression as an example gene delivery vector. Virus replication, cytotoxicity and biomarker production were low in quiescent normal human foreskin keratinocytes and high in cancer cells in vitro. Following intravenous injection of virus >90% of tumor-bearing mice exhibited higher levels of biomarker than non-tumor-bearing mice and upon necropsy, we detected virus exclusively in tumors. Our strategy of forcing tumors to secrete a serum biomarker could be useful for cancer screening in high-risk patients, and possibly for monitoring response to therapy. In addition, because oncolytic vectors for tumor specific gene delivery are cytotoxic, they may supplement our screening strategy as a "theragnostic" agent. The cancer screening approach presented in this work introduces a paradigm shift in the utility of gene delivery which we foresee being improved by alternative vectors targeting gene delivery and expression to tumors. Refining this approach will usher a new era for clinical cancer screening that may be implemented in the developed and undeveloped world.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0019530PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3092745PMC
May 2011

Submucosal gland development in the human fetal trachea xenograft model: implications for fetal gene therapy.

J Pediatr Surg 2011 Jan;46(1):33-8

The Center for Molecular Fetal Therapy, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA.

Background/purpose: Our previous work in a human-fetal trachea xenograft model suggests potential benefits of treating cystic fibrosis in utero. The target for postnatal gene therapy in cystic fibrosis is tracheal submucosal glands (SMGs). The aim of this study was to determine if SMG development in our model recapitulates normal trachea development and its validity for studying fetal gene transfer.

Methods: Fetal tracheas were divided into developmental phases: early, mid, and late. Fetal tracheas were xenografted onto immunocompromised mice and analyzed for SMG developmental staging and mucopolysaccharide production.

Results: There were no significant differences in gland number, size, or density from early through late phase between groups. Xenografted tracheas demonstrated a similar progression through the stages of SMG development as controls after an initial phase shift. Control and xenografted tracheas demonstrated characteristic patterns of acidic mucin production at the base of the SMGs.

Conclusions: Fetal trachea xenograft SMG recapitulates normal development and is a valid model for studying human fetal gene transfer. The accessibility of SMG stem cells in early tracheal development may afford a unique window of opportunity for gene transfer. This model has the benefit of providing access to human fetal tracheas in vivo and permits the study of novel fetal gene therapy strategies.
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http://dx.doi.org/10.1016/j.jpedsurg.2010.09.064DOI Listing
January 2011

Decompressive abdominal laparotomy for abdominal compartment syndrome in an unengrafted bone marrow recipient with septic shock.

Crit Care Res Pract 2010 23;2010. Epub 2010 Jun 23.

Division of Critical Care Medicine, Department of Pediatrics, Cincinnati Children's Hospital Medical Center, 3333 Burnet Avenue MLC 2005, Cincinnati, OH 45229, USA.

Objective. To describe a profoundly immunocompromised (panleukopenia) child with septic shock who developed abdominal compartment syndrome (ACS) and was successfully treated with surgical decompression. Design. Individual case report. Setting. Pediatric intensive care unit of a tertiary children's hospital. Patient. A 32-month-old male with Fanconi anemia who underwent bone marrow transplantation (BMT) 5 days prior to developing septic shock secondary to Streptococcus viridans and Escherichia coli ACS developed after massive fluid resuscitation, leading to cardiopulmonary instability. Interventions. Emergent surgical bedside laparotomy and silo placement. Measurements and Main Results. The patient's cardiopulmonary status stabilized after decompressive laparotomy. The abdomen was closed and the patient survived to hospital discharge without cardiac, respiratory, or renal dysfunction. Conclusions. The use of laparotomy and silo placement in an unengrafted BMT patient with ACS and septic shock did not result in additional complications. Surgical intervention for ACS is a reasonable option for high risk, profoundly immunocompromised patients.
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http://dx.doi.org/10.1155/2010/102910DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2951079PMC
July 2011

The transanal approach with laparoscopy or laparotomy for the treatment of rectal strictures in Crohn's disease.

J Laparoendosc Adv Surg Tech A 2010 Nov 27;20(9):791-5. Epub 2010 Sep 27.

Colorectal Center for Children, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio 45229, USA.

Introduction: Rectal strictures in patients with Crohn's colitis are common and options described for their treatment include direct steroid injection, injection of tumor necrosis factor (TNF) inhibitors, endoscopic balloon dilatation, use of Hegar dilators, stricturoplasty, and proctectomy. Adequate treatment is a challenge, especially with respect to the prevention of stricture recurrence. We present an option for the surgical treatment of these strictures using a transanal resection of the rectum with the addition of laparoscopy or laparotomy.

Methods: Three patients who had medically refractory or chronic Crohn's colitis with rectal strictures were referred to us after failed medical management, rectal dilation, and balloon dilation of the strictures. In each case, we performed a transanal sphincter preserving dissection in the prone position and used the lithotomy position for intraabdominal mobilization, completion of the rectosigmoid resection, pull-through of the left colon, and coloanal anastomosis.

Results: We resected the rectal strictures transanally in all three cases. One case provided the opportunity to perform a laparoscopy-assisted procedure, whereas the other 2 patients had laparotomy-assisted rectosigmoid resections. We did a coloanal anastomosis in 2 patients with healthy left colon. In the third case, the anal canal was preserved, but the patient was left with a stoma.

Conclusions: Transanal resection is feasible in the surgical treatment of rectal strictures in patients with Crohn's colitis. It preserves the anal sphincteric mechanism and may help in avoiding a permanent stoma in a subgroup of patients. We found the prone position very helpful in performing the transanal rectal dissection.
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http://dx.doi.org/10.1089/lap.2009.0470DOI Listing
November 2010

Crohn's disease limited to the appendix: a case report in a pediatric patient.

Pediatr Surg Int 2010 Nov;26(11):1125-8

Department of Pediatric General and Thoracic Surgery, Colorectal Center for Children, Cincinnati Children's Hospital Medical Center, College of Medicine, University of Cincinnati, 3333 Burnet Avenue, MLC-2023, Cincinnati, OH 45229, USA.

In the original description of Crohn's disease, the appendix was not believed to be involved in the inflammatory process. Later on, case reports started to appear in publications demonstrating that the appendix could be involved in the inflammatory changes of Crohn's disease, and it could also be the primary or the sole manifestation of the disease. Being that appendectomies are one of the most common procedures performed by pediatric surgeons, the knowledge about this diagnosis, all be it rare, is important. Our aim was to report a case and discuss the results of our literature review in order to elucidate the probability of a pediatric patient subsequently developing full Crohn's disease and the follow up that is indicated in such patients. A 12-year-old male patient presented with a history of chronic abdominal pain (3-4 times per week) for 1 year, crampy in nature, localized in the left lower quadrant, and associated with diarrhea (2 episodes per day). There were no extraintestinal manifestations of Crohn's, such as arthralgia or uveitis. Important family history included two paternal uncles with ulcerative colitis both of whom currently have stomas. The only abnormal laboratory value in our patient was an elevated fecal calprotectin level. An esophagogastroduodenoscopy and colonoscopy were performed and found to be unremarkable except for the cecum where it appeared that an exudate was emanating from the appendiceal orifice. A magnetic resonance enterography was ordered and showed an enlarged enhancing appendix. An exploratory laparoscopy identified an appendix with macroscopic cobblestone or lymphoid reaction that histologically was consistent with Crohn's disease. It appears that the Crohn's appendix is more indolent than Crohn's disease of the ileum or colon, with a recurrence rate in the largest series of 8%. The interval time from diagnosis to recurrence varied from 1 to 48 months with an average of 19 months. Some authors debate the need of follow up at all in those patients, believing that the appendectomy alone is curative in the majority of patients. Others recommend follow up for up to 5 years.
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http://dx.doi.org/10.1007/s00383-010-2689-zDOI Listing
November 2010

Gastric tube-pericardial fistula: a remote complication of esophageal replacement for long gap esophageal atresia.

J Pediatr Surg 2009 Jul;44(7):1440-2

Division of Pediatric Surgery, Morgan Stanley Children's Hospital of New York Presbyterian, Columbia University Medical Center, New York, NY 10032, USA.

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.
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http://dx.doi.org/10.1016/j.jpedsurg.2009.02.010DOI Listing
July 2009