X-ray micro-computed-tomography in pediatric surgery: a new tool for studying embryos.

PURPOSE: The embryology of common congenital malformations is discussed controversially. Studies are hampered by a shortage of study material and techniques which require partial or complete preparation and therewith destruction of embryos. X-ray micro-computed-tomography (µCT) is a technical opportunity keeping the embryos intact. Thus, the aim of this study was to assess the applicability of µCT in embryonic research compared to the anatomical information obtained by scanning electron microscopy (SEM). METHODS: Chicken, rat, mouse and sheep embryos, processed either for SEM studies or as whole embryos, were imaged in three-dimensional (3D) using µCT. The obtained two-dimensional (2D) digital datasets were volume rendered by tomographic reconstruction software and studied using analysis software. RESULTS: All embryos were µCT scanned without technical problems. The quality of the µCT images (image contrast, anatomical details) was excellent, but varied depending on age and species studied. µCT imaging allowed a more comprehensive anatomical/morphological analysis but showed less surface details compared to SEM. CONCLUSION: µCT is a technique suitable and innovative for pediatric surgical research, which allows detailed evaluation of entire embryos without time- and specimen-consuming micro-dissection. Samples prepared for SEM can be used for µCT and vice versa.

Appendectomy in the pediatric population-a German nationwide cohort analysis.

BACKGROUND: Meta-analyses indicate advantages of laparoscopic compared to open appendectomy. Nationwide analyses on results of laparoscopic appendectomy are scarce and studies from Germany are not available. This observational cohort study based on a nationwide insurance database was performed to analyze results of pediatric laparoscopic versus open appendectomy in general use. METHODS: Data were extracted from the largest German statutory health insurance TK (∼9 million clients) in a 3-year period (2010-2012). All patients aged 4-17 years with International Classification of Procedures in Medicine (ICPM) code "appendectomy" were included. Logistic regression analysis for the risk of a surgical complication within 180 postoperative days was performed. RESULTS: Appendectomy was performed in 8110 patients (52.6 % male; 47.4 % female) and conducted laparoscopically in 75.0 % of the patients (conversion rate = 1.2 %). Laparoscopic compared to open surgery was associated with a shorter length of hospital stay in both uncomplicated and complicated appendicitis. Patients with complicated appendicitis had lower readmission rates for surgical complications after laparoscopic appendectomy and logistic regression analysis confirmed a significantly lower risk of readmission for surgical complications after laparoscopic compared to open operation in adolescents. Pediatric surgeons operated 23.9 % and general surgeons 76.1 % of patients. Laparoscopy was less frequently used and the conversion rate was significantly higher in pediatric surgical departments. CONCLUSION: This first nationwide German cohort study confirms that laparoscopic appendectomy is associated with a less complicated postoperative course compared to open appendectomy, particularly in patients with complicated appendicitis. Pediatric surgeons used laparoscopy less frequently compared to general surgeons. Laparoscopic appendectomy should therefore be further promoted in pediatric surgical centers in Germany.

Early complications after esophageal atresia repair: analysis of a German health insurance database covering a population of 8 million.

The treatment of esophageal atresia is not centralized in Germany. Therefore, high numbers of departments are involved. Data on the results of esophageal atresia repair from Germany are lacking. The aim of this study was to evaluate the early postoperative results after repair of esophageal atresia based on unbiased data of a German health insurance. We aimed to determine whether characteristics of the departments had an impact on outcome and compared the results from this study with the literature data from centers with a high caseload. Data of a German health insurance covering ∼10% of the population were analyzed. All patients who had undergone esophageal atresia repair from January 2007 to August 2012 were included. Follow-up data of 1 year postoperatively were analyzed. The potential impact of various characteristics of the treating surgical institutions was assessed. Results were compared with the latest international literature. Seventy-five patients with esophageal atresia underwent reconstructive surgery in 37 departments. The incidences of anastomotic leak (3%) and recurrent tracheoesophageal fistula (7%) were comparable with the literature (both 2-8%). Anastomotic stricture required dilatation in 57% of patients (mean 5.1 ± 5.6 dilatations) comparing unfavorably to most, but not all international reports. During 1-year follow-up, 93% of the patients were readmitted at least once (mean 3.9 ± 3.1 admissions). The incidence of complications did not correlate with any of the characteristics of the treating institutions such as academic affiliation, the number of consultants, beds, and preterm infants treated per year (all P > 0.05). Based on unbiased data, postoperative results after repair of esophageal atresia in Germany are comparable with recently published reports from international single centers. A correlation between the complication rate and characteristics of the treating institutions was not identified.

Comparison of environmental risk factors for esophageal atresia, anorectal malformations, and the combined phenotype in 263 German families.

Esophageal atresia with or without tracheoesophageal fistula (EA/TEF) and anorectal malformations (ARM) represent the severe ends of the fore- and hindgut malformation spectra. Previous research suggests that environmental factors are implicated in their etiology. These risk factors might indicate the influence of specific etiological mechanisms on distinct developmental processes (e.g. fore- vs. hindgut malformation). The present study compared environmental factors in patients with isolated EA/TEF, isolated ARM, and the combined phenotype during the periconceptional period and the first trimester of pregnancy in order to investigate the hypothesis that fore- and hindgut malformations involve differing environmental factors. Patients with isolated EA/TEF (n = 98), isolated ARM (n = 123), and the combined phenotype (n = 42) were included. Families were recruited within the context of two German multicenter studies of the genetic and environmental causes of EA/TEF (great consortium) and ARM (CURE-Net). Exposures of interest were ascertained using an epidemiological questionnaire. Chi-square, Fisher's exact, and Mann-Whitney U-tests were used to assess differences between the three phenotypes. Newborns with isolated EA/TEF and the combined phenotype had significantly lower birth weights than newborns with isolated ARM (P = 0.001 and P < 0.0001, respectively). Mothers of isolated EA/TEF consumed more alcohol periconceptional (80%) than mothers of isolated ARM or the combined phenotype (each 67%). Parental smoking (P = 0.003) and artificial reproductive techniques (P = 0.03) were associated with isolated ARM. Unexpectedly, maternal periconceptional multivitamin supplementation was most frequent among patients with the most severe form of disorder, i.e. the combined phenotype (19%). Significant differences in birth weight were apparent between the three phenotype groups. This might be attributable to the limited ability of EA/TEF fetuses to swallow amniotic fluid, thus depriving them of its nutritive properties. Furthermore, the present data suggest that fore- and hindgut malformations involve differing environmental factors. Maternal periconceptional multivitamin supplementation was highest among patients with the combined phenotype. This latter finding is contrary to expectation, and warrants further analysis in large prospective epidemiological studies.

Duhamel versus transanal endorectal pull through (TERPT) for the surgical treatment of Hirschsprung's disease.

For the surgical treatment of Hirschsprung's disease, several surgical techniques are used to resect the distal aganglionic colon. Two frequently used techniques are the Duhamel procedure and the transanal endorectal pull-through procedure. During the '8th Pediatric Colorectal Course' in Nijmegen, November 2015, a workshop was organized to share experiences of both techniques by several experts in the field and to discuss (long term) outcomes. Specifically, the objective of the meeting was to discuss the main controversies in relation to the technical execution of both procedures in order to make an initial assessment of the limitations of available evidence for clinical decision-making and to formulate a set of preliminary recommendations for current clinical care and future research.

European consensus meeting of ARM-Net members concerning diagnosis and early management of newborns with anorectal malformations.

The ARM-Net (anorectal malformation network) consortium held a consensus meeting in which the classification of ARM and preoperative workup were evaluated with the aim of improving monitoring of treatment and outcome. The Krickenbeck classification of ARM and preoperative workup suggested by Levitt and Peña, used as a template, were discussed, and a collaborative consensus was achieved. The Krickenbeck classification is appropriate in describing ARM for clinical use. The preoperative workup was slightly modified. In males with a visible fistula, no cross-table lateral X-ray is needed and an anoplasty or (mini-) posterior sagittal anorectoplasty can directly be performed. In females with a small vestibular fistula (Hegar size <5 mm), a primary repair or colostomy is recommended; the repair may be delayed if the fistula admits a Hegar size >5 mm, and in the meantime, gentle painless dilatations can be performed. In both male and female perineal fistula and either a low birth weight (<2,000 g) or severe associated congenital anomalies, prolonged preoperative painless dilatations might be indicated to decrease perioperative morbidity caused by general anesthesia. The Krickenbeck classification is appropriate in describing ARM for clinical use. Some minor modifications to the preoperative workup by Levitt and Peña have been introduced in order to refine terminology and establish a comprehensive preoperative workup.

Towards the perfect ARM center: the European Union's criteria for centers of expertise and their implementation in the member states. A report from the ARM-Net.

BACKGROUND: Pediatric surgeons and patient organisations agree that fewer centers for anorectal malformations with larger patient numbers are essential to reach better treatment. The European Union transacts a political process which aims to realize such centers of expertise for a multitude of rare diseases. All the centers on a specific rare disease should constitute an ERN on that disease. ARM-Net members in different countries report on first experiences with the implementation of national directives, identifying opportunities and risks of this process. METHODS: Relevant details from the official European legislation were analyzed. A survey among the pediatric surgeons of the multidisciplinary ARM-Net consortium about national implementation was conducted. RESULTS: European legislation calls for multidisciplinary centers treating children with rare diseases, and proposes a multitude of quality criteria. The member states are called to allocate sufficient funding and to execute robust governance and oversight, applying clear methods for evaluation. Participation of the patient organisations is mandatory. The national implementations all over Europe differ a lot in respect of extent and timeframe. CONCLUSIONS: Establishing Centers of Expertise and a ERN for anorectal malformations offers great opportunities for patient care and research. Pediatric surgeons should be actively engaged in this process.

Video of the Month: Pulsating Umbilicus in a Neonate with Left Ventricular Diverticulum.

Left ventricular diverticulum (LVD) is a rare malformation presenting in 0.05% of all congenital cardiac anomalies. It is associated with additional cardiac and extracardiac malformations. We report on a female neonate with prenatally diagnosed heterotaxia and dextrocardia who was born with a pulsating supraumbilical mass. Echocardiography revealed a diverticulum originating from the left ventricle, which was connected to the umbilicus. Magnetic resonance imaging confirmed an LVD without evidence of a diaphragmatic hernia on the day of life 9. The child underwent laparotomy/lower sternotomy, and the diverticulum and epigastric hernia were closed. The postoperative course was uneventful, and the girl was discharged on the 10th postoperative day. In a neonate with a pulsatile supraumbilical mass, the diagnosis of a congenital LVD should be taken into consideration. The treatment is straightforward and was successful in this single case.

Blood group AB increases risk for surgical necrotizing enterocolitis and focal intestinal perforation in preterm infants with very low birth weight.

Necrotizing enterocolitis (NEC) and focal intestinal perforation (FIP) are two of the most common emergencies of the gastrointestinal tract in preterm infants with very low birth weight (VLBW, birth weight < 1500 g). Identification of risk factors among these children is crucial for earlier diagnosis and prompt intervention. In this study, we investigated a relationship between ABO blood groups and the risk for surgical NEC/FIP. We genotyped the ABO locus (rs8176746 and rs8176719) in VLBW infants enrolled in a prospective, population-based cohort study of the German Neonatal Network (GNN). Of the 10,257 VLBW infants, 441 (4.3%) had surgical NEC/FIP. In univariate analyses, the blood group AB was more prevalent in VLBW infants with surgical NEC/FIP compared to non-AB blood groups (OR 1.51, 95% CI 1.07-2.13, p = 0.017; absolute risk difference 2.01%, 95% CI 0.06-3.96%). The association between blood group AB and surgical NEC/FIP was observed in a multivariable logistic regression model (OR of 1.58, 95% CI 1.10-2.26, p = 0.013) as well. In summary, our study suggests that the risk of surgical NEC and FIP is higher in patients with blood group AB and lower in those having non-AB blood groups.

Association of the interleukin-23 receptor gene variant rs11209026 with Crohn's disease in German children.

AIM: Genome-wide association studies have described variants within the interleukin-23 receptor (IL23R) locus to be associated with Crohn's disease (CD) and ulcerative colitis (UC). We investigated the association of rs11209026 (p.Arg381Gln) and rs7517847 (c.799-3588T>G) into German paediatric inflammatory bowel disease (IBD) patients and analysed IL23R transcriptional activity in colonic tissues. METHODS: The rs11209026 and rs7517847 nucleotide substitutions were determined in 353 German children with IBD (221 CD, 132 UC) and 253 controls using pre-designed TaqMan((R)) SNP genotyping assays. In selected IBD patients and controls, IL23R mRNA expression was measured using real-time PCR. RESULTS: The prevalence of the rs11209026 A allele was lower in CD patients, but not in UC patients, when compared with controls (1.8% vs 7.1%, p < 0.01). The rs7517847 variant, in contrast, was associated neither with CD nor with UC. IL23R expression was variable in IBD patients compared with controls without significant overexpression or downregulation. CONCLUSION: Our study provides additional support for the strong protection of the rs11209026 (p.Arg381Gln) variant against paediatric CD. IL23R was expressed in both CD and UC with a great variability. However, expression levels showed no significant association with the disease.

Early and long term outcome in children with esophageal atresia treated over the last 22 years.

BACKGROUND: The survival of infants born with esophageal atresia (EA) is > 90% at present. The purpose of this study was to evaluate early complications and long term outcome in children with EA treated at our institution. METHODS AND PATIENTS: Retrospective analysis of 111 children with EA undergoing repair of EA or tracheoesophageal fistula (TEF). Assessment of early and intermediate complications as well as long term morbidity and mortality. RESULTS: Primary anastomosis was performed in 90 (81%) and secondary anastomosis in 7 patients (6%). Gastric transposition was carried out in 14 children (13%). The postoperative mortality was 14/111 (12.6%) and could be estimated by the Spitz classification. At the age of 10 years, 33 patients (72%) were swallowing without problems, 39 children (85%) were eating at least most of the time with pleasure but 19 children (41%) had a body weight less than the 25 (th) percentile. Staged repair by gastric transposition resulted in the least amount of motility dysfunction. Long-term respiratory morbidity was high. CONCLUSION: The survival of children with EA has improved in the last two decades. For risk assessment the Spitz' classification is valid. Long term gastrointestinal and respiratory morbidity remains high. In children with long-gap EA gastric transposition performed as a staged procedure has satisfactory results and seems superior to techniques preserving the native esophagus.

Surgery for Pediatric Ureteropelvic Junction Obstruction-Comparison of Outcomes in Relation to Surgical Technique and Operating Discipline in Germany.

INTRODUCTION: Surgery for ureteropelvic junction obstruction (UPJO) is performed by both pediatric surgeons (PS) and urologists (URO). The aim of this study was to analyze treatment modalities for UPJO and results in relation to the surgical technique and the operating discipline in Germany. MATERIALS AND METHODS: Data of patients aged 0 to 18 years were extracted from a major public health insurance (covering ∼5.7 million clients) during 2009 to 2016 and were analyzed for sociodemographic variables, surgical technique, and treating discipline. Logistic regression analysis was performed for the risk of a complication within the first postoperative year. RESULTS: A total of 229 children (31.0% female) were included. Laparoscopic pyeloplasty (LP) was performed in 58 (25.3%) patients (8.6 ± 6.4 years), and open pyeloplasty (OP) was applied in 171 (74.7%; 4.6 ± 5.9 years). LP was the dominant technique in females (p < 0.02); males preferentially underwent OP (p < 0.02). Length of hospital stay was 4.3 days (p = 0.0005) shorter in LP compared with that in OP, especially in children ≤ 2 years (6.7 days, p = 0.007). PS operated on 162 children (70.7%), and URO performed surgery on 67 patients (29.3%). The mean age of children operated by PS (3.5 ± 4.7 years) was significantly younger compared with that operated by URO (10.8 ± 6.5 years, p < 0.0001). Complication rates were independent of surgical technique or treating specialty. CONCLUSION: In Germany, UPJO was treated by LP in 25.3% of patients, which was associated with a shorter length of stay, especially in children ≤ 2 years. Complication rates were independent of the operating specialty and surgical technique. Therefore, LP should be further promoted for the treatment of UPJO in small children.

Fetal urinary bladder rupture and urinary ascites secondary to posterior urethral valves. A case report.

Megacystis is a typical prenatal sonographic finding in cases of lower urinary tract obstruction. Urinary bladder perforation represents a rare complication in this condition. We report on a boy with in utero bladder perforation and urinary ascites secondary to posterior urethral valves. The pre- and postnatal therapy is described and the current literature is reviewed.

Gastric outlet obstruction after long-term prostaglandin administration mimicking hypertrophic pyloric stenosis.

Prostaglandin E1 (PGE1) is widely used in neonates with cyanotic congenital heart disease who depend on the patency of the ductus arteriosus for oxygenation. Side effects of prostaglandin therapy are common and include respiratory depression, generalized flushing, and cardiovascular and neurological effects. Little is known about the complex effects on the gastrointestinal tract. We report on an infant with gastric outlet obstruction after long-term prostaglandin administration. At the age of 1 month, feeding problems developed with projectile vomiting. Ultrasonography showed progressive elongation of the antropyloric channel without wall thickening, which was causing gastric outlet obstruction. Three days after cardiac surgery and cessation of prostaglandin therapy, the infant fed normally and rapidly gained weight. The clinical signs in such patients can mimic hypertrophic pyloric stenosis. Therefore, the sonographic findings should not be confused with pyloric wall thickening to avoid a false diagnosis and unnecessary surgery. The symptoms diminish with cessation of the prostaglandin therapy after a corrective cardiac operation.

Expression of the coxsackievirus- and adenovirus receptor in gastrointestinal cancer correlates with tumor differentiation.

Modified adenoviruses represent a new approach to treatment of gastrointestinal cancer. However, their uptake by cells in many cases requires the major receptor for adenoviruses, the coxsackievirus and adenovirus receptor (CAR). Thus, lack of CAR expression is a potential cause of intrinsic resistance of tumor cells to this type of treatment. To evaluate this, we studied the localization of CAR protein in normal and malignant gastrointestinal tissues. In normal tissues, CAR was concentrated at sites of cell-cell interaction, in particular at the apico-lateral cellular surface. Expression was particularly strong around bile and pancreatic ducts, which is in agreement with CAR's physiological function as a tight-junction protein. In GI malignancies (esophageal, pancreatic, colorectal and liver cancer), expression of the receptor varied substantially. Loss of CAR expression at cell-cell junction was evident in many samples. A significant correlation between CAR expression and histological grade was found, with moderately to poorly differentiated tumors most frequently demonstrating loss or reduction of CAR expression. These data indicate that CAR expression is frequently altered in gastrointestinal malignancy, potentially reducing the efficacy of adenovirus-based therapies.

Patterns of mortality among commercial pressmen.

A proportionate analysis of cause of death in 1,401 commercial pressmen was initiated following a report of a cancer cluster in this group. The study found a significant elevated risk of all cancers [proportionate mortality ratio (PMR) = 127] and cancers of the lymphatic and hematopoietic system (PMR = 122), with non-Hodgkin's lymphomas responsible for much of the excess. Three deaths in the cohort were attributed to myelofibrosis, a rare disease associated with benzene exposure. A significantly elevated PMR was also detected for colorectal cancer (PMR = 171) and, among those employed 20 years or more, for cancers of the liver (PMR = 216) and pancreas (PMR = 162). No excess risk of bladder or lung cancer or leukemia was seen. Proportionate mortality analyses rarely show excess risk of both cancer and heart disease in a working population. Surprisingly, a significantly elevated risk of arteriosclerotic heart disease (PMR = 113) was found in this group. These findings indicate that solvent exposure may be associated with excess mortality risk in commercial pressmen.

Role of DDC-4/sFRP-4, a secreted frizzled-related protein, at the onset of apoptosis in mammary involution.

Using differential display, we isolated DDC-4, a secreted frizzled-related protein (sFRP), which is induced in the physiological apoptosis of hormonally regulated, reproductive tissues such as mammary gland, prostate, corpus luteum and uterus. The role of this gene in apoptosis was studied in animals overexpressing ectopic DDC-4/sFRP-4. Transgenic mice bearing the DDC-4/sFRP-4 cDNA under the control of the MMTV-LTR promoter showed lactational insufficiency and many apoptotic cells in the alveoli between day 19 of pregnancy and day 4 of lactation as demonstrated by TUNEL reaction and the presence of activated caspase-3. We performed a PKB/Akt kinase assay and studied several of its substrates using phosphorylation-specific antibodies to show reduced phosphorylation in PKB/Akt itself, as well as in glycogen synthetase kinase-3beta (GSK-3beta), BAD, and Forkhead. Taken together, our results show a role for DDC-4/sFRP-4 in abrogating an epithelial cell survival pathway at the onset of mammary gland involution.

Semen cryopreservation and artificial insemination for Hodgkin's disease.

Seventy-nine men with Hodgkin's disease were treated with chemotherapy protocols at Memorial Sloan-Kettering Cancer Center and had pretreatment semen analysis performed at the area semen bank. The patients were evaluated to determine: the quality of pretreatment semen, the effect of treatment on spermatogenesis, and the success rate of artificial insemination after semen cryopreservation. Pretreatment sperm concentration, fresh motility, fresh progression, postthaw motility and postthaw progression were all significantly decreased in men with Hodgkin's disease compared with normal controls. Posttreatment semen analysis in 44 men showed azoospermia in 80%, sperm concentration, less than or equal to 10 X 10(6)/mL in 11%, and sperm concentration greater than 10 X 10(6)/mL in 9%. Eleven couples attempted artificial insemination using cryopreserved semen, thus far resulting in three pregnancies. Semen cryopreservation and artificial insemination offer a partial solution to posttreatment azoospermia in this population, but further methods are needed to minimize gonadal toxicity without compromising therapy for Hodgkin's disease.

Bone mineralization in women following successful treatment of Hodgkin's disease.

PURPOSE: Women with Hodgkin's disease in whom a cure has been achieved may be at risk for osteoporosis because of therapy-induced premature menopause. Our objective was to gather information regarding the integrity of bone mass in such long-term cancer survivors. SUBJECTS AND METHODS: Bone mineral density was measured using photon absorptiometry in five groups of women: 11 patients with Hodgkin's disease and ovarian failure (Group I); six patients with Hodgkin's disease and ovarian failure who received estrogen replacement (Group II); 15 patients with Hodgkin's disease and normal ovarian function (Group III); 16 premenopausal control subjects (Group IV); and 11 postmenopausal control subjects (Group V). All patients with Hodgkin's disease were in remission and had completed treatment more than five years earlier. RESULTS: Subjects in Group I were found to have significantly decreased radial (p = 0.0009), lumbar spine (p = 0.002), and femoral neck (p = 0.0001) bone mineral density measurements compared with those in subjects in Group IV; the bone mineral density measurements at all sites of subjects in Group I were no different than those of subjects in Group V. Subjects in Group III had bone density measurements that were similar to those in Group IV, although the radial bone mineral density value was significantly lower (p = 0.0004). Determination of serum gonadotropins and estradiol was consistent with the menstrual status defining the five groups. No secondary causes for decreased bone mineral density values could be detected, since the mean serum levels of parathyroid hormone, calcium, phosphorus, and vitamin D metabolites were similar among the groups, and all prolactin levels were normal. CONCLUSION: We have identified a new population of patients with a high risk of osteoporosis, and these results emphasize the importance of treatment-related ovarian failure in the pathogenesis of osteoporosis.

Exposure of sheet-metal workers to asbestos during the construction and renovation of commercial buildings in New York City. A case study in social medicine.

New York City sheet-metal workers have a history of significant exposure to asbestos. Prior to 1972 when the use of sprayed asbestos insulation was banned in New York City, sheet-metal workers involved in building construction were exposed as they worked adjacent to spraying operations. Subsequent to that date, exposure continued as they renovated these same buildings. In 1982 the Occupational Health Program of Montefiore Medical Center and the Albert Einstein College of Medicine initiated a multidimensional asbestos evaluation and intervention program for the sheet-metal industry and union in New York. The long-term goal of the program was to eliminate asbestos exposure through the safe, systematic removal of asbestos in New York City buildings, most likely a legislated solution. In the short term, we attempted to assess and reduce asbestos exposure in the sheet-metal trade by a series of steps consisting of: mortality and morbidity studies; a medical audit of clinical screening services provided to sheet-metal workers; a comprehensive health education program; development of safe work practices; evaluation of personal protective equipment; and investigation into and support of legislative and regulatory solutions to the problem of asbestos contamination of commercial buildings. This intervention can be seen as a case study in the practice of social medicine.