Congenital small bowel obstruction: Prenatal detection and outcome.

OBJECTIVE: To evaluate and compare the outcome of fetuses and neonates with congenital small bowel obstructions (SBO), evaluate the screening performance of prenatal ultrasound for SBO and identify possible risk factors for adverse outcomes. METHODS: All cases referred to the Amsterdam University Medical Centers between 2007 and 2021 for a prenatal suspected SBO, supplemented by cases of postnatal diagnosis of SBO, were included. The primary outcome was survival after 24 weeks of gestation until the first year of life. RESULTS: 147 cases of SBO were included with a survival rate of 86.2% (119/138) after 24 weeks of gestation until the first year of age. Additional structural or chromosomal anomalies were found to have an increased risk of adverse outcomes. Intrauterine fetal demise occurred in 10/147 (6.8%) cases and 9/147 (6.1%) cases died during postnatal follow-up. The overall positive predictive value of all prenatally diagnosed cases was 91.5%. Surgical correction was performed in 123/128 (96.0%) of the live-born cases. CONCLUSIONS: Congenital SBO has an overall favorable prognosis, but the outcome is negatively impacted by the possible presence of additional structural or chromosomal anomalies. Fetal monitoring in the early third trimester should be considered, since all cases of Intrauterine fetal demise occurred between 30 and 35 weeks of gestation.

Distress and post-traumatic stress in parents of patients with congenital gastrointestinal malformations: a cross-sectional cohort study.

BACKGROUND: Congenital gastrointestinal malformation (CGIM) require neonatal surgical treatment and may lead to disease-specific sequelae, which have a potential psychological impact on parents. The aim of this study is to assess distress and symptoms of post-traumatic stress disorder (PTSD) in parents of patients with CGIM. In this cross-sectional study, seventy-nine parents (47 mothers and 32 fathers) of 53 patients with CGIM completed the Distress Thermometer for Parents (DT-P) and the Self Rating Scale for Posttraumatic Stress Disorders (SRS-PTSD) as part of the multidisciplinary follow-up of their children (aged 5-35 months). Group differences were tested between parents and representative Dutch reference groups with regard to rates of (clinical) distress and PTSD, and severity of overall distress and PTSD, for mothers and fathers separately. Mixed model regression models were used to study factors associated with the risk of (clinical) distress, PTSD and with severity of symptoms of PTSD (intrusion, avoidance and hyperarousal). RESULTS: Prevalence of clinical distress was comparable to reference groups for mothers (46%) and fathers (34%). There was no difference in severity of overall distress between both mothers as well as fathers and reference groups. Prevalence of PTSD was significantly higher in mothers (23%) compared to the reference group (5.3%) (OR = 5.51, p < 0.001), not in fathers (6.3% vs 2.2.%). Symptoms of intrusion were commonly reported by all the parents (75%). Longer total length of child's hospital stay was associated with more severe symptoms of intrusion, avoidance and hyperarousal. Child's length of follow-up was negatively associated with severity of intrusion. CONCLUSIONS: Having a child with CGIM has a huge impact on parents, demonstrated by a higher prevalence of PTSD in mothers, but not fathers, compared to parents in the general population. Monitoring of symptoms of PTSD of parents in follow-up is necessary.

Usefulness of CT scan as part of an institutional protocol for proactive leakage management after low anterior resection for rectal cancer.

PURPOSE: Highly selective fecal diversion after low anterior resection (LAR) for rectal cancer requires a strict postoperative protocol for early detection of anastomotic leakage (AL). The purpose of this study was to evaluate C-reactive protein (CRP)-based CT imaging in diagnosis and subsequent management of AL. METHODS: All patients that underwent a CT scan for suspicion of AL after transanal total mesorectal excision for rectal cancer in a university center (2015-2020) were included. Outcome parameters were diagnostic yield of CT and timing of CT and subsequent intervention. RESULTS: Forty-four out of 125 patients underwent CT (35%) with an overall median interval of 5 h (IQR 3-6) from CRP measurement. The anastomosis was diverted in 7/44 (16%). CT was conclusive or highly suspicious for AL in 23, with confirmed AL in all those patients (yield 52%), and was false-negative in one patient (sensitivity 96%). CT initiated subsequent intervention after median 6 h (IQR 3-25). There was no or minor suspicion of AL on imaging in all 20 patients without definitive diagnosis of AL. After CT imaging on day 2, AL was confirmed in 0/1, and these proportions were 6/6 for day 3, 7/10 for day 4, 2/4 for day 5, and 9/23 beyond day 5. CONCLUSION: In the setting of an institutional policy of highly selective fecal diversion and pro-active leakage management, the yield of selective CT imaging using predefined CRP cut-off values was 52% with a sensitivity of 96%, enabling timely and tailored intervention after a median of 6 h from imaging.

Diagnostic accuracy of calretinin and acetylcholinesterase staining of rectal suction biopsies in Hirschsprung disease examined by unexperienced pathologists.

Rectal suction biopsy (RSB) is a gold standard for diagnosing Hirschsprung disease (HD). Calretinin staining of RSB is increasingly used by experienced pathologists due to non-complex examination and comparable diagnostic accuracy with acetylcholinesterase (AChE). However, the diagnostic accuracy of calretinin examined by unexperienced pathologists remains to be elucidated. Therefore, we aim to compare diagnostic accuracy of calretinin with AChE on RSB for diagnosing HD when examined by unexperienced pathologists. We prospectively analyzed sections from RSB stained with AChE + HE and calretinin. Blinded examination was done by five unexperienced pathologists (pathology residents) and three experienced pathologists (senior pediatric gastro-enterology pathologists) assessing for the presence of HD. Cases for the study included ones proven to be HD on resection specimens and cases without HD. Diagnostic accuracy was determined calculating area under the curve (AUC), sensitivity, specificity, likelihood ratio, and posttest probability. Fleiss' kappa analysis was performed to assess interobserver agreement between reviewers. Eleven of 18 included patients (61%) were diagnosed with HD. Comparing the diagnostic accuracy of unexperienced pathologists, calretinin versus AChE + HE showed sensitivity of 80.0% versus 74.5% and specificity of 100% versus 65.4%, AUC of 0.87 (0.78-0.96) versus 0.59 (0.45-0.72). Unexperienced pathologists showed substantial agreement with calretinin (kappa 0.72 [0.61-0.84]) and fair agreement with AChE + HE (kappa 0.34 [0.23-0.44]). We found calretinin having higher diagnostic accuracy in diagnosing HD compared to AChE + HE when examined by unexperienced pathologists. Therefore, we recommend to use calretinin as the standard technique for staining RSB in diagnosing HD.

Diagnostic accuracy of abdominal ultrasound to detect pathology that needs surgical exploration in children with umbilical discharge.

BACKGROUND: Umbilical discharge is common in children and mostly attributed to infection or granuloma. However, an underlying congenital abnormality warranting surgery might also be present. Ultrasound is the imaging modality of choice to diagnose the presence of a congenital abnormality. The aim of this study is to investigate diagnostic accuracy of the ultrasound to detect pathology requiring surgical excision. METHODS: All patients ≤18 years with umbilical discharge from January 2008 to September 2019 were retrospectively included. Diagnostic accuracy, i.e., sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), positive likelihood ratio (LR+) and negative likelihood ratio (LR-), were calculated. RESULTS: Eighty-one patients were included and 56 were operated. The ultrasound was false positive in 10 patients and false negative in 13 patients. The sensitivity of ultrasound was 71.1% (95% CI 55.7-83.6), specificity 72.2% (54.8-85.8), PPV 76.2% (64.7-84.8), NPV 66.7% (54.8-76.8), LR+ 2.6 (1.5-4.5) and LR- 0.40 (0.2-0.7). CONCLUSIONS: This study shows that the diagnostic accuracy of ultrasound for detecting underlying congenital abnormalities warranting surgery for umbilical discharge in the pediatric population is low, even with experienced pediatric radiologists. Therefore, the role of the ultrasound in the diagnostic workup and value in clinical decision making is limited. TYPE OF STUDY: Study of diagnostic test. LEVEL OF EVIDENCE: III.

IMARI: multi-Interventional program for prevention and early Management of Anastomotic leakage after low anterior resection in Rectal cancer patIents: rationale and study protocol.

BACKGROUND: Anastomotic leakage (AL) is still a common and feared complication after low anterior resection (LAR) for rectal cancer. The multifactorial pathophysiology of AL and lack of standardised treatment options requires a multi-modal approach to improve long-term anastomotic integrity. The objective of the IMARI-trial is to determine whether the one-year anastomotic integrity rate in patients undergoing LAR for rectal cancer can be improved using a multi-interventional program. METHODS: IMARI is a multicentre prospective clinical effectiveness trial, whereby current local practice (control cohort) will be evaluated, and subsequently compared to results after implementation of the multi-interventional program (intervention cohort). Patients undergoing LAR for rectal cancer will be included. The multi-interventional program includes three preventive interventions (mechanical bowel preparation with oral antibiotics, tailored full splenic flexure mobilization and intraoperative fluorescence angiography using indocyanine green) combined with a standardised pathway for early detection and active management of AL. The primary outcome is anastomotic integrity, confirmed by CT-scan at one year postoperatively. Secondary outcomes include incidence of AL, protocol compliance and association with AL, temporary and permanent stoma rate, reintervention rate, quality of life and functional outcome. Microbiome analysis will be conducted to investigate the role of the rectal microbiome in AL. In a Dutch nationwide study, the AL rate was 20%, with anastomotic integrity of 90% after one year. Based on an expected reduction of AL due to the preventive approaches of 50%, and increase of anastomotic integrity by a standardised pathway for early detection and active management of AL, we hypothesised that the anastomotic integrity rate will increase from 90 to 97% at one year. An improvement of 7% in anastomotic integrity at one year was considered clinically relevant. A total number of 488 patients (244 per cohort) are needed to detect this difference, with 80% statistical power. DISCUSSION: The IMARI-trial is designed to evaluate whether a multi-interventional program can improve long-term anastomotic integrity after rectal cancer surgery. The uniqueness of IMARI lies in the multi-modal design that addresses the multifactorial pathophysiology for prevention, and a standardised pathway for early detection and active treatment of AL. TRIAL REGISTRATION: Trialregister.nl ( NL8261 ), January 2020.

New national recommendations for the treatment of pediatric differentiated thyroid carcinoma in the Netherlands.

BACKGROUND: Currently, there are no European recommendations for the management of pediatric thyroid cancer. Other current international guidelines are not completely concordant. In addition, medical regulations differ between, for instance, the US and Europe. We aimed to develop new, easily accessible national recommendations for differentiated thyroid carcinoma (DTC) patients <18 years of age in the Netherlands as a first step toward a harmonized European Recommendation. METHODS: A multidisciplinary working group was formed including pediatric and adult endocrinologists, a pediatric radiologist, a pathologist, endocrine surgeons, pediatric surgeons, pediatric oncologists, nuclear medicine physicians, a clinical geneticist and a patient representative. A systematic literature search was conducted for all existing guidelines and review articles for pediatric DTC from 2000 until February 2019. The Appraisal of Guidelines, Research and Evaluation (AGREE) instrument was used for assessing quality of the articles. All were compared to determine dis- and concordances. The American Thyroid Association (ATA) pediatric guideline 2015 was used as framework to develop specific Dutch recommendations. Discussion points based upon expert opinion and current treatment management of DTC in children in the Netherlands were identified and elaborated. RESULTS: Based on the most recent evidence combined with expert opinion, a 2020 Dutch recommendation for pediatric DTC was written and published as an online interactive decision tree (www.oncoguide.nl). CONCLUSION: Pediatric DTC requires a multidisciplinary approach. The 2020 Dutch Pediatric DTC Recommendation can be used as a starting point for the development of a collaborative European recommendation for treatment of pediatric DTC.

Diagnostic accuracy of serum alpha-fetoprotein levels in diagnosing recurrent sacrococcygeal teratoma: A systematic review.

BACKGROUND: The incidence of children developing recurrent sacrococcygeal teratoma (SCT) is 2-35%. Serum alpha-fetoprotein (AFP) is often used as a tumor marker for (malignant) recurrences of SCT and could potentially be used during routine follow-up after SCT resection. However, the diagnostic accuracy of serum AFP levels during follow-up has not been well established. Therefore, we aimed to systematically review the diagnostic accuracy of serum AFP levels in recurrent SCT. METHODS: We queried Search Premier, COCHRANE Library, EMCARE, EMBASE, PubMed, ScienceDirect and Web of Science databases to identify studies regarding patients with SCT with follow-up using serum AFP levels postoperative. We estimated sensitivity and specificity of serum AFP levels. RESULTS: Fifteen studies (613 patients, 121 recurrences) were included and these mainly described serum AFP levels in patients with recurrent SCT (n = 111); 83 (75%) patients with recurrent SCT had elevated serum AFP levels. A subgroup analysis of articles that measured serum AFP levels in all patients (n = 6, 136 patients, 14 recurrences) showed a sensitivity and specificity of 79% and 95%, respectively. The sensitivity of AFP levels to detect malignant recurrence was 96%. CONCLUSION: Diagnostic accuracy of serum AFP levels to detect recurrent SCT seems promising, though sensitivity could be overestimated since serum AFP levels are mainly described in patients with elevated AFP levels or at recurrent SCT. Furthermore, serum AFP levels could be helpful to detect malignant recurrences. TYPE OF STUDY: Systematic review of level 2-4 studies. LEVEL OF EVIDENCE: Level 2-4 (mostly level 2).

Diagnostic accuracy of urinary intestinal fatty acid binding protein in detecting colorectal anastomotic leakage.

BACKGROUND: Anastomotic leakage (AL) remains a severe complication following colorectal surgery, having a negative impact on both short- and long-term outcomes. Since timely detection could enable early intervention, there is a need for the development of novel and accurate, preferably, non-invasive markers. The aim of this study was to investigate whether urinary intestinal fatty acid binding protein (I-FABP) could serve as such a marker. METHODS: This prospective multicenter cross-sectional phase two diagnostic study was conducted at four centers in the Netherlands between March 2015 and November 2016. Urine samples of 15 patients with confirmed colorectal AL and 19 patients without colorectal AL on postoperative day 3 were included. Urinary I-FABP levels were determined using enzyme-linked immunosorbent assays and adjusted for urinary creatinine to compensate for renal dysfunction. RESULTS: Urinary I-FABP levels were significantly elevated in patients with confirmed AL compared to patients without AL on postoperative day 3 (median: 2.570 ng/ml vs 0.809 ng/ml, p = 0.006). The area under the receiver operating characteristics curve (AUROC) was 0.775, yielding a sensitivity of 80% and specificity of 74% at the optimal cutoff point (> 1.589 ng/ml). This difference remained significant after calculation of I-FABP/creatinine ratios (median: 0.564 ng/µmol vs. 0.158 ng/µmol, p = 0.040), with an AUROC of 0.709, sensitivity of 60% and specificity of 90% at the optimal cutoff point (> 0.469 ng/µmol). CONCLUSIONS: Levels of urinary I-FABP and urinary I-FABP/creatinine were significantly elevated in patients with confirmed AL following colorectal surgery, suggesting their potential as a non-invasive biomarker for colorectal anastomotic leakage.

Diagnostic accuracy of preoperative ultrasonography in predicting contralateral inguinal hernia in children: a systematic review and meta-analysis.

OBJECTIVES: The incidence of children developing metachronous contralateral inguinal hernia (MCIH) is 7-15%. Contralateral groin exploration during unilateral hernia repair can prevent MCIH development and subsequent second surgery and anaesthesia. Preoperative ultrasonography is a less invasive strategy and potentially able to detect contralateral patent processus vaginalis (CPPV) prior to MCIH development. METHODS: We queried MEDLINE, Embase and Cochrane library to identify studies regarding children aged < 18 years diagnosed with unilateral inguinal hernia without clinical signs of contralateral hernia, who underwent preoperative ultrasonography of the contralateral groin. We assessed heterogeneity and used a random-effects model to obtain pooled estimates of sensitivity, specificity and area under the receiver operating characteristic curve (AUC). RESULTS: Fourteen studies (2120 patients) were included, seven (1013 patients) in the meta-analysis. In studies using surgical exploration as reference test (n = 4, 494 patients), pooled sensitivity and specificity were 93% and 88% respectively. In studies using contralateral exploration as reference test following positive and clinical follow-up after negative ultrasonographic test results (n = 3, 519 patients), pooled sensitivity was 86% and specificity 98%. The AUC (0.984) shows high diagnostic accuracy of preoperative ultrasonography for detecting CPPV, although diagnostic ultrasonographic criteria largely differ and large heterogeneity exists. Reported inguinal canal diameters in children with CPPV were 2.70 ± 1.17 mm, 6.8 ± 1.3 mm and 9.0 ± 1.9 mm. CONCLUSION: Diagnostic accuracy of preoperative ultrasonography to detect CPPV seems promising, though may result in an overestimation of MCIH prevalence, since CPPV does not invariably lead to MCIH. Unequivocal ultrasonographic criteria are mandatory for proper diagnosis of CPPV and subsequent prediction of MCIH. KEY POINTS: • Diagnostic accuracy of preoperative ultrasonography for detection of CPPV in children with unilateral inguinal hernia is high. • Preoperative ultrasonographic evaluation of the contralateral groin assumedly results in an overestimation of MCIH prevalence. • Unequivocal ultrasonographic criteria are mandatory for proper diagnosis of CPPV and risk factor identification is needed to predict whether CPPV develops into clinically apparent MCIH.

Functional mucous layer and healing of proximal colonic anastomoses in an experimental model.

BACKGROUND: Anastomotic leakage (AL) is the most dreaded complication after colorectal surgery, causing high morbidity and mortality. Mucus is a first line of defence against external factors in the gastrointestinal tract. In this study, the structural mucus protein Muc2 was depleted in genetically engineered mice and the effect on healing of colonic anastomoses studied in an experimental model. METHODS: Mice of different Muc2 genotypes were used in a proximal colonic AL model. Tissues were scored histologically for inflammation, bacterial translocation was determined by quantitative PCR of bacterial 16S ribosomal DNA, and epithelial cell damage was determined by assessing serum levels of intestinal fatty acid-binding protein. RESULTS: Of 22 Muc2-deficient (Muc2-/- ) mice, 20 developed AL, compared with seven of 22 control animals (P < 0·001). Control mice showed normal healing, whereas Muc2-/- mice had more inflammation with less collagen deposition and neoangiogenesis. A tendency towards higher bacterial translocation was seen in mesenteric lymph nodes and spleen in Muc2-/- mice. Intestinal fatty acid-binding protein levels were significantly higher in Muc2-/- mice compared with controls (P = 0·011). CONCLUSION: A functional mucous layer facilitates the healing of colonic anastomoses. Clinical relevance Colorectal anastomotic leakage remains the most dreaded complication after colorectal surgery. It is known that the aetiology of anastomotic leakage is multifactorial, and a role is suggested for the interaction between intraluminal content and mucosa. In this murine model of proximal colonic anastomotic leakage, the authors investigated the mucous layer at the intestinal mucosa, as the first line of defence, and found that a normal, functioning mucous layer is essential in the healing process of colonic anastomoses. Further research on anastomotic healing should focus on positively influencing the mucous layer to promote better postoperative recovery.

Mannose-binding lectin null alleles are associated with preserved epithelial cell integrity following intestinal ischemia reperfusion in man.

Mannose-binding lectin (MBL) deficiency is associated with reduced intestinal ischemia-reperfusion (IR) damage in rodents. We set out to investigate an association between frequently observed MBL deficiency and IR associated intestinal cell damage in man. Using a newly developed IR model of the human small intestine 29 patients were consecutively included. Part of the jejunum was subjected to 30 min of ischemia and reperfusion. The MBL genotype was assessed by means of quantitative-PCR analysis. Enterocyte loss was explored by measuring plasma intestinal-fatty acid binding protein (I-FABP) levels. Arterial and venous MBL plasma levels were measured to assess MBL consumption, MBL deposition was analyzed by immunofluorescence. Ethical approval and informed consent were obtained. The amount of epithelial cell damage varied significantly between the carriers of different mbl2 genotypes (ANOVA, p=0.02). I-FABP release, representing disintegration of differentiated enterocytes, observed in homozygous wildtype individuals was twice (p=0.03) that measured in heterozygous and ten times (p=0.04) that observed in homozygous variant individuals. No MBL deposition was observed over the course of reperfusion. The data indicate that MBL influences intestinal epithelial cell integrity in an immediate and non-complement dependent manner during ischemia and reperfusion.

Loss of enterocyte mass is accompanied by diminished turnover of enterocytes after myeloablative therapy in haematopoietic stem-cell transplant recipients.

BACKGROUND: Intestinal mucosal barrier injury (MBI), resulting from myeloablative conditioning for haematopoietic stem-cell transplantation (HSCT), is an important cause of morbidity. Despite its frequency, recognition presents a challenge, while the aetiology needs still to be unravelled. The relationship between enterocyte mass and enterocyte loss was explored by examining citrulline serum levels and by assessing circulating intestinal fatty acid-binding protein (I-FABP) and ileal bile acid-binding protein (I-BABP), proteins released by dying mature enterocytes. PATIENTS AND METHODS: Thirty-four adult patients with haematological malignancy received allogeneic HSCT (HSCT day 0) 12 days after being given idarubicin, cyclophosphamide and total body irradiation as myeloablative conditioning, a regimen known to induce oral and intestinal MBI. Serum levels of citrulline, I-FABP and I-BABP were measured on HSCT days -12, -6, 0, +7, +14 and +21. RESULTS: Myeloablative conditioning resulted in a significant decrease in serum citrulline with the nadir on HSCT day +7; thereafter, levels rose gradually. Simultaneously, a significant decrease in I-FABP and I-BABP levels occurred from the day of transplant until day +14. CONCLUSIONS: Simultaneous reduction and subsequent increase of citrulline and I-FABP and I-BABP levels following cytotoxic treatment show that enterocyte mass corresponds to lower rate of dying enterocytes, indicating reduced turnover of enterocytes. Assessment of enterocyte turnover and mass offers opportunities for evaluation of new MBI therapies.

Factors associated with recurrence and metastasis in sacrococcygeal teratoma.

BACKGROUND: Sacrococcygeal teratoma (SCT) is a relatively uncommon tumour, with a high risk of recurrence and metastasis. The factors associated with recurrence and metastatic disease were studied. METHODS: A retrospective review was conducted of 173 children with SCT treated between January 1970 and February 2003 at the paediatric surgical centres in the Netherlands. Risk factors were identified by univariate and multivariate analysis. RESULTS: Eight children died shortly after birth or around the time of operation. Nine children, all over 18 months old, had metastases at presentation. Four teratomas with metastasis showed mature histology of the primary tumour. Nineteen children had recurrence of SCT a median interval of 10 months (range 32 days to 35 months) after primary surgery. Risk factors for recurrence were pathologically confirmed incomplete resection (odds ratio (OR) 6.54 (95 per cent confidence interval (c.i.) 2.11 to 20.31)), immature histology (OR 5.74 (95 per cent c.i. 1.49 to 22.05)) and malignant histology (OR 12.83 (95 per cent c.i. 3.27 to 50.43)). Size, Altman classification, age and decade of diagnosis were not risk factors for recurrence. One-third of the recurrences showed a shift towards histological immaturity or malignancy, compared with the primary tumour. Seven patients died after recurrence, five with malignant disease. CONCLUSION: This national study showed that SCT recurred in 11 per cent of the children within 3 years of operation. Risk factors were immature and malignant histology, or incomplete resection. Mature teratoma has the biological capability to become malignant.