Pediatric hepatocellular carcinoma: challenges and solutions

Hepatocellular carcinoma (HCC) is a very rare entity in children, making it nearly impossible to orchestrate Phase II/III studies even as multinational cooperative trials. In contrast to adults, nearly 50% of the children have a response (a-fetoprotein decline and/or tumor shrinkage) to chemotherapeutic agents such as cisplatin and doxorubicin (PLADO), demonstrating that HCC in childhood can be chemotherapy sensitive. As a result, the main treatment options in pediatric HCC focus on systemic drug therapies and resection as the central therapy. In nonmetastatic patients with complete resection upfront, the 5-year event-free survival and overall survival has reached 80%-90%. In almost all reported studies, children received adjuvant chemotherapy (mostly PLADO), but it has never been proven that postoperative chemotherapy is superior to observation. No data are available for the effects of sorafenib. The 3-year survival is <20% in children with unresectable HCC independent of the chemotherapy given preoperatively. Currently, PLADO in combination with sorafenib is recommended with the goal of achieving operability status. Alternatively, data are promising for the combination of sorafenib with gemcitabine and oxaliplatin. For children with nonresectable and nonmetastastic liver tumors, it has been shown that the Milan criteria regarding liver transplantation are not applicable - individual decisions have to be made. Transarterial chemoembolization could be offered to patients with chemotherapy-resistant liver tumors for palliative care or potentially to achieve surgical resectability, and therefore cure. Information about the feasibility or effects of new agents or approaches as discussed in adult HCC patients is not available for childhood HCC. Research has to be done for characterizing the molecular and genomic mechanisms of pediatric HCC to support the development of novel therapeutic approaches and the implementation of personalized medicine

Surgical treatment of massive bleeding of a right aberrant subclavian artery after oesophageal stent removal

We report a case of a 9-year-old female who required surgical treatment and resuscitation after severe transoesophageal bleeding of a right aberrant subclavian artery (RASA). Bleeding of this RASA was caused by a mechanical irritation due to an oesophageal stent. The stent was placed weeks before to dilate the oesophagus after accidental ingestion of a caustic agent. Although conservative management of benign oesophageal stenosis in children is highly recommended, there are still some major complications to be considered. To avoid erosion of aberrant subclavian artery vascular rings and slings, as described in several case reports, these vessels should be excluded by computed tomography (CT) or magnetic resonance imaging (MRI) scans before placement of oesophageal stents. This case suggests that management of caustic ingestion in children is still a major challenge in paediatric surgical departments

Prophylactic Drain Placement in Childhood Perforated Appendicitis: Does Spillage Matter?

Background: Prophylactic abdominal drains for perforated appendicitis in children have generally been regarded as obsolete because several studies showed inferior results for drain placement in the past. Despite these results, prophylactic abdominal drains for perforated appendicitis remain omnipresent in pediatric surgery especially when gross spillage is observed at the time of appendectomy. Here, we hypothesize that even if accounting for gross intra-abdominal spillage, prophylactic drain placement for perforated appendicitis in children is not beneficial. Patients and Methods: The charts of all children (<18 years) who underwent an appendectomy at our institution from July 2013 to March 2020 were analyzed. The data from 65 patients who presented with perforated appendicitis were included. Patients were grouped according to the amount of intraoperative spillage. Demographics, laboratory data, operative findings, and postoperative outcomes were analyzed. Results: Of all patients, 34 were male, and 31 were female, with a mean age of 10.5 ± 3.7 years. There were no statistically significant differences between the groups for age and sex (p = 0.6985 and p = 0.6222, respectively). Prophylactic drains were placed according to the surgeon's preference in 32 children. There were no statistically significant differences between the groups in the rate of intra-abdominal abscess formation, wound infection, and bowel obstruction, regardless of the amount of spillage encountered during an appendectomy. However, independently of the amount of spillage, the length of hospital stay was longer in the children in which a drain had been placed (p = 0.0041). Conclusion: In our cohort, we could not find a benefit from drain placement even in case of gross spillage at the time of appendectomy. Rather, drain placement was associated with an increase in length of hospital stay

Long-Term Follow-Up Examination of the Internal Jugular Vein After Vessel-Sparing Implantation of a Hickman Catheter or Port Catheter

Introduction: Both a Hickman catheter (HC) and port catheter (Port) can be inserted either percutaneously by the Seldinger technique or by surgical venous cut-down. Catheters are inserted with a vessel-sparing technique when they are placed in the internal jugular vein (IJV) by venous cut-down. Although this technique is common, data are sparse regarding the vessel's state at long-term follow-up. This study was aimed at determining the flow pattern and constitution of the IJV after vessel-sparing implantation of an HC or Port and comparing the outcomes to those of implantation with the Seldinger technique.Methods: One hundred children (58 boys, 42 girls) between 33 days and 18 years of age who underwent a vessel-sparing implantation of an HC or Port in the IJV were prospectively included. All patients underwent surgical venous cut-down at a single institution. Patency and shape of the IJV were determined by ultrasound and categorized according to 2 possible outcomes: relevant alteration (including occlusion of the IJV) and no relevant alteration, with relevant alteration defined as changes that caused an altered flow pattern.Results: Median age was 6 years at the time of operation, and the median indwelling time of catheters was 271 days. Twenty-two of our patients (22%) showed relevant alterations. These changes included high-grade stenosis or lesion in 13 patients (13%) and occlusion in 9 patients (9%). There were no operation-associated complications, such as pneumothorax, hematopericardium, or accidental puncture of the carotid artery. Statistical analysis did not reveal any specific parameter as a risk factor for relevant structural abnormalities.Discussion: In a comparison of our data to the literature, venous cut-down showed an alteration rate of 26% and a patency rate of 85%, whereas the Seldinger technique was found to cause alteration in 15%, with a patency rate of 97% but a successful placement rate of only 90.3–91.6%.Conclusion: The indication for long-term catheter placement may determine which method is preferable. A child who is likely to need more catheters in the future might benefit from the Seldinger technique, since there is a higher chance of long-term patency of the vessel. A patient undergoing chemotherapy might benefit more from the surgical venous cut-down with less placement-associated complications

Esophageal Perforation and EVAC in Pediatric Patients: A Case Series of Four Children

Introduction: In pediatric patients, esophageal perforation (EP) is rare but associated with significant morbidity and mortality rates of up to 20–30%. In addition to standard treatment options, endoscopic esophageal vacuum-assisted closure (EVAC) therapy has shown promising results, especially in adult patients. Thus far, the only data on technical success and effectiveness of EVAC in pediatric patients were published in 2018 by Manfredi et al. at Boston Children's Hospital. The sparse data on EVAC in children indicates that this promising technique has been barely utilized in pediatric patients. More data are needed to evaluate efficacy and outcomes of this technique in pediatric patients. Method: We reviewed five cases of therapy using EVAC, ArgyleTM Replogle Suction Catheter (RSC), or both on pediatric patients with EP in our institution between October 2018 and April 2020. Results: Five patients with EP (median 3.4 years; 2 males) were treated with EVAC, RSC, or a combination. Complete closure of EP was not achieved after EVAC alone, though patients' health stabilized and inflammation and size of EP decreased after EVAC. Four patients then were treated with RSC until the EP healed. One patient needed surgery as the recurrent fistula did not heal sufficiently after 3 weeks of EVAC therapy. Two patients developed stenosis and were successfully treated with dilatations. One patient treated with RSC alone showed persistent EP after 5 weeks. Conclusion: EVAC in pediatric patients is technically feasible and a promising method to treat EP, regardless of the underlying cause. EVAC therapy can be terminated as soon as local inflammation and C-reactive protein levels decrease, even if the mucosa is not healed completely at that time. A promising subsequent treatment is RSC. An earlier switch to RSC can substantially reduce the need of anesthesia during subsequent treatments. Our findings indicate that EVAC is more effective than RSC alone. In some cases, EVAC can be used to improve the tissues condition in preparation for a re-do surgery. At 1 year after therapy, all but one patient demonstrated sufficient weight gain. Further prospective studies with a larger cohort are required to confirm our observations from this small case series

Outcome of Patients With Esophageal Atresia and Very Low Birth Weight (<= 1,500 g)

Introduction: Primary repair of esophageal atresia (EA) in infants with very low birth weight (VLBW) and extremely low birth weight (ELBW) has been widely performed in pediatric surgery. However, several studies have shown that complication rates in infants with VLBW are high. We hypothesize preterm children benefit from a shorter, less-traumatizing operation in the first days of life, as staged repair implies. Methods: Patients with EA and VLBW were retrieved from the database of a large national patient organization KEKS e.V. Structured questionnaires were sent to all the patients' families; the responses were pseudonymized and sent to our institution. Results: Forty-eight questionnaires from patients were analyzed. The mean birth weight was 1,223 g (720–1,500 g). Primary repair was performed in 25 patients (52%). Anastomotic insufficiency (AI) was reported in 9 patients (19%), recurrent fistula (RF) in 8 (17%), and anastomotic stenosis in 24 patients (50%). Although AI was almost twice as common after primary repair than after staged repair (24 vs. 13%; p = 0.5), the difference was not statistically significant. RF was more frequent after primary repair (28 vs. 4%; p = 0.04), gastroesophageal reflux was more frequent in the group after staged repair (78 vs. 52%; p = 0.04), and both correlations were statistically significant. Intracranial hemorrhage (ICH) was reported in 11 patients (23%) and was observed in 7 of them (64%, p = 0.4) after primary repair. ICH was reported in 60% of patients with ELBW and 75% of patients when ELBW was paired with primary repair. Conclusion: This study demonstrates the complication rate in patients with VLBW is higher than the average of that in patients with EA. The study indicates that a staged approach may be an option in this specific patient group, as less RF and AI are seen after staged repair. ICH rate in patients with ELBW seemed to be especially lower after staged repair. Interestingly, gastroesophageal reflux was statistically significantly higher in the group after staged repair, and postoperative ventilation time was longer. It is therefore necessary to individually consider which surgical approach is appropriate for this special patient group

IGFBP3 impedes aggressive growth of pediatric liver cancer and is epigenetically silenced in vascular invasive and metastatic tumors

<p>Abstract</p> <p>Background</p> <p>Hepatoblastoma (HB) is an embryonal liver neoplasm of early childhood with a poor prognosis for patients with distant metastases and vascular invasion. We and others have previously shown that the overexpression of <it>insulin-like growth factor 2 </it>(<it>IGF2</it>), loss of imprinting at the <it>IGF2</it>/<it>H19 </it>locus, and amplification of <it>pleomorphic adenoma gene 1 </it>(<it>PLAG1</it>) are common features in HB, suggesting a critical role of the IGF axis in hepatoblastomagenesis. In this study, we investigated the role of the insulin-like growth factor binding protein 3 (IGFBP3), a known competitor of the IGF axis, in pediatric liver cancers.</p> <p>Results</p> <p>The <it>IGFBP3 </it>gene was highly expressed in normal pediatric livers but was heavily downregulated in four HB cell lines and the majority of HB primary tumors (26/36). Detailed methylation analysis of CpG sites in the <it>IGFBP3 </it>promoter region by bisulfite sequencing revealed a high degree of DNA methylation, which is causatively associated with the suppression of <it>IGFBP3 </it>in HB cell lines. Consequently, the treatment of HB cell lines with 5-aza-2'-deoxycytidine resulted in DNA demethylation and reactivation of the epigenetically silenced <it>IGFBP3 </it>expression. Interestingly, <it>IGFBP3 </it>promoter methylation predominantly occurred in metastatic HB with vascular invasion. Restoring <it>IGFBP3 </it>expression in HB cells resulted in reduced colony formation, migration, and invasion.</p> <p>Conclusion</p> <p>This study provides the first direct evidence that the reactivation of <it>IGFBP3 </it>decreases aggressive properties of pediatric liver cancer cells and that <it>IGFBP3 </it>promoter methylation might be used as an indicator for vessel-invasive tumor growth in HB patients.</p

Combined Scintigraphy and Tumor Marker Analysis Predicts Unfavorable Histopathology of Neuroblastic Tumors with High Accuracy

Objectives Our aim was to improve the prediction of unfavorable histopathology (UH) in neuroblastic tumors through combined imaging and biochemical parameters. Methods I-123-MIBG SPECT and MRI was performed before surgical resection or biopsy in 47 consecutive pediatric patients with neuroblastic tumor. Semi-quantitative tumor-to-liver count-rate ratio (TLCRR),MRI tumor size and margins, urine catecholamine and NSE blood levels of neuron specific enolase (NSE) were recorded. Accuracy of single and combined variables for prediction of UH was tested by ROC analysis with Bonferroni correction. Results 34 of 47 patients had UH based on the International Neuroblastoma Pathology Classification (INPC). TLCRR and serum NSE both predicted UH with moderate accuracy. Optimal cut-off for TLCRR was 2.0, resulting in 68% sensitivity and 100% specificity (AUC-ROC 0.86, p < 0.001). Optimal cut-off for NSE was 25.8 ng/ml, resulting in 74% sensitivity and 85% specificity (AUC-ROC 0.81, p = 0.001). Combination of TLCRR/NSE criteria reduced false negative findings from 11/9 to only five, with improved sensitivity and specificity of 85% (AUC-ROC 0.85, p < 0.001). Conclusion Strong I-123-MIBG uptake and high serum level of NSE were each predictive of UH. Combined analysis of both parameters improved the prediction of UH in patients with neuroblastic tumor. MRI parameters and urine catecholamine levels did not predict UH

Effects on the maternofetal unit of the rabbit model after substitution of the amniotic fluid with perfluorocarbons

Objectives: Exchanging amniotic fluid (AF) with perfluorocarbon (PFC) may serve as a medium for fetoscopic surgery. This study evaluates the distribution and physiologic effects of intraamniotic PFC as a medium for fetoscopy. Methods: Fetuses of 17 pregnant rabbits underwent either exchange of the AF with PFC, electrolyte solution (ES), or control. The quality of vision during fetoscopy was assessed in AF and PFC. After 6 h, we determined the distribution of PFC in the maternofetal unit. Results: Quality of vision during fetoscopy was better in PFC than with AF. There was no difference in fetal survival between the study groups. PFC was demonstrated on X-ray in the pharynx of 4 fetuses, and the esophagus in 1. Conclusions: PFC provided an ideal medium for fetoscopy without fetal compromise. Copyright (c) 2005 S. Karger AG, Basel

Comorbidity and long‐term clinical outcome of laryngotracheal clefts types III and IV: Systematic analysis of new cases

Background Long segment laryngotracheoesophageal clefts (LTECs) are very rare large‐airway malformations. Over the last 40 years mortality rates declined substantially due to improved intensive care and surgical procedures. Nevertheless, long‐term morbidity, comorbidity, and clinical outcomes have rarely been assessed systematically. Methods In this retrospective case series, the clinical presentation, comorbidities, treatment, and clinical outcomes of all children with long‐segment LTEC that were seen at our department in the last 15 years were collected and analyzed systematically. Results Nine children were diagnosed with long segment LTEC (four children with LTEC type III and five patients with LTEC type IV). All children had additional tracheobronchial, gastrointestinal, or cardiac malformations. Tracheostomy for long‐time ventilation and jejunostomy for adequate nutrition was necessary in all cases. During follow‐up one child died from multiorgan failure due to sepsis at the age of 43 days. The clinical course of the other eight children (median follow‐up time 5.2 years) was stable. Relapses of the cleft, recurrent aspirations, and respiratory tract infections led to repeated hospital admissions. Conclusions Long‐segment LTECs are consistently associated with additional malformations, which substantially influence long‐term morbidity. For optimal management, a multidisciplinary approach is essential