Monitoring of plexiform neurofibroma in children and adolescents with neurofibromatosis type 1 by [18 F]FDG-PET imaging. Is it of value in asymptomatic patients?

PURPOSE: About 10% of patients with neurofibromatosis type 1 (NF-1) develop malignant peripheral nerve sheath tumours (MPNST) mostly arising in plexiform neurofibroma (PN); 15% of MPNST arise in children and adolescents. 2-[18 F]fluoro-2-deoxy-d-glucose ([18 F]FDG)-PET (where PET is positron emission tomography) is a sensitive method in differentiating PN and MPNST in symptomatic patients with NF-1. This study assesses the value of [18 F]FDG-PET imaging in detecting malignant transformation in symptomatic and asymptomatic children with PN. METHODS: Forty-one patients with NF-1 and extensive PN underwent prospective [18 F]FDG imaging from 2003 to 2014. Thirty-two of the patients were asymptomatic. PET data, together with histological results and clinical course were re-evaluated retrospectively. Maximum standardised uptake values (SUVmax) and lesion-to-liver ratio were assessed. RESULTS: A total of 104 examinations were performed. Mean age at first PET was 13.5 years (2.6-22.6). Eight patients had at least one malignant lesion; four of these patients were asymptomatic. Two of four symptomatic patients died, while all patients with asymptomatic malignant lesions are alive. All malignant tumours could be identified by PET imaging in both symptomatic and asymptomatic patients. All lesions judged as benign by [18 F]FDG imaging and clinical judgment were either histologically benign if removed or remained clinically silent during follow-up. SUVmax of malignant and benign lesions overlapped, but no malignant lesion showed FDG uptake ≤3.15. Asymptomatic malignant lesions were detected with a sensitivity of 100%, a negative predictive value of 100% and a specificity of 45.1%. CONCLUSION: Malignant transformation of PN also occurs in asymptomatic children and adolescents. Detection of MPNST at early stages could increase the possibility of oncologically curative resections.

Management of hypertrophic pylorus stenosis with ultrasound guided single shot epidural anaesthesia--a retrospective analysis of 20 cases.

AIM: To retrospectively describe the performance of ultrasound guided thoracic epidural anaesthesia under sedation for anaesthesia management of open pyloromyotomy. BACKGROUND: Anaesthesia management for hypertrophic pylorus stenosis (HPS) is usually performed under general anaesthesia with tracheal intubation. Only a few publications describe avoidance of tracheal intubation in infants by using spinal or caudal anaesthesia. The present retrospective analysis describes the performance of ultrasound guided thoracic epidural anaesthesia under sedation for anaesthetic management of open pyloromyotomy. METHODS: Twenty consecutive infants scheduled for pyloromyotomy according to the Weber-Ramstedt technique were retrospectively analysed. After sedation with nalbuphine and propofol, an ultrasound guided single shot thoracic epidural anaesthesia was performed with 0.75 ml·kg(-1) ropivacaine 0.475%. Insufficient blockade was defined as increase of HR > 15% from initial value and/or any movements at skin incision. In those cases we were prepared for rapid sequence intubation according to the departmental standard. RESULTS: All pyloromyotomies could be performed under single shot thoracic epidural anaesthesia and sedation. One case of moderate oxygen desaturation was treated with intermittent ventilation via face mask. CONCLUSIONS: Thoracic epidural anaesthesia under sedation for pyloromyotomy has been a useful technique in this retrospective series of infants suffering from HPS. In 1/20 infants short term assisted ventilation via face mask was required. Undisturbed surgery was possible in all cases.

Is There a Role for Elective Early Upper Gastrointestinal Contrast Study in Neurologically Impaired Children following Laparoscopic Nissen Fundoplication?

Assessment of discomfort as a sign for early postoperative complications in neurologically impaired (NI) children is challenging. The necessity of early routine upper gastrointestinal (UGI) contrast studies following laparoscopic Nissen fundoplication in NI children is unclear. We aimed to evaluate the role of scheduled UGI contrast studies to identify early postoperative complications following laparoscopic Nissen fundoplication in NI children. Data for laparoscopic Nissen fundoplications performed in NI children between January 2004 and June 2021 were reviewed. A total of 103 patients were included, with 60 of these being boys. Mean age at initial operation was 6.51 (0.11-18.41) years. Mean body weight was 16.22 (3.3-62.5) kg. Mean duration of follow up was 4.15 (0.01-16.65 years) years. Thirteen redo fundoplications (12.5%) were performed during the follow up period; eleven had one redo and two had 2 redos. Elective postoperative UGI contrast studies were performed in 94 patients (91%). Early postoperative UGI contrast studies were able to identify only one complication: an intrathoracal wrap herniation on postoperative day five, necessitating a reoperation on day six. The use of early UGI contrast imaging following pediatric laparoscopic Nissen fundoplication is not necessary as it does not identify a significant number of acute postoperative complications requiring re-intervention.

Interleukin-6 serum levels predict surgical intervention in infants with necrotizing enterocolitis.

BACKGROUND: Symptoms at suspicion of necrotizing enterocolitis (NEC) are often nonspecific and several biomarkers have been evaluated for their discriminative power to both diagnose and predict the course from NEC suspicion to complicated disease requiring surgical intervention. Thus, we aimed to assess the utility of interleukin-6 (IL-6) to predict surgical intervention in infants suffering from NEC and, furthermore, to discriminate infants with starting NEC or late-onset sepsis (LOS). METHODS: IL-6 serum levels at disease onset were retrospectively analyzed in 24 infants suffering from NEC as well as 16 neonates with LOS. RESULTS: IL-6 serum levels at disease onset were significantly higher in infants suffering from NEC necessitating surgical intervention in the disease course compared to infants with medical NEC (5000 [785-5000] vs. 370 [78-4716] pg/ml, p = 0.0008) as well as gram-positive LOS (5000 [785-5000] vs. 84 [12-269] pg/ml, p = 0.0001). Infants suffering from gram-negative LOS exhibited elevated IL-6 serum levels at disease onset comparable to infants with surgical NEC (5000 [1919-5000] vs. 5000 [785-5000] pg/ml, p = 1.00). CONCLUSION: The proinflammatory cytokine IL-6 appears to be a promising marker to distinguish surgical NEC from medical NEC at the onset of disease but cannot discriminate between surgical NEC and gram-negative LOS. LEVEL OF EVIDENCE: II.

The plasma activities of lysosomal enzymes in infants with necrotizing enterocolitis: new promising class of biomarkers?

BACKGROUND: Intestinal ischemia plays a major role in the pathogenesis of necrotizing enterocolitis (NEC). The diagnosis of intestinal ischemia would be highly desirable, as it is impossible to achieve with the current diagnostic regimes. Preliminary data from an animal NEC model indicate a possible correlation between the plasma activity of the lysosomal enzyme beta-glucosidase and intestinal ischemia. METHODS: In this case-control study the plasma activities of six different lysosomal enzymes were detected by high-performance liquid-chromatography tandem mass-spectrometry in 15 infants with NEC and compared to 18 controls. RESULTS: The plasma activities of ß-glucosidase (ABG), α-glucosidase (GAA), and galactocerebrosidase (GALC) were significantly higher in the NEC group compared with controls (ABG, p=0.009; GAA, p<0.001; GALC, p<0.001). GAA and GALC showed the highest diagnostic value with areas under the curve of 0.91 and 0.87. CONCLUSIONS: We identified GAA and GALC as new promising biomarkers for gut wall integrity in infants with NEC, and report first results on the plasma activity of ABG. The present study supports the hypothesis that the plasma activity of ABG might serve as a marker of intestinal ischemia in NEC. The identification of intestinal ischemia could facilitate early discrimination of infants at risk for NEC from infants with benign gastrointestinal disorders.

In vivo induction of dendritic cell-mediated cytotoxicity against allogeneic pancreatic carcinoma cells.

The objective of this study was to assess the toxicity and immunological response induced by autologous dendritic cells (DCs) pulsed with allogeneic tumor lysate in a pancreatic cancer patient. The lack of available tumor peptides in pancreatic cancer strongly supports the idea to use allogeneic tumor cells as a source of antigens. The patient suffering from a stage IV pancreatic cancer received 1-2x10(7) autologous monocyte-derived DCs in three-week intervals injected into a groin lymph node. Monocytes from peripheral blood were isolated by magnetic bead selection. For the first ten vaccinations DCs were loaded with autologous tumor cell lysate obtained during surgical exploration. After consumption of the autologous lysate, equal numbers of DCs were pulsed with lysate of the tumor cell line AsPc-1 and BxPc-3 for a further five vaccinations. Peripheral mononuclear cells (PMNCs) were harvested after the seventh and compared with PMNCs obtained after the fourteenth vaccination for immunological response. Delayed type hypersensitivity reactivity to DCs pulsed with autologous and allogeneic tumor lysate was also assessed. The patient received a total of fifteen vaccinations. There was no toxicity or evidence of autoimmunity observed. Delayed type hypersensitivity was found to be positive for the autologous as well as the allogeneic tumor lysate pulsed DCs. in vitro cytotoxicity assays demonstrated a dramatic increase of the PMNC killing capacity against the pancreatic cancer cell lines AsPc-1 and BxPc-3 after the fourteenth compared to the seventh vaccination. CT scans revealed a stable disease for six months. The administration of autologous DCs pulsed with allogeneic tumor lysate is non-toxic and suitable for inducing an immunological anti-tumor response. Even though this study was confined to a single patient, the data might open a door for novel immunotherapeutical strategies.

Hyperthermia improves cellular immune response to human hepatocellular carcinoma subsequent to co-culture with tumor lysate pulsed dendritic cells.

Dendritic cells play a major role in cellular immunity. The crucial steps of antigen presentation and processing by DCs may be limiting factors for adoptive cellular immunotherapy. Here, we investigated whether hyperthermia of human hepatocellular carcinoma (HCC) cells induces enhanced cytotoxic cellular immune response. Peripheral blood mononuclear cell (PBMC)-derived DCs were pulsed with tumor cell lysate of the human HCC cell line HepG2, which had been heat shocked prior to incubation for 5 h. Subsequent to TNFalpha-induced maturation DCs were co-cultured with autologous CD4+ and/or CD8+ cells, and T cell mediated cytolysis of HepG2 cells was assessed. We observed enhanced CD4+/8+ cellular cytotoxicity against HepG2 cells subsequent to co-culture with the heat shocked tumor lysate pulsed DCs as compared to pulsing DCs with lysate of non-heat shocked tumor cells. The improved cellular immune response can be related to enhanced expression of HSP 70 and 90 in HepG2 cells upon hyperthermia.

Interleukin-8 predicts 60-day mortality in premature infants with necrotizing enterocolitis.

OBJECTIVE: The purpose of this study was to evaluate the predictiveness of circulating interleukin (IL)-8 for 60-day mortality in premature infants with necrotizing enterocolitis (NEC). BACKGROUND: NEC affects up to 5% of premature infants and remains a leading cause of mortality among neonates. METHODS: A total of 113 infants with surgically (n=50) or medically (n=63) treated NEC were retrospectively analyzed. Laboratory parameters including serum IL-8 were assessed at the diagnosis of NEC and during the preoperative workup. RESULTS: The 60-day mortality was 19% (22/113), 10% (6/63) in medical and 33% (16/50) in surgical NEC. IL-8 levels significantly correlated with 60-day mortality (odds ratio: 1.38; CI 1.14-1.67; p=0.001). Median IL-8 levels at diagnosis were significantly higher in neonates who were later treated surgically (median=2625 pg/ml; range: 27-7500) compared with those treated medically (median=156 pg/ml; range: 5-7500; p<0.001). The AUC to discriminate between medical and surgical NEC was 0.82 (CI, 0.74-0.90), and an exploratory IL-8 cutoff point could be established at 1783 pg/ml (sensitivity of 90.5%; specificity of 59.2%). CONCLUSIONS: Our findings that serum IL-8 (i) correlates directly with 60-day mortality and (ii) differs significantly between medically and surgically treated infants may change the process of therapeutic decision making in NEC.

Serum levels of interleukin-8 and gut-associated biomarkers in diagnosing necrotizing enterocolitis in preterm infants.

BACKGROUND: In recent years several potential biochemical markers have been evaluated to facilitate a reliable diagnosis of necrotizing enterocolitis (NEC), but none have made progress to clinical routine. We performed a comparative assessment in premature infants to evaluate the diagnostic value of the routinely available cytokine interleukin (IL)-8, and two promising experimental biomarkers, the gut barrier proteins liver fatty acid binding protein (L-FABP) and intestinal fatty acid binding protein (I-FABP), respectively, for the diagnosis of NEC. METHODS: IL-8, L-FABP, and I-FABP concentrations were analyzed in the serum of 15 infants with NEC and compared with 14 gestational age-matched infants serving as a control group. RESULTS: Serum concentrations of I-FABP, L-FABP and IL-8 were significantly higher in infants with NEC compared with controls. IL-8 showed the highest diagnostic value with an area under the curve of 0.99, followed by L-FABP and I-FABP. In addition we found a significant correlation between IL-8 and both FABPs in infants with NEC. CONCLUSION: Our results further advocate the possible role of IL-8 as a specific marker for NEC. The diagnostic value of IL-8 seems to be superior to I-FABP, and similar to L-FABP. The routinely availability facilitates IL-8 as a possible candidate for further clinical investigations.

Comprehensive evaluation of 11 cytokines in premature infants with surgical necrotizing enterocolitis.

OBJECTIVE: A prospective study to investigate the pattern of pro- and anti-inflammatory cytokine responses in neonates with surgical necrotizing enterocolitis (NEC) and identify those cytokines being the most promising for future research. METHODS: A panel of 11 different cytokines were measured in 9 infants with proven NEC and compared with 18 age-matched healthy neonates. RESULTS: The serum concentrations of the interleukins (IL)-6, IL-8, and IL-10 were significantly (32-fold to 56-fold) higher in NEC infants compared with controls. In contrast, IL-5, IFN gamma, IL-4 and IL-2 showed slightly (1.4-fold to 5.9-fold) lower levels in the NEC samples. However, these cytokines showed a very low absolute concentration in infants with NEC and in controls. The sum of the serum concentrations of IL-6, IL-8 and IL-10 was able to clearly separate infants with NEC from control samples. IL-1 beta and TNF-alpha showed no statistically different levels. The serum levels of TNF-beta and IL-12p70 were below the detection limit in more than 50% of all samples per group. CONCLUSION: In spite of strong local inflammation only three out of eleven cytokines (IL-6, IL-8, and IL-10) showed strongly increased serum levels indicating an important role of them in the pathogenesis of NEC. At least two of these three cytokines were elevated in every single NEC patient. Thus, longitudinal monitoring of combined IL-8, IL-6, and IL-10 levels could reveal their potency in being clinical relevant markers in NEC.

Interleukin 8 correlates with intestinal involvement in surgically treated infants with necrotizing enterocolitis.

PURPOSE: The aim of this study was to test the predictive value of interleukin (IL) 8 in the assessment of intestinal involvement in necrotizing enterocolitis (NEC). METHODS: Forty infants with surgically treated NEC were classified into 3 groups based on intestinal involvement during laparotomy: focal (n = 11), multifocal (n = 16), and panintestinal (n = 13). Preoperatively obtained serum levels of IL-8, C-reactive protein, white blood cell count, and platelet count were correlated with intestinal involvement using logistic regression models. RESULTS: Interleukin 8 correlated significantly with intestinal involvement in infants with surgically treated NEC (odds ratio, 1.74; confidence interval, 1.27-2.39; P < .001). An exploratory IL-8 cutoff value of 449 pg/mL provided a specificity of 81.8% and sensitivity of 82.8% to discriminate focal from multifocal and panintestinal disease. An IL-8 cutoff value of 1388 pg/mL provided a specificity of 77.8% and a sensitivity of 76.9% to discriminate panintestinal disease from focal and multifocal disease. CONCLUSIONS: To our knowledge, this is the first study to demonstrate a significant correlation of IL-8 with intestinal involvement in advanced NEC in a large patient population. Our results indicate that IL-8 may be a promising biomarker for assessing intestinal involvement in infants with advanced NEC.