Targeting B7-H3-A Novel Strategy for the Design of Anticancer Agents for Extracranial Pediatric Solid Tumors Treatment.

Recent scientific data recognize the B7-H3 checkpoint molecule as a potential target for immunotherapy of pediatric solid tumors (PSTs). B7-H3 is highly expressed in extracranial PSTs such as neuroblastoma, rhabdomyosarcoma, nephroblastoma, osteosarcoma, and Ewing sarcoma, whereas its expression is absent or very low in normal tissues and organs. The influence of B7-H3 on the biological behavior of malignant solid neoplasms of childhood is expressed through different molecular mechanisms, including stimulation of immune evasion and tumor invasion, and cell-cycle disruption. It has been shown that B7-H3 knockdown decreased tumor cell proliferation and migration, suppressed tumor growth, and enhanced anti-tumor immune response in some pediatric solid cancers. Antibody-drug conjugates targeting B7-H3 exhibited profound anti-tumor effects against preclinical models of pediatric solid malignancies. Moreover, B7-H3-targeting chimeric antigen receptor (CAR)-T cells demonstrated significant in vivo activity against different xenograft models of neuroblastoma, Ewing sarcoma, and osteosarcoma. Finally, clinical studies demonstrated the potent anti-tumor activity of B7-H3-targeting antibody-radioimmunoconjugates in metastatic neuroblastoma. This review summarizes the established data from various PST-related studies, including in vitro, in vivo, and clinical research, and explains all the benefits and potential obstacles of targeting B7-H3 by novel immunotherapeutic agents designed to treat malignant extracranial solid tumors of childhood.

Abiotrophia defectiva liver abscess in a teenage boy after a supposedly mild blunt abdominal trauma: a case report.

BACKGROUND: A pyogenic liver abscess (PLA) represents a pus-filled cavity within the liver parenchyma caused by the invasion and multiplication of bacteria. The most common offender isolated from the PLA in children is Staphylococcus aureus. Abiotrophia defectiva is a Gram-positive pleomorphic bacterium, commonly found in the oral cavity, intestinal, and genitourinary mucosa as part of the normal microbiota. It has been proven to be an etiological factor in various infections, but rarely in cases of PLA. The case presented here is, to the best of our knowledge, the first pediatric case of PLA caused by A. defectiva. CASE PRESENTATION: A 13-year-old Caucasian boy presented with a two-day history of abdominal pain, fever up to 40 °C, and polyuria. Contrast-enhanced computed tomography (CT) scan revealed a single, multiloculated liver lesion, suggestive of a liver abscess. The boy had sustained a bicycle handlebar injury to his upper abdomen 3 weeks before the symptoms appeared and had been completely asymptomatic until 2 days before admission. He was successfully treated with antibiotic therapy and open surgical drainage. A. defectiva was isolated from the abscess material. Histopathology report described the lesion as a chronic PLA. CONCLUSIONS: A. defectiva is a highly uncommon cause of liver abscess in children. In such cases, various predisposing factors should be considered, including antecedent blunt abdominal trauma.

Appendiceal involvement in a patient with Gaucher disease.

Almost any anatomical compartment may be involved in Gaucher disease (GD). Abdominal lymphadenopathy occurred during enzyme replacement therapy in more than a dozen children with GD so far. A fourteen-year-old boy from Serbia developed clinical signs of acute appendicitis six years after the onset of GD type 3 related abdominal lymphadenopathy. Ultrasound examination showed diffuse thickening of the intestinal wall in the ileocoecal region with periappendicular infiltration. An appendectomy was performed four months after conservative treatment with antibiotics. Histopathology revealed macrophages with cytological characteristics of Gaucher cells densely crammed in mesoappendiceal adipose tissue. Also the multifocal replacement of subserosal tissue by Gaucher cells and their infiltration to a variable depth of muscularis propria of the appendix were verified. Frank infiltration of the vermiform appendix with Gaucher cells represents a novel observation in a wide spectrum of manifestations reported in GD. A possible causative relationship of this infiltration with appendicitis is considered.

Splenic hamartomas in children.

Splenic hamartomas (SHs) are uncommon, benign vascular lesions of unclear etiology and are mostly found incidentally on abdominal images, at surgery, or at autopsy. Since the first case description, in 1861, less than 50 pediatric SH cases have been reported in the literature. In this article, we have performed an analysis of all SH cases in children published in the literature to date and presented our case of an 8-year-old male with SH. These lesions in children were shown to cause symptoms more often than in the adult population. The observed SH sizes in children ranged from a few millimeters to 18 cm, and the symptomatic lesions were mostly larger or multiple. The most common clinical finding was splenomegaly. Signs of hypersplenism were present in children with a single SH larger than 4.5 cm (diameter range: 4.5-18.0 cm) and in those with multiple hamartomas, ranging from a few millimeters to 5 cm. Eighty percent of patients with available laboratory findings had hematological abnormalities such as anemia, thrombocytopenia, or pancytopenia. Other symptoms and signs included abdominal pain, recurrent infections, fever, night sweats, lethargy, growth retardation, and weight loss. The use of multiple imaging modalities may suggest the preoperative diagnosis of a splenic mass in children and determine the therapeutic approach. However, the final diagnosis of SH relies on histopathological evaluation. Surgery, including total or partial splenectomy (PS), is the mainstay of SH management. Although total splenectomy carries a greater risk of overwhelming post-splenectomy infection than PS it has remained the most performed surgical procedure in children with SH. In the majority of pediatric patients with symptomatic SH, resolution of symptoms and resolution or improvement of cytopenias occurred after surgical treatment.

Age-specific causes of upper gastrointestinal bleeding in children.

The etiology of upper gastrointestinal bleeding (UGIB) varies by age, from newborns to adolescents, with some of the causes overlapping between age groups. While particular causes such as vitamin K deficiency and cow's milk protein allergy are limited to specific age groups, occurring only in neonates and infants, others such as erosive esophagitis and gastritis may be identified at all ages. Furthermore, the incidence of UGIB is variable throughout the world and in different hospital settings. In North America and Europe, most UGIBs are non-variceal, associated with erosive esophagitis, gastritis, and gastric and duodenal ulcers. In recent years, the most common causes in some Middle Eastern and Far Eastern countries are becoming similar to those in Western countries. However, variceal bleeding still predominates in certain parts of the world, especially in South Asia. The most severe hemorrhage arises from variceal bleeding, peptic ulceration, and disseminated intravascular coagulation. Hematemesis is a credible indicator of a UGI source of bleeding in the majority of patients. Being familiar with the most likely UGIB causes in specific ages and geographic areas is especially important for adequate orientation in clinical settings, the use of proper diagnostic tests, and rapid initiation of the therapy. The fundamental approach to the management of UGIB includes an immediate assessment of severity, detecting possible causes, and providing hemodynamic stability, followed by early endoscopy. Unusual UGIB causes must always be considered when establishing a diagnosis in the pediatric population because some of them are unique to children. Endoscopic techniques are of significant diagnostic value, and combined with medicaments, may be used for the management of acute bleeding. Finally, surgical treatment is reserved for the most severe bleeding.

B7 homologue 3 as a prognostic biomarker and potential therapeutic target in gastrointestinal tumors.

The most common digestive system (DS) cancers, including tumors of the gastrointestinal tract (GIT) such as colorectal cancer (CRC), gastric cancer (GC) and esophageal cancer (EC) as well as tumors of DS accessory organs such as pancreatic and liver cancer, are responsible for more than one-third of all cancer-related deaths worldwide, despite the progress that has been achieved in anticancer therapy. Due to these limitations in treatment strategies, oncological research has taken outstanding steps towards a better understanding of cancer cell biological complexity and heterogeneity. These studies led to new molecular target-driven therapeutic approaches. Different in vivo and in vitro studies have revealed significant expression of B7 homologue 3 (B7-H3) among the most common cancers of the GIT, including CRC, GC, and EC, whereas B7-H3 expression in normal healthy tissue of these organs was shown to be absent or minimal. This molecule is able to influence the biological behavior of GIT tumors through the various immunological and nonimmunological molecular mechanisms, and some of them are shown to be the result of B7-H3-related induction of signal transduction pathways, such as Janus kinase 2/signal transducer and activator of transcription 3, phosphatidylinositol 3-kinase/protein kinase B, extracellular signal-regulated kinase, and nuclear factor-κB. B7-H3 exerts an important role in progression, metastasis and resistance to anticancer therapy in these tumors. In addition, the results of many studies suggest that B7-H3 stimulates immune evasion in GIT tumors by suppressing antitumor immune response. Accordingly, it was observed that experimental depletion or inhibition of B7-H3 in gastrointestinal cancers improved antitumor immune response, impaired tumor progression, invasion, angiogenesis, and metastasis and decreased resistance to anticancer therapy. Finally, the high expression of B7-H3 in most common cancers of the GIT was shown to be associated with poor prognosis. In this review, we summarize the established data from different GIT cancer-related studies and suggest that the B7-H3 molecule could be a promising prognostic biomarker and therapeutic target for anticancer immunotherapy in these tumors.

Possible cytokine biomarkers in pediatric acute appendicitis.

BACKGROUND: Diagnosis of acute appendicitis (AA) and decisions about its treatment remain among the most common dilemmas of pediatric surgical teams. Monitoring of immune response may be of importance for this purpose. Our aim was to measure and analyze serum and peritoneal fluid cytokines, in children who had undergone surgery for suspected AA. METHODS: Prospective investigation of serum and peritoneal fluid cytokine values was performed in 127 consecutive patients. According to the pathohistological findings, patients were divided into three groups: normal/early, uncomplicated and complicated AA. Determination of cytokine concentrations for 20 different cytokines was done using a commercial flow cytometry kit: Human Inflammation 20 plex BMS 819. RESULTS: Statistically significant differences in serum cytokine values between pathohistological groups were found for IP-10, MIP-1α and IL-10. Preoperative cut-off values of IP-10, MIP-1α and IL-10 between groups were obtained using ROC curve analysis. Positive correlations between serum and peritoneal concentrations were recorded for most of the analyzed cytokines. CONCLUSION: IP-10, MIP-1α and IL-10 showed potential in assessment of AA in children. Confirmatory studies with a larger number of patients are required to prove reliability of these biomarkers.

Torsion of malignant ovarian tumors in childhood and adolescence.

AIM: To investigate the frequency of torsion of malignant ovarian tumors in children and adolescents. METHODS: We evaluated all patients treated for adnexal torsion in a tertiary care referral pediatric institution during the last 20 years. Presentation, tumor markers and pathology reports were evaluated. We reviewed the literature on torsion of malignant ovarian tumors. RESULTS: Ninety-two girls (age 6 months to 19 years), 41 of them premenarchal, were surgically treated for adnexal torsion. Symptoms and signs that led to clinical investigation and subsequent surgery were not specific. Histological findings of torsioned masses showed 69 non-neoplasms and 23 tumors, including five malignant. Origin of the malignant disease included four germ cell tumors and one sex-cord stromal tumor. The morphology index score for malignant tumors was > or = 7 in all five patients. Tumor markers were elevated in 12 patients, including four of the patients with malignant tumors. Complete staging was performed in three adolescents with stage Ia, IIa and IIIa of disease. We found tumor origin for 11 previous reported patients with torsion of malignant ovarian tumor, including seven germ cell and four granulosa cell tumors. CONCLUSION: Torsion of malignant ovarian tumors in pediatric and adolescent patients occurs very rarely, but it is nevertheless possible at any stage of disease. The most common torsioned malignant ovarian tumors were of germ cell origin, in both premenarchal and postmenarchal girls. A torsioned adnexal mass with index > or = 7 needs to be considered as a potential malignant tumor.

Ovarian Preservation from Tumors and Torsions in Girls: Prospective Diagnostic Study.

STUDY OBJECTIVE: To develop a new decision tree system (DTS) for the management of adnexal masses in prepubertal and adolescent girls, aimed to improve the distinction between benign and malignant masses, help preserve affected ovaries during surgery, and reduce the rate of surgical management of uncomplicated functional ovarian cysts. DESIGN: A prospective diagnostic study using clinical and ultrasound data collected for all patients younger than 19 years of age with adnexal masses managed between 2006 and 2015. SETTING: Mother and Child Health Institute of Serbia 'Dr Vukan Cupic' (Belgrade, Serbia). PARTICIPANTS: Patients (N = 1499) with adnexal masses, of whom 318 were surgically treated. INTERVENTIONS AND MAIN OUTCOME MEASURES: Ultrasonographic characteristics (Ueland's Morphology Index [MI] and the ovarian crescent sign [OCS]). Patients were managed expectantly or surgically, in line with 3 rules of the DTS. Rule 1: asymptomatic patients having a mass with MI of 4 or less and OCS present, were managed expectantly. Rule 2 (emergency): malignancy was suspected if the MI was 7 or more and no edema of the OCS was present. Rule 3 (nonemergency): malignancy was suspected if the OCS was absent and MI was 5 or more. The diagnostic accuracy was assessed using sensitivity and specificity (P < .05). RESULTS: No malignancy was found in the group of 1236 patients selected according to the DTS rule 1. Torsion was confirmed in 36% of surgically treated masses (n = 115). The OCS was present in 96% of benign masses in the non-emergency group (n = 149) and in three with microscopic malignancy. In predicting malignancy, the DTS (rules 2 and 3) showed a sensitivity of 93 (95% confidence interval [C.I.]: 82-98); and a specificity of 97 (C.I.: 95-99). Ovarian tissue was preserved from benign (n = 254, 93%) and malignant tumors (n = 3, 7%). Only five (2%) uncomplicated ovarian cysts were surgically treated. CONCLUSION: The DTS with 3 rules is a very accurate diagnostic tool in the differentiation between benign and malignant ovarian masses. The DTS rule 1 reduces the number of surgical procedures on functional cysts, rules 2 and 3 are very useful in choosing the optimal treatment of adnexal masses, whether or not they are twisted.

Pre-operative differentiation of pediatric ovarian tumors: morphological scoring system and tumor markers.

OBJECTIVE: To investigate the importance of morphological scoring systems in differentiation of ovarian tumors in childhood. METHODS: Morphological assessment using DePriest's index was performed for all patients with histopathological confirmation of ovarian tumor, with evaluation of tumor markers, from January 1997. RESULTS: Fifty-three girls (age range 13 months to 19 years) were surgically treated for 59 ovarian tumors, including six bilateral. All lesions with cystic appearance on ultrasonography were benign, 23 of 35 semisolid, and four of ten solid tumors were also benign. Stage of malignant disease was as follows: stage I, ten; stage II, two; stage III, six. Sensitivity, positive predictive value and accuracy by DePriest's and Ueland's indexes for benign tumors (score <7) were: 0.88, 0.79; 0.89; and 0.94, 0.84; 0.93; respectively. Elevated levels of tumor markers were observed in 17 patients, including four patients with endocrine manifestations. In 24 patients ovaries were successfully preserved, including two patients with foci of immature teratoma in a dermoid cyst. CONCLUSION: Ultrasonographic assessment with morphological analysis recommended by DePriest and Ueland is a very useful procedure for differentiating benign from malignant ovarian tumors in children. Tumor markers and endocrinological investigation are also useful for preoperative evaluation.

Downregulation of nicotinic and muscarinic receptor function in rats after subchronic exposure to diazinon.

Diazinon (DZN) is an organophosphate insecticide which exerts its effect through the inhibition of acetylcholinesterase enzyme (AChE). In this work, we studied the development of tolerance to subchronic p.o. administration of DZN in rats, under both in vivo and in vitro conditions. A group of 20 rats (2 groups, n = 10) was administered p.o. the 1/10 of established LD50 DZN (namely 55.87 mg/kg bw) for 28 days. On the 14th and 28th day of study with isolated diaphragm and ileum, we examined the downregulation of nicotinic and muscarinic receptor function through Electrical Field Stimulation (EFS). Maximum contractility of the diaphragm was recorded on the 14th day of the study (25% higher compared to the non-treated rats), while on the 28th day the contractions almost did not differ from the values found in non-treated rats. EFS of isolated ileum on the 14th day of study caused significantly higher contractions compared to the non-treated rats, but after 28 days, ileum contractions decreased approximately to the level of contractions in non-treated rats. On the 14th study day, we also recorded increased amplitude of spontaneous ileum contractions, compared to non-treated rats. The application of increasing ACh concentrations caused dose-dependent ileum contractions, without statistically significant differences of median effective concentration (EC50) values in non-treated and treated rats. Tolerance to subchronic DZN administration develops due to various adaptation mechanisms, including the most important one-downregulation of nicotinic and muscarinic receptor function.

Gastric tube esophageal reconstruction in children with esophageal atresia and caustic stricture Study of clinical value based on 25 single-center. Centre experience.

AIM: The aim of this study was estimation of clinical value of gastric tube esophagoplasty in children based on one single center experience. METHODS: Forty-nine patients with diagnosis of EA (n=22) and caustic esophageal injury (n=27) had undergone reverse gastric tube esophagoplasty during 25 years at our institution. Almost all EA patients received initially gastrostomy and cervical esophagostomy. Majority of CS patients had initially repeated dilatation therapy. Demographics, preoperative features (initial condition, initial treatment and nutritional status) and postoperative features (leakage, stenosis, nutritional status and disease-specific symptoms) were retrospectively reviewed and analyzed. Mean follow up time was 8.2 years. RESULTS: Of 49 patients, 2 patients died and gastric tube failed in one patient. The most common complications were anastomotic leak (52%) and anastomotic stricture (47,8%). Disease-specific symptoms (dysphagia and reflux symptoms) with important clinical manifestations were observed in 10.87% of patients. Preoperatively, all patients were eutrophic. One year after operation 96% of patients stayed eutrophic and two EA patients were malnourished. CONCLUSION: The most common complications such as anastomotic leak and anastomotic stricture may be considered benign. Postoperative nutrition, as good indicator of the procedure's adequacy, for the majority of patients is satisfactory. Gastric tube esophagoplasty is an appropriate alternative for esophageal replacement in children. KEY WORDS: Children, Gastric tube, Esophagoplasty.

Analysis of Prognostic Factors and Mortality in Children with Esophageal Atresia.

OBJECTIVE: The survival rate in newborns with congenital esophageal atresia (EA) is about 85-90 %, and it raises over 95 % in the developed countries. The survival rate in developing countries is much lower and the authors describe their experience with 60 newborns. METHODS: Medical records of 60 newborns (40 boys and 20 girls) with congenital EA were reviewed for the prognostic factors and mortality. RESULTS: The birth weight, mean Apgar score (AS) value, gestational age and birth-operative treatment time had significant influence on the mortality of treated patients (p < 0.05). Thirty five percent newborns had aspirational pneumonia at the moment of hospitalization and 86.7 % of them were operated during the first 48 h. The presence of associated anomalies considerably affected the death rate of treated patients (p < 0.05). The incidence of postoperative complications was similar to those in developed countries but the total mortality was higher (28.3 %); sepsis being the main cause of mortality. The postoperative complications and sepsis significantly influenced the mortality of patients (p < 0.05). CONCLUSIONS: Total mortality in newborns with EA was high; sepsis being the most frequent cause of death. The high total mortality was also caused by prematurity, delay in diagnosis, increased incidence of the aspiration pneumonia and shortage of qualified nurses.