The Association Between C-Reactive Protein Levels and Pediatric Appendicitis Score and the Severity of Appendicitis in Children.

BACKGROUND: Acute appendicitis is a common cause of abdominal pain leading to emergent abdominal surgery in children. C-reactive protein (CRP), an inflammatory marker typically elevated in acute appendicitis, and Pediatric Appendicitis Score (PAS), a clinical scoring system used for the diagnosis of appendicitis, have the potential to predict the severity of inflammation of the appendix. This may be useful in helping the physician make a treatment plan prior to surgery. OBJECTIVE: The purpose of this study was to assess whether CRP value and PAS differ with the extent of inflammation of the appendix seen on histologic examination. METHODS: This was a prospective observational study of patients diagnosed with acute appendicitis via computed tomography or ultrasound. Enrolled patients had CRP levels drawn, PAS calculated, and appendix pathology reviewed. Appendix pathology was categorized by the pathologist on the basis of the level of inflammation: simple, suppurative, gangrenous, and perforated. RESULTS: One hundred sixty-three patients were enrolled. CRP levels and PAS were statistically different (p < 0.002) among the four pathology classifications. Patients with simple appendicitis (n = 3) had a mean CRP of 2.95 mg/L and PAS of 3.9, patients with suppurative appendicitis (n = 99) had a mean CRP of 26.89 mg/L and PAS of 6.5, patients with gangrenous appendicitis (n = 56) had a mean CRP of 91.11 mg/L and PAS of 7.5, and patients with perforated appendicitis (n = 6) had a mean CRP of 154.17 mg/L and PAS of 7. The results remained statistically significant (p < 0.002) after adjusting for age, race, and sex. When combined-PAS ≥ 8 and CRP level > 40 mg/L-the specificity of complicated appendicitis was 91.2% and positive predictive value was 72.7%. CONCLUSIONS: Higher CRP levels and PAS were associated with increased histologic inflammation of the appendix. This study provides preliminary evidence that CRP and PAS could potentially assist in treatment decisions for appendicitis.

Clinicopathologic and molecular analysis of a BCOR-CCNB3 undifferentiated sarcoma of the kidney reveals significant epigenetic alterations.

Undifferentiated soft tissue sarcomas (UDSTSs) are a group of mesenchymal tumors that remain a diagnostic challenge because of their morphologic heterogeneity and unclear histologic origin (Peters et al., Mod Pathol28: 575 [2015]). In this case report, we present the first multiomics molecular signature for a BCOR-CCNB3 sarcoma (BCS) that includes mutation analysis, gene expression, DNA methylation, and micro RNA (miRNA) expression. We identify a paucity of additional mutations in this tumor and detail that there is significant dysregulation of gene expression of epigenetic remodeling agents including key members of the PRC, Sin3A/3b, NuRD, and NcoR/SMRT complexes and the DNA methyltransferases DNMT1, DNMT3a, and DNMT3b. This is accompanied by significant DNA methylation changes and dysregulation of multiple miRNAs with known links to tumorigenesis. This study significantly increases our understanding of the BCOR effects on fusion-positive undifferentiated sarcomas at both the genomic and epigenomic level and suggests that as better-tailored and more refined treatment algorithms continue to evolve, epigenetic modifying agents should be further evaluated for their efficacy against these tumors.

Calcifying nested stromal-epithelial tumor: a clinicopathologic and molecular genetic study of eight cases highlighting metastatic potential and recurrent CTNNB1 and TERT promoter alterations.

Calcifying nested stromal-epithelial tumor (CNSET) is a rare hepatic tumor that occurs in children and young adults. With <40 cases in the literature, the mechanism for tumorigenesis and the biological behavior of CNSET remain uncertain. Here, we studied the clinicopathologic and molecular genetic features of eight CNSETs. Six patients (75%) were female, and the median age at presentation was 22.5 years (range 14-34 years). The median tumor size was 14 cm (range 2.7-18 cm). All tumors had fibrous stroma that contained organoid nests of epithelioid to spindled tumor cells with moderate amounts of palely eosinophilic cytoplasm and ovoid, vesicular nuclei. Five tumors showed calcifications, and one showed lymphovascular invasion. Necrosis was absent in all. Immunohistochemistry demonstrated nuclear ß-catenin expression in five of five tested tumors and focal to diffuse nuclear WT-1 positivity in five of seven. Hepatocellular markers (HepPar-1, arginase-1, and albumin in situ hybridization) and neuroendocrine markers (synaptophysin, chromogranin, and INSM1) were uniformly negative. Next-generation sequencing demonstrated CTNNB1 alterations in all seven sequenced tumors. Sanger sequencing demonstrated TERT promoter mutations in all six sequenced tumors. Clinical follow-up was available for seven patients (median duration 4.4 years; range 1.2-6.2 years): four (57%) developed metastatic disease; all four developed lung metastases; and two also had abdominal metastases. All four patients with metastatic disease also had persistent or recurrent liver tumors. Three patients with metastases were alive with disease at the most recent follow-up and one died of disease. The other three patients with available follow-up did not develop metastasis or recurrence. One tumor treated with neoadjuvant chemotherapy showed no response, and another showed 90% tumor fibrosis; the latter patient remained disease-free at 6.2 years of follow-up. Our series demonstrates the presence of TERT promoter mutations and CTNNB1 alterations in all sequenced tumors and suggests that CNSET might perhaps be more aggressive than previously reported.

Anaplastic lymphoma kinase inhibitor therapy in the treatment of inflammatory myofibroblastic tumors in pediatric patients: Case reports and literature review.

BACKGROUND: Inflammatory myofibroblastic tumors (IMTs) are a rare subtype of inflammatory pseudotumor frequently associated with rearrangement of the anaplastic lymphoma kinase (ALK) gene. Their treatment has historically relied on at-times challenging and morbid surgical excision. Recent studies have shown that neo/adjuvant therapy with ALK inhibitors can significantly enhance outcomes in select patients. METHODS: A systematic literature review was performed to characterize comprehensive treatment of ALK-positive IMTs in the pediatric population. This report also includes two patients from our home institutions not previously reported in the literature. RESULTS: We identified a total of 27 patients in 12 studies in addition to 2 patients from the senior authors' institution for a total of 29 patients (median age, 7 years; 52% male). The IMTs comprised a wide range of anatomic locations. Almost half (12, 41.3%) were treated with ALK-inhibitors alone and felt to be in remission. The remainder was treated with ALK-inhibitors either before or after surgery and had a curative response. CONCLUSIONS: ALK-positive IMTs can be successfully treated with ALK-inhibition alone or in combination with surgical resection. Further genetic characterization may be helpful in determining more precise treatment and defining needed durations thereof.

Do Histological Features of Eosinophilic Esophagitis in Children Correlate With Peripheral Eosinophils?

AIM: Eosinophilic esophagitis (EoE) is a chronic, relapsing inflammatory disease of the esophagus. We investigate whether peripheral eosinophils can be a good indicator of esophageal eosinophilia and whether they correlate with histological findings, such as basilar hyperplasia, spongiosis, microabscesses, number of lymphocytes, and number of neutrophils. METHODS: A retrospective chart review was conducted with EoE patients ages <18 years after obtaining IRB approval. Biopsies obtained from 57 EoE patients were analyzed. Patient demographics, symptoms; complete blood count with differentials obtained at the time of endoscopies or within a month of the procedure, were documented. RESULTS: A significant correlation was observed between peripheral absolute eosinophil count (AEC) and peak esophageal eosinophil count (P value: 0.0009). Subjects with biopsies suggestive of ongoing disease activity or active status had a higher mean of AEC at 577.41 ±â€Š202.60 compared with subjects with inactivity with mean of 305.26 ±â€Š526.67. However, when the subjects were broadly divided with 500 AEC as a cut off (<500 and >500 AEC), it was found that, out of 27 EoE inactive patients, 24 had AEC count less than or equal to 500 and out of 66 EoE active patients, 32 had AEC more than 500. CONCLUSION: Active EoE status meant a higher mean of AEC compared with inactive status; but AEC was not found to be a sensitive tool for detecting active EoE.

Anemia in Pediatric Inflammatory Bowel Disease.

OBJECTIVES: Anemia is the most frequent extra-intestinal finding in inflammatory bowel disease (IBD). The aim of this study is to determine the prevalence and types of anemia in pediatric patients with IBD at diagnosis and at approximately 1 year follow-up. METHODS: This is a retrospective chart review of patients diagnosed with IBD from 2005 to 2012, ages 1 to 18 years. Patients who had hemoglobin, hematocrit, mean corpuscular volume, and iron indices obtained at the time of diagnosis and at approximately 1 year follow-up were included in the study. The prevalence of anemia at the beginning and the end of the study was recorded. Using the soluble transferrin receptor index the type of anemia was determined. RESULTS: At diagnosis, 67.31% of patients were anemic. Overall, 28.85% of patients had either iron deficiency anemia (IDA) or a combination of IDA and anemia of chronic disease (ACD), whereas 38.46% had ACD alone. At follow-up, 20.51% were anemic. 15.38% had either IDA or a combination of IDA and ACD; 5.13% had ACD alone. The pattern of anemia and response to therapy differed among the IBD phenotypes CONCLUSIONS:: Anemia is frequent in inflammatory bowel disease. The prevalence was higher in Crohn disease (CD). At 1 year, the prevalence of anemia decreased significantly, but persisted. Anemia of chronic disease predominated in CD. Iron deficiency anemia continued to be present in CD and ulcerative colitis.

Multi-targeting therapeutic mechanisms of the Chinese herbal medicine QHD in the treatment of non-alcoholic fatty liver disease.

Beneficial effects of the Chinese herbal medicine Qushi Huayu Decoction (QHD) were observed with non-alcoholic fatty liver disease (NAFLD) patients and animal models. The impact of QHD or its active components (geniposide and chlorogenic acid, GC) on NAFLD liver transcriptome and gut microbiota was examined with NAFLD rats. Increased expression for genes required for glutathione production and decreased expression for genes required for lipid synthesis was observed in NAFLD livers treated with QHD and GC. GC treatment decreased serum LPS, which could be explained by reduced mucosal damage in the colon of GC-treated rats. Further, our data suggest an increased abundance of Treg-inducing bacteria that stimulated the Treg activity in GC treated colon, which in turn down-regulated inflammatory signals, improved gut barrier function and consequently reduced hepatic exposure to microbial products. Our study suggests that QHD simultaneously enhanced the hepatic anti-oxidative mechanism, decreased hepatic lipid synthesis, and promoted the regulatory T cell inducing microbiota in the gut.

Early Use of Inhaled Nitric Oxide in Preterm Infants: Is there a Rationale for Selective Approach?

Background Inhaled nitric oxide (iNO) is being increasingly used in preterm infants < 34 weeks with hypoxemic respiratory failure (HRF) and/or pulmonary hypertension (PH). Objective To evaluate the risk factors, survival characteristics, and lung histopathology in preterm infants with PH/HRF. Methods Retrospective chart review was conducted to determine characteristics of 93 preterm infants treated with iNO in the first 28 days and compared with 930 matched controls. Factors associated with survival with preterm HRF and smooth muscle actin from nine autopsies were evaluated. Results Preterm neonates treated with iNO had a higher incidence of preterm prolonged rupture of membrane (pPROM ≥ 18 hours), oligohydramnios and delivered by C-section. In infants treated with iNO, antenatal steroids (odds ratio [OR],3.7; confidence interval [CI], 1.2-11.3; p = 0.02), pPROM (OR, 1.001; CI, 1.0-1.004; p = 0.3), and oxygenation response to iNO (OR, 3.7; CI, 1.08-13.1; p = 0.037) were associated with survival. Thirteen infants with all three characteristics had 100% (13/13) survival without severe intraventricular hemorrhage (IVH)/periventricular leukomalacia (PVL) compared with 48% survival (12/25, p = 0.004) and 16% severe IVH/PVL without any of these factors. Severity of HRF correlated with increased smooth muscle in pulmonary vasculature. Conclusion Preterm infants with HRF exposed to antenatal steroids and pPROM had improved oxygenation with iNO and survival without severe IVH/PVL. Precisely targeting this subset may be beneficial in future trials of iNO.

Presenting Pattern of Pediatric Celiac Disease.

OBJECTIVES: Celiac disease (CD) is an autoimmune disease that can be complicated by impaired nutrition and growth. With the development of sensitive serologic tests, safe endoscopy, and efforts to educate primary care physicians, more children are diagnosed as having CD. The aim of this study is to evaluate the pattern of the presentation of pediatric CD in western New York. METHODS: Chart review of pediatric patients with CD was undertaken. Patients' demographics, presenting features, disaccharidase assay (DA), celiac serology, and Marsh score were reviewed from patients seen at the Digestive Diseases and Nutrition Center, State University of New York at Buffalo from January 2003 through March 2013. RESULTS: A total of 165 patients with CD were evaluated. Mean age was 10.7 ± 4.3 years, 76 male patients. The presenting features were abdominal pain (n = 87, 52.7%), constipation (n = 65, 38.9%), diarrhea (n = 52, 31.1%), family history of first-degree relative (n = 47, 28.1%), diabetes mellitus type 1 (n = 37, 22.2%), failure to thrive (n = 36, 21.8%), reflux (n = 25, 15.1%), vomiting (n = 24, 14.5%), fatigue (n = 15, 9%), short stature (n = 9, 5.4%), thyroid disease (n = 9, 5.4%), Down syndrome (n = 8, 4.8%). We found no correlation between Marsh score and serum tissue transglutaminase (tTG) immunoglobulin (Ig) A level at diagnosis and no correlation between DA and serum tTG IgA level, presenting feature and tTG IgA level, presenting feature and Marsh score, tTG IgA and DA, or between the age and the presenting feature. CONCLUSIONS: Children newly diagnosed as having CD in western New York presented most frequently with abdominal pain and constipation and were older at the time of diagnosis than those described in the classical presentation of CD. We speculate that our patients may have a different long-term natural history and risk factors than originally described for patients with CD.

Induction of CYP2E1 in non-alcoholic fatty liver diseases.

Mounting evidence supports a contribution of endogenous alcohol metabolism in the pathogenesis of non-alcoholic steatohepatitis (NASH). However, it is not known whether the expression of alcohol metabolism genes is altered in the livers of simple steatosis. There is also a current debate on whether fatty acids induce CYP2E1 in fatty livers. In this study, expression of alcohol metabolizing genes in the liver biopsies of simple steatosis patients was examined by quantitative real-time PCR (qRT-PCR), in comparison to biopsies of NASH livers and normal controls. Induction of alcohol metabolizing genes was also examined in cultured HepG2 cells treated with ethanol or oleic acid, by qRT-PCR and Western blots. We found that the mRNA expression of alcohol metabolizing genes including ADH1C, ADH4, ADH6, catalase and CYP2E1 was elevated in the livers of simple steatosis, to similar levels found in NASH livers. In cultured HepG2 cells, ethanol induced the expression of CYP2E1 mRNA and protein, but not ADH4 or ADH6; oleic acid did not induce any of these genes. These results suggest that elevated alcohol metabolism may contribute to the pathogenesis of NAFLD at the stage of simple steatosis as well as more severe stages. Our in vitro data support that CYP2E1 is induced by endogenous alcohol but not by fatty acids.

Novel pathway for iron deficiency in pediatric non-alcoholic steatohepatitis.

BACKGROUND & AIMS: Iron may be an important factor in the pathogenesis of non-alcoholic steatohepatitis (NASH) as it catalyzes the production of potent reactive oxygen species. We aim to examine iron status in pediatric NASH. METHODS: Serum indices of NASH patients (N = 36) were compared to those in the U.S. National Health and Nutrition Examination Survey database (N = 802). Iron related gene expression was examined in NASH livers and normal livers, using microarray and quantitative real-time PCR (10 NASH livers and 6 controls). Transferrin and catalase expression were also examined in hydrogen peroxide treated HepG2 cells. RESULTS: Serum iron concentration (P < 0.01) and soluble transferrin receptor 1 (P < 0.0001) were decreased while serum ferritin was elevated in NASH patients (P < 0.01). No detectable iron was observed in NASH liver by Perls' Prussian blue staining. Transferrin (P < 0.01) and transferrin receptor 2 (P < 0.01) mRNA were elevated in NASH patients. Of particular interest, transferrin mRNA was positively correlated with catalase mRNA (r = 0.9338, P < 0.0001). H2O2 treatment of HepG2 cells induced mRNA expression of transferrin and catalase. CONCLUSIONS: Pediatric NASH patients exhibited decreased serum iron concentration and no detectable iron was observed in any NASH liver by Perls' Prussian blue staining. These changes are consistent with the facts that most NASH patients are obese and exhibit chronic inflammation. In line with a status of iron deficiency, gene expression studies suggested decreased expression of transferrin and transferrin receptor 2 in NASH livers. Induction of transferrin by H2O2, and consequently, decreased iron absorption, suggests a novel mechanism for iron deficiency in NASH patients.

Evaluation of calretinin immunohistochemistry as an additional tool in confirming the diagnosis of Hirschsprung disease.

Hirschsprung disease (HD) is a congenital malformation defined as the absence of myenteric and submucosal ganglion cells (GCs) in the distal rectum and variable length of the contiguous bowel. The aim of this study was to assess the utility of calretinin immunochemistry in comparison with that of standard histology complemented with acetylcholinesterase (AChE) histochemistry routinely employed at our institution to evaluate rectal biopsies carried out for suspicion of HD. Twenty-one rectal biopsies were reviewed, including 14 from patients with suspected HD, 6 from infants with necrotizing enterocolitis (NEC), and 1 from a patient diagnosed with spontaneous intestinal perforation (SIP). Sections stained with hematoxylin-eosin (HE) revealed absence of ganglion cells in 13 cases which included 11 patients with HD and 2 patients with NEC. Among 13 cases of aganglionosis the AChE reaction pattern was consistent with HD in 2 patients. Calretinin positivity was observed in all rectal biopsies showing the presence of GC, and the staining was consistently absent in all cases of aganglionosis. In 6 rectal biopsies in which abnormal acetylcholinesterase (AChE) staining was not seen, loss of calretinin immunoreactivity helped establish the diagnosis of HD.

Early prenatal detection of an intra-abdominal cryptorchid testicular teratoma.

Intra-abdominal prenatally detected testicular neoplasms are rare; however, increased use of prenatal ultrasonography has led to the discovery of these uncommon neoplasms. We report the fifth case of a prenatally detected intra-abdominal testicular teratoma, which, in this instance, was detected early in pregnancy as a cystic mass within the fetal abdomen that subsequently underwent torsion later in pregnancy before delivery.

Immunoglobulin G4-related sclerosing disease with orbital inflammation in a 12-year-old girl.

Immunoglobulin G4-related sclerosing disease is a rare but potentially debilitating cause of orbital inflammation, with a predilection for older males. We report the case of a 12-year-old African girl with immunoglobulin G4-related sclerosing disease, including possible extraorbital involvement. Because of an escalating severity of illness leading to oculomotor nerve palsy and cavernous sinus thrombosis that was resistant to steroids, systemic immunosuppressive therapy with rituximab was used to achieve disease remission. The diagnosis was histologically confirmed with a tissue biopsy.

Vulvar atypical granular cell tumor in a preadolescent patient.

BACKGROUND: Granular cell tumor is an uncommon benign neoplasm with a predisposition for upper aerodigestive tract, skin and soft tissue involvement. Malignant and atypical granular cell tumors account for less than 2% of the lesions and in the pediatric population they are extremely rare and atypia has not been previously reported. CASE: We present a case of a rapidly growing granular cell tumor of the vulva of a 12-year-old girl exhibiting atypical histology. The lesion demonstrated prominent Ki-67 proliferation index (up to 20%), localized areas of spindling of tumor cells, scattered apoptotic bodies and p53 overexpression. CONCLUSION: The current histologic diagnostic criteria of atypical granular cell tumors are evaluated while physician awareness and the need for follow-up of patients for potential recurrences of this rare entity are emphasized.