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.

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.

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.

Ovarian yolk sac tumor associated with major fibrosarcoma component in a 13-year-old girl.

We are presenting a case of a 13-year-old girl with a chief complaint of lower abdominal pain. A computed tomographic scan showed a 10-cm right ovarian mass. The serologic testing showed high alpha-fetoprotein level. The patient underwent a right adnexectomy and an omentectomy. The final diagnosis was a yolk sac tumor with a major (95%) fibrosarcoma component, based on morphology and further confirmed by an extensive panel of immunohistochemistry. Postoperatively, the alpha-fetoprotein level dropped to normal. The patient completed 7 cycles of multiagent chemotherapy with cisplatin without major complications. At her 7-month follow-up, the patient still remains disease free. To our knowledge, our case is the first of its kind in the literature to document yolk sac tumor associated with fibrosarcoma in a teenage female. Owing to the rarity of this entity, the prognosis of this patient is widely unknown and it is yet still to be seen.

Magnetic resonance urography in the evaluation of prenatally diagnosed hydronephrosis and renal dysgenesis.

PURPOSE: We present our experience with dynamic contrast enhanced magnetic resonance urography for evaluation and treatment in infants born with prenatally recognized hydronephrosis. We determined the characteristics of renal dysgenesis in this population. MATERIALS AND METHODS: We reviewed magnetic resonance urography images done within the first 6 months of life in 67 infants born with prenatally recognized hydronephrosis. High resolution imaging was used to establish a morphological diagnosis. Functional evaluation was used to assess obstruction and individual renal function. Voiding cystourethrography was performed in 62 patients. RESULTS: Our study included 67 infants (87 renal units). There were 54 boys and 13 girls with a mean age of 2.8 months (range 0.9 to 4.6). Of these 87 renal units 30 (35%) had ureteropelvic junction obstruction, 18 (21%) had primary megaureters, 10 (11%) had nondilating vesicoureteral reflux, 10 (11%) had fetal folds, 8 (9%) had posterior urethral valves, 6 (7%) had ectopic ureters, 4 (5%) had multicystic dysplastic kidneys and 1 (1%) had a normal study. Magnetic resonance urography revealed renal dysgenesis in 24 renal units (28%), consisting of loss of corticomedullary differentiation, renal cystic changes distinct from multicystic dysplastic kidneys, solid renal dysplasia, hypoplasia and dysmorphic calyces. CONCLUSIONS: Magnetic resonance urography is an excellent addition to our armamentarium for evaluating neonatal hydronephrosis and renal dysgenesis. Due to its comprehensiveness magnetic resonance urography has the potential to become the study of choice for evaluating infants with significant prenatally recognized hydronephrosis. However, further prospective, comparative studies in larger patient populations are needed to justify the cost and the need for sedation in infants.

Cyclooxygenase-2 expression does not correlate with outcome in osteosarcoma or rhabdomyosarcoma.

PURPOSE: To determine if expression of cyclooxygenase (COX)-2, an inducible enzyme with known tumor-promoting activity, correlates with outcome in pediatric sarcomas. COX-2 overexpression correlates with more aggressive disease in a variety of adult solid tumors. METHODS: Archived human osteosarcoma, rhabdomyosarcoma, and Ewing sarcoma tumors were retrospectively evaluated, blinded to outcome, for COX-2 expression by immunohistochemistry and correlated with patient characteristics and survival. RESULTS: COX-2 expression was detected in 94 of 142 (66%) tumors (osteosarcoma, 66/99 [67%]; rhabdomyosarcoma, 21/35 [60%]; Ewing sarcoma, 7/8 [88%]) and 51 of 85 (60%) diagnostic biopsies (osteosarcoma, 26/45 [58%]; rhabdomyosarcoma, 21/35 [60%]; Ewing sarcoma, 4/5 [80%]). COX-2 expression did not vary with clinicopathologic features and was not predictive of prognosis in these cases. CONCLUSIONS: This study does not support the use of COX-2 expression as an upfront prognostic variable in patients with osteosarcoma or rhabdomyosarcoma. Results from the small number of patients studied with Ewing sarcoma suggest a similar lack of predictive value for COX-2 expression. However, COX-2 inhibitors are not entirely dependent upon enzyme expression for their antitumor effects; this study does not necessarily preclude the use of COX-2 inhibitors for the treatment of pediatric sarcomas.

Cyclooxygenase-2 expression in pediatric sarcomas.

Therapies for metastatic pediatric sarcomas have reached maximum tolerated doses, but continue to provide suboptimal cure rates. Additionally, these treatments are associated with numerous short- and long-term side effects. Therefore, the search for newer, less toxic therapeutic agents is warranted. Overexpression of the inducible enzyme, cyclooxygenase-2 (COX-2), has been discovered in a variety of adult solid tumors and numerous studies have shown COX-2 inhibitors to have significant antiproliferative effects. Therefore, we sought to determine the expression of COX-2 in pediatric sarcomas. We evaluated rhabdomyosarcoma (RMS), osteosarcoma (OS), and Ewing sarcoma (EWS) samples for COX-2 expression by immunohistochemical analysis as well as by cDNA microarray analysis. COX-2 expression was detected in 48/58 (82.8%) tumors by immunohistochemistry and in an additional 52/59 (88.1%) tumors tested by microarray gene analysis. There was a trend toward increased COX-2 expression in metastatic rhabdomyosarcoma and osteosarcoma, though it did not reach clinical significance. The degree of COX-2 immunoreactivity did not vary significantly with other clinicopathologic features such as age, gender, or histologic classification. We conclude that the majority of these pediatric sarcoma samples express COX-2 to varying degrees. Therefore, studies testing the efficacy of COX-2 inhibitors in the treatment of pediatric sarcomas are warranted.