Feasibility of 18F-DOPA and 18F-FDG PET/CT for guiding decision-making for localized incidental neuroblastoma in infants under 18 months of age.

BACKGROUND: Neuroblastoma varies widely in risk. Risk indicators in infants with incidental neuroblastoma refine treatment confidence for observation or intervention. The potential of functional imaging, particularly PET/CT, remains to be defined. PROCEDURE: A retrospective review of infants under 18 months diagnosed with incidental neuroblastoma from 2008 to May 2022 in our institute was conducted. Before October 2015, incidental patients were treated similarly to symptomatic cases, undergoing biopsy or surgical excision upon diagnosis (early cohort). Post October 2015 (late cohort), treatment decisions were guided by PET/CT findings, with 18F-DOPA PET/CT confirming diagnosis and staging. For tumors with low 18F-FDG uptake, an expectant observation approach was considered. Patient characteristics, diagnostic methods, image findings at diagnosis, treatment courses, and responses were compared between cohorts. RESULTS: Thirty infants less than 18 months were identified with incidental neuroblastoma and completed PET/CT at diagnosis. The early and late cohorts each comprised 15 patients. In the late cohort, nine out of 15 patients (60%) presented with localized FDG non-avid tumors were offered the option of expectant observation. Of these, seven patients opted for observation, thereby avoiding surgery. Treatment outcomes were comparable between early and late cohorts, except for one mortality of a patient who, despite showing 18F-FDG activity, declined treatment. CONCLUSIONS: This study demonstrates the potential utility of 18F-DOPA and 18F-FDG PET/CT scans in aiding clinical decision-making for infants with localized, incidental neuroblastoma. Given the concerns regarding radiation exposure, such imaging may be valuable for cases with suspected metastasis, initial large tumor size, or growth during follow-up.

The magnetic resonance imaging and age-adjusted matrix metalloproteinase-7 assist the diagnosis of biliary atresia.

BACKGROUND: We investigated the utilities of the liver-to-psoas apparent diffusion coefficient ratios (LTPAR) yielded by diffusion-weighted magnetic resonance imaging (DWMRI) and the age-adjusted serum matrix metalloproteinase-7 (MMP-7) for the diagnosis of biliary atresia (BA) in cholestatic infants. METHODS: In total, 170 cholestatic infants were recruited, of whom 50 (29.41%) were diagnosed with BA after cholestatic workups. The LTPAR and MMP7 levels were assessed. RESULTS: The LTPAR was significantly lower in BA infants, and the age-adjusted MMP7 ratio was significantly higher, compared to other cholestatic infants (both p < 0.001). Receiver operating characteristic curve analysis yielded a cutoff > 0.1 ng/mL.day for the age-adjusted MMP-7 ratio, and an LTPAR < 1.01 for the optimal prediction of BA (both p < 0.001). Univariate logistic regression analysis revealed that both an age-adjusted MMP-7 ratio > 0.1 ng/mL.day and an LTPAR < 1.01 were significant predictors of BA among cholestatic infants (odds ratio = 30.98 and 13.28; p < 0.001 and < 0.001, respectively). The significance of the age-adjusted MMP-7 ratio and the LTPAR persisted on multivariate logistic regression analysis after adjusting for sex and the serum gamma-glutamyl transferase level (p < 0.001 and < 0.001, respectively). The negative predictive values (NPVs) for BA were 91.49% and 94.17%, respectively, for the LTPAR and age-adjusted MMP-7 ratio. CONCLUSION: The age-adjusted MMP-7 ratio and the LTPAR are both significant non-invasive predictors of BA. The consideration of both serum and imaging parameters may enhance BA diagnostic performance in cholestatic infants.

Clinical utility of anal sphincter relaxation integral in water-perfused and solid-state high-resolution anorectal manometry.

BACKGROUND/PURPOSE: We investigated the diagnostic performance of the anal sphincter relaxation integral (ASRI) for infants with Hirschsprung's disease (HD). METHODS: We performed water-perfused high-resolution anorectal manometry (HRAM) in 18 infants (9 with HD), and solid-state HRAM in another 18 infants (4 with HD). We calculated the ASRI during the rectoanal inhibitory reflex (RAIR) maneuver at pressure cutoffs of <10 mmHg (ASRI 10) and <15 mmHg (ASRI 15). We investigated the diagnostic performance of the ASRI for HD in infants undergoing water-perfused and solid-state HRAM. RESULTS: HD infants who underwent either water-perfused or solid-state HRAM had significantly lower ASRI 10 and ASRI 15 values, compared with non-HD infants (P < 0.05 and P < 0.05, respectively). Using the water-perfused HRAM system, ASRI 10 and ASRI 15 values of <7 and <29 mmHg s.cm, respectively, exhibited good diagnostic performance for HD (88.89% and 88.89%, respectively). Receiver operating characteristic curve analysis indicated that ASRI 10 and ASRI 15 values of <5.5 and <20 mmHg s.cm, respectively, were optimal for the diagnosis of HD infants when using the solid-state HRAM system, with high diagnostic accuracies of 83.33% and 83.33%, respectively. CONCLUSION: ASRI may assist the diagnosis of HD infants using either water-perfused or solid-state HRAM. These systems require different catheter-specific ASRI cutoffs for the prediction of HD.

The prevalence and impact of small intestine bacterial overgrowth in biliary atresia patients.

BACKGROUND: Acute cholangitis is an ominous complication in biliary atresia (BA) patients. We investigated the prevalence of small intestine bacterial overgrowth (SIBO) in BA patients and its role in predicting acute cholangitis. METHODS: There are 69 BA patients with native liver recruited into this study prospectively. They received hydrogen and methane-based breath testing (HMBT) to detect SIBO after recruitment and were followed prospectively in our institute. RESULTS: There are 16 (23.19%) subjects detected to have SIBO by HMBT. BA subjects with SIBO were noted to have higher serum alanine aminotransferase levels than others without SIBO (P = 0.03). The risk of acute cholangitis is significantly higher in BA patients with SIBO than in others without SIBO (62.50% vs. 15.09%, P < 0.001). The logistic regression analysis demonstrated that BA subjects with SIBO have a higher risk of acute cholangitis than others without SIBO (odds ratio = 9.38, P = 0.001). Cox's proportional hazard analysis further confirmed the phenomena in survival analysis (hazard ratio = 6.43, P < 0.001). CONCLUSIONS: The prevalence of SIBO in BA patients is 23.19% in this study. The presence of SIBO is associated with the occurrence of acute cholangitis in BA patients. IMPACT: What is the key message of your article? Acute cholangitis is common in BA, and is associated with SIBO after hepatoportoenterostomy in this study. What does it add to the existing literature? This study demonstrated that SIBO is common in BA after hepatoportoenterostomy, and is predictive of acute cholangitis and elevated serum ALT levels in BA. What is the impact? This prospective cohort study provides data regarding the significance of SIBO on the risk of acute cholangitis in BA patients.

Genotype-phenotype correlation in Taiwanese children with diazoxide-unresponsive congenital hyperinsulinism.

Objective: Congenital hyperinsulinism (CHI) is a group of clinically and genetically heterogeneous disorders characterized by dysregulated insulin secretion. The aim of the study was to elucidate genetic etiologies of Taiwanese children with the most severe diazoxide-unresponsive CHI and analyze their genotype-phenotype correlations. Methods: We combined Sanger with whole exome sequencing (WES) to analyze CHI-related genes. The allele frequency of the most common variant was estimated by single-nucleotide polymorphism haplotype analysis. The functional effects of the ATP-sensitive potassium (KATP) channel variants were assessed using patch clamp recording and Western blot. Results: Nine of 13 (69%) patients with ten different pathogenic variants (7 in ABCC8, 2 in KCNJ11 and 1 in GCK) were identified by the combined sequencing. The variant ABCC8 p.T1042QfsX75 identified in three probands was located in a specific haplotype. Functional study revealed the human SUR1 (hSUR1)-L366F KATP channels failed to respond to intracellular MgADP and diazoxide while hSUR1-R797Q and hSUR1-R1393C KATP channels were defective in trafficking. One patient had a de novo dominant mutation in the GCK gene (p.I211F), and WES revealed mosaicism of this variant from another patient. Conclusion: Pathogenic variants in KATP channels are the most common underlying cause of diazoxide-unresponsive CHI in the Taiwanese cohort. The p.T1042QfsX75 variant in the ABCC8 gene is highly suggestive of a founder effect. The I211F mutation in the GCK gene and three rare SUR1 variants associated with defective gating (p.L366F) or traffic (p.R797Q and p.R1393C) KATP channels are also associated with the diazoxide-unresponsive phenotype.

Homoharringtonine as a PHGDH inhibitor: Unraveling metabolic dependencies and developing a potent therapeutic strategy for high-risk neuroblastoma.

Neuroblastoma, a childhood cancer affecting the sympathetic nervous system, continues to challenge the development of potent treatments due to the limited availability of druggable targets for this aggressive illness. Recent investigations have uncovered that phosphoglycerate dehydrogenase (PHGDH), an essential enzyme for de novo serine synthesis, serves as a non-oncogene dependency in high-risk neuroblastoma. In this study, we show that homoharringtonine (HHT) acts as a PHGDH inhibitor, inducing intricate alterations in cellular metabolism, and thus providing an efficient treatment for neuroblastoma. We have experimentally verified the reliance of neuroblastoma on PHGDH and employed molecular docking, thermodynamic evaluations, and X-ray crystallography techniques to determine the bond interactions between HHT and PHGDH. Administering HHT to treat neuroblastoma resulted in effective cell elimination in vitro and tumor reduction in vivo. Metabolite and functional assessments additionally disclosed that HHT treatment suppressed de novo serine synthesis, initiating intricate metabolic reconfiguration and oxidative stress in neuroblastoma. Collectively, these discoveries highlight the potential of targeting PHGDH using HHT as a potent approach for managing high-risk neuroblastoma.

ONC201 Suppresses Neuroblastoma Growth by Interrupting Mitochondrial Function and Reactivating Nuclear ATRX Expression While Decreasing MYCN.

Neuroblastoma (NB) is characterized by several malignant phenotypes that are difficult to treat effectively without combination therapy. The therapeutic implication of mitochondrial ClpXP protease ClpP and ClpX has been verified in several malignancies, but is unknown in NB. Firstly, we observed a significant increase in ClpP and ClpX expression in immature and mature ganglion cells as compared to more malignant neuroblasts and less malignant Schwannian-stroma-dominant cell types in human neuroblastoma tissues. We used ONC201 targeting ClpXP to treat NB cells, and found a significant suppression of mitochondrial protease, i.e., ClpP and ClpX, expression and downregulation of mitochondrial respiratory chain subunits SDHB and NDUFS1. The latter was associated with a state of energy depletion, increased reactive oxygen species, and decreased mitochondrial membrane potential, consequently promoting apoptosis and suppressing cell growth of NB. Treatment of NB cells with ONC201 as well as the genetic attenuation of ClpP and ClpX through specific short interfering RNA (siRNA) resulted in the significant upregulation of the tumor suppressor alpha thalassemia/mental retardation X-linked (ATRX) and promotion of neurite outgrowth, implicating mitochondrial ClpXP proteases in MYCN-amplified NB cell differentiation. Furthermore, ONC201 treatment significantly decreased MYCN protein expression and suppressed tumor formation with the reactivation of ATRX expression in MYCN-amplified NB-cell-derived xenograft tumors. Taken together, ONC201 could be the potential agent to provide diversified therapeutic application in NB, particularly in NB with MYCN amplification.

Surgical resection for congenital lung malformation: Lessons learned from thoracotomy to biportal thoracoscopy under one-lung ventilation.

BACKGROUND: The purpose of this study is to compare the clinical characteristics and surgical outcomes of thoracotomy and video-assisted thoracoscopic surgery (VATS) in children with congenital lung malformations (CLMs) in a tertiary referring center and to report our modified biportal VATS setting. METHODS: This is a single-center retrospective chart review study including children who underwent surgical resection for CLMs between January 2007 and December 2020. Patient characteristics and surgical outcomes were compared between open and thoracoscopy, as well as conventional VATS and biportal VATS. Biportal setting included an anterior utility wound and a camera trocar wound with one-lung ventilation. RESULTS: A total of 100 patients were identified. Twenty patients received thoracotomy, and 80 patients received VATS (67 conventional and 13 biportal VATS). The median age at operation was 0.4 months in the thoracotomy group and 4.7 months in the VATS group. More patients in the thoracotomy group had preoperative symptoms, comorbidities, and emergent operations. The patients who underwent thoracotomy had significantly longer postoperative ICU stays, chest tube durations, hospital stays, and more complications. The pathological analysis revealed 67 congenital pulmonary airway malformations, 27 pulmonary sequestration, 6 hybrid lesions, and one accompanying pleuropulmonary blastoma. Compared to conventional VATS, the ICU stay was shorter in the biportal VATS group, with comparable operative durations, hospital stay and complications. CONCLUSION: VATS for CLMs is associated with better postoperative recovery and fewer complications. Biportal VATS is also a safe and feasible approach.

C1GALT1 expression predicts a favorable prognosis and suppresses malignant phenotypes via TrkA signaling in neuroblastoma.

Neuroblastoma (NB) is a childhood tumor derived from the sympathoadrenal lineage of the neural crest progenitor cells. Core 1 ß1,3-galactosyltransferase (C1GALT1) controls the crucial step of GalNAc-type O-glycosylation, and its altered expression affects cancer behaviors. However, the role of C1GALT1 in NB tumors remains unclear. Our data showed that C1GALT1 expression was significantly associated with differentiated tumor histology, correlated with TrkA expression, and predicted good prognosis independently in NB. Downregulation of C1GALT1 promotes malignant behaviors of NB cells in vitro and in vivo. Mechanistic investigation showed that knockdown of C1GALT1 in NB cells increased TrkA pulled down through Vicia villosa agglutinin beads, indicating the modulation of O-glycans on TrkA by C1GALT1, and silencing C1GALT1 suppressed the TrkA expression on the NB cell surface. Overexpression of C1GALT1 increased the protein levels of TrkA and promoted the differentiation of NB cells, whereas knockdown of TrkA inhibited C1GALT1-induced neuronal differentiation. Moreover, the inhibitory effects of migration and invasion in C1GALT1-overexpressing NB cells were blocked by TrkA downregulation. C1GALT1 knockdown enhanced AKT phosphorylation but attenuated ERK phosphorylation, and these properties were consistent in C1GALT1-overexpressing NB cells with TrkA knockdown. Taken together, our data provided the first evidence for the existence of GalNAc-type O-glycans on TrkA and altered O-glycan structures by C1GALT1 can regulate TrkA signaling in NB cells. This study sheds light on the novel prognostic role of C1GALT1 in NB and provides new information of C1GALT1 and TrkA on the pathogenesis of NB.

Prognostic Value of Interim 18F-DOPA and 18F-FDG PET/CT Findings in Stage 3-4 Pediatric Neuroblastoma.

PURPOSE: This retrospective study aimed to determine the prognostic value of imaging parameters derived from midtherapy 18F-fluorodihydroxyphenylalanine (18F-DOPA) and 18F-FDG PET in pediatric patients with stage 3-4 neuroblastoma. METHODS: We enrolled 32 stage 3-4 pediatric neuroblastoma patients who underwent 18F-DOPA and 18F-FDG PET/CT scans before and after 3 chemotherapy cycles. We measured metabolic and volumetric parameters and applied a metabolic burden scoring system to evaluate the primary tumor extent and soft tissue metastases and that of bone/bone marrow involvement. The associations between these parameters and clinical outcomes were investigated. RESULTS: Over a median follow-up period of 47 months (range, 3-137 months), 16 patients experienced disease progression, and 13 died. After adjustment for clinical factors, multivariate Cox proportional hazard models showed that interim tumor FDG/FDOPA SUVmax (hazard ratio [HR], 5.94; 95% confidence interval [CI], 1.10-34.98) and interim FDOPA whole-body metabolic burden scores (WBMB) (HR, 7.30; 95% CI, 1.50-35.50) were significant prognostic factors for overall survival (OS). Only interim FDOPA WBMB scores (HR, 7.05; 95% CI, 1.02-48.7) were predictive of progression-free survival. Based on median cutoff values, prognosis (OS and progression-free survival) was significantly associated with an interim FDOPA WBMB score ≥21.92 (all P < 0.05) and interim tumor FDG/FDOPA (SUVmax) score ≥0.57 with poor OS (P < 0.05). CONCLUSIONS: Our results indicate that midtreatment FDG and FDOPA PET/CT could serve as prognostic markers in stage 3-4 neuroblastoma patients.

The Clinical Feature and Treatment Outcome of Ocular Melanoma: A 34-Year Experience in a Tertiary Referral Center.

Malignant melanoma can arise from melanocytes in various structures of the eye, orbit, and ocular adnexa. We reviewed the clinical features and long-term results of all subjects with histologically proved melanoma originating from any of the ocular and periocular structures in a tertiary referral center. Overall, 88 patients including 47 men were recruited. The tumor was primarily located in the uvea, followed by the conjunctiva, orbit, eyelid, and lacrimal sac. Patients with uveal melanoma were diagnosed at a relatively younger age (47.0 years), while those with orbital and eyelid melanomas were older at presentation (79.5 years and 78.5 years, respectively). The overall local recurrence rate was 9% at a median follow-up of 41.0 months, among which orbital and eyelid melanomas recurred most commonly. The overall mortality rate was 41% in a median duration of 27.2 months (IQR, 13-58 months) from diagnosis, with the highest for lacrimal sac melanoma, followed by melanoma of the orbit, uveal, conjunctiva, and eyelid. Despite prompt local control, the risk for metastasis and mortality was high. Therefore, efficient modalities for early diagnosis and treatment of ocular melanoma are necessary.

Diagnostic Performance of Transient Elastography in Biliary Atresia Among Infants With Cholestasis.

Biliary atresia (BA) is a challenging liver disease in infancy. Early diagnosis of BA is important for timely hepatoportoenterostomy. We evaluated the age-specific diagnostic performance of transient elastography (TE) with a liver stiffness measurement (LSM) greater than 7.7 kPa in BA among infants with cholestasis. A total of 61 infants with cholestasis (5-121 days of age) were enrolled in this prospective follow-up study; 15 infants were BA. Four age groups were defined (≤30, 31-60, 61-90, and 91-180 days). Picrosirius red staining was performed to quantify the percentage of collagen fibers in liver specimens. The utility of an LSM greater than 7.7 kPa for diagnosis of BA among infants with cholestasis was compared among age groups. In all four groups, TE showed high diagnostic power for BA using the criterion of an LSM greater than 7.7 kPa. Positive predictive values were 100%, 100%, and 100% in the groups aged 30 days or younger, 31 to 60 days, and 61 to 90 days, respectively. Respective negative predictive values were 90.9%, 94.7%, and 100%, and respective diagnostic accuracies were 92.9%, 95.2%, and 100%. The positive predictive value, negative predictive value, and diagnostic accuracy were 100%, 100%, and 100%, respectively, for LSM greater than 8.8 kPa in the group aged 91 to 180 days. The LSM was positively correlated with the percentage of collagen fibers stained by picrosirius red (P = 0.03). Conclusion: In this prospective follow-up study, TE had good diagnostic accuracy for differentiation of BA from non-BA cholestasis in infants with cholestasis who were 90 days of age or younger. The LSM was significantly positive correlated with the liver fibrosis status stained by picrosirius red in infants with cholestasis.

Dual-Specificity Phosphatase 15 (DUSP15) Modulates Notch Signaling by Enhancing the Stability of Notch Protein.

Dual-specificity phosphatases (DUSPs) comprise a unique group of enzymes that dephosphorylate signaling proteins at both phospho-serine/threonine and phospho-tyrosine residues. Since Notch signaling is an essential pathway for neuronal cell fate determination and development that is also upregulated in Alzheimer's disease tissues, we sought to explore whether and how DUSPs may impact Notch processing. Our results show that overexpression of DUSP15 concomitantly and dose-dependently increased the steady-state levels of recombinant Notch (extracellular domain-truncated Notch, NotchΔE) protein and its cleaved product, Notch intracellular domain (NICD). The overall ratio of NotchΔE to NICD was unchanged by overexpression of DUSP15, suggesting that the effect is independent of γ-secretase. Interestingly, overexpression of DUSP15 also dose-dependently increased phosphorylated ERK1/2. Phosphorylated ERK1/2 is known to be positively correlated with Notch protein level, and we found that DUSP15-mediated regulation of Notch was dependent on ERK1/2 activity. Together, our findings reveal the existence of a previously unidentified DUSP15-ERK1/2-Notch signaling axis, which could potentially play a role in neuronal differentiation and neurological disease.

Recurrence rate and risk factors for recurrence after thoracoscopic surgery for primary spontaneous pneumothorax: A nationwide population-based study.

PURPOSE: This large-scale nationwide population-based study aimed to determine the recurrence rate and risk factors for recurrence after video-assisted thoracoscopic surgery (VATS) for primary spontaneous pneumothorax (PSP). METHODS: This retrospective study used data from the Taiwan National Health Insurance Database to identify individuals who underwent VATS for PSP from 2007 to 2014. All patients were followed up until December 31, 2017. Study variables included demographic characteristics, intensive care unit admission, lung resection status, use of non-steroidal anti-inflammatory drugs (NSAIDs), and hospital level. The primary outcome was 1-year recurrence, and the secondary outcomes were the 1-year rate of reintervention for recurrence and overall recurrence rate. RESULTS: During the study period, 6654 patients underwent VATS for PSP (average age: 23.2 years, 89.1% male), including 910 patients (13.7%) who experienced recurrence within 1 year and 531 patients (8.0%) who required reintervention within 1 year. The overall recurrence rate was 24.8%, with an average follow-up time of 6.7 years. Age ≤18 years and the use of NSAIDs, especially ketorolac, were significant risk factors for 1-year recurrence and overall recurrence. Younger age was a risk factor for 1-year reintervention. In subgroup analysis, NSAID use was a significant risk factor for 1-year recurrence, 1-year reintervention, and overall recurrence in pediatric patients but not in adult patients. CONCLUSIONS: In Taiwan, the 1-year recurrence rate was 13.7% after VATS for PSP. Younger age and the use of NSAIDs, especially ketorolac, were significant risk factors for short- and long-term recurrence after VATS for PSP.

BI-2536 Promotes Neuroblastoma Cell Death via Minichromosome Maintenance Complex Components 2 and 10.

DNA replication is initiated with the recognition of the starting point of multiple replication forks by the origin recognition complex and activation of the minichromosome maintenance complex 10 (MCM10). Subsequently, DNA helicase, consisting of the MCM protein subunits MCM2-7, unwinds double-stranded DNA and DNA synthesis begins. In previous studies, replication factors have been used as clinical targets in cancer therapy. The results showed that MCM2 could be a proliferation marker for numerous types of malignant cancer. We analyzed samples obtained from patients with neuroblastoma, revealing that higher levels of MCM2 and MCM10 mRNA were associated with poor survival rate. Furthermore, we combined the results of the perturbation-induced reversal effects on the expression levels of MCM2 and MCM10 and the sensitivity correlation between perturbations and MCM2 and MCM10 from the Cancer Therapeutics Response Portal database. Small molecule BI-2536, a polo-like kinase 1 (PLK-1) inhibitor, is a candidate for the inhibition of MCM2 and MCM10 expression. To test this hypothesis, we treated neuroblastoma cells with BI-2536. The results showed that the drug decreased cell viability and reduced the expression levels of MCM2 and MCM10. Functional analysis further revealed enrichments of gene sets involved in mitochondria, cell cycle, and DNA replication for BI-2536-perturbed transcriptome. We used cellular assays to demonstrate that BI-2536 promoted mitochondria fusion, G2/M arrest, and apoptosis. In summary, our findings provide a new strategy for neuroblastoma therapy with BI-2536.

A noninvasive index to predict liver cirrhosis in biliary atresia.

BACKGROUND: Biliary atresia is a progressive obliterative cholangiopathy affecting both extrahepatic and intrahepatic biliary trees, resulting in fibrous obliteration of the biliary tract and subsequent development of cirrhosis. OBJECTIVE: The aim of this study was to find noninvasive indices to predict the status of hepatic fibrosis in children with biliary atresia. MATERIALS AND METHODS: We retrospectively measured the volume of the hepatic lobes and spleen from MR images, obtained biochemical data and analyzed the relationship between the imaging and biochemical indices, and the pathological status of hepatic fibrosis in 35 children with biliary atresia. RESULTS: A combined index was obtained by logistic regression: logit (likelihood of cirrhosis) = 0.00043 x age at MR examination + 1.67 x aspartate aminotransferase and platelet ratio index (APRI) + 0.0029 x body-surface-area-adjusted left liver lobe volume (BSA adLLV) - 6.57 (log-likelihood chi-square P<0.05, pseudo-R2=0.59). The area under the receiver operator characteristic curve of age at MR examination, APRI, BSA adLLV and the combined index for prediction of cirrhosis were 0.91, 0.86, 0.83 and 0.94, respectively. The optimal cut-off value (sensitivity and specificity) of age at MR examination, APRI, BSA adLLV and combined index were 132 (86% and 92%), 1.3 (91% and 85%), 855.5 (96% and 62%) and 0.689 (91% and 92%). The accuracy of age at MR examination, APRI, BSA adLLV and combined index were 89%, 89%, 83% and 91%, respectively. CONCLUSION: A combined noninvasive index of age, aspartate aminotransferase and platelet ratio index, and the body-surface-area-adjusted left liver lobe volume measured from MR images is a potential marker of liver cirrhosis in children with biliary atresia.

Risk factors for digestive morbidities after esophageal atresia repair.

Esophageal atresia with/without tracheoesophageal fistula (EA/TEF) is a congenital digestive tract anomaly that represents a major therapeutic challenge. Postoperative digestive morbidities such as gastroesophageal reflux disease (GERD) and esophageal stricture are common. The aim of this study was to identify the incidence of and potential risk factors for digestive morbidities after EA/TEF repair. We retrospectively reviewed all EA/TEF patients who underwent repair at a single institution between January 1999 and December 2018, excluding patients who died prior to discharge. Patient demographics, perioperative management, and postoperative GERD and esophageal stricture rates were collected. We performed univariate and multivariate analyses to examine risk factors associated with postoperative GERD and esophageal stricture. The study enrolled 58 infants (58.6% male, 17.2% with type A EA/TEF, 62.1% with associated anomalies). Postoperative GERD occurred in 67.2% of patients and was the most common digestive morbidity. Esophageal stricture occurred in 37.9% of patients after EA/TEF repair. Multivariate analysis showed that long-gap EA/TEF and postoperative GERD were independent risk factors for esophageal stricture after repair surgery.Conclusion: The incidence of postoperative GERD and esophageal stricture was 67.2% and 37.9%, respectively. The risk factors for postoperative esophageal stricture were long-gap EA/TEF and postoperative GERD. What is Known: • EA/TEF is a congenital digestive tract anomaly with a high postoperative survival rate but can be complicated by many long-term morbidities. What is New: • Long-gap EA/TEF and postoperative GERD are risk factors of anastomotic stricture after repair. • Surgeons and pediatricians should be highly experienced in managing anastomotic tension and the GERD.

Risk factors and management for anastomotic stricture after surgical reconstruction of esophageal atresia.

BACKGROUND/PURPOSE: Anastomotic stricture (AS) is a major morbidity of patients with esophageal atresia (EA) after surgical reconstruction. Our study determined the risk factors of AS after EA reconstruction. The therapeutic efficacy and complications of esophageal dilatation for children with AS were also evaluated. METHODS: Forty children treated for EA between January 2008 and December 2018 were included in this retrospective analysis. Esophageal dilatation was performed when AS was diagnosed. The therapeutic effect of esophageal dilatation was determined based on nutritional status, as assessed by the weight-for-age z-score. RESULTS: Sixteen EA patients developed AS. A gap >1.5 cm between the esophageal pouches (P = 0.02) in patients with EA and type A EA was a risk factor for developing AS. A mean of 7.7 sessions of esophageal dilatation were performed per patient, and no complications occurred. The nutritional status of EA children with AS after dilatation was not inferior to that of the children without AS at the 6-month follow-up. CONCLUSION: A gap >1.5 cm between the esophageal pouches and type A EA are risk factors for AS after esophageal reconstruction. Esophageal dilatation is both safe and effective for managing strictures and improves nutritional status in EA children with AS.

5-aza-2'-Deoxycytidine Induces a RIG-I-Related Innate Immune Response by Modulating Mitochondria Stress in Neuroblastoma.

BACKGROUND: Neuroblastoma (NB) is one of the most common malignant solid tumors to occur in children, characterized by a wide range of genetic and epigenetic aberrations. We studied whether modifications of the latter with a 5-aza-2'-deoxycytidine (decitabine, Dac) DNA methyltransferase inhibitor can provide a therapeutic advantage in NB. METHODS: NB cells with or without MYCN amplification were treated with Dac. We used flow cytometry to measure cell apoptosis and death and mitochondrial reactive oxygen species (mtROS), microarray to analyze gene expression profile and bisulfite pyrosequencing to determine the methylation level of the DDX58/RIG-I promoter. Western blot was used to detect markers related to innate immune response and apoptotic signaling, while immunofluorescent imaging was used to determine dsRNA. We generated mtDNA depleted ρ0 cells using long-term exposure to low-dose ethidium bromide. RESULTS: Dac preferentially induced a RIG-I-predominant innate immune response and cell apoptosis in SK-N-AS NB cells, significantly reduced the methylation level of the DDX58/RIG-I promoter and increased dsRNA accumulation in the cytosol. Dac down regulated mitochondrial genes related to redox homeostasis, but augmented mtROS production. ρ0 cells demonstrated a blunted response in innate immune response and apoptotic cell death, as well as greatly diminished dsRNA. The response of NB cells to CDDP and poly(I:C) was potentiated by Dac in association with increased mtROS, which was blunted in ρ0 cells. CONCLUSIONS: This study indicates that Dac effectively induces a RIG-I-related innate immune response and apoptotic signaling primarily in SK-N-AS NB cells by hypomethylating DDX58/RIG-I promoter, elevated mtROS and increased dsRNA. Dac can potentiate the cytotoxic effects of CDDP and poly(I:C) in NB cells.

Phosphatidylinositol-4-phosphate 5-kinase type 1α attenuates Aß production by promoting non-amyloidogenic processing of amyloid precursor protein.

Alzheimer's disease (AD) is characterized by a chronic decline in cognitive function and is pathologically typified by cerebral deposition of amyloid-ß peptide (Aß). The production of Aß is mediated by sequential proteolysis of amyloid precursor protein (APP) by ß- and γ-secretases, and has been implicated as the essential determinant of AD pathology. Previous studies have demonstrated that the level of phosphatidylinositol-4,5-bisphosphate [PI(4,5)P2] in the membrane may potentially modulate Aß production. Given that PI(4,5)P2 is produced by type 1 phosphatidylinositol-4-phosphate 5-kinases (PIP5Ks), we sought to determine whether the level of PIP5K type Iα (PIP5K1A) can affect production of Aß by modulating the lipid composition of the membrane. Using a HEK-derived cell line that constitutively expresses yellow fluorescent protein-tagged APP (APP-YFP), we demonstrated that overexpression of PIP5K1A results in significant enhancement of non-amyloidogenic APP processing and a concomitant suppression of the amyloidogenic pathway, leading to a marked decrease in secreted Aß. Consistently, cells overexpressing PIP5K1A exhibited a significant redistribution of APP-YFP from endosomal compartments to the cell surface. Our findings suggest that PIP5K1A may play a critical role in governing Aß production by modulating membrane distribution of APP, and as such, the pathway may be a valuable therapeutic target for AD.