A multicenter prospective study on the management of hepatoblastoma in children: a report from the Chinese Children's Cancer Group.

BACKGROUND: This study aimed to identify survival risk factors in Chinese children with hepatoblastoma (HB) and assess the effectiveness of the new treatment protocol proposed by the Chinese Children's Cancer Group (CCCG) in 2016. METHODS: A multicenter, prospective study that included 399 patients with HB from January 2015 to June 2020 was conducted. Patient demographics, treatment protocols, and other related information were collected. Cox regression models and Kaplan-Meier curve methods were used. RESULTS: The 4-year event-free survival (EFS) and overall survival (OS) were 76.9 and 93.5%, respectively. The 4-year EFS rates for the very-low-risk, low-risk, intermediate-risk, and high-risk groups were 100%, 91.6%, 81.7%, and 51.0%, respectively. The 4-year OS was 100%, 97.3%, 94.4%, and 86.8%, respectively. Cox regression analysis found that age, tumor rupture (R +), and extrahepatic tumor extension (E +) were independent prognostic factors. A total of 299 patients had complete remission, and 19 relapsed. Patients with declining alpha-fetoprotein (AFP) > 75% after the first two cycles of neoadjuvant chemotherapy had a better EFS and OS than those ≤ 75%. CONCLUSIONS: The survival outcome of HB children has dramatically improved since the implementation of CCCG-HB-2016 therapy. Age ≥ 8 years, R + , and E + were independent risk factors for prognosis. Patients with a declining AFP > 75% after the first two cycles of neoadjuvant chemotherapy had better EFS and OS.

Exportin-T: A Novel Prognostic Predictor and Potential Therapeutic Target for Neuroblastoma.

Exportins as the key mediators of nucleocytoplasmic transport have been identified as the controllers of the passage of numerous types of crucial cancer-related proteins. Targeting exportins in cancer cells might represent an emerging strategy in cancer intervention with the potential to affect clinical outcomes. Here, we focused on the prognostic and therapeutic values of Exportin-T (XPOT) in neuroblastoma. The correlation between the expression and prognostic values of XPOT in patients with neuroblastoma was investigated based on both published transcriptome data and our clinical data. Then, decision curve analysis (DCA) was implemented to identify a XPOT risk prediction model. In addition, RNA inference was performed to silence the expression of XPOT to further investigate the specific roles of XPOT in the progression of neuroblastoma in vitro. Overexpression of XPOT mRNA was associated with poor clinical characteristics, such as age at diagnosis more than 18 months, amplification of MYCN, and advanced International Neuroblastoma Staging System (INSS) stage, and XPOT expression was identified as an independent poor prognosis factor for neuroblastoma using Cox proportional hazards model (P < .001). DCA suggested that neuroblastoma patients could benefit from XPOT risk prediction model-guided interventions (status of MYCN + INSS stage + XPOT). Experimentally, knockdown of XPOT by small interfering RNA inhibited the proliferation and migration in neuroblastoma cells. XPOT is identified as a novel prognostic predictor and potential therapeutic target for neuroblastoma patients. Further investigation should focus on the profound molecular mechanism underlying the tumor inhibition activity of XPOT inhibitors.

Multidisciplinary effort in treating children with hepatoblastoma in China.

The purpose of this study is to report the first nationwide protocol (Wuhan Protocol) developed by Chinese Children's Cancer Group and the results of multidisciplinary effort in treating hepatoblastoma. In this study, we reported the final analysis, which includes 153 hepatoblastoma patients in 13 hospitals from January 2006 to December 2013. The 6-year overall survival and event-free survival rates were 83.3 ± 3.1% and 71.0 ± 3.7%, respectively, in this cohort. The univariate analysis revealed that female (P = 0.027), under 5 years of age (P = 0.039), complete surgical resection (P = 0.000), no metastases (P = 0.000), and delayed surgery following neoadjuvant chemotherapy (P = 0.000) had better prognosis. In multivariate analysis, male, 5 years of age or above, stage PRETEXT III or IV, and incomplete surgical resection were among the some adverse factors contributing to poor prognosis. The preliminary results from this study showed that patients who underwent treatment following Wuhan Protocol had similar OS and EFS rates compared to those in developed countries. However, the protocol remains to be further optimized in standardizing surgical resection (including liver transplantation), refining risk stratification and risk-based chemotherapy.

Long-term outcome of laparoscopic Nissen-Rossetti fundoplication versus Thal fundoplication in children with esophageal hiatal hernia: a retrospective report from two children's medical centers in Shanghai.

BACKGROUND: This study was undertaken to investigate the intraoperative and postoperative complications, efficacy and outcome of two laparoscopic fundoplications for the treatment of esophageal hiatal hernia in children. METHODS: To find a rational procedure, we performed a retrospective analysis of 136 children with esophageal hiatal hernia who underwent laparoscopic Nissen-Rossetti or Thal fundoplication at two children's hospitals in Shanghai over 13 years. The median follow-up time of the children was 42 months (range: 1-138 months). Their age varied from 1 month to 11 years (median: 18.6 months). RESULTS: All the children underwent laparoscopic fundoplications (72 cases of Nissen-Rossetti and 60 cases of Thal fundoplication) and 4 children converted to open surgery. The mean age of the children at the time of operation was 1.6±1.9 years, and the mean weight was 9.1±5.6 kg. Gastroesophageal reflux was significantly more severe after a Thal fundoplication (P=0.003) and slight esophageal stenosis was significant after a Nissen-Rossetti fundoplication (P=0.02). The recurrent rate of hiatal hernia was 2.8% (2/72) after Nissen-Rossetti fundoplication in contrast to 5% (3/60) after Thal fundoplication. No death occurred after surgery. CONCLUSION: There was no statistical difference of recurrence between laparoscopic Nissen-Rossetti and Thal fundoplication in the long-term outcomes. The rate of slight dysphagia was higher in the Nissen-Rossetti group. The Thal group had a significantly higher recurrence rate of gastroesophageal reflux. There still exited learning curve for this procedure. The incidence rate of complications is significantly related to the proficiency of pediatric surgeon.

The Surgical Management of H-Type Rectovestibular Fistula: A Novel Modification.

Introduction H-type rectovestibular fistulas could be rare anorectal malformations or acquired diseases secondary to perianal infection. Various surgical procedures have been described in the literature, however the problem of recurrence still remains to be solved. We describe a novel modified surgical procedure and outcome in the management of these patients. Methods From 1999 to 2014, 14 patients who had an H-type rectovestibular fistula underwent the same surgical procedure performed by the same surgical team. Rectal-vestibular pull-through inside-out and endorectal mucosal advancement flap was used, including circumferential incision of the fistula from the opening on the rectal side, pulling the fistula inside-out, ligating the fistula, and mobilizing a rectal mucosal flap to cover the internal opening. Results All the patients have been followed-up for 12 months to 15 years with no recurrences and no incontinence. Conclusion Our surgical management is a simple, safe, and probable choice for the treatment of H-type rectovestibular fistula with favorable outcomes.

[Evaluation of pharmacokinetics and in vitro/in vivo correlation of ibuprofen with essential oils as penetration enhancer following transdermal administration].

The study was carried out to investigate the pharmacokinetics and in vitro/in vivo correlation of ibuprofen with essential oils as penetration enhancers (PE) following transdermal administration. With Azone as the positive control, ibuprofen hydrogels containing Chuanxiong oil, Angelica oil or Cinnamon oil as PE were prepared and administered to the rat abdominal skin. Then the pharmacokinetics of ibuprofen following transdermal administration were investigated and compared. In comparison with negative control (no PE was added), the relative bioavailability values with the addition of Chuanxiong oil, Angelica oil, Cinnamon oil and Azone as PE were determined to be 161.87%, 171.05%, 151.37% and 148.66%, respectively. In vitro/in vivo correlation analysis was performed by deconvolution method and the results demonstrated a good correlation between in vitro and in vivo percutaneous absorption studies. The correlation coefficients were measured to be 0.999 7, 0.995 2 and 0.999 4 for Chuanxiong oil, Angelica oil and Cinnamon oil respectively. In summary, Chuanxiong oil, Angelica oil and Cinnamon oil as PE could significantly enhance the bioavailability of ibuprofen following transdermal administration. A satisfactory in vitro/in vivo correlation could be obtained by using hydrogel as the dosage form.

Potential of Essential Oils as Penetration Enhancers for Transdermal Administration of Ibuprofen to Treat Dysmenorrhoea.

The present study was conducted to evaluate and compare five essential oils (EOs) as penetration enhancers (PEs) to improve the transdermal drug delivery (TDD) of ibuprofen to treat dysmenorrhoea. The EOs were prepared using the steam distillation method and their chemical compositions were identified by GC-MS. The corresponding cytotoxicities were evaluated in epidermal keartinocyte HaCaT cell lines by an MTT assay. Furthermore, the percutaneous permeation studies were carried out to compare the permeation enhancement effect of EOs. Then the therapeutic efficacy of ibuprofen with EOs was evaluated using dysmenorrheal model mice. The data supports a decreasing trend of skin cell viability in which Clove oil >Angelica oil > Chuanxiong oil > Cyperus oil > Cinnamon oil >> Azone. Chuanxiong oil and Angelica oil had been proved to possess a significant permeation enhancement for TDD of ibuprofen. More importantly, the pain inhibitory intensity of ibuprofen hydrogel was demonstrated to be greater with Chuanxiong oil when compared to ibuprofen without EOs (p < 0.05). The contents of calcium ion and nitric oxide (NO) were also significantly changed after the addition of Chuanxiong oil (p < 0.05). In summary, we suggest that Chuanxiong oil should be viewed as the best PE for TDD of ibuprofen to treat dysmenorrhea.

Preliminary analysis of stem cell-like cells in human neuroblastoma.

BACKGROUND: Neuroblastoma is an embryonic neoplasm originating from the neural crest with cellular heterogeneity as one of its oncobiological characteristics. This study was undertaken to determine whether human neuroblastoma contains stem cell-like cells. METHODS: Twenty patients with neuroblastoma who have been treated in our hospital since January 2005 were divided into pre-operative chemotherapy (10 patients) and non-chemotherapy (10) groups. Tumor specimens of the patients were taken and paraffin sections were made. The expressions of stem cell markers CD133, ABCG2, CD117 and nestin were immunohistochemically detected in the specimens. Neuroblastoma cells were stained with Hoechst 33342 and PI. The side population (SP) cells were analyzed by the fluorescence-activated cell sorter. The disparity drug resistance to cisplatin (DDP) of SP and non-SP cells was measured with MTT colorimetric assay. The oncogenicity of SP and non-SP cells was identified in nude mice. RESULTS: There was no significant difference in the expression intensity of CD117 and nestin between the two groups of specimens (P>0.05). There was a significant difference between the two groups in terms of the expression intensity of CD133 and ABCG2 (P<0.05). The SP cells accounted for 0.2%-1.3% of the total human neuroblastoma cells and were decreased to 0.1%-0.5% after verapamil treatment. The SP and non-SP cells showed disparity in cell growth experiment and drug resistance to DDP. Oncogenicity experiment revealed that nude mice could erupt tumor by an injection of l×10(6) SHSY5Y and WIV SP cells. However, the nude mice could not form tumor by an injection of l×10(6) non-SP cells. CONCLUSION: Neuroblastoma might contain cancer stem cell-like cells.

Delivery room surgery: an applicable therapeutic strategy for gastroschisis in developing countries.

BACKGROUND: The survival rate of infants with gastroschisis has improved significantly. It is over 90% in developed countries, but 50% in developing countries. This study aimed to investigate the factors improving the survival rate of infants with gastroschisis in developing countries. METHODS: Neonates meeting the inclusion criteria, who presented to our center since the establishment of delivery room surgery, were enrolled into this retrospective study. Data were evaluated specifically to determine the role of delivery room surgery in reducing the mortality and morbidity of infants with gastroschisis and to identify factors optimizing the conditions of outborn infants. RESULTS: A total of 64 infants were identified. The overall survival rate of the infants was 60.9%. The survival rate of infants in inborns was 76.5%, and the survival rate of infants in outborns was 43.3%. Infants of the outborn group took more time to reach full enteral feeding, and were more likely to require a prolonged stay in hospital when compared with those of the inborn group. Logistic analysis identified that the surgical technique, the presence of sepsis and intestinal necrosis could be expected to influence the outcome of gastroschisis. CONCLUSIONS: The strategy of delivery of patients in a center prepared to perform delivery room closure of gastroschisis appears to improve the survival of patients with gastroschisis. Further reduction in mortality rates will depend on improved conditions of outborn infants.

RACK1 downregulation suppresses migration and proliferation of neuroblastoma cell lines.

Neuroblastoma is the most common extracranial solid tumor in childhood, whose molecular mechanism on clinically heterogeneous behavior is still unclear. Receptor for activated C-kinase 1 (RACK1) has been shown to be involved in the regulation of growth and migration in many types of cells. Two types of human neuroblastoma cell lines, SK-N-SH and SK-N-BE (2), were used to explore the role of RACK1 in neuroblastoma cell migration and proliferation. Cell migration and proliferation were detected by a transwell system and colorimetric bromodeoxyuridine (BrdU) ELISA, respectively. The expressions of RACK1, N-Myc, phospho-Src(Tyr416), phospho-Src(Tyr527), phospho-Akt, phospho-ERK1/2 and phospho-p38 were analyzed by Western blotting. The expression of RACK1 was then repressed by target RNA interference (RNAi) in both types of neuroblastoma cells, and the expression of signaling molecules, migration and proliferation of cells was analyzed. Compared with SK-N-SH, the migration and proliferation of SK-N-BE(2) cells was remarkably higher which was accompanied by higher expression of RACK1 and phospho-Src(Tyr416). RACK1 RNAi repressed cell migration and proliferation, and decreased the expression of phospho-Src(Tyr416) in both cell lines. In summary, RACK1 was expressed in the neuroblastoma cells and positively regulated cell migration and proliferation probably via modulating the activation of Src on Tyr416 residue.

Glial fibrillary acidic protein expression is an indicator of teratoma maturation in children.

BACKGROUND: The present diagnosis of teratomas is limited to visual examination of their tissues. For the sake of treatment, teratomas are graded according to degrees of nerve tissue maturation. Mature fetal nerve tissue contains the astrocyte-specific intermediate filament protein, the glial fibrillary acidic protein (GFAP). This study aimed to investigate GFAP expressions in the nerve tissue of immature and mature teratomas, and to evaluate if GFAP is indicative of teratoma maturation in pediatric patients. METHODS: Nerve tissue specimens were collected from immature (10 children) and mature teratomas (45 children). Nerve tissue specimens as a control group were taken from 33 children with neuroblastoma. GFAP expression of the specimens was studied by immunohistochemical and semi-quantitative analyses. RESULTS: GFAP expression was low in the nerve tissue of immature teratomas and high in that of mature ones. A semi-quantitative analysis confirmed statistically significant difference between the GFAP expressions of immature and mature teratomas (P=0.0001). CONCLUSION: GFAP is highly expressed in the nerve tissue of mature teratomas and low in that of immature ones, suggesting that the GFAP expression is a meaningful indicator of teratoma maturation. It is helpful for pathologists to diagnose and classify teratomas.

Modified silo technique-An easy and effective method to improve the survival rate of neonates with gastroschisis in Shanghai.

OBJECTIVES: To introduce the clinical practice and experience of using a modified silo technique to treat neonates with severe gastroschisis in three referral medical centers in Shanghai, China. STUDY DESIGN: Seventeen neonates with severe gastroschisis, whose viscera could not be reduced primarily, were admitted to three referral hospitals in Shanghai in the period of April 2004-July 2008. We placed a spring-loaded silo bag to hold the viscera as a bedside procedure and without anesthesia. Five to eight days later, after the bowel had been reduced to the abdominal cavity, we explored the intestines and closed the abdominal wall defect secondarily. Three of the cases had been diagnosed prenatally. Immediately after these 3 infants had been born and while still in the delivery room, the pediatric surgeons placed the silo bag. RESULTS: In 16 of the 17 cases, we performed a secondary surgery to explore the abdominal cavity and to close the defective abdominal wall 5-8 days after the silo bag had been inserted. When closing the abdominal wall, omphaloplasty was performed in 12 cases and transverse skin closure was done in 4 cases. All 16 cases recovered well. The follow-up periods ranged from 1 to 51 months, during which 15 babies developed well. One baby, however, incurred an intestinal obstruction 1 month after discharge and died, because his parents failed to send him to the hospital immediately. Due to an improper placement of the silo bag, one patient's bowel became incarcerated, ischemic and necrotic locally, causing the death of the patient. CONCLUSIONS: Placing a spring-loaded silo bag as a bedside procedure without anesthesia on newborns with severe gastroschisis whose viscera cannot be reduced primarily has increased the survival rate (94.1%, 16/17, 2004-2008) of infants with severe gastroschisis in comparison to our previous experience (60.9%, 14/23, 1996-2003, p=0.026, Chi-square test) in Shanghai, China. This modified procedure deviates from the classic silo procedure, which is carried out under anesthesia..