Management of Familial Adenomatous Polyposis in Children and Adolescents: Position Paper From the ESPGHAN Polyposis Working Group.

Familial adenomatous polyposis (FAP) is a well-described inherited syndrome, characterized by the development of hundreds to thousands of adenomas in the colorectum, with implications in children and adolescents. Almost all adult patients will develop colorectal cancer if they are not identified and treated early enough. Identifying and screening for FAP commences in adolescence. The syndrome is inherited as an autosomal dominant trait and caused by mutations in the adenomatous polyposis (APC) gene. This European Society for Paediatric Gastroenterology, Hepatology and Nutrition (ESPGHAN) position paper provides a guide for diagnosis, assessment, and management of FAP in children and adolescents.This is the first position paper regarding FAP published by ESPGHAN. Literature from PubMed, Medline, and Embase was reviewed and in the absence of evidence, recommendations reflect the opinion of paediatric and adult experts involved in the care of polyposis syndromes. Because many of the studies that form the basis for the recommendations were descriptive and/or retrospective in nature, these of the recommendations are supported on expert opinion. This position paper will instruct on the appropriate management and timing of procedures in children and adolescents with FAP.

BH3-mimetic drugs prevent tumour onset in an orthotopic mouse model of hepatoblastoma.

Drug resistance and metastasis remain major challenges in the treatment of high-risk hepatoblastoma (HB) and require the development of alternative therapeutic strategies. Modulation of apoptosis in HB cells enhances the sensitivity of these cells towards various drugs and has been discussed to enforce treatment. We investigated the impact of apoptosis sensitisers, BH3-mimetics, on the interaction between the host and HB to reduce tumour growth and dissemination while enhancing immunity. BH3-mimetics, such as obatoclax and ABT-737, enhanced the apoptosis-inducing effect of TRAIL and TNF-α resistant HB cells (HepT1 and HUH6). Tumour cell migration was inhibited by ABT-737 and more markedly by obatoclax. In an orthotopic model of HB, tumour uptake was reduced when the cells were pretreated with low concentrations of obatoclax. Only 1 of 7 mice developed HB in the liver, compared with an incidence of 0.8 in the control group. In summary, our study showed that apoptosis sensitisers had broader effects on HB cells than expected including migration and susceptibility to cytokines in addition to the known effects on drug sensitization. Sensitising HB to apoptosis may also allow resistant HB to be targeted by immune cells and prevent tumour cell dissemination.

Solar UV radiation and cancer in young children.

BACKGROUND: Studies have shown that higher solar UV radiation exposure (UVR) may be related to lower risk of some cancers in adults. Recently, an ecologic study reported lower risks of some cancers among children living in higher UVR cities and countries. In a large population-based case-control study in California, we tested the hypothesis that childhood cancers may be influenced by UVR. METHODS: Cancers in children ages 0 to 5 years were identified from California Cancer Registry records for 1988 to 2007 and linked to birth certificate data. Controls were sampled from the birth certificates at a ratio of 20:1. Based on birth address, we assigned UVR exposure in units of Watt-hours/m(2) using a geostatistical exposure model developed with data from the National Solar Radiation Database. RESULTS: For cases with UVR exposure of 5,111 Watt-hours/m(2) or above, we estimated a reduction in odds of developing acute lymphoblastic leukemia (OR: 0.89, 95% CI: 0.81-0.99), hepatoblastoma (OR: 0.69, 95% CI: 0.48-1.00), and non-Hodgkin's lymphoma (OR: 0.71, 95% CI: 0.50-1.02) adjusting for mother's age, mother's race, and child's year of birth. We also observed a small increase in odds for intracranial/intraspinal embryonal tumors (OR: 1.29, 95% CI: 1.01-1.65). CONCLUSIONS: Our findings suggest that UVR during pregnancy may decrease the odds of some childhood cancers. Future studies should explore additional factors that may be correlated with UVR exposure and possibly include biomarkers of immune function and vitamin D. IMPACT: This study shows protective associations of UVR with some childhood cancers.

[Retrospective analysis of maternal and infant birth features of hepatoblastoma patients].

OBJECTIVE: To explore the risk factors for hepatoblastoma. METHODS: A case-cohort study using Logistic regression multiple variables analysis of medical record data sets was conducted to examine infant and perinatal risk factors for hepatoblastoma. RESULTS: Birth weight less than 1,000 g was associated with a strongly increased risk of hepatoblastoma (odds risk, OR = 26.0, 95% confidence interval, CI: 14.0 to 65.7). After adjustment of birth weight, a moderately increased risk of hepatoblastoma was found for older maternal age ( > 35 years vs. 20 to 34 years: OR = 2.6, 95% CI: 0.9 to 5.9), maternal smoking (OR = 2.9, 95% CI: 1.1 to 4.2) and higher maternal pregnancy body mass index (OR = 3.2, 95% CI: 1.0 to 6.7). CONCLUSION: Very low birth weight and maternal characteristics including overweight, smoking are associated with hepatoblastoma risk.

Drug resistance in hepatoblastoma.

Treatment results of human hepatoblastoma (HB) have been improved remarkably during recent years, mainly through the establishment of integrated regimens controlled and coordinated by multicentric treatment studies. Today, neoadjuvant and adjuvant chemotherapy is combined with surgical resection of the tumors. The main therapeutic goal is a complete surgical removal of tumor masses, which is also essential for the survival of the patients. Despite improved overall survival rates, treatment results of advanced tumors are still far from being satisfying. Multidrug resistance has been identified as a major factor responsible for the bad prognosis of children suffering from advanced staged hepatoblastoma. During recent years investigations focused on factors contributing to drug resistance in hepatoblastoma and on possible approaches towards overcoming this therapeutical challenge. Alternative approaches that are currently evaluated in experimental and clinical settings comprise new cytotoxic agents, chemosensitizers, gene directed applications but also surgical techniques and an expansion of indication for liver transplantation.

Enhancement of glutathione and g-glutamylcysteine synthetase, the rate limiting enzyme of glutathione synthesis, by chemoprotective plant-derived food and beverage components in the human hepatoma cell line HepG2.

Glutathione (GSH) is an important antioxidant and cofactor of detoxifying metabolism. Therefore, elevation of GSH as achieved by inducing g-glutamylcysteine synthetase (GCS), the limiting enzyme of GSH synthesis, may contribute to chemoprevention against cancer. In previous animal studies, increases in GCS were mainly found in liver and other organs that are not easily accessible in humans. Thus, employment and evaluation of alternative systems such as human-derived cell lines are encouraged. In the present experiment, we used the hepatoma cell line HepG2 to investigate the response of GCS and GSH to five plant-derived chemoprotectants contained in regularly consumed foodstuffs and beverages (kahweol/cafestol [K/C] [15.5-62.0 mM], a-angelicalactone [100-400 mM], benzyl isothiocyanate [1.7-5.0 mM], diallyl sulfide [175-700 mM], and quercetin [10-50 mM]). All treatments led to dose-dependent increases in both GCS activity and GSH concentration. Time course studies with K/C indicated that the enhancement of GCS preceded that of GSH, suggesting a causal relationship. K/C did not enhance g-glutamyl transpeptidase, a further enzyme that assists GSH-related chemoprotection. Although GCS induction has been suggested to require an initial short-lived GSH depletion, we did not find any decrease in GSH after 3 h of incubation with K/C. In summary, HepG2 cells were shown to be a useful model to investigate the capacity of potential chemoprotectants to enhance GCS and GSH. To our knowledge, the present study is also the first to show increases in GCS by K/C and a-angelicalactone in vitro and by diallyl sulfide and quercetin in any system.

Effects of mustard sprouts and allylisothiocyanate on benzo(a)pyrene-induced DNA damage in human-derived cells: a model study with the single cell gel electrophoresis/Hep G2 assay.

The aim of this study was to investigate the chemoprotective effects of mustard sprouts on benzo(a)pyrene [B(a)P]-induced DNA damage in the single cell gel electrophoresis (SCGE)/Hep G2 assay. This model combines the advantages of the SCGE assay with that of human-derived cells that possess inducible phase I and phase II enzymes. Treatment of the cells with small amounts of mustard juice (0.1-1.25 microl/ml) and B(a)P reduced the genotoxic effect of the carcinogen in a dose-dependent manner. Contrary to the results with the juice, unexpected synergistic effects were observed with allyl isothiocyanate (AITC, 0.3 microM), a breakdown product of sinigrin, which is contained in black mustard and many other cruciferous vegetables. Although these concentrations of AITC did not cause DNA damage per se, pronounced dose-dependent DNA damage was seen with higher concentrations of AITC (>or= 25 microM). In parallel with the comet assays, also enzyme measurements were carried out which showed that exposure of the cells to mustard juice (2.0 microl/ml) causes a moderate induction of ethoxyresorufin-O-deethylase, and more pronounced (approximately 2-fold) increase of the activity of glutathione-S-transferase. In conclusion, our findings indicate that i) mustard juice is highly protective against B(a)P-induced DNA damage in human derived cells and ii) that induction of detoxifying enzymes may account for its chemoprotective properties. iii) Furthermore, our findings show that the effects of crude juice can not be explained by its allyl isothiocyanate contents.