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ABSTRACT: Abstract Objectives: Laparoendoscopic single-site surgery (LESS) in pediatric patients has emerged as a viable alternative to standard laparoscopy. The aim of our investigation was to assess different surgical approaches for LESS, stratifying by weight. Subjects and Methods: From March 2010 to April 2012 LESS was performed in 42 children. Children weighing below 10 kg underwent LESS through an umbilical incision using two 3-mm trocars and one 5-mm trocar. Patients above 10 kg were operated on using a metal multiuse single-site single port (X-Cone™; Karl Storz Endoskope, Tuttlingen, Germany). Conventional straight laparoscopic instruments were used in all cases. Results: Mean age at operation was 100 months (range, 0.25-207 months), and mean weight was 27 kg (range, 3.1-82 kg). Median operating time was 74 minutes (range, 36-300 minutes). Eighteen children underwent LESS using two 3-mm trocars and one 5-mm trocar; 1 case required two 5-mm trocars and one 10-mm trocar. Twenty-three patients were operated on with the multiuse device. All operations were carried out safely in a standard laparoscopic transperitoneal technique with full achievement of the surgical target. In none of the patients was an intraoperative complication noticed. Postoperatively two complications were noted, which resolved spontaneously. Conclusions: LESS for pediatric patients can be done safely and efficiently with even less trauma than in conventional laparoscopy irrespective of age and weight. However, different surgical approaches have to be considered as disposable single-site ports are not available for infants and small children. To decrease operative expenses, conventional multiuse trocars and a multiuse single-site port were used with conventional laparoscopic instruments.
Journal of Laparoendoscopic & Advanced Surgical Techniques 03/2013; 23(3):281-6. · 1.40 Impact Factor
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ABSTRACT: Hepatoblastoma (HB) is the most common liver cancer in children. Recurrence of HB after chemotherapy and surgery is frequent among high-risk patients and is associated with chemoresistance. Immunotherapy may improve poor treatment outcomes in HB patients. Cytotoxic leukocytes of the innate and adaptive immune system including different populations of cytotoxic T cells play a major role in fighting developing tumors. In this setting, monoclonal antibodies may be employed to specifically direct immune responses toward tumor cells. We addressed this issue by using humanized antibodies that recognize the cell surface molecule EpCAM (CD326, overexpressed in hepatic tumor cells) to enhance immune responses against HB. EpCAM was constantly expressed on HB cells and its expression was independent of previous therapy based on the DNA-damaging agent cisplatin. Co-culture assays performed with two well-described HB cell lines and tumor tissue cultures demonstrated that tumor cell lysis by γδ T cells can be dramatically augmented by applying EpCAM-specific monoclonal antibodies. These data emphasize the value of antitumor immune responses and encourage adapting immunotherapeutic regimens to improve the outcome of high risk HB.
Oncoimmunology. 01/2013; 2(1):e22620.
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ABSTRACT: PURPOSE: Duplex drugs are promising anticancer agents. After in vivo cleavage into active nucleoside analogues, they exert their anti-tumour activity with reduced toxicity and side effects. Here we evaluated the impact of two duplex drugs on the viability of hepatoblastoma (HB) cells lines and their toxicity against human fibroblasts. METHODS: The duplex drugs 2'-deoxy-5-fluorouridylyl-(3'-5')- 3'-C-ethynylcytidine (5-FdU(3'-5')ECyd) and 3'-C-ethynylcytidinylyl-(5'→1-O)-2-O-octadecyl-sn-glycerylyl-(3'-Ο→5')-2'-deoxy-5-fluorouridine (ECyd-lipid-5-FdU) were analysed in two HB cell lines (HUH6, HepT1) and fibroblasts by MTT assay. The treatment potential was compared to the single substances 2'-deoxy-5-fluorourindine (5-FdU), 3'-C-ethynylycytidine (ECyd) and an equimolar mixture of both. Cell cycle analyses were performed using flow cytometry after 7-AAD staining. RESULTS: Both duplex drugs achieve a potent cytotoxic effect at low μM concentrations, which was more pronounced than the mixture of ECyd + 5-FdU. Further, both substances exert toxicity on fibroblasts of tumour samples, with less toxicity in foreskin fibroblasts cultures. Cell cycle analyses revealed a shift towards apoptotic cells for both drugs in HB cells. CONCLUSION: 5-FdU(3'-5')ECyd and ECyd-lipid-5-FdU exert a highly potent anti-tumoural effect on HB cells and might therefore be a treatment option in HB. Pharmacological formulations of both duplex drugs have to be evaluated in vivo to reduce possible side effects.
Pediatric Surgery International 11/2012; · 1.25 Impact Factor
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ABSTRACT: BACKGROUND: Chemoresistance and advanced tumour stage at time of diagnosis are the major reasons for poor treatment results in hepatoblastoma (HB) and paediatric hepatocellular carcinoma (HCC). Positive results with transplantation of liver and bone marrow revealed the impact of the immune system on the treatment of liver malignancies. AIM: Cytotoxic-immune-cells-like natural killer (NK) and T cells are major player in the defence against developing tumours. This study aimed to specifically analyse the ability of ex-vivo expanded γδ T cells to recognise and lyse HB and HCC cell lines in coculture assays. METHODS: Cell viability after treatment with γδ T cells was evaluated with two HB (HUH6 and HepT1) and one HCC cell line (HC-AFW1) using a MTT-based cytotoxicity assay. The binding of T cells to target cells was monitored using immunofluorescence microscopy. RESULTS: Incubation of hepatic tumour cell lines with γδ T cells led to a significant decrease in tumour cell viability. This was enhanced by zoledronic acid and histone deacetylase inhibitors. MT110, an EpCAM/CD3-bispecific BiTE antibody could bluntly enhance tumour cell lysis close to completion. γδ T cells efficiently interacted with HB and HCC cells in a spheroid culture model. CONCLUSION: Bispecific antibodies such as MT110 might be used to intensify the antitumoural effect of γδ T cells in context of adoptive immune cell transfer. Optimised immunotherapeutic strategies might therefore improve the outcome of high risk hepatoblastoma and hepatocellular carcinoma.
Liver international: official journal of the International Association for the Study of the Liver 10/2012; · 3.82 Impact Factor
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ABSTRACT: Extrahepatic portal vein (PV) obstruction (EHPVO) is a rare disorder in early childhood with unknown incidence and mostly unknown etiology. In children with EHPVO, the hepatopedal flow of the mesenteric venous blood is hindered by an obstruction of the PV resulting in prehepatic portal hypertension. The curative treatment with a meso-Rex shunt connects the superior mesenteric vein to the left PV by a venous autograft. Despite good primary patency, reocclusion of a meso-Rex bypass and its treatment can be challenging. We present 2 patients with EHPVO with subtotal functional occlusion of a meso-Rex shunt treated by percutaneous interventions with short- and mid-term follow-up.
Journal of Pediatric Surgery 09/2012; 47(9):e23-8. · 1.45 Impact Factor
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ABSTRACT: Hepatoblastoma is the most common primary malignant neoplasm of the liver in children. Improvements in chemotherapy and surgical techniques have increased survival rates for those with localized disease. The prognosis for patients with progressive or relapsed disease continues to be dismal. Complete resection by surgery or liver transplantation is necessary for cure. Few conventional chemotherapy agents have demonstrated activity in progressive or relapsed hepatoblastoma. Irinotecan has shown activity in relapsed and progressive hepatoblastoma. The efficacy of high-dose chemotherapy in this setting is unknown. Newer targeted agents that 'selectively' interfere with pathway targets involved in tumor growth and progression such as insulin-like growth factor, phosphatidylinositol 3-kinase (PI3K), Akt, and mammalian target of rapamycin (mTOR) are currently under development. Because of the rarity of hepatoblastoma, only a small minority of these agents will ever be evaluated in children with this disorder. Gene-directed therapy and immunotherapy have shown promising results in the preclinical setting, and should be investigated as future treatment options for advanced hepatoblastoma.
Paediatric Drugs 08/2012; 14(4):221-32. · 1.79 Impact Factor
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ABSTRACT: The aim of this study was to evaluate outcome of patients with congenital diaphragmatic hernia (CDH) undergoing open versus minimally invasive surgery.
Patient records of 33 children undergoing surgery for CDH between March 2002 and September 2008 were reviewed. Patient data were compared regarding operating time, intraoperative maximum CO(2) partial pressure (pCO(2 max)) values, postoperative ventilation time, complications, and recurrences.
Median age at time of operation was 4 days (range, 0-1017 days), and median weight was 3800 g (range, 2000-13,200 g). Laparotomy was performed in 12 children. Seventeen patients underwent thoracoscopic repair, and four children had a laparoscopic approach. Operating time was significantly longer (P=.004) in the minimally invasive group. Median values of pCO(2 max) during operation were not significantly different (P=.25) in the minimally invasive surgery group. The pCO(2 max) values in the postoperative course were significantly lower (P=.013) in the minimally invasive group, whereas median ventilation times postoperatively were significantly longer (P=.024) in the open surgery group.
Median values of pCO(2 max) in the postoperative course were significantly lower in the minimally invasive surgery group. In addition, postoperative ventilation time was shorter when children underwent minimally invasive surgery. In conclusion, minimally invasive surgery seems to offer advantages for selected patients with CDH.
Journal of Laparoendoscopic & Advanced Surgical Techniques 02/2012; 22(3):285-9. · 1.40 Impact Factor
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ABSTRACT: Distant metastases regularly occur in children with solid tumors. The most affected organ is the lung. Nearly in all extracranial pediatric solid tumors, the presence of lung metastases is associated with an adverse prognosis for the children. Therefore, the correct treatment of lung metastases is essential and influences the outcome. Despite different national and international trials for pediatric tumor entities, specific surgical aspects or guidelines for lung metastases are usually not addressed thoroughly in these protocols. The aim of this article is to present the diagnostic challenges and principles of surgical treatment by focusing on the influence of surgery on the outcome of children. Special points of interest are discussed that emphasize sarcomas, nephroblastomas, hepatoblastomas, and other tumors. Surgery of lung metastases is safe, has a positive impact on the patients' prognosis, and should be aggressive depending on the tumor entity. An interdisciplinary approach, including pediatric oncology and radiology, is mandatory in any case.
Seminars in Pediatric Surgery 02/2012; 21(1):79-87. · 2.93 Impact Factor
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ABSTRACT: Necrotizing enterocolitis (NEC) and focal intestinal perforation (FIP) are major causes of morbidity in infants with extremely low birth weight (ELBW).
To evaluate the surgical procedures applied, and the survival and long-term outcome of ELBW infants with NEC and FIP in a single-center study.
Inborn and outborn ELBW infants (<1000 g) with NEC and FIP were analyzed retrospectively from 2002 to 2007. Data collected include surgical procedures, survival as well as complications, length of partial parenteral nutrition and hospital stay. The short-term and long-term outcomes after 2-7 years were assessed and compared with a matched control group.
Out of 280 ELBW infants, 28 underwent surgery, 19 because of FIP and 9 for NEC. Fourteen infants in the FIP group were treated with primary laparotomy and 5 with peritoneal drainage (PD). In the NEC group, only 1 infant was treated with PD. PD was used for unstable patients and was always followed by secondary laparotomy after stabilization. Five of 28 (18%) surgically treated ELBW infants and 4 (14%) matched controls died. The following complications occurred in the surgical group: complete (n = 1) or minor wound dehiscence (n = 4), stoma prolapse (n = 5), parastomal hernia (n = 2), stoma fistula (n = 1), and wound infection (n = 2). Dependency on parenteral nutrition was significantly shorter in infants with FIP, while there were no differences in time to stoma closure and length of hospital stay between those with FIP and those with NEC. Eleven of 23 (47.8%) surviving patients with FIP or NEC showed developmental delay, compared with 9 of 24 (37.5%) in the controls.
The management of EBLW infants with NEC and FIP remains challenging. Our treatment approach was associated with low mortality. Developmental delay seems to be caused by extreme prematurity rather than NEC- or FIP-related bowel perforation.
Neonatology 01/2012; 101(4):285-92. · 2.66 Impact Factor
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ABSTRACT: Molecular imaging is a novel field in cancer research combining various in vivo imaging modalities with molecular biology. Different techniques such as magnetic resonance tomography (MRI), positron emission tomography (PET), optical imaging methods (bioluminescence, fluorescence), or combination of these are used in basic research as well as in patients in different tumor entities. In hepatoblastoma (HB), there are only few reports on molecular imaging methods in a preclinical (optical imaging) and clinical setting (PET, PET-CT). Unimprovable treatment outcomes of patients in advanced tumor stages require novel treatment approaches. Photodynamic diagnosis (PDD) and photodynamic therapy (PDT) are novel diagnostic and therapeutic tools. Photodynamic diagnosis allows in vitro and in vivo detection of tumor cells using their fluorescending behaviour. PDT is a novel anticancer treatment approach leading to tumor cell destruction via apoptosis. In hepatoblastoma, there are only few reports on in vitro and in vivo studies using this treatment modality. First results seem to be promising and further studies will be required to further evaluate these techniques and to transfer them into clinical settings. This paper reviews different modalities of molecular imaging, photodynamic diagnosis and photodynamic therapy in childhood hepatoblastoma.
Frontiers in bioscience (Elite edition) 01/2012; 4:487-92.
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ABSTRACT: Complete surgical resection of the primary tumor is one of the most important prognostic factors for hepatoblastoma (HB). This goal can mean a relevant challenge in some cases of advanced HB, especially since an anatomical resection should be realised. Over recent years several surgical techniques for advanced liver resections in children have been developed and refined. In this article the authors summarize their own experience with advanced liver resections for HB and give an overview over indications and specifications for the different approaches.
Frontiers in bioscience (Elite edition) 01/2012; 4:462-9.
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ABSTRACT: Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is responsible for cell death in many cancer cells while being non-toxic for most normal cells. In this study, we investigated the role of TRAIL in human hepatoblastoma (HB) cells and analyzed different approaches to reverse TRAIL resistance in these tumors. Death receptors DR4 and DR5 expression was found on all analyzed primary HB samples and on the cell lines HuH6 and HepT1 by immunofluorescence staining. Recombinant TRAIL alone did not induce in vitro cytotoxicity. Decoy receptor blocking by antibodies led to moderate effects in HepT1 but not in HUH6 cells, whereas FLIP knock-down using siRNA rendered HUH6 cells but not HepT1 cells sensible to TRAIL. Bcl-2 inhibition with ABT-737 enhanced TRAIL-mediated apoptosis in all HB cells. Strongest cytotoxic TRAIL effects were seen in HB cell lines with synchronous proteasome inhibition using bortezomib. FLIP and Bcl-2 contributed to the TRAIL resistance in HB. Overcoming TRAIL resistance in HB by proteasome inhibitors has been identified a possible additive to improve treatment results in HB patients with drug resistant tumors.
Frontiers in bioscience (Elite edition) 01/2012; 4:2194-202.
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ABSTRACT: Multidrug resistance is a major reason for poor treatment results in advanced hepatoblastoma (HB). Several alternative treatment options are currently under investigation to improve the prognosis of affected patients
This study aimed to analyse the impact of sorafenib on the viability of HB cells and xenotransplanted HB tumours.
Cell viability and apoptosis were evaluated in two HB cell lines (HUH6 and HepT1) after treatment with sorafenib using MTT and Caspase 3 activation assay. Extracellular signal-regulated kinase (ERK) phosphorylation was investigated using Western blot. In addition, sorafenib (30 mg/kg) was administered orally to NMRI mice bearing subcutaneous HUH6 derived tumours. Tumour progression and viability were monitored by tumour volume and α-fetoprotein (AFP) levels, and apoptosis was assessed using TUNEL assay. Tumour angiogenesis and mean vascular density (MVD) was determined using CD31 staining, ERK phosphorylation was detected using indirect immunofluorescence.
Treatment with sorafenib led to decreased ERK phosphorylation, reduced cell viability and induction of apoptosis in HepT1 and HUH6 cells. In HB xenografts, sorafenib significantly reduced tumour growth compared with control (P < 0.05). AFP levels were lower in the sorafenib group (P = 0.07). Relative apoptotic areas detected using TUNEL assay were increased (P = 0.003). CD31 staining revealed inhibition of angiogenesis, and mean vascular density was lower in the sorafenib group (P = 0.02). ERK phosphorylation was reduced in tumours tissues after sorafenib treatment.
Treatment with sorafenib led to a potent inhibition of cell viability, tumour progression and angiogenesis. Sorafenib might therefore also be a promising treatment option for high risk or recurrent HB.
Liver international: official journal of the International Association for the Study of the Liver 12/2011; 32(4):574-81. · 3.82 Impact Factor
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ABSTRACT: Pancreatic tumors (PT) in childhood are rare. Standard therapeutic approaches are lacking. Our aim was to analyze treatment modalities and outcome in children with PT.
Between 1980 and 2007, 55 patients with exocrine PT < 16 years old were registered. Data were obtained from the German Pediatric Tumour Registry. Medical records were evaluated and patient data were pseudonymized.
Patient records of 29 children were available (9 male, 20 female, median age 11.2 years, range 3.1-16). In 18 patients a solid-pseudopapillary tumor (SPT) was diagnosed, in 7 patients a pancreatic carcinoma (P-CA) (5 acinar cell carcinoma (ACC), 2 ductal adenocarcinoma (DCA)), and in 4 patients a pancreatoblastoma (PBL). In 69% of the patients the initial radiological findings led to an incorrect tentative diagnosis. Initial histopathological diagnoses were differing from the reference pathology in 50% of the SPT and 45% of the P-CA. In the group of SPT survival rate was 100%; all patients underwent surgical resection. There were two cases of tumor relapse and one late secondary malignancy of the pancreas (DCA). In P-CA patients, survival rate was 14%, in the PBL group the survival rate was 25%. Concepts of chemotherapy, radiotherapy, and surgical intervention in P-CA and PBL were varying widely.
In all cases of pediatric PT reference pathology and reference radiology should be involved. Standardized treatment concepts as well as prospective data registrations need to be entrenched.
Pediatric Blood & Cancer 06/2011; 58(3):366-71. · 1.89 Impact Factor
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ABSTRACT: Thoracoscopic approach for repair of esophageal atresia (EA) and tracheo-esophageal fistula (TEF) has become a standard procedure in many pediatric surgical centers. Thoracoscopic surgery in a newborn is demanding from both the surgeon and the patient. The potential benefits for the newborn are still discussed by neonatologists, pediatric intensive care physicians, and also parents. The aim of our investigation was to clearly define perioperative outcome and complication rates in children undergoing thoracoscopic versus open surgery for EA and TEF repair.
We reviewed the records of 68 newborns undergoing surgery for EA and TEF between March 2002 and February 2010. Patient data of open versus thoracoscopic approach were compared regarding operating time, intraoperative as well as postoperative pCO(2)max values, postoperative ventilation time, and complications. Specific patient data are reported with the median and range. Data analysis was done with the JMP(®) 7.0.2 statistical software (SAS Institute, Cary, NC).
For the 68 patients, the mean gestational age was 35 weeks (28-41), the median birth weight was 2720 g (1500-3510 g) in the thoracoscopic group and 2090 g (780-3340 g) in the open group. There were 36 girls and 32 boys. Thirty-two children had associated anomalies. Twenty-five children were undergoing a thoracoscopic procedure. In 8 cases, the operation was converted to open thoracotomy. Another 32 children received a thoracotomy. In 11 newborns, a cervical esophagostomy was performed because of long-gap EA and these patients were excluded from the study. Operating time was 141 minutes (77-201 minutes) in the thoracoscopic group and 106 minutes (48-264 minutes) in the thoracotomy group, with significant difference (P=.014). Values of pCO(2)max during operation were 62 mm Hg (34-101 mm Hg) in the thoracoscopic group and 48 mm Hg (28-89 mm Hg) in the open group, with significant difference (P=.014). Postoperative ventilation time was 3 days (1-51 days) in all groups, with no significant difference (P=.79). Early complications were noticed in 9 children undergoing thoracoscopy and in 8 patients of the thoracotomy group, again with no significant difference (P>.05).
Thoracoscopic repair of EA with TEF is justified because of a comparable perioperative outcome to open surgery, competitive operating times, decreased trauma to the thoracic cavity, and improved cosmesis despite skeptical considerations. Complication rates are not higher than in children operated on through a thoracotomy. However, a learning curve has to be taken into account and large experience in minimal invasive surgery is mandatory for this procedure. Larger series have to be expected for a more objective evaluation of perioperative as well as long-term outcomes. To our opinion, the thoracoscopic approach appears to be favorable and could be a future standard.
Journal of Laparoendoscopic & Advanced Surgical Techniques 06/2011; 21(5):439-43. · 1.40 Impact Factor
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Jan Godzinski,
Harm van Tinteren,
Jan de Kraker,
Norbert Graf,
Christophe Bergeron,
Hugo Heij,
Dietrich von Schweinitz, Joerg Fuchs,
Giovanni Cecchetto,
George Audry,
Frederic Gauthier,
Bengt Sandstedt
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ABSTRACT: Partial nephrectomy (NSS) for unilateral nephroblastoma may be beneficial, although in case of regional lymph node (LN) involvement, radiotherapy counteracts the functional benefit of NSS. The aim is to verify whether decrease of tumor volume under preoperative chemotherapy implies clearance of regional LN.
SIOP 9301 (1993-2001) collected 1,450 localized nephroblastoma patients of whom 1,360 (93%) had sufficiently available data and were retrospectively reviewed.
Histologic subtypes were classically distributed. Patients were divided in those with tumor positive LN (76, 5.5%) and those with tumor negative LN (1,284, 94.5%) at surgery. In the LN(+) group, the tumor volume changed from a median of 554 (318-772) to 192 (63-458) ml = 67% (27-88%) during preoperative ChT. In the LN(-) group-377 (200-612) to 130 (44-294) ml = 62% (28-83%) (NS). Increase of tumor volume was observed in 16% of patients with LN(+), and 11% of those with LN(-) (NS); ranges are interquartile. Initial tumor volume was significantly larger in the LN(+) patients (P = 0.00091) but not different (NS) at surgery; patients with initial tumor volume under 318 ml had the regional LN involved significantly less frequently (P = 0.00751).
Change in tumor volume under preoperative chemotherapy is not a predictor for LN status at surgery, although larger initial volume is associated with a higher risk of LN invasion. The decrease of tumor volume is not a good criterion for the safety of NSS. The low rate of LN(+) (5.5%) indicates that this risk is low.
Pediatric Blood & Cancer 04/2011; 57(7):1266-9. · 1.89 Impact Factor
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ABSTRACT: To demonstrate a rare case of urological pathology, we report a combination of a single kidney and ureteral atresia. The treatment concept and outcome are outlined.
Antenatal ultrasound had revealed urinary ascites which lead to caesarean section in the 34th gestational week. Persisting anuria was confirmed postnatally and peritoneal dialysis started on the second day of life. Subsequent laparotomy revealed ureteral atresia after 3 cm of patent ureter. We created an ileum conduit after discussing various other therapeutic options.
A follow up of 12 months has shown steady function of the stoma with stable renal parameters. An ileal conduit represents a good option if high drainage is necessary in early childhood.
Journal of pediatric urology 03/2011; 7(5):576-8. · 1.38 Impact Factor
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ABSTRACT: Carcinogenesis is often linked to aberrant activation of Wnt/β-catenin signalling, in many cases caused by activating CTNNB1 mutations (encoding β-catenin). Recently, β-catenin was established as a decisive regulator of hepatic glutamine synthetase (GS) and cytochrome P450 (CYP) expression in mouse hepatocarcinogenesis. This study was aimed to analyse the connection of β-catenin signalling and GS/CYP expression in human paediatric tumours. Samples from 23 paediatric tumours were analysed for activating mutations in CTNNB1. Protein expression of the model β-catenin target GS and of various CYP isoforms was analysed and correlated with CTNNB1 mutational status and histological findings. Activating CTNNB1 mutations were frequent in hepatoblastoma (80%) and nephroblastoma (31%). In CTNNB1-mutated hepatoblastoma, expression of GS was only detected in tumour areas with epithelial, not with mesenchymal differentiation. Particularly high expression of glutamine synthetase was found in hepatoblastoma cells directly neighbouring a mesenchymal-type tumour area or stroma cells, associated with above-average cell proliferation. GS expression was not observed in CTNNB1-mutated nephroblastoma. Hepatoblastoma with activated β-catenin expressed different CYPs relevant for the metabolism of cytostatic drugs, but with high interindividual variance and heterogeneity within a single tumour. GS and different CYPs are co-expressed in hepatoblastoma with activated β-catenin. Moreover, other factors like histological subtype of tumour cells and cell-cell-interactions at the borders between different areas of the tumours affect expression of these β-catenin target genes. Analysis of CYP expression in resected tumour tissue might be useful for the selection of appropriate cytostatics for post-operative chemotherapy.
Toxicology 03/2011; 281(1-3):7-14. · 3.68 Impact Factor
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ABSTRACT: Investigation of hepatoblastoma in experimental conditions contributes relevantly to a detailed understanding of tumor biology and the investigation of new treatment approaches. Most systematical analyses currently use subcutaneous xenografts. We established a reproducible intrahepatic model with the hepatoblastoma-cell lines HuH6 and HepT1. The cells were stably transfected with a plasmid vector encoding for Gaussia luciferase. HuH6 and HepT1 were injected intrasplenically in NOD/LtSz-scid IL2Rγnull mice. Mice were splenectomized in order to avoid intrasplenical tumor growth. Multifocal intrahepatic tumor growth was observed in 85% (11/13) of HuH6 tumors and 55% (5/9) of HepT1 tumors. Serum Alpha-fetoprotein and Gaussia luciferase increased 5 weeks after tumor-cell inoculation. Tumors were detected by MRI at this time point. Immunhistochemical analysis such as vascularity (CD31), proliferation index (Ki-67), cytokeratin 7 and distribution of β-catenin in intrahepatic tumors were different to subcutaneous tumors. We established a reproducible xenograft model for intrahepatic hepatoblastoma growth with a high tumor incidence. Monitoring of tumor cell viability was optimized by measuring GLuc. This model enables further experimental investigations of HB in a more physiological milieu as emphasized by the β-catenin distribution.
PLoS ONE 01/2011; 6(8):e23419. · 4.09 Impact Factor
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ABSTRACT: NK cells are involved in the lysis of different solid tumors and leukemias. NK-activity is thereby regulated by activating and inhibitory receptors. Until now, nothing is known about the NK-activity against hepatoblastoma and the involved receptors. We tested NK cells for cytotoxicity against HB in vitro. Expression levels of activating NK ligands were analysed on 13 primary HB samples as well as on 3 HB cell lines. All HB cell lines showed low HLA-class-I-expression. CD155 expression was strong on primary HB samples and cell lines. NKG2D-ligands (MICA/B, ULBP1-3) were heterogeneous expressed in primary samples and cell cultures. There were no differences between the various histological subtypes. NK cells showed strong cytotoxicity in vitro which was significantly increased through interleukin-2 and -15 stimulation (p less than 0.001). Blockade of CD155 resulted in decreased lysis rates. Our findings show that NK cells exert high activity against hepatoblastoma in vitro and that CD155 is involved in the NK mediated killing of HB. The inclusion of a NK-based immunotherapy into novel treatment strategies might be a promising alternative especially for advanced tumors.
Frontiers in bioscience (Elite edition) 01/2011; 3:1456-66.
