Cure of multifocal panhepatic hepatoblastoma: is liver transplantation always necessary?

Purpose

Multifocal panhepatic hepatoblastoma (HB) without extrahepatic disease is generally considered as an indication for total hepatectomy and liver transplantation. However, after initial chemotherapy, downstaging of the tumor sometimes allows complete macroscopic resection by partial hepatectomy. This procedure is no longer recommended because of the risk of persistent viable tumor cells in the hepatic remnant. We report our experience with conservative surgery in such cases.

Method

Between 2000 and 2005, 4 children were consecutively referred to our unit with multinodular pan-hepatic HBs (classification PRETEXT IV of the International Society of Pediatric Oncology Liver Tumor Study Group SIOPEL). Three of them had extrahepatic disease at diagnosis. All patients were treated according to SIOPEL 3 and 4 protocols.

Results

Extrahepatic metastases were still viable in 2 of 3 patients after initial chemotherapy. These patients eventually died of tumor recurrence. In the 2 patients without residual extrahepatic disease, liver tumors had regressed, and complete macroscopic excision of hepatic tumor remnants could be achieved by conservative surgery. These 2 children are alive and well and free of tumor 7 years after diagnosis.

Conclusions

Conservative surgery may be curative in some multinodular PRETEXT IV HB patients, with a good response to preoperative chemotherapy and complete excision of all macroscopic tumor remnants. However, because of the lack of reliable predictors of sterilization of the microscopic disease in the residual liver, with subsequent poor prognosis, total hepatectomy and liver transplantation remain currently recommended in patients with multinodular PRETEXT IV HB without extrahepatic disease, even though some of these children are probably overtreated.     

Transplantation of mouse embryonic stem cells induces hematopoietic and tissue chimerism in rats

Embryonic stem cells (ESC) can differentiate into all cell lineages, and ESC-like cells were shown to induce hematopoietic chimerism and tolerance in allogeneic models. The aim of our study was to test the capacity of mouse ESC (mESC) to engraft in rats in a xenotransplantation setting. Forty-six rats were transplanted intravenously with 1 million mESC, without immunosuppression (group 1, n = 23) or with cyclosporine (group 2, n = 23). Three months after mESC transplantation, skin grafts were performed from allogeneic, xenogeneic identical to mESC, or xenogeneic third party donors. At day 27 post-transplant, we detected circulating mouse cells in the blood of 4/23 and 5/23 animals of group 1 and group 2, respectively. Chimerism was confirmed by PCR. We also identified long-term surviving murine cells within livers of chimeric animals. Skin grafts showed no difference in survival between allogeneic and xenogeneic donors. Transplantation of xenogeneic mouse ESC induced short-term chimerism in the blood and persistent tissue chimerism in the liver of recipient rats, but did not induce tolerance to skin grafts. Improved immunosuppressive protocols should be tested to prolong chimerism and allow tolerance.     

Interaction of vitamin K antagonists with heparin affect monitoring by activated clotting times

Background

Unfractionated heparin is recommended during atrial fibrillation (AF) ablation to achieve activated clotting time (ACT) above 250–300 s to prevent clot. Many patients on therapeutic international normalised ratio (INR) undergo AF ablation procedures; however, it is unknown whether they require less heparin to achieve similar ACT levels.

Methods

During AF ablation, the ACT was measured before and 10 min after administration of i.v. unfractionated heparin in patients with and without anticoagulation. The association of INR, heparin, pre-procedure ACT and body weight with ACT after heparin administration was tested using multivariable linear regression models.

Results

The subjects of this study were 149 patients undergoing AF ablation, among them 40 (27%) with subtherapeutic INR?<?2, 79 (53%) with an INR between 2 and 3, and 30 (20%) patients with INR?>?3. Baseline ACT was associated with INR (r?=?0.33, p?<?0.001). After a mean of 8,685?±?2,015 U (range, 5,000–15,000 IU) unfractionated heparin, univariate predictors of ACT were baseline INR (p?<?0.001), heparin dose (p?=?0.012) and baseline ACT (p?=?0.027). In the multivariable model, baseline INR (part r?=?0.64, p?<?0.001) and heparin dose (part r?=?0.33, p?<?0.001) strongly predicted post-heparin ACT. Estimated from the regression model, the heparin dose reductions by approximately one third in those with an INR of 2–3 and by at least two thirds in those with an INR above 3 may be favourable. Over the following 3 months, no thromboembolism and acute bleeding were observed.

Conclusion

The INR was the strongest predictor of post-heparin ACT, even more important than the heparin dose itself. The reduction of heparin dose by one third if INR is between 2–3 and by two thirds if INR is above 3 may be favourable.     

Non-invasive detection of cocaine dissolved in wine bottles by (1) H magnetic resonance spectroscopy

Recently, a number of cases of smuggling dissolved cocaine in wine bottles have been reported. The aim of the present study was to determine whether cocaine dissolved in wine can be detected by proton magnetic resonance spectroscopy ((1) H MRS) on a standard clinical MR scanner, in intact (i.e. unopened) wine bottles. (1) H MRS experiments were performed with a 3 Tesla clinical scanner on wine phantoms with or without cocaine contamination. The aromatic protons of cocaine displayed resonance peaks in the 7-8 ppm region of the spectrum, where no overlapping resonances of wine were present. Additional cocaine resonances were detected in the 2-3 ppm region of the spectrum, between the resonances of ethanol and other wine constituents. Detection of cocaine in wine (at 5 mM, i.e. ～1.5 g/L) was feasible in a scan time of 1 min. We conclude that dissolved cocaine can be detected in intact wine bottles, on a standard clinical MR scanner. Thus, (1) H MRS is the technique of choice to examine this type of suspicious cargo, since it allows for a non-destructive and rapid content characterization.     

Anatomical markers of sleep slow wave activity derived from structural magnetic resonance images

Sleep studies often observe differences in slow wave activity (SWA) during non-rapid eye movement sleep between subjects. This study investigates to what extent these absolute differences in SWA can be explained with differences in grey matter volume, white matter volume or the thickness of skull and outer liquor rooms. To do this, we selected the 10-min interval showing maximal SWA of 20 young adult subjects and correlated these values lobe-wise with grey matter, skull and liquor thickness and globally with white matter as well as segments of the corpus callosum. Whereas grey matter, skull thickness and liquor did not correlate significantly with maximal slow wave activity, there were significant correlations with the anterior parts of the corpus callosum and with one other white matter region. In contrast, electroencephalogram power of higher frequencies correlates positively with grey matter volumes and cortical surface area. We discuss the possible role of white matter tracts on the synchronization of slow waves across the cortex.     

The use of CpG-free plasmids to mediate persistent gene expression following repeated aerosol delivery of pDNA/PEI complexes

Aerosol gene therapy offers great potential for treating acquired and inherited lung diseases. For treatment of chronic lung diseases such as cystic fibrosis, asthma and emphysema, non-viral gene therapy will likely require repeated administration to maintain transgene expression in slowly dividing, or terminally differentiated, lung epithelial cells. When complexed with plasmid DNA (pDNA), the synthetic polymer, 25?kDa branched Polyethylenimine (PEI), can be formulated for aerosol delivery to the lungs. We show that pDNA/PEI aerosol formulations can be repeatedly administered to airways of mice on at least 10 occasions with no detectable toxicity. Interestingly, peak reporter gene activity upon repeated delivery was significantly reduced by up to 75% compared with a single administration, despite similar pDNA lung deposition at each subsequent aerosol exposure. Although the precise mechanism of inhibition is unknown, it is independent of mouse strain, does not involve an immune response, and is mediated by PEI. Importantly, using a dosing interval of 56 days, delivery of a fourth-generation, CpG-free plasmid generated high-level, sustained transgene expression, which was further boosted at subsequent administrations. Together these data indicate that pDNA/PEI aerosol formulations offer a versatile platform for gene delivery to the lung resulting in sustained transgene expression suitable for treatment of chronic lung diseases.     

9β-hydroxyparthenolide esters from Inula montbretiana and their antiprotozoal activity

In continuation of ongoing studies on the potential of natural products as antiprotozoal leads or drugs, it was found that the CH?Cl? extract obtained from the flowering aerial parts of Inula montbretiana DC. (Asteraceae, tribe Inuleae) displays antiprotozoal activity, especially against Trypanosoma brucei rhodesiense (IC??: 3.38?μg/mL). Isolation of the possible active constituents led to the identification of six sesquiterpene lactones, all esters of 9 β-hydroxyparthenolide. Two isolates, namely, 9 β-(3',4'-epoxy-3'-methylpentanoyloxy)-parthenolide and 9 β-(3'-oxo-2'-methylbutanoyloxy)-parthenolide, represented diastereomeric mixtures differing only in the configuration within the acyl moieties. According to in vitro test results, the mixture of esters with diastereomeric 3,4-epoxy-3-methylpentanoic acid was the most active constituent against Trypanosoma brucei rhodesiense (IC??: 0.26?μg/mL) and was less cytotoxic against rat skeletal myoblasts (L6 cell line) with a selectivity index of about 9. The mixture of diastereomeric 2-methyl-3-oxobutyric acid esters was the most potent against Plasmodium falciparum (IC??: 1.48?μg/mL) and displayed a selectivity index of about 35.