Desmoplastic small round cell tumor in children: a new therapeutic approach

Purpose

Desmoplastic small round cell tumor (DSRCT) is a rare, highly aggressive malignancy with distinctive histologic and immunohistochemical features occurring in a young population with a male predominance. The tumor appears to arise as masses in the abdominal cavity without a clear visceral origin. Five patients with DSRCT were treated as usual with combined chemoradiation and surgery. In addition, in our center, patients underwent autologous bone marrow transplant (BMT), which is a novel approach to this disease.

Methods

Charts of 5 patients (4 males, mean age of 11 years) treated between 2000 and 2007 were reviewed. The diagnosis of DSRCT was made on the basis of clinical examination, computed tomographic scan, and explorative laparotomy with biopsy, and biochemical markers were negative. All patients were treated with aggressive chemoradiation and surgery. Three patients also had autologous BMT.

Results

Three patients (BMT recipients) responded to treatment. The responding patients had surgery with the intent of removing all disease. Two patients died of their cancer, neither of whom underwent BMT.

Conclusion

The patients DSRCT are sensitive to an aggressive combination of chemotherapy, surgical debulking, and radiation therapy, followed by autologous BMT. It appears that this new multifaceted treatment offers good palliation, which may prolong survival and a possible cure.     

P53 oncosuppressor influences selection of genomic imbalances in response to ionizing radiations in human osteosarcoma cell line SAOS-2

Purpose: To investigate the impact of TP53 (tumor protein 53, p53) on genomic stability of osteosarcoma (OS).

Materials and methods: In first instance, we expressed in OS cell line SAOS-2 (lacking p53) a wild type (wt) p53 construct, whose protein undergoes nuclear import and activation in response to ionizing radiations (IR). Thereafter, we investigated genomic imbalances (amplifications and deletions at genes or DNA regions most frequently altered in human cancers) associated with radio-resistance relative to p53 expression by mean of an array-based comparative genomic hybridization (aCGH) strategy. Finally we investigated a putative marker of radio-induced oxidative stress, a 4,977 bp deletion at mitochondrial (mt) DNA usually referred to as ‘common’ deletion, by mean of a polimerase chain reaction (PCR) strategy.

Results: In radio-resistant subclones generated from wt p53-transfected SAOS-2 cells DNA deletions were remarkably reduced and the accumulation of ‘common’ deletion at mtDNA (that may let the persistence of oxidative damage by precluding detoxification from reactive oxygen species [ROS]) completely abrogated.

Conclusions: The results of our study confirm that wt p53 has a role in protection of OS cell DNA integrity. Multiple mechanisms involved in p53 safeguard of genomic integrity and prevention of deletion outcome are discussed.     

(R)-[11C]verapamil is selectively transported by murine and human P-glycoprotein at the blood–brain barrier,and not by MRP1 and BCRP

IntroductionPositron emission tomography (PET) with [¹¹C]verapamil, either in racemic form or in form of the (R)-enantiomer, has been used to measure the functional activity of the adenosine triphosphate-binding cassette (ABC) transporter P-glycoprotein (Pgp) at the blood–brain barrier (BBB). There is some evidence in literature that verapamil inhibits two other ABC transporters expressed at the BBB, i.e. multidrug resistance protein 1 (MRP1) and breast cancer resistance protein (BCRP). However, previous data were obtained with micromolar concentrations of verapamil and do not necessarily reflect the transporter selectivity of verapamil at nanomolar concentrations, which are relevant for PET experiments. The aim of this study was to assess the selectivity of verapamil, in nanomolar concentrations, for Pgp over MRP1 and BCRP.MethodsConcentration equilibrium transport assays were performed with [³H]verapamil (5 nM) in cell lines expressing murine or human Pgp, human MRP1, and murine Bcrp1 or human BCRP. Paired PET scans were performed with (R)-[¹¹C]verapamil in female FVB/N (wild-type), Mrp1^(?/?), Mdr1a/b^(?/?), Bcrp1^(?/?) and Mdr1a/b^(?/?)Bcrp1^(?/?) mice, before and after Pgp inhibition with 15 mg/kg tariquidar.ResultsIn vitro transport experiments exclusively showed directed transport of [³H]verapamil in Mdr1a- and MDR1-overexpressing cells which could be inhibited by tariquidar (0.5 μM). In PET scans acquired before tariquidar administration, brain-to-blood ratio (K_b,brain) of (R)-[¹¹C]verapamil was low in wild-type (1.3 ± 0.1), Mrp1^(?/?) (1.4 ± 0.1) and Bcrp1^(?/?) mice (1.8 ± 0.1) and high in Mdr1a/b^(?/?) (6.9 ± 0.8) and Mdr1a/b^(?/?)Bcrp1^(?/?) mice (7.9 ± 0.5). In PET scans after tariquidar administration, K_b,brain was significantly increased in Pgp-expressing mice (wild-type: 5.0 ± 0.3-fold, Mrp1^(?/?): 3.2 ± 0.6-fold, Bcrp1^(?/?): 4.3 ± 0.1-fold) but not in Pgp knockout mice (Mdr1a/b^(?/?) and Mdr1a/b^(?/?)Bcrp1^(?/?)).ConclusionOur combined in vitro and in vivo data demonstrate that verapamil, in nanomolar concentrations, is selectively transported by Pgp and not by MRP1 and BCRP at the BBB, which supports the use of (R)-[¹¹C]verapamil or racemic [¹¹C]verapamil as PET tracers of cerebral Pgp function.     

Berechnungsgenauigkeit von Volumina zur Evaluierung von Dosis-Volumen-Histogrammen

Background

Modern 3-dimensional treatment planning systems on the basis of sectional imaging allow the calculation of volumes for organs of interest. The aim of this study is to investigate systematically the accuracy of calculations of volumes by the use of a phantom for 4 different treatment planning systems.

Material and Method

The tests were done with a phantom with 5 cylindrical structures and 6 spherical shaped structures. After performing a CT-scan and reading the data into the planning systems the structures were contoured and the volumes were calculated in order to compare these values with the values calculated by mathematical equations. This was systematically done as a function of different parameters.

Results

Comparing different methods of contouring showed notable influence on the result. Parameters as number of calculation points or length of cylinders showed no significant differences. In summary, the mean deviations for cylinders were +7% for system A, ?2% for B, ?17% for C, and 0% for D. For larger spheres (radii between 5 and 2.5 cm) the mean deviations were ?5% for A, +3% for B, +1% for C, and +5% for D. For smaller spheres (radii between 1.75 and 1.25 cm) the mean deviations were ?14% for A, ?2% for B, ?10% for C, and ?4% for D.

Conclusion

Verifying results of planning systems is important for the daily routine, but it has to be taken into account, that small changes of the radius of a cylinder or sphere cause substantial volume changes. The differences are also caused by inaccuracies of the whole procedure, e. g., the CT study, the shape and dimensions of the cylinders and the spheres and the CT information and the delineariation of the structures.     

Control results on a sample of patients subjected to total thyroidectomy for papillary carcinoma: proposal for a personal diagnostic-therapeutic follow-up

Well-differentiated thyroid neoplasms may be included among the most frequently occurring thyroid carcinomas. Papillary ca. is without doubt the best behaved type. The aim of the present work is to perform a retrospective case history study to assess patients with con papillary ca. who have been treated surgically over the last 17 years and have been subjected to periodic checks. A sample of patients was therefore extrapolated who had all undergone total thyroidectomy for papillary ca. of the thyroid. The incidence of local recurrence of the disease was verified, together with the results at distance. Furthermore, the assessments performed were evaluated and compared. From the sample of patients observed we inferred that papillary carcinoma of the thyroid can have a good prognosis over time provided periodic random checks are carried out.     

Expansion of natural killer cells in patients with head and neck cancer: detection of "noninhibitory" (activating) killer Ig-like receptors on circulating natural killer cells

BACKGROUND: In a group of patients with head and neck cancers (H&NC), the expansion of the population of CD3-,CD16+ natural killer (NK) cells in the peripheral blood was studied. METHODS: Cytofluorimetric analysis of the expression of killer Ig-like receptors (KIR, namely p58.1, p58.2, p58.3, p70, and p140) and CD94-NKG2a was performed. Cytolytic activities were studied using 51Cr release assay. T and NK cell cloning was performed using limiting dilution culture conditions. Cytokine production was analyzed using commercial enzyme immunoassays. RESULTS: Phenotypic analysis showed that the expanded populations were heterogeneous. Even in the presence of a large number of circulating NK cells, "nonspecific" cytolytic capacities were heavily reduced, whereas cytolytic capacity related to T cells was virtually normal. Unlike NK cell clones derived from healthy donors, most NK cells derived from H&NC patients expressed surface "activating" NK cell receptors (KAR) for HLA, detected by use of a redirected cytolytic assay. Analysis of the CD4+ subpopulation at the clonal level demonstrated that they had a severe proliferative defect. CONCLUSION: These experimental data indicated that H&NC patients have a polyclonal expansion of functionally deficient NK cells expressing KAR. In addition, the proliferative capacity of patients' "helper" cells was strongly inhibited, thus accounting for a severe impairment of cytolytic activity of the expanded NK cells.     

Cellular mechanisms of ischemia-reperfusion injury

As of yet, only a few strategies to prevent myocardial reperfusion injury have been tested clinically. In the first minutes of reperfusion, the myocardium can be damaged by contracture development, causing mechanical stiffness, tissue necrosis, and the "stone heart" phenomenon. Reperfusion-induced contracture can have two different causes, namely, Ca2+overload-induced contracture or rigor-type contracture. Ca2+ contracture results from rapid re-energization of contractile cells with a persistent Ca2+ overload. Strategies to prevent this type of injury are directed at cytosolic Ca2+ control or myofibrillar Ca2+ sensitivity. Rigor-contracture occurs when re-energization proceeds very slowly. It does not depend on Ca2+ overload. It may be prevented by strategies improving early mitochondrial reactivation     

Voxel-based diffusion tensor magnetic resonance imaging evaluation of low-grade hepatic encephalopathy

PURPOSE: To quantify the changes in brain water diffusivity in hepatic encephalopathy (HE) associated with cirrhosis using diffusion tensor imaging (DTI) and to correlate with neuropsychological (NP) scores. MATERIALS AND METHODS: DTI was performed in 14 patients with low-grade HE and age/gender-comparable 16 healthy controls. Whole brain mean diffusivity (MD) and fractional anisotropy (FA) maps were calculated, normalized to common space, smoothed, and compared voxel-by-voxel between groups using analysis of covariance with age included as a covariate. The average MD and FA values were also calculated from individual subjects for selected brain regions and correlated with the neuropsychological scores. RESULTS: Patients with HE showed increased MD in the cortical gray and white matter and the internal capsule. Less extensive brain regions with decreased FA were observed in the bilateral frontal and occipital white matter. MD values from the corpus callosum correlated inversely with several NP scores among HE patients and controls. Positive correlations were observed with FA values and cognitive scores. CONCLUSION: Voxel-based DTI analysis showed widespread brain regions with increased MD values, indicating enhanced water content and decreased FA in cirrhotic patients with HE. The MD and FA values from selected regions correlated with the NP scores.