Hemangioendotelioma epiteloide pulmonar

Epithelioid hemangioendothelioma is a multifocal tumor that rarely metastasizes. It is difficult to diagnose and is most often an incidental finding in young asymptomatic women. It has a heterogeneous radiologic pattern. The most important diagnostic information is histologic confirmation of Weibel-Palade bodies or immunohistochemistry based on specific tumor markers such as factor VIII and CD34. We report the case of a 73-year-old woman in whom multiple pulmonary nodules detected by chance in a radiograph were subsequently diagnosed as epithelioid hemangioendothelioma.     

Abnormal methylation of the common PARK2 and PACRG promoter is associated with downregulation of gene expression in acute lymphoblastic leukemia and chronic myeloid leukemia

The PARK2 gene, previously identified as a mutated target in patients with autosomal recessive juvenile parkinsonism (ARJP), has recently been found to be a candidate tumor suppressor gene in ovarian, breast, lung and hepatocellular carcinoma that maps to the third common fragile site (CFS) FRA6E. PARK2 is linked to a novel described PACRG gene by a bidirectional promoter containing a defined CpG island in its common promoter region. We have studied the role of promoter hypermethylation in the regulation of PARK2 and PACRG expression in different tumor cell lines and primary patient samples. Abnormal methylation of the common promoter of PARK2 and PACRG was observed in 26% of patients with acute lymphoblastic leukemia and 20% of patients with chronic myelogenous leukemia (CML) in lymphoid blast crisis, but not in ovarian, breast, lung, neuroblastoma, astrocytoma or colon cancer cells. Abnormal methylation resulted in downregulation of PARK2 and PACRG gene expression, while demethylation of ALL cells resulted in demethylation of the promoter and upregulation of PARK2 and PACRG expression. By FISH, we demonstrated that a lack of PARK2 and PACRG expression was due to biallelic hypermethylation and not to deletion of either PARK2 or PACRG in ALL. In conclusion, our results demonstrate for the first time that the candidate tumor suppressor genes PARK2 and PACRG are epigenetically regulated in human leukemia, suggesting that abnormal methylation and regulation of PARK2 and PACRG may play a role in the pathogenesis and development of this hematological neoplasm.     

Perioperative high-dose-rate brachytherapy in soft tissue sarcomas of the extremity and superficial trunk in adults: initial results of a pilot study

PURPOSE: This study was undertaken to determine the feasibility of perioperative high-dose-rate brachytherapy (PHDRB) as an alternative to standard low-dose-rate brachytherapy in adult patients with soft tissue sarcomas. METHODS AND MATERIALS: Twenty-five adult patients with soft tissue sarcomas of the extremities or the superficial trunk were treated with surgical resection and PHDRB (16, 24, or 32Gy) for negative, close/microscopically positive, or grossly involved surgical resection margins, respectively. External beam radiation therapy (45Gy) was added postoperatively. Adjuvant chemotherapy with ifosfamide and doxorubicin was given to patients with high-grade tumors. RESULTS: Resection margins were negative in 6 patients (24.0%), close/microscopically positive in 18 (72.0%), and grossly involved in 1 (4.0%). One patient (4.0%) with wound dehiscence needed reoperation. Three patients failed in the anatomical region treated, but relapse sites were not adjacent to the area treated with PHDRB. After a median followup of 23.2 months (range 2.8-48.0), the 4-year local and regional control rates were 100% and 80.5%, respectively. Four-year overall survival was 78.2%. CONCLUSIONS: Locoregional control and survival results are encouraging for this high-risk patient population. PHDRB results seem to be similar to those obtained with low-dose-rate brachytherapy.     

Genetic and epigenetic alterations of the cell cycle regulators and tumor suppressor genes in pediatric osteosarcomas

PURPOSE: To analyze the genetic and epigenetic alterations affecting the RB1, TP53, p16INK4, and p21WAF1 tumor suppressor genes, loss of heterozygosity (LOH) at 3q and 18q, and the clinical variables of a series of Spanish children with osteosarcoma. These genetic changes were tested for an association with prognosis. METHODS: Peripheral blood samples and clinical data were available from 76 patients with osteosarcoma. Paired tissue was available from 41 of them. The mutation and methylation status of p16INK4, p21WAF1, TP53, and RB1 was screened as well as LOH at 3q and 18q. RESULTS: Loss of heterozygosity affecting RB1 (37.2%), TP53 (42.3%), and 18q (30.8%) and TP53 mutation (39%) were frequently encountered. TP53 mutation was associated with diagnosis at a later age. RB1 alteration was associated with reduced survival and event-free survival. The clinical variables associated with poor prognosis were the presence of metastasis at diagnosis (P = 0.035) or during treatment (P = 0.016) and the chondroblastic histologic subtype (P = 0.007); the response to induction chemotherapy (<90% necrosis) also tended to be related to poor prognosis (P = 0.08). CONCLUSIONS: RB1, TP53, and possibly other tumor suppressor genes located at 18q and other localizations are involved in pediatric osteosarcoma carcinogenesis, together with other genetic alterations not fully understood to date. Based on these results, the presence of an altered RB1 gene should be regarded as a poor prognostic factor for pediatric osteosarcoma.     

Age-related changes in pharmacokinetics and pharmacodynamics of lerisetron in the rat: a population pharmacokinetic model

BACKGROUND: The importance of studying the effects of age on the pharmacokinetics and pharmacodynamics of lerisetron - a new 5-hydroxytryptamine-3 (serotonin) receptor antagonist - comes from the facts that lerisetron will be administered to patients that are being treated with cytotoxic drugs and that the elderly frequently suffer from neoplastic diseases. OBJECTIVE: The present study was designed to explore the effects of age on the pharmacokinetics and pharmacodynamics of lerisetron by using an aged rat model. A mixed-effects population study was carried out in order to analyze the sparse data and to create covariate models which could be used to derive dosage recommendations. METHODS: Fischer 344 rats (n = 44) were divided into three groups, depending on their age: 5, 13, and 25 months. Blood samples were collected before administration of 200 micro g/kg of lerisetron for measurements of albumin, alpha(1)-acid glycoprotein, and unbound fraction of lerisetron. The lerisetron plasma concentrations were measured by high-performance liquid chromatography. A two-compartment model was fitted to the data using the nonlinear mixed-effects computer program WinNonMix. The population analysis was performed with the complete set of the collected data, and the potential sources of variability in the population parameters were investigated. Additionally, a pharmacodynamic study was performed. The effect of lerisetron (inhibition of the von Bezold-Jarisch reflex) was evaluated in young, adult, and senescent Fischer 344 rats. RESULTS: The mean values of the individual Bayes estimates of the parameters showed a decrease in total clearance and distribution volume of the central compartment in old rats. The lerisetron free (unbound) fraction remained unchanged among the groups, and there were no significant differences in alpha(1)-acid glycoprotein levels. The concentration-effect relationship was best described by a sigmoid E(max) model. Since the drug concentration in plasma at half-maximal effect (EC(50)) decreased in old rats, an increased sensitivity to the effect of lerisetron in old animals could be expected. CONCLUSION: Both pharmacokinetic changes (decreased volume of distribution and clearance and increased elimination half-life) and pharmacodynamic alterations (decrease in total and unbound EC(50)) may be responsible for the different responses to lerisetron observed in old rats.     

CpG island methylator phenotype redefines the prognostic effect of t(12;21) in childhood acute lymphoblastic leukemia.

PURPOSE: To examine cancer genes undergoing epigenetic inactivation in a set of ETV6/RUNX1-positive acute lymphoblastic leukemias in order to define the CpG island methylator phenotype (CIMP) in the disease and evaluate its relationship with clinical features and outcome. EXPERIMENTAL DESIGN: Methylation-specific PCR was used to analyze the methylation status of 38 genes involved in cell immortalization and transformation in 54 ETV6/RUNX1-positive samples in comparison with 190 ETV6/RUNX1-negative samples. RESULTS: ETV6/RUNX1-positive samples had at least one gene methylated in 89% of the cases. According to the number of methylated genes observed in each individual sample, 20 patients (37%) were included in the CIMP- group (0-2 methylated genes) and 34 (67%) in the CIMP+ group (>2 methylated genes). Remission rate did not differ significantly among either group of patients. Estimated disease-free survival and overall survival at 9 years were 92% and 100% for the CIMP- group and 33% and 73% for the CIMP+ group (P = 0.002 and P = 0.04, respectively). Multivariate analysis showed that methylation profile was an independent prognostic factor in predicting disease-free survival (P = 0.01) and overall survival (P = 0.05). A group of four genes (DKK3, sFRP2, PTEN, and P73) showed specificity for ETV6/RUNX1-positive subset of samples. CONCLUSION: Our results suggest that methylation profile may be a potential new biomarker of risk prediction in ETV6/RUNX1-positive acute lymphoblastic leukemias.     

Living with Chronic Illness Scale: International validation through the classic test theory and Rasch analysis among Spanish‐speaking populations with long‐term conditions

BackgroundThe Living with Chronic Illness (LW‐CI) Scale is a comprehensive patient‐reported outcome measure that evaluates the complex process of living with long‐term conditions.ObjectiveThis study aimed to analyse the psychometric properties of the LW‐CI scale according to the classic test theory and the Rasch model among individuals living with different long‐term conditions.DesignThis was an observational, international and cross‐sectional study.MethodsA total of 2753 people from six Spanish‐speaking countries living with type 2 diabetes mellitus, chronic obstructive pulmonary disease, chronic heart failure, Parkinson''s disease, hypertension and osteoarthritis were included. The acceptability, internal consistency and validity of the LW‐CI scale were analysed using the classical test theory, and fit to the model, unidimensionality, person separation index, item local independency and differential item functioning were analysed using the Rasch model.ResultsCronbach''s α for the LW‐CI scale was .91, and correlation values for all domains of the LW‐CI scale ranged from .62 to .68, except for Domain 1, which showed correlation coefficients less than .30. The LW‐CI domains showed a good fit to the Rasch model, with unidimensionality, item local independency and moderate reliability providing scores in a true interval scale. Except for two items, the LW‐CI scale was free from bias by long‐term condition type.DiscussionAfter some adjustments, the LW‐CI scale is a reliable and valid measure showing a good fit to the Rasch model and is ready for use in research and clinical practice. Future implementation studies are suggested.Patient and Public ContributionPatient and public involvement was conducted before this validation study ‐ in the pilot study phase.