Imatinib inhibits proliferation of Ewing tumor cells mediated by the stem cell factor/KIT receptor pathway, and sensitizes cells to vincristine and doxorubicin-induced apoptosis.

PURPOSE AND EXPERIMENTAL DESIGN: The stem cell factor/KIT receptor loop may represent a novel target for molecular-based therapies of Ewing tumor. We analyzed the in vitro impact of KIT blockade by imatinib in Ewing tumor cell lines. RESULTS: KIT expression was detected in 4 of 4 Ewing tumor cell lines and in 49 of 110 patient samples (44.5%) by immunohistochemistry and/or Western blot analysis. KIT expression was stronger in Ewing tumors showing EWS-FLI1 nontype 1 fusions. Despite absence of c-kit mutations, constitutive and ligand-inducible phosphorylation of KIT was found in all tumor cell lines, indicating an active receptor. Treatment with KIT tyrosine kinase inhibitor imatinib (0.5-20 micro M) induced down-regulation of KIT phosphorylation and dose response inhibition of cell proliferation (IC(50), 12-15 micro M). However, imatinib administered alone at doses close to IC(50) for growth inhibition (10 micro M) did not induce a significant increase in apoptosis. We then analyzed if blockade of KIT loop through imatinib (10 micro M) was able to increase the antitumor in vitro effect of doxorubicin (DXR) and vincristine (VCR), drugs usually used in Ewing tumor treatment. Addition of imatinib decreased in 15-20 and 15-36% of the proliferative rate of Ewing tumor cells exposed to DXR and VCR, respectively, and increased in 15 and 30% of the apoptotic rate of Ewing tumor cells exposed to the same drugs. CONCLUSIONS: Inhibition of Ewing tumor cell proliferation by imatinib is mediated through blockade of KIT receptor signaling. Inhibition of KIT increases sensitivity of these cells to DXR and VCR. This study supports a potential role for imatinib in the treatment of Ewing tumor.     

Hibernoma pleural

Hibernoma is a rare benign tumor arising in brown fat arising in young adults with similar incidence in both sexes. They are generally subcutaneous reaching in some instances a considerable size. The interscapular region, shoulders, head and neck are the main locations, but rare cases have been described in a wide variety of sites. Histologically three types of cells mixed in different proportions corresponding to the stages of maduration of the fatty cells. They are benign tumors with not recurrence after excision. We report a pleural hibernoma, a location not reported previously in the literature.     

Expression profiling of T-cell lymphomas differentiates peripheral and lymphoblastic lymphomas and defines survival related genes.

PURPOSE: T-Cell lymphomas constitute heterogeneous and aggressive tumors in which pathogenic alterations remain largely unknown. Expression profiling has demonstrated to be a useful tool for molecular classification of tumors. EXPERIMENTAL DESIGN: Using DNA microarrays (CNIO-OncoChip) containing 6386 cancer-related genes, we established the expression profiling of T-cell lymphomas and compared them to normal lymphocytes and lymph nodes. RESULTS: We found significant differences between the peripheral and lymphoblastic T-cell lymphomas, which include a deregulation of nuclear factor-kappaB signaling pathway. We also identify differentially expressed genes between peripheral T-cell lymphoma tumors and normal T lymphocytes or reactive lymph nodes, which could represent candidate tumor markers of these lymphomas. Additionally, a close relationship between genes associated to survival and those that differentiate among the stages of disease and responses to therapy was found. CONCLUSIONS: Our results reflect the value of gene expression profiling to gain insight about the molecular alterations involved in the pathogenesis of T-cell lymphomas.     

Tratamiento del cáncer de esófago localizado y localmente avanzado: ¿algo ha cambiado?

Esophageal cancer has a dismal prognosis and the surgical treatment only cures a small percentage of patients. The survival achieved by traditional surgical procedures is being improved with extended resections, but at the cost of greater morbidity. Concurrent radiochemotherapy can obtain results similar to those of surgery. Nowadays, locally advanced esophageal cancer should have a multimodal approach, because neoadjuvant chemotherapy, with or without radiotherapy, has demonstrated to improve the survival of chemosensitive patients. Recently, the role of hyperfractionated radiotherapy and new drugs such as paclitaxel, docetaxel and irinotecan in neoadjuvant treatment is being evaluated.     

Spontaneous involution of pulmonary sequestration in children: a report of two cases and review of the literature

Background. Two cases of pulmonary sequestration which regressed spontaneously are presented. Objective. To demonstrate the value of imaging studies in the diagnosis and follow-up of some forms of congenital masses of the lung in asymptomatic patients. Material and methods. We reviewed the clinical records and imaging studies of two asymptomatic children, one newborn and the other 3 months old, with thoracic masses which demonstrated variable degrees of spontaneous involution. Results. Abdominal ultrasound performed on the newborn with a palpable mass showed a triangular echogenic mass with a large central feeding vessel arising from the aorta. The mass had disappeared on follow-up US exam performed 6 years later. CT was performed in the 3-month-old patient with a persistent retrocardiac mass. A soft-tissue density mass in the left pulmonary base with a large feeding vessel arising from the aorta was visualised on contrast-enhanced CT. Five years later, a new CT scan showed significant shrinkage of the mass and no vessel. Conclusion. Radiological techniques such as real-time US with Doppler imaging and contrast-enhanced CT may establish the diagnosis of pulmonary sequestration by demonstrating the mass and its systemic vessel, thereby eliminating the need for more aggressive imaging procedures. Partial or total disappearance of these masses represents a further example of involutive pathology and suggests that not all cases of pulmonary sequestration should be surgically treated. Received: 12 September 1997 Accepted: 18 September 1997     

Visual inspection with acetic acid for cervical cancer screening outside of low-resource settings.

OBJECTIVES: To assess visual inspection with acetic acid (VIA) as a screening tool for use in a well-equipped health center in Peru, to evaluate VIA as an alternative or adjunct to the Papanicolaou (Pap) smear, and to determine if VIA can play a role in settings other than low-resource ones. METHODS: This was a prospective study of 1 921 asymptomatic women living in Lima, Peru, carried out in 1999 and 2000. The study was performed at a cancer center equipped with the latest-generation technology and highly trained oncologists. The women underwent a complete clinical evaluation, including a Pap smear and VIA. Participants with any positive test were referred for colposcopy and biopsy. RESULTS: More women tested positive by VIA than on the Pap smear (6.9% vs. 4.2%; P = 0.0001). There were 35 women with histologic cervical intraepithelial neoplasia grade 1 (CIN 1); of these, 15 were detected by Pap and 20 by VIA (P = 0.4). A diagnosis of CIN 2 or 3 (CIN 2-3) was confirmed in a total of 13 cases; Pap detected 5 of the cases and VIA 11 of the cases (P = 0.06). The positive predictive value for detection of CIN 2+ was 8.3% for VIA and 6.3% for Pap (P = 0.5). Most importantly, while only 2.3% of patients with a positive VIA were lost to follow-up before colposcopy, that was true for 26.3% of the women with a positive Pap smear (P < 0.0001). CONCLUSIONS: VIA is useful for detection of precursor lesions of cervical cancer not only in low-resource settings but also in well-equipped health centers and cancer centers. In these non-low-resource settings, VIA has a positive predictive value comparable to the conventional Pap smear, but it is more likely to achieve earlier diagnosis, follow-up, and treatment than cytology-based screening.     

Chronic oral treatment with 13-cis-retinoic acid (isotretinoin) or all-trans-retinoic acid does not alter depression-like behaviors in rats.

Oral treatment with the anti-acne drug Accutane (isotretinoin, 13-cis-retinoic acid) has been associated with suicide ideation and depression. Here, depression-like behaviors (i.e., behavioral despair and anhedonia) were quantified in adult Sprague-Dawley rats gavaged daily beginning at postnatal day (PND) 82 with 13-cis-RA (7.5 or 22.5 mg/kg) or all-trans-retinoic acid (10 or 15 mg/kg ). Tested at PND 130-131 in the Forced Swim Test, 7.5 mg/kg 13-cis-RA marginally decreased immobility and slightly increased climb/struggle durations whereas neither all-trans-retinoic acid group differed from controls. Voluntary saccharin solution (0.03%) intake at PND 102-104 and PND 151-153 was not different from controls in any treated group, although all RA-treated groups had lower intakes. Swim speed in a water maze at PND 180 was similar across groups, indicating no RA-induced differences in physical ability. Open field activity was mildly decreased at PND 91 in 7.5 mg/kg-treated males only, but it was within the control range at PND 119, 147, and 175. Thus, at serum levels similar to those in humans receiving the drug, chronic 13-cis-RA treatment did not severely affect depression-like behaviors in rats. These data do not substantiate the hypothesis of 13-cis-RA-induced depression.     

Functional significance of a natural allelic variant of human carbonyl reductase 3 (CBR3).

Human carbonyl reductase (CBR) activity accounts for a significant fraction of the metabolism of endogenous and xenobiotic carbonyl compounds. It is possible that genetic polymorphisms in CBR1 and CBR3 are key for the wide interindividual variability in the disposition of CBR drug substrates. We pinpointed a single nucleotide polymorphism in CBR3 (CBR3 V244M) that encodes for a V244 to M244 change. Blacks showed a higher frequency of the M244 allele (q = 0.51, n = 49) than did whites (q = 0.31, n = 70; p = 0.003). In addition, DNA variation panels from 10 ethnic groups presented a wide range of CBR3 V244M genotype distributions. Kinetic experiments with the recombinant CBR3 protein variants and menadione revealed that CBR3 M244 has significantly higher V(max) than does CBR3 V244 (V(max) CBR3 M244 = 40.6 +/- 1.3 micromol/min x mg versus V(max) CBR3 V244 = 19.6 +/- 2.0 micromol/min x mg, p = 0.002). In contrast, both isoforms presented similar K(m) values (K(m) CBR3 M244 = 22.9 +/- 2.9 microM versus K(m) CBR3 V244 = 24.6 +/- 3.2 microM, p = 0.43). Assays with NADP(H) demonstrated a higher V(maxNADP(H)) (1.6-fold) and increased catalytic efficiency (V(maxNADP(H))/K(mNADP(H))) for CBR3 M244 compared with CBR3 V244 (p = 0.013). Comparative three-dimensional analyses based on the structure of the homologous porcine carbonyl reductase suggested that the V244M substitution is positioned in a region critical for interactions with the NADP(H) cofactor. These studies demonstrate that the common CBR3 V244M polymorphism encodes for CBR3 isoforms with distinctive enzymatic properties.     

Antimicrobial activity of myotoxic phospholipases A2 from crotalid snake venoms and synthetic peptide variants derived from their C-terminal region.

A short peptide derived from the C-terminal region of Bothrops asper myotoxin II, a Lys49 phospholipase A(2) (PLA(2)), was previously found to reproduce the bactericidal activity of its parent molecule. In this study, a panel of eight PLA(2) myotoxins purified from crotalid snake venoms, including both Lys49 and Asp49-type isoforms, were all found to express bactericidal activity, indicating that this may be a common action of the group IIA PLA(2) protein family. A series of 10 synthetic peptide variants, based on the original C-terminal sequence 115-129 of myotoxin II and its triple Tyr-->Trp substituted peptide p115-W3, were characterized. In vitro assays for bactericidal, cytolytic and anti-endotoxic activities of these peptides suggest a general correlation between the number of tryptophan substitutions introduced and microbicidal potency, both against Gram-negative (Salmonella typhimurium) and Gram-positive (Staphylococcus aureus) bacteria. Peptide variants with high bactericidal activity also tended to be more cytolytic towards skeletal muscle C2C12 myoblasts, thus limiting their potential in vivo use. However, the peptide variant pEM-2 (KKWRWWLKALAKK) showed reduced toxicity towards muscle cells, while retaining high bactericidal potency. This peptide also showed the highest endotoxin-neutralizing activity in vitro, and was shown to functionally interact with lipopolysaccharide (LPS) using a chimeric bacteria model. The bactericidal and anti-endotoxic properties of pEM-2, combined with its relatively low toxicity towards eukaryotic cells, highlight it as a promising candidate for further evaluation of its antimicrobial potential in vivo.