Effects of 0.2 T static magnetic field on human skin fibroblasts

Human skin fibroblasts were exposed to 0.2 T static magnetic field generated by a magnetic resonance tomograph. After 1h exposure, cell morphology was modified in association with a concomitant decrease in the expression of some sugar residues of glycoconjugates. Study of cell proliferation and mitogenic signal transduction showed a decrease of thymidine incorporation and of second messenger formation. However, cell viability, assessed by colony forming assay, was unaffected. These results demonstrate that the static magnetic field generated by routinely used magnetic resonance tomograph induces alterations on human skin fibroblasts.     

Stomal recurrence following total laryngectomy: clinical and molecular analysis of a series

The aim of the present study was to analyze the risk features and to discuss the preventive measures and treatment of stomal recurrence (SR) after total laryngectomy (TL), and to investigate the clonal relationship between the primary and recurrent lesions. We reviewed a series of 25 patients affected by SR after TL for laryngeal squamous cell carcinoma. A subset of 7 coupled primary and recurrent carcinomas were examined for microsatellite alterations that were used as a marker of genetic lineage. The incidence of SR was higher in patients with initial subglottic lesions (subglottic, transglottic, or glottic-subglottic tumors) than in those with other locations of laryngeal cancer (p = .013). In addition, the frequency of SR was significantly higher in patients who underwent preoperative tracheotomy, performed 48 hours or more before the TL, than in the group of patients who did not receive preoperative tracheotomy (23.3% versus 0.46%, p < .001). According to microsatellite analysis, of the 5 informative patients, 2 demonstrated discordant alterations in the recurrent tumor indicative of clonal heterogeneity, 2 demonstrated identical alterations, and 1 showed an additional alteration in the recurrent tumor. Our analysis supports the hypothesis that a subset of SRs after TL may be second primary tumors, genetically unrelated to the primary laryngeal lesion.     

Multicenter, phase II trial of exemestane as third-line hormonal therapy of postmenopausal women with metastatic breast cancer. Aromasin Study Group.

PURPOSE: To assess the antitumor activity, safety, and hormone-suppressive effects of the irreversible aromatase inactivator, exemestane (Aromasin, Pharmacia & Upjohn, Kalamazoo, MI), administered as third-line hormone therapy to postmenopausal women with metastatic breast cancer that is refractory to tamoxifen and megestrol acetate. PATIENTS AND METHODS: Exemestane was administered at a dose of 25 mg/d orally until patients experienced disease progression. The efficacy and safety of exemestane were clinically and radiographically evaluated. The impact of exemestane treatment on tumor-related signs and symptoms was assessed. The effect of exemestane on serum levels of estrogens and other steroidal hormones was determined. RESULTS: Ninety-one patients were treated. There were four complete responses (CR) and eight partial responses (PR), for an objective response rate of 13% in the entire treated population. The overall success rate (CR, PR, or stable disease [SD] >/= 24 weeks) was 30%. The median duration of response and overall success was 9 months and 8 months, respectively. Most patients with CR/PR (83%; 10 of 12 patients) and SD >/= 24 weeks (80%; 12 of 15 patients) had improved or stable tumor-related signs and symptoms. Mean levels of circulating estrone (E(1)), estradiol (E(2)), and estrone sulfate decreased to 11%, 22%, and 13% of baseline levels, respectively (at week 8 or 16 of treatment). One half of the patients had undetectable E(1) and E(2) levels during treatment, including at the time of disease progression. Mild nausea (20% of patients) and hot flashes (20%) were the most common drug-related adverse events and were generally grade 1. CONCLUSION: Exemestane is an active and well-tolerated third-line hormonal therapy that represents a new treatment option for postmenopausal patients with advanced breast cancer that has become refractory to standard first- and second-line hormonal therapies.     

Role of P-Glycoprotein on the CNS Disposition of Amprenavir (141W94), an HIV Protease Inhibitor

Purpose. To determine the role of P-glycoprotein (Pgp) on the CNS penetration of the HIV protease inhibitor (PI) amprenavir (141W94) and to test the hypothesis that co-administration of a second HIV PI (ritonavir) could enhance amprenavir's brain penetration in vivo. Methods. Pgp-mediated efflux was investigated in vitro with Caco-2 cells and in vivo by whole-body autoradiography (WBA). 'Genetic'mdrla/lbdouble knockout mice, 'chemical' Pgp knockout mice generated by administration of the Pgp inhibitor GF120918, and mice pretreated with ritonavir were used in WBA studies to investigate the effects of Pgp modulation on the CNS penetration of amprenavir. Results. Amprenavir, indinavir, ritonavir, and saquinavir had 2-to 23-fold higher transport rates from the basolateral to apical direction than from the apical to basolateral direction across Caco-2 monolayers. Incubation with GF 120918 negated this difference, suggesting that the efflux was Pgp-mediated. WBA studies demonstrated a 13- and 27-fold increase in the brain and a 3.3-fold increase in the CSF concentrations of amprenavir in mice pretreated with GF120918 and in mdrla/lbdouble knockout mice. In contrast, pretreatment with ritonavir did not alter the CNS exposure of amprenavir. Conclusions. These results provide evidence that amprenavir and other HIV PIs are Pgp substrates and that co-administration of a specific Pgp inhibitor will enhance amprenavir's CNS penetration in vivo. These results will have an important therapeutic impact in the treatment of AIDS dementia.     

Acute gangrene of the scrotum and penis in four hematologic patients. The usefulness of hyperbaric oxygen therapy in one case

We describe four cases of Fournier's gangrene complicating the postchemotherapy aplastic phase (polymorphonuclear cells [PMN] less than 500/microliter) in three patients with acute leukemia and one patient with non-Hodgkin's lymphoma. Blood and local cultures from two patients contained Pseudomonas aeruginosa, and local cultures from another patient grew both P. aeruginosa and Proteus rettgeri. Early recognition and aggressive antibiotic and surgical treatment with granulocyte recovery were fundamental factors in resolution of the gangrene in three of the four patients. Hyperbaric oxygen therapy, never reported in hematologic patients, was also very useful in one patient in whom the clinical course was particularly acute.     

Primary retroperitoneal myxoid/round cell liposarcoma is a nonexisting disease: an immunohistochemical and molecular biological analysis

Almost all primary retroperitoneal liposarcomas can be classified as well-/dedifferentiated liposarcoma. Rarely, however, primary retroperitoneal liposarcoma is classified as myxoid/round cell liposarcoma, based on the presence of myxoid areas and vascular crow's feet pattern, which has resulted in a debate on the classification of liposarcoma in the retroperitoneum. Genetically, myxoid/round cell liposarcoma and well-/dedifferentiated liposarcoma are different diseases. Myxoid/round cell liposarcoma is characterized by a translocation causing FUS-CHOP or EWSR1-CHOP fusion, whereas well-/dedifferentiated liposarcoma is characterized by an amplification of the 12q13-15 region, including MDM2 and CDK4 genes. As myxoid/round cell liposarcoma is highly radio- and chemosensitive, differentiation between subtypes is important to optimize treatment. We studied whether primary retroperitoneal liposarcomas diagnosed as myxoid/round cell liposarcoma represent molecularly true myxoid/round cell liposarcoma or are histopathological mimics and represent well-/dedifferentiated liposarcoma. Primary retroperitoneal myxoid/round cell liposarcoma (n=16) were compared to primary extremity myxoid/round cell liposarcoma (n=20). Histopathological and immunohistochemical features were studied. Amplification status of the 12q13-15 region was studied using a multiplex ligation-dependent probe amplification analysis, and FUS-CHOP or EWS-CHOP translocations were studied using RT-PCR. In primary retroperitoneal myxoid/round cell liposarcoma, MDM2 and CDK4 staining was both positive in 12 of 15 cases. In primary extremity myxoid/round cell liposarcoma, MDM2 was negative in 18/20 and CDK4 was negative in all cases. Multiplex ligation-dependent probe amplification showed the amplification of 12q13-15 region in 16/16 primary retroperitoneal myxoid/round cell liposarcomas and in 1/20 primary extremity myxoid/round cell liposarcomas. Translocation was present in all (18/18) primary extremity myxoid/round cell liposarcomas, but absent in all primary retroperitoneal myxoid/round cell liposarcomas. On the basis of immunohistochemical and molecular characteristics, apparent primary retroperitoneal myxoid/round cell liposarcoma can be recognized as well-/dedifferentiated liposarcoma with morphological features mimicking myxoid/round cell liposarcoma. In these cases, treatment should probably be specifically designed as for well-/dedifferentiated liposarcoma. Moreover, finding of myxoid/round cell liposarcoma translocations in a retroperitoneal localization is highly suggestive of metastasis and should prompt search for a primary localization outside the retroperitoneum.     

Total parotidectomy--a routine treatment for parotid gland swellings?

The results of 25 years of quasi-routine total parotidectomy performance are shown. At the Department of Otolaryngology of the University of Florence, 582 patients were treated as follows: on 527 occasions by total parotidectomy with facial nerve preservation; 24 occasions by lateral lobectomy; 27 occasions by total parotidectomy with removal of the whole facial nerve; four times by enucleo-resection of the disease. Benign tumours were 378; primary and metastatic malignant tumours--100; non tumoral lesions--104. The benign tumours follow-up showed three recurrences only (two pleomorphic adenomas--one of them proved to be an adenoid-cystic carcinoma, and one monomorphic adenoma, which also proved to be an adenoid-cystic carcinoma), respectively 6, 6 and 8 years later. The malignant tumours were also treated by total parotidectomy with adequate management both of the facial nerve and the neck lymph nodes. The results thoroughly justify the nerve preservation, when preserved.     

Prediction of dissolution-absorption relationships from a continuous dissolution/Caco-2 system

The objectives were 1) to design a continuous dissolution Caco-2 system to predict the dissolution-absorption relationships for fast and slow dissolving formulations of piroxicam, metoprolol tartrate, and ranitidine HCl, and compare the predicted relationships with observed relationships from clinical studies; 2) to estimate the effect of croscarmellose sodium on ranitidine dissolution-absorption relationships; and 3) to estimate the effect of solubilizing agents on piroxicam dissolution-absorption relationships. A continuous dissolution/Caco-2 system was constructed from a dissolution apparatus and a diffusion cell, such that drug dissolution and permeation across a Caco-2 monolayer would occur sequentially and simultaneously. The continuous system generally matched observed dissolution-absorption relationships from clinical studies. For example, the system successfully predicted the slow metoprolol and slow ranitidiine formulations to be permeation-rate-limited. The system predicted the slow piroxicam formulation to be dissolution-rate-limited, and the fast piroxicam formulation to be permeation-rate-limited, in spite of piroxicam’s high permeability and low solubility. Additionally, the system indicated croscarmellose sodium enhanced ranitidine permeability and predicted solubilizing agents to not modulate permeability. These results suggest a dissolution/Caco-2 system to be an experimentally based tool that may predict dissolution-absorption relationships from oral solid dosage forms, and hence the relative contributions of dissolution and permeation to oral drug absorption kinetics.