Promising survival for patients with newly diagnosed glioblastoma multiforme treated with concomitant radiation plus temozolomide followed by adjuvant temozolomide.

PURPOSE: Temozolomide is a novel oral alkylating agent with demonstrated efficacy as second-line therapy for patients with recurrent anaplastic astrocytoma and glioblastoma multiforme (GBM). This phase II study was performed to determine the safety, tolerability, and efficacy of concomitant radiation plus temozolomide therapy followed by adjuvant temozolomide therapy in patients with newly diagnosed GBM. PATIENTS AND METHODS: Sixty-four patients were enrolled onto this open-label, phase II trial. Temozolomide (75 mg/m(2)/d x 7 d/wk for 6 weeks) was administered orally concomitant with fractionated radiotherapy (60 Gy total dose: 2 Gy x 5 d/wk for 6 weeks) followed by temozolomide monotherapy (200 mg/m(2)/d x 5 days, every 28 days for six cycles). The primary end points were safety and tolerability, and the secondary end point was overall survival. RESULTS: Concomitant radiation plus temozolomide therapy was safe and well tolerated. Nonhematologic toxicities were rare and mild to moderate in severity. During the concomitant treatment phase, grade 3 or 4 neutropenia, thrombocytopenia, or both were observed in 6% of patients, including two severe infections with Pneumocystis carinii. During adjuvant temozolomide, 2% and 6% of cycles were associated with grade 3 and 4 neutropenia or thrombocytopenia, respectively. Median survival was 16 months, and the 1- and 2-year survival rates were 58% and 31%, respectively. Patients younger than 50 years old and patients who underwent debulking surgery had the best survival outcome. CONCLUSION: Continuous daily temozolomide and concomitant radiation is safe. This regimen of concomitant chemoradiotherapy followed by adjuvant chemotherapy may prolong the survival of patients with glioblastoma. Further investigation is warranted, and a randomized trial is ongoing.

Evaluation of pig esophageal mucosa as a permeability barrier model for buccal tissue.

Porcine buccal mucosa is frequently used for in vitro drug absorption studies as its structure and permeability characteristics are close to those of human tissue. However, this tissue model suffers from practical disadvantages, including a limited surface area, damage caused by mastication, and a fastidious and time-consuming excision procedure. It has been hypothesized that such limitations may be overcome by replacing the buccal tissue with the pig esophageal mucosa. The latter has a very similar structure and is easier to separate from the underlying tissue; furthermore, its surface area is greater and is generally intact. The aims of this work, therefore, were (i) to perform histological studies on the two membranes; (ii) to compare the transport of fentanyl citrate across buccal and esophageal mucosae; and (iii) to evaluate the effects of freezing on the tissue permeability. The results show that their histology is comparable, that the permeability of fentanyl citrate across the two epithelial barriers is similar, and that freezing the tissues did not alter their permeability.

Comparison of the lipid composition of porcine buccal and esophageal permeability barriers.

Pig esophageal mucosa has been shown to be a useful and practical substitute for buccal mucosa in in vitro permeability studies in that it offers a larger surface area and it is much easier to prepare. Further, the tissues demonstrate similar histological characteristics. The objectives of this work were to characterize the lipid composition of the esophageal mucosa, to compare it to that of the buccal tissue, and to correlate lipid composition with the membranes' permeability to fentanyl. The major lipid classes of buccal and esophageal epithelia were separated and analysed by automated multiple development high-performance thin-layer chromatography (AMD-HPTLC). The two epithelia presented a very similar lipid pattern. In general, there were more polar lipids than non-polar; glycosylceramides were relatively abundant whereas the amount of ceramides present was very small. The flux of fentanyl applied as the citrate in aqueous solution was comparable across the buccal and esophageal barriers. Lipid extraction provoked a significant increase in permeability. In conclusion, this research confirms the suitability of the esophageal mucosa as a model for buccal permeability studies.

Actin isoform pattern expression: a tool for the diagnosis and biological characterization of human rhabdomyosarcoma.

The diagnosis and characterization of rhabdomyosarcoma requires the use of combined histological and immunohistochemical criteria due to the variety of its histological patterns. The identification of actin isoform expression is accepted as a useful adjunct to the diagnosis and classification of soft tissue tumors. Using a new antibody specific for alpha-cardiac actin, obtained according to a recently described strategy for the production of polyclonal antibodies against actin isoforms [9], we have analyzed a series of 17 rhabdomyosarcomas, including all histological subtypes. In addition, we have evaluated the presence in these tumors of alpha-skeletal and alpha-smooth muscle actins. All specimens examined revealed a positive immunostaining for alpha-cardiac actin. Tumoral cells of eight cases also expressed alpha-smooth muscle actin and only three cases (all embryonal subtypes) were positive for alpha-skeletal actin. Our results indicate that immunohistochemical screening for alpha-cardiac actin expression is a useful tool for the diagnosis of rhabdomyosarcoma. They also suggest that the expression of alpha-skeletal actin is valuable in determining the subtype and possibly the state of differentiation of these tumors.

Intermediate filament protein synemin is present in human reactive and malignant astrocytes and associates with ruffled membranes in astrocytoma cells.

Synemin, a very unique type VI intermediate filament (IF) protein, exhibits alternative splice variants termed alpha and beta. Unlike other IF proteins, synemin binds to actin-associated proteins, including alpha-actinin, vinculin, and alpha-dystrobrevin. Our previous work has demonstrated the presence of synemin in differentiating astrocytes. In this study, we have examined the presence of synemin in human astrocytes under pathological conditions, using rabbit antibodies raised against the C-terminal domain of human synemin produced in bacteria. Western blotting shows that astrocytic tumors contain greater amounts of alpha-synemin than do normal brain tissues. These tumors also contain beta-synemin, which is not detectable in normal brain. Immunohistochemistry demonstrates that, while synemin is present in normal adult brain only in vascular smooth muscle cells, it is newly synthesized by reactive and neoplastic astrocytes. Alpha- and beta-Synemins have also been detected by Western blotting and polymerase chain reaction in several human glioblastoma cell lines. In these cell lines, surprisingly, synemin is associated with ruffled membranes in addition to being distributed along the IF network. In ruffled membranes, synemin was found to co-localize with alpha-actinin. This unusual cellular localization for an IF protein is maintained after nocodazole-induced perinuclear coiling of the vimentin IF network. In addition, immunoprecipitation experiments demonstrate that synemin forms a complex with alpha-actinin in glioblastoma cells. Taken together with synemin localization within ruffled membranes, this finding suggests that synemin plays a role in motility of glioblastoma cells.

Anterior shoulder instability: histomorphometric study of the subscapularis and deltoid muscles.

Recurrent traumatic anterior shoulder dislocation results in soft tissues lesions around the glenohumeral joint. The subscapularis muscle is a major active stabilizer of the shoulder and the hypothesis of the current study is that one would expect pathologic changes within its substance secondary to the trauma. A histomorphometric study of the subscapularis muscle was done of 52 patients operated on for recurrent traumatic anterior shoulder dislocation. At the time of surgery biopsy specimens were taken of the subscapularis muscle and the ipsilateral deltoid muscle as a comparison and to see if any changes were present. The results revealed interstitial fibrosis within the subscapularis muscle compatible with muscle scarring, and modifications in the ratio of fiber types as usually is seen with disuse atrophy. Both of these findings may alter strength and stability and therefore the function of the glenohumeral joint. The histologic findings were not compatible with a denervation pattern. After traumatic anterior shoulder dislocation rehabilitation of the subscapularis muscle is recommended.

Pituitary corticotroph adenoma with crooke's hyalinization.

The diagnosis of pituitary corticotroph adenoma relies on the demonstration of a loss of the normal feedback control of adrenocorticotropic hormone (ACTH) biosynthesis by cortisol. The marked variability in the degree of ACTH suppression by glucocorticoids in these tumors, however, greatly enhances the difficulty in distinguishing Cushing's disease from other syndromes of glucocorticoid excess. To illustrate this variability, we describe the clinical, biochemical, and morphological characteristics of a pituitary corticotroph adenoma in a 63-year-old woman, who presented with symptoms of a sellar mass but did not initially have florid Cushing's disease. Light and electron microscopy of the pituitary tumor showed a corticotroph adenoma with Crooke's hyalinization of the tumor cells, characterized by the accumulation of keratin immunoreactive microfilaments similar to those observed in normal corticotrophs in the presence of excess glucocorticoids. This case illustrates an unusual clinical presentation that may be associated with pituitary corticotroph adenoma showing Crooke's hyalinization.

Survivin in brain tumors: an attractive target for immunotherapy.

Survivin, a member of the inhibitor of apoptosis proteins gene family, was recently shown to be expressed by tumors originating from different cell lineages. There are also cumulative evidences that spontaneous immune response against survivin derived epitopes may occur. Here, using RT-PCR, Western-blot analysis and immunohistochemistry, we show that survivin is widely expressed by gliomas, meningiomas and schwannomas, both in vitro and in vivo. These data indicate that survivin may serve as an attractive target for immunotherapies designed for brain tumors.