Efatutazone, an oral PPAR-γ agonist, in combination with paclitaxel in anaplastic thyroid cancer: results of a multicenter phase 1 trial.

PURPOSE: A phase 1 study was initiated to determine the safety, potential effectiveness, and maximal tolerated dose and recommended phase 2 dose of efatutazone and paclitaxel in anaplastic thyroid cancer. EXPERIMENTAL DESIGN: Patients received efatutazone (0.15, 0.3, or 0.5 mg) orally twice daily and then paclitaxel every 3 weeks. Patient tolerance and outcomes were assessed, as were serum efatutazone pharmacokinetics. RESULTS: Ten of 15 patients were women. Median age was 59 years. Seven patients received 0.15 mg of efatutazone, 6 patients received 0.3 mg, and 2 patients received 0.5 mg. One patient receiving 0.3 mg of efatutazone had a partial response from day 69 to day 175; 7 patients attained stable disease. Median times to progression were 48 and 68 days in patients receiving 0.15 mg of efatutazone and 0.3 mg of efatutazone, respectively; corresponding median survival was 98 vs 138 days. The median peak efatutazone blood level was 8.6 ng/mL for 0.15-mg dosing vs 22.0 ng/mL for 0.3-mg twice daily dosing. Ten patients had grade 3 or greater adverse events (Common Terminology Criteria for Adverse Events), with 2 of these (anemia and edema) related to efatutazone. Thirteen events of edema were reported in 8 patients, with 2 of grade 3 or greater. Eight patients had ≥1 serious adverse event, with 1 of these (anemia) attributed to efatutazone and 1 (anaphylactic reaction) related to paclitaxel. The maximal tolerated dose was not achieved. Angiopoietin-like 4 was induced by efatutazone in tissue biopsy samples of 2 patients. CONCLUSIONS: Efatutazone and paclitaxel in combination were safe and tolerated and had biologic activity.

Mechanisms of multidrug resistance: the potential role of microtubule-stabilizing agents.

Antimitotic agents that target the dynamic equilibrium between the microtubule polymer and tubulin heterodimers are key components of chemotherapeutic regimens for various solid tumors. These agents can be divided into two major classes based on their effect on microtubule polymerization and the mass of microtubule polymers: those that inhibit polymerization, such as the vinca alkaloids and those that stabilize microtubules, such as the taxanes and epothilones. The taxanes paclitaxel (Taxol) and docetaxel (Taxotere) were the first antimicrotubule agents approved for use in solid tumors, but their usefulness is often limited by development of drug resistance. The epothilones are distinguished from the taxanes structurally and functionally and have been shown in vitro and in preclinical models to have superior potency to the taxanes. The epothilones are not susceptible to P-glycoprotein-mediated efflux and have shown activity against taxane-resistant tumors. Other natural-product microtubule-stabilizing agents also have promising pharmacologic profiles. This article discusses mechanisms of drug resistance and summarizes scientific and clinical data supporting the potential of novel microtubule-stabilizing agents for achieving broad antitumor efficacy without the emergence of drug resistance. The ability to reduce the development of resistance with the epothilones and other microtubule-stabilizing agents may provide additional treatment options at the time of presentation and in the setting of taxane resistance.

Multiple congenital ocular anomalies with bilateral agenesis of the urinary tract.

A 1,350 gm female infant with features of the Potter syndrome (dysplasia renofacialis) had multiple ocular anomalies. Absence of keratocytes in the central corneal stroma, cataract, retinal ganglion cell and nerve fiber hypoplasia, loss of optic nerve bundles, and angiomatoid proliferation in the area of the optic disc are most striking. Some of these findings, especially in the cornea, may reflect mesoectodermal dysgenesis. Abnormal ocular angiogenesis may well comprise a part of Potter's syndrome.

Ocular abnormality in myotonic dystrophy.

A 61-year-old white woman with terminal myotonic dystrophy exhibited advanced peripheral and central retinopathy. Retinal lesions were characterized by hyperpigmentation, common, though nonspecific, in myotonic dystrophy. They resemble both heredo (tapetoretinal) and idiopathic involutional degenerations but rarely cause severe visual impairment. Neither the type nor degree of retinopathy appears to correlate with other ocular features or with the stage of the underlying disease. Our histologic observations confirm and extend those previously described. Electron microscopy suggests a primary disorder of mitochondria which may also affect smooth muscle and the myocardium.

The Sézary syndrome. A case with fetal-type glycogen and lymphocytic lymphoma.

A patient had Sézary syndrome and lymphocytic lymphoma. Cytoplasmic inclusions within the Sézary cells were demonstrated by histochemistry and electron microscopy to be composed of fetal-type glycogen. Results of tests for the presence of virus were negative. It is suggested that the Sézary cell represents a reversion of metabolic systems to more youthful types. Previously reported differences in diastase reactivity of the PAS-positive cytoplasmic inclusions are probably based on whether the glycogen is in fetal or mature configuration.

Chlamydia trachomatis endocarditis.

A case of infective endocarditis due to Chlamydia trachomatis immunotype F is reported. Multiple negative blood cultures were a major deterrant from the initial clinical diagnosis of infective endocarditis. Postmortem ultrastructural identification of Chlamydia in the aortic valve vegetation led to an intensive retrospective study of retrieved serum samples utilizing microimmunofluorescent tests. Likewise an unusual echocardiographic finding was discovered to be the ultrasonic visualization of an aortic ring abscess. No similar case could be found in the literature. Clinicopathologic correlations are presented.

Muscle capillaries and retinopathy among Israeli diabetics. With special reference to measurement techniques, relationship to age and the pericyte.

Our investigation of the capillaries of 64 Israeli diabetics confirm the fact that retinopathy is consistently associated with thickening of the basal lamina of peripheral muscle capillaries but the converse is not so. The change in pericapillary structure may affect the capillary function. The primary cell involved, either causally or as a consequence of the lexion, is the pericyte.

Light microscopic and ultrastructural observations of a metastasizing malignant epithelioid schwannoma.

The light microscopy and ultrastructure of a malignant epithelioid schwannoma are described. Characteristic cells resembling perineural elements with various degrees of differentiation were observed. Primitive epithelioid cells contained scant ergastoplasm, and few tubules and filaments, but did have abundant free ribosomes and Golgi membranes. Also noted were junctional complexes and focal fusion of plasma membranes, basal laminae were absent. Better differentiated cells were completely limited by a well-developed basal membrane and had an abundance of intracytoplasmic filaments and multiple pinocytotic vesicles. The intercellular ground substance was composed of numerous fine collagen fibrils and amorphous, basement membrane-like, electron-dense material. A striking ultrastructural similarity of the tumor cells to those encountered in ethylnitrosourea-induced malignant schwannomas in rats was noteworthy.

Hereditary hemorrhagic telangiectasia (Osler-Weber-Rendu disease). An electron microscopic study of the vascular lesions before and after therapy with hormones.

Eight patients with hereditary hemorrhagic telangiectasia and severe epistaxis were treated with norethynodrel with mestranol (Enovid). Biopsy specimens of typical lesions from two patients were taken for electron microscopy before and after several months of therapy. Characteristic endothelial cell damage and nectosis were noted in the dilated venules of patients before treatment but not after. Unlined channels of blood were found in connective tissue before treatment but not after. These are thought to arise from leaks in the affected venules, and it is suggested that later indothelial ingrowth gives rise to the propagation of lesions that are known to develop with age. Reduplicated basal laminae and regenerating endothelial cells were found both before and after treatment.

Capillaries of South African diabetics. IV. Relation to retinopathy.

The muscle capillaries of diabetic subjects, with and without retinopathy, have been measured. The groups with retinopathy had significantly thicker laminae than those without the fundal changes. No significant difference was found between the group with proliferative retinopathy and the group with nonproliferative retinopathy. The focal and segmental nature of the basal lamina thickening was confirmed by the increasing standard deviation of the measurements within and among capillaries. This study also confirms the fact that, at least for muscle capillaries, an apparent relationship exists between the thickness of the basal lamina of these vessels and the presence of clinical retinopathy.