Citations

Abstract Purpose: 2-Methoxyestradiol (2ME2) is an endogenous product of estradiol metabolism with antiangiogenic and antineoplastic properties. We report on the first phase II trial of 2ME2 in multiple myeloma. Experimental Design: 2ME2 was administered orally at a dose of 1,000 mg daily. Sixty patients (31 men and 29 women) were treated. After 39 patients were accrued, the dose was increased to 800 mg twice daily for the remaining patients. Results: Thirty-one patients had relapsed or refractory multiple myeloma, and 29 had plateau phase multiple myeloma. Median age was 60 years (range, 27-84 years). Therapy was well tolerated. Common adverse events included anemia (35%), fatigue (35%), nausea (25%), diarrhea (20%), hot flushes (20%), headache (17%), muscle cramps (15%), and upper respiratory tract infection (15%). Most adverse events were mild (grade 1-2); 12% experienced grade 3-4 adverse events. Median time to progression was 3.8 months, with 5.6 months for plateau phase disease and 2.3 months for relapsed multiple myeloma. Estimated progression-free survival rates for all patients at 1, 2, and 3 years were 24%, 17%, and 11%, respectively. Three patients, all with plateau phase disease, have been on study for over 4 years without progression at 50, 60, and 63 months, respectively. Minor response was noted in 2 patients. Conclusions: Although no partial responses have been seen thus far, the minor responses and prolonged stable disease seen with 2ME2 therapy are promising. Plasma levels indicate that the dose of 2ME2 was inadequate. A new formulation with better bioavailability will be tested soon in multiple myeloma.

Background and Purpose — We sought to determine pedigree availability for a concordant sibling pair study of genetic risk factors in ischemic stroke. Methods — Probands with confirmed ischemic stroke were prospectively enrolled. Family histories were obtained by systematic interview. A study neurologist prospectively assigned stroke subtype. Results — Of 310 probands (median age, 75 years; range, 26 to 97 years; 48% women), 75% had at least 1 living sibling; 10%, at least 1 concordant living sibling; 2%, at least 1 concordant sibling living in the same city; and 7%, at least 1 concordant living and 1 discordant living sibling. Likelihood of having a concordant sibling increased significantly with proband age, even after adjustment for sibship size ( P =0.002). Positive family history of stroke was not related to either proband stroke subtype or risk factor profile. Conclusions — Approximately 10 probands were screened to find 1 potentially concordant living sibling. A concordant sibling pair study should be multicentered and enable enrollment of siblings from diverse geographic areas.

Abnormal mucociliary clearance in the paranasal sinuses is a significant factor in the pathogenesis of sinusitis. This study examined effects of chronic sinusitis on ciliary beat frequency (CBF), mucociliary transport (MCT) velocity, mucociliary transport patterns, and histology of sinus mucosa in rabbits. Two groups of rabbits were studied: uninfected (n = 9) and infected (n = 18). Maxillary sinus ostia in all animals were occluded, and sinuses in the infected group were inoculated with 10 8 cfu of Streptococcus pneumoniae. Chronic sinusitis developed over 6 weeks and was confirmed by histopathology and culture. Evaluation of the MCT mechanism included 1) measurement of CBF using a photometric technique, 2) direct measurement of MCT velocity, and 3) analysis of MCT patterns with inert India ink. In seven of nine (77.8%) uninfected animals, the mean CBF was 11.5 Hz (±.39 Hz) initially and 11.3 Hz (±.32 Hz) 6 weeks after occlusion (P = 0.69). MCT velocity measured 20.6 mm/min (±1.40 mm/min) initially and 16.85 mm/min (±1.96 mm/min) 6 weeks after occlusion (P = 0.16). In the infected group, there were statistically significant decreases in CBF (P < 0.05) and measured MCT velocity (P < 0.05). Examination of MCT in infected animals showed patterns of misdirected flow, pooling, and stagnation. Histopathologic changes included significant losses of ciliated epithelium and mucosal abnormalities consistent with chronic sinusitis. Chronic sinusitis secondary to long-standing bacterial infection leads to alterations in CBF, MCT velocity, and MCT patterns in the paranasal sinuses of rabbits.

The purpose of this study was to compare the effects on human nasal cilia of various freezing and thawing methods in order to determine a reliable method of cryopreservation. Ten samples each were preserved by a slow freezing and a fast freezing method. All samples were stored in liquid nitrogen (–196°C) for 1 week. The frozen samples were thawed by one of two methods: 1) rapid thawing—37°C water bath for 3–4 minutes; and 2) slow thawing—room temperature for 15 minutes. Prefreeze and postthaw ciliary beat frequency (CBF) was measured. The slow freezing and fast thawing method (SFFT) resulted in the best viability. An additional 10 samples preserved using the SFFT method stored at –70°C to –90°C did not retain ciliary function. Thirty ciliated samples preserved by the SFFT method were examined after freezing in liquid nitrogen (–196°C) for 1 week, 2 weeks, and 1 month. There was no significant decrease in CBF after cryopreservation at –196°C for 1 week or 2 weeks (P> 0.05). As the storage time increased to 1 month, postthaw CBF decreased 7.25 ± 0.87% when compared to the prefreeze CBF (P < 0.05). We conclude that human nasal cilia preserved by SFFT at –196°C retain activity for up to 1 month.

Normal mucociliary clearance in the paranasal sinuses must be restored to reverse the effects of chronic sinusitis. This study examined effects of middle meatal antrostomy (MMA) on ciliary beat frequency (CBF), mucociliary transport (MCT) velocity, MCT patterns, and histology of sinus mucosa in rabbits with chronic sinusitis to determine whether objective measures of mucociliary function and histology could be reversed. Two groups of rabbits were compared: uninfected (Group A controls, n = 9) and infected (Group B, n = 11). Maxillary sinus ostia were occluded; 10 8 cfu of Streptococcus pneumoniae were inoculated into sinuses of rabbits in group B, and chronic sinusitis developed. This was confirmed by histopathology and culture 6 weeks after infection. Middle meatal antrostomies were performed in the infected group, and sinuses were studied 6 weeks later. Control animals (Group A) had mean CBF = 11.5 Hz (±.39 Hz). Animals with chronic sinusitis (Group B) had mean CBF = 8.6 Hz (±.24 Hz). This was statistically different from control (P < 0.05). Six weeks following MMA, group B had mean CBF = 12.9 Hz (±.75 Hz). This was not different from control. There were changes in MCT velocity that correlated with the CBF (r = 0.72). Examination of MCT patterns after MMA demonstrated minimal pooling and stagnation; however, small areas of misdirected flow persisted. After MMA, there were decreased numbers of inflammatory and goblet cells and increased numbers of ciliated epithelial cells. This study demonstrated that mucociliary clearance and histological changes seen in rabbits with chronic sinusitis are reversed by MMA.

Abstract Rationale Prostaglandin (PG) E2, a cyclooxygenase-derived lipid mediator, is a potent down-regulator of fibroblast activation in normal lung fibroblasts. Although fibroblasts from patients with idiopathic pulmonary fibrosis are known to exhibit a defect in PGE2 synthesis, there is little information about their responsiveness to this lipid mediator. Objectives To compare responses to PGE2 in normal, usual interstitial pneumonia (UIP), and other diffuse parenchymal lung disease (DPLD) fibroblasts. Methods Fibroblasts were grown in vitro from well characterized control (n = 7), UIP (n = 17), or other DPLD (n = 13) lung tissue. The effects of PGE2 on fibroblast proliferation and collagen expression were determined. Measurements and Main Results Only 3 of 12 UIP fibroblast lines exhibited PGE2-mediated inhibition of both collagen synthesis and cell proliferation, as opposed to 6 of 6 nonfibrotic control cell lines. The degree of PGE2 resistance in DPLD fibroblasts was quite variable, with UIP cells exhibiting the greatest degree of resistance to PGE2, whereas other DPLD fibroblasts manifested a degree of resistance intermediate to control and UIP. The resistance to suppression of collagen expression correlated with worse lung function. Molecular mechanisms for resistance included altered E prostanoid receptor profiles and diminished expression of the downstream kinase, protein kinase A. Conclusions The recognition that UIP fibroblasts manifest variable refractoriness to PGE2 suppression sheds new light on the activation phenotype of these cells and on the pathogenesis of fibrotic lung disease.