Double-masked, placebo-controlled safety and efficacy trial of diquafosol tetrasodium (INS365) ophthalmic solution for the treatment of dry eye.

PURPOSE: To investigate the safety and efficacy of diquafosol tetrasodium, a P2Y2 receptor agonist that stimulates fluid and mucin secretion on the ocular surface, as a novel topical treatment of dry eye disease. METHODS: Subjects with dry eye (n=527) were evaluated in a randomized, double-masked, parallel-group trial comparing 24 weeks of treatment with 2 concentrations of diquafosol (1% and 2%) versus placebo instilled 4 times daily. Corneal staining, conjunctival staining, Schirmer tests, and subjective symptoms of dry eye were evaluated. Use of artificial tears was permitted as necessary. RESULTS: Subjects treated with 2% diquafosol had significantly lower corneal staining scores compared with placebo at the 6-week, primary efficacy time point (P<0.001), and superiority continued throughout the 24-week study. Reductions in corneal staining were observed as early as after 2 weeks of treatment, were maintained throughout the 24-week study, and were observed to worsen slightly (toward baseline) when diquafosol treatment was discontinued (week 25). Results for conjunctival staining were consistent with those observed for corneal staining. Schirmer scores at week 6 were significantly higher with diquafosol treatment than with placebo (P

Comparative efficacy and safety of twice daily fluticasone propionate powder versus placebo in the treatment of moderate asthma.

BACKGROUND: Fluticasone propionate, an inhaled corticosteroid with negligible systemic bioavailability via the oral route, is efficacious in the treatment of asthma when administered via metered-dose inhaler. OBJECTIVE: To evaluate the efficacy and safety of inhaled fluticasone propionate powder in patients with moderate asthma previously treated with an inhaled corticosteroid. METHODS: This was a randomized, double-blind, placebo-controlled, parallel-group, multicenter study of 342 adolescent and adult patients with moderate asthma [forced expiratory volume in 1 second (FEV1) between 50% and 80% of predicted] treated previously by beclomethasone dipropionate or triamcinolone acetonide. Patients received fluticasone propionate powder 50 micrograms, 100 micrograms, 250 micrograms, or placebo via a breath-actuated inhalation device, the Diskhaler, twice daily for 12 weeks. RESULTS: Patients in the fluticasone propionate groups experienced a mean increase from baseline to endpoint in FEV1 ranging from 0.43 L to 0.47 L. Patients in the placebo group experienced a mean decrease from baseline of 0.22 L (P < .001). The probability of patients remaining in the study over time without developing signs of exacerbating asthma was significantly greater in the fluticasone propionate groups than in the placebo group (P = .001). Asthma symptom scores, supplemental rescue albuterol use, and number of nighttime awakenings due to asthma requiring treatment also improved significantly with all fluticasone propionate treatment regimens compared with placebo (P < .001). There were no statistically significant differences at endpoint among the three fluticasone propionate groups. No serious drug-related adverse events occurred. CONCLUSIONS: Fluticasone propionate powder (50, 100, and 250 micrograms) was well-tolerated and significantly improved lung function in patients with moderate asthma.

Impact of fluticasone propionate powder on health-related quality of life in patients with moderate asthma.

Because biological indicators alone do not adequately represent the comprehensive health status of a patient with asthma, we also assessed patients' health-related quality of life (HRQOL) in a randomized, double-blind, placebo-controlled study of the effects of the inhaled corticosteroid fluticasone propionate (FP). A total of 342 patients with moderate asthma were treated twice daily for 12 weeks with FP powder (50, 100, or 250 micrograms) or placebo. At regular intervals, patients completed the Medical Outcomes Study Short Form-36, acute version (SF-36A), a general health status questionnaire measuring eight dimensions of HRQOL; the 20-item Living with Asthma (LWA-20) questionnaire, a disease-specific instrument measuring HRQOL; and three additional questions related to sleep loss and number of nighttime awakenings. Each of the three FP groups compared with placebo had significantly higher scores at study endpoint on the Physical Functioning (p < 0.001) and Role-Physical (p < or = 0.0001) dimensions of the SF-36A; the FP 100- or 250-micrograms groups compared with placebo also had significantly higher scores on General Health Perceptions (p < 0.03), Vitality (p < 0.007), and Mental Health (p < 0.02). At endpoint, all three FP groups compared with placebo had significantly better scores on the LWA questionnaire (p < 0.05) and on the sleep-related items (p < 0.0001). These data, collected using both a general health status questionnaire and an asthma-specific questionnaire, demonstrate that fluticasone propionate powder can improve HRQOL in patients with mild-to-moderate asthma.

Effectiveness of fluticasone propionate in patients with moderate asthma: a dose-ranging study.

This study was undertaken to evaluate the efficacy and safety of fluticasone propionate, an inhaled corticosteroid, in adolescents and adults with moderate asthma who were previously taking inhaled corticosteroids. After a 2-week, open-label screening period, a double-masked, randomized, parallel-group, dose-ranging study was conducted over 12 weeks in 21 outpatient centers throughout the United States. Patients (N = 304) > or = 12 years of age with moderate asthma previously treated with inhaled corticosteroids and beta-sympathomimetic bronchodilators were enrolled. Patients were assigned to receive placebo or fluticasone propionate 100, 250, or 500 micrograms twice daily via a metered-dose inhaler without a spacer device. These doses refer to the amount of fluticasone propionate released from the valve of the metered-dose inhaler; the corresponding doses released from the activator of the metered-dose inhaler are 88 micrograms, 220 micrograms, and 440 micrograms, respectively. Between baseline and end point, mean values of forced expiratory volume in 1 second decreased 0.31 L in the placebo group and improved 0.39 L, 0.30 L, and 0.43 L in patients receiving 100-micrograms, 250-micrograms, and 500-micrograms fluticasone propionate, respectively. The differences between placebo and all treatment groups were statistically significant. More patients were withdrawn from placebo (72%) than from fluticasone propionate (13% to 16%) because of failure to meet predetermined asthma stability criteria. Differences in baseline-to-end point changes in morning peak expiratory flow rate, physician overall assessments and patient-rated assessment of symptoms, and albuterol use for symptom control also significantly favored each fluticasone propionate group over placebo. There were essentially no differences in efficacy among the three fluticasone propionate groups. Treatment-related adverse events occurred in 8% of placebo-treated patients and 13% to 15% of fluticasone propionate-treated patients; these events were mainly localized to the oropharynx/ larynx. A 12-week course of fluticasone propionate (100, 250, and 500 micrograms twice daily) was well tolerated and more effective than placebo based on maintenance of asthma stability, pulmonary function tests, physician and patient assessments, and rescue bronchodilator use. No dose-related effects were observed with the dosages of fluticasone propionate used in this study.

Fluticasone propionate aerosol: efficacy in patients with mild to moderate asthma. Fluticasone Propionate Asthma Study Group.

BACKGROUND: This double-blind, randomized, parallel-group, placebo-controlled study investigated the efficacy and tolerability of fluticasone propionate aerosol (25, 50, or 100 mg bid for 12 weeks) administered as primary maintenance therapy to patients whose mild to moderate asthma was inadequately controlled by as-needed use of an inhaled beta-agonist. RESULTS: At all clinic visits, fluticasone propionate compared with placebo was associated with significant (P<.05) improvement in pulmonary function indexed by forced expiratory volume in 1 second (FEV1) as well as fewer night awakenings and less use of rescue albuterol. Values for patient-measured morning peak expiratory flow rates (PEFR) were significantly (P<.05) higher and the use of rescue albuterol was significantly (P<.05) lower beginning 3 to 5 days after initiation of therapy in the groups treated with fluticasone propionate, compared with the placebo group. Maximal improvement in FEV1 was achieved during the second week of treatment and maintained throughout the course of therapy. Differences among the three fluticasone propionate dosing groups for these efficacy measures were not statistically significant. The incidence of adverse events was similar across groups. CONCLUSIONS: These data indicate that fluticasone propionate aerosol is an effective and well-tolerated treatment for asthma and significantly improves pulmonary function within days of initiation of treatment in patients whose asthma is inadequately controlled with as-needed beta-agonists.

A 12-week dose-ranging study of fluticasone propionate powder in the treatment of asthma.

Fluticasone propionate (FP) administered via metered-dose inhaler is a potent corticosteroid effective in the treatment of asthma. To evaluate the efficacy and safety of FP powder administered via a breath-activated inhaler (Diskhaler), a multicenter, double-blind, randomized, placebo-controlled, parallel-group study was conducted in adolescent and adult patients (n = 331) with mild-to-moderate asthma previously treated with beta 2-agonist therapy alone. Patients received FP powder 50, 100, or 250 micrograms or placebo twice daily for 12 weeks. FP-treated patients compared with placebo-treated patients had significantly (p < 0.001) greater improvements in morning predose forced expiratory volume in 1 sec (21-22% increase vs. 9%). Improvement in morning peak flow rate were also significantly (p < 0.001) greater with FP than with placebo (8-10% increase vs. 2% increase). There was also a significant overall treatment difference in the frequency of inhaled albuterol use (p < 0.001) and number of nighttime awakenings due to asthma (p = 0.005). There were no statistically significant difference among the FP treatment groups in any outcome measure. Physicians' global assessments also indicated significant (p < 0.001) differences in efficacy, with 67-74% of FP-treated patients rated as having "effective" or "very effective" treatment compared with 41% of placebo-treated patients. Significant beneficial effects of FP were observed in lung function and diary card parameters after just 1 week of treatment. Adverse events were similar across treatment groups and primarily related to local irritation. Effect on hypothalamic-pituitary-adrenal axis function was minimal. In summary, all three dosages of inhaled FP powder were well tolerated and improved various asthma-related variables. Improvements in pulmonary function, beyond those achieved with beta 2-agonist therapy alone, were maintained for the duration of the 12-week study.

Flow cytometric DNA ploidy analysis of ovarian granulosa cell tumors.

The nuclear DNA content of 50 ovarian tumors initially diagnosed as granulosa cell tumors was measured by flow cytometry using paraffin-embedded archival material. The follow-up period of the patients ranged from 4 months to 19 years. Thirty-eight tumors were diploid or near-diploid, while 5 were aneuploid. DNA profiles of 7 tumors could not be evaluated. All 50 tumors were immunohistochemically tested for expression of intermediate filament proteins vimentin and cytokeratin and epithelial membrane antigen. The cells of all but 3 tumors expressed vimentin. These 3 vimentin-negative tumors were positive for cytokeratin and epithelial membrane antigen. They were highly aneuploid and though originally diagnosed as granulosa cell tumors, most likely represent undifferentiated carcinomas. Hence, only 2 typical granulosa cell tumors were aneuploid. In addition, frozen tissue samples from 9 of 10 granulosa cell tumors showed a DNA diploid content. Our results indicate that granulosa cell tumors tend to be diploid or have only minor ploidy abnormalities which is in line with their relatively benign character. An undifferentiated carcinoma should be considered in the differential diagnosis of tumors with a high DNA index.

Solid teratomas and mixed müllerian tumors of the ovary: a clinical, histological, and immunocytochemical comparative study.

The differential diagnosis between solid teratomas and malignant mixed Müllerian tumors (MMTs) can be difficult, because both tumours have an epithelial as well as a mesenchymal component. Sometimes an MMT is incorrectly diagnosed as a solid teratoma. This has prognostic and therapeutic consequences, because MMTs have a worse prognosis. In this study 20 solid ovarian teratomas and 15 MMTs of the ovary have been compared according to their clinical, histomorphological, and immunocytochemical characteristics. Teratomas occur in the younger age group and are characterized by the presence of argyrophil cells which are immunoreactive to a wide range of neurohormonal peptides and are in addition characterized by the presence of GFAP immunoreactive tissues (glial fibrillar acidic protein). MMTs occur in the older age group and are characterized by the presence of sarcomatous elements and by the absence of an organoid arrangement, neuroectoderm, skin, argyrophilia, and immunoreactivity to GFAP and neurofilament.

Malignant transformation in benign cystic teratomas: dermoids of the ovary.

Twenty-four cases with a malignant change involving one of the elements of a benign ovarian dermoid cyst are reported. Squamous cell carcinoma was most frequent. Eighteen patients (75%) were over 50 years of age. The prognosis is rather good if the tumor has not extended beyond the capsule, 85% surviving without detectable disease after 4 months to 9 years. The prognosis is very poor if the tumor has extended beyond the capsule, over 80% dying within 2 years. Hysterectomy with bilateral salpingo-oophorectomy is the treatment of choice, certainly in older patients. Additional treatment with cytostatics or radiation seems to have little influence on the prognosis.

The treatment of advanced ovarian carcinoma (I): clinical variables associated with prognosis.

New therapy regimens including cytoreductive surgery and cisplatin-based combination chemotherapy have improved survival for a small group of patients with advanced ovarian carcinoma. However, for the entire group survival remains poor. In this analysis of 65 patients treated at Leiden University Medical Center, the patient group that benefited the most from this approach was characterized by a younger age, good performance status, less extensive disease, low histologic grade and the absence of peritoneal carcinomatosis and ascites, and residual disease less than or equal to 15 mm (successful cytoreduction) after the first operation. Patients who did not have these favorable characteristics but in whom the first operation resulted in residual disease less than or equal to 15 mm, did survive worse than the other patients with individual tumor nodules less than or equal to 15 mm, but still better than those in whom a successful cytoreduction at the first operation could not be achieved. The diameter of the largest residual disease, the diameter of the largest metastasis before cytoreduction, and the presence of ascites and peritoneal carcinomatosis influenced prognosis. Thus the initial tumor burden as well as the burdened tumor volume left behind are of significance with respect to prognosis. However, in the Cox regression analysis the performance status and ascites proved to be the only independent factors influencing survival. A prospective study is needed to establish the proper value of cytoreductive surgery in advanced ovarian carcinoma.

Clinical relevance of various microscopical features of the second-look specimen in advanced ovarian cancer.

The second-look specimens of 70 patients with advanced ovarian cancer (FIGO 2B, 3, and 4) were reviewed and classified according to four categories: no response to chemotherapy (category a), predominantly histologically viable tumor with some necrotic and/or fibrotic tissue (category b), predominance of fibrosis and recrosis (category c), and no evidence of tumor, i.e., pathologically proven complete response (PCR) (category d). All of the patients in categories a and b had died because of ovarian cancer at the end of the observation period. In category c, 17/25 patients eventually achieved a PCR as established at a third-look procedure. The median survival of 56 months in this group was lower than that of the patients in category d (64 months), although this difference was without statistical significance. These observations underscore the importance of the microscopical features of the second-look specimen for the treatment of advanced ovarian cancer.

Raised serum alpha-fetoprotein in Sertoli-Leydig cell tumor (androblastoma) of ovary: report of two cases.

Two cases of Sertoli-Leydig cell tumor (SLCT) of the ovary associated with elevated serum alpha-fetoprotein (AFP) levels are described. A 16-year-old girl (case 1) had a Sertoli-Leydig cell tumor containing heterologous elements in the form of mucinous epithelium; AFP was demonstrated within the Sertoli cells by immunohistochemical techniques. An 11-month-old girl (case 2) had a SLCT with a retiform pattern and heterologous elements in the form of cells resembling hepatocytes; AFP was localized in the hepatocytes by immunohistochemical techniques.

Computed tomography in untreated adults with virilizing congenital adrenal cortical hyperplasia.

Thirteen adult patients with biochemically proven congenital adrenal hyperplasia (CAH) were examined by computed tomography (CT). Six patients had never received glucocorticoid therapy. In three of those six patients, CT revealed a tumorous transformation in one of the hyperplastic adrenal glands. In the seven patients with CAH who were treated since childhood, no mass could be demonstrated on CT. The development of an adrenocortical tumour due to chronic adrenal cortical stimulation by excessive adreno-cortico-trophic hormone (ACTH) production in adult patients with untreated CAH may not be a rare occurrence, as is demonstrated in this series. It is important not to confuse this entity with a primary virilizing adrenal tumour which requires a different form of treatment. In case of tumorous transformation in untreated adults with CAH, suppressive therapy with CT control should be favoured over surgery, as long as the tumour is ACTH-dependent. Moreover, these observations illustrate the desirability of lifelong glucocorticoid therapy in patients with CAH, including adult males who biochemically may not require suppression of steroid androgen excess.

Morphologic characteristics of benign and malignant adrenocortical tumors.

Differentiation between benign and malignant tumors of the adrenal cortex was studied by means of seven histologic parameters. Each separate criterion was significantly different in two groups, one consisting of patients without metastases within 10 years after operation and one of patients with metastatic tumors. Discrimination on the basis of single parameters in individual patients, however, was of little value. When a histologic index was calculated using the same parameters but after "weighing," a much better discrimination was obtained. The histologic index and, to a lesser degree, the mitotic activity seems to be related to the survival time of the patients with adrenal cortical carcinoma. The authors conclude that the calculation of a histologic index based on a summation of different parameters makes it possible to differentiate between malignant and benign adrenal cortical tumors. As single parameters, tumor weight and mitotic activity have the highest discriminating value.

Placental-site trophoblastic tumor: diagnosis, treatment, and biological behavior.

The clinical history of a patient with a placental-site trophoblastic tumor is presented. The diagnostic and therapeutic value of dilatation and curettage, the human chorionic gonadotropin titer, hysteroscopy, laparoscopy, chemotherapy, and hysterectomy is discussed, as well as the possibility of metastatic disease. In this patient there was radiological evidence of pulmonary metastasis with apparent spontaneous regression. A proposal is made to change the name of this disease to gestational trophoblastic neoplasia of low potential malignancy.

Immunocytochemical localization of neuroendocrine hormones and oncofetal antigens in ovarian teratomas.

The presence of neurohormonal peptides, human chorionic gonadotropin (hCG), alpha-fetoprotein (AFP), and carcinoembryonic antigen (CEA) was evaluated using immunocytochemical techniques in 170 benign cystic teratomas and 19 solid teratomas. The latter ranged from grade 0 to 3. The presence of hCG, AFP, and CEA was associated with a high histological grade and may therefore play a role in the grading of solid teratomas. Gastroenteropancreatic neuroendocrine cells frequently occurred in cystic teratomas without coexisting neural tissue. This finding is contrary to the neural crest origin previously suggested by other investigators and is in accordance with an endodermal origin of these cells.

Carcinoma of the adrenal cortex causing primary hyperaldosteronism. A case report and review of the literature.

A male patient presenting with primary hyperaldosteronism after a three-year delay, was found to have an aldosterone producing adrenocortical carcinoma. Evidence is presented that aldosterone was the only steroid produced in excess. Only six other patients with adrenocortical carcinoma and isolated primary hyperaldosteronism could be traced in the literature. The relation between histology and endocrine functions of the tumor cells is discussed.

Neuroendocrine cells in cystic mucinous tumours of the ovary.

This histogenesis of cystic mucinous ovarian tumours is still controversial. It has been proposed that these neoplasms may arise from metaplastic ovarian surface epithelium. Others have suggested that these tumours represent monophyletic (intestinal) types of teratoma. Against this background we have studied the presence of different types of neuroendocrine cells in a series of cystic mucinous ovarian tumours. Argyrophil neuroendocrine cells were found almost exclusively in tumours which were histologically classified as borderline or low-grade mucinous carcinomas, whereas these cells were very rare in mucinous cystadenomas and in grade III and IV carcinomas. Several gut peptide hormones could be demonstrated in these cells, but only in borderline tumours and low-grade mucinous carcinomas. Mucin histochemistry did not reveal characteristic patterns in these neoplasms. The results confirm that with regard to the presence of endocrine cells the epithelium of borderline mucinous cystadenomas and mucinous cystadenocarcinomas bears strong resemblance to intestinal epithelium. These findings do not rule out the possibility that these tumours arise by metaplasia from ovarian germinal epithelium but are equally compatible with a teratomatous origin. The epithelium of most benign mucinous cystadenomas resembles that of ovarian inclusion cysts.