Citations

Purpose The trial objectives were to identify the maximum-tolerated dose (MTD) of first-line gemcitabine plus nab-paclitaxel in metastatic pancreatic adenocarcinoma and to provide efficacy and safety data. Additional objectives were to evaluate positron emission tomography (PET) scan response, secreted protein acidic and rich in cysteine (SPARC), and CA19-9 levels in relation to efficacy. Subsequent preclinical studies investigated the changes involving the pancreatic stroma and drug uptake. Patients and Methods Patients with previously untreated advanced pancreatic cancer were treated with 100, 125, or 150 mg/m 2 nab-paclitaxel followed by gemcitabine 1,000 mg/m 2 on days 1, 8, and 15 every 28 days. In the preclinical study, mice were implanted with human pancreatic cancers and treated with study agents. Results A total of 20, 44, and three patients received nab-paclitaxel at 100, 125, and 150 mg/m 2 , respectively. The MTD was 1,000 mg/m 2 of gemcitabine plus 125 mg/m 2 of nab-paclitaxel once a week for 3 weeks, every 28 days. Dose-limiting toxicities were sepsis and neutropenia. At the MTD, the response rate was 48%, with 12.2 median months of overall survival (OS) and 48% 1-year survival. Improved OS was observed in patients who had a complete metabolic response on [ 18 F]fluorodeoxyglucose PET. Decreases in CA19-9 levels were correlated with increased response rate, progression-free survival, and OS. SPARC in the stroma, but not in the tumor, was correlated with improved survival. In mice with human pancreatic cancer xenografts, nab-paclitaxel alone and in combination with gemcitabine depleted the desmoplastic stroma. The intratumoral concentration of gemcitabine was increased by 2.8-fold in mice receiving nab-paclitaxel plus gemcitabine versus those receiving gemcitabine alone. Conclusion The regimen of nab-paclitaxel plus gemcitabine has tolerable adverse effects with substantial antitumor activity, warranting phase III evaluation.

Abstract Objective: Mullerian inhibiting substance type II receptor (MISRII) is a tissue-specific target for therapy in gynecologic cancers. MISRII plays a specialized role in regression of the mullerian tracts embryologically. Analogous to other TGF-β family members, ligand (MIS) binding to the type II receptor leads to a heteromeric complex with type I receptors, downstream Smad signaling, cell cycle arrest and regression. We previously published that the majority of epithelial ovarian cancers (EOC) and endometrial cancers (EC) express MISRII in a tissue specific manner. The purpose of these studies was to investigate the biologic significance of MISRII expression in EOC. Methods: For in vitro studies, we developed both chimeric and endogenous cell models to study MISRII. Chimeric MIS type I and II receptors were created by fusing the ligand binding domain of GM-CSF (α or β subunit) to the transmembrane and cytoplasmic domains of the type I/II receptor; these receptors were stably transfected into Ovcar8 cells. The chimera system allows specific signaling of the receptor complex and the ability to separately analyze candidate type I receptors. The endogenous cell model was created in SKOV3 (MISRII- EOC cell line) by stably expressing full-length MISRII. Growth inhibition was assessed by colony formation in soft agar in response to receptor activation and cisplatin. A BRE-luciferase reporter construct was used to measure Smad 1/5 activation after exposure to MIS. FACS analysis was used to assess cell cycle progression. Results: In the chimeric model, receptor activation resulted in up to 60% inhibition of colony formation (dependent on which candidate type I receptor was targeted). Additionally, receptor activation sensitized cells to the effects of cisplatin (1μM) with nearly 4-fold inhibition of colony formation. In the endogenous MISRII expressing EOC cell model, functional signaling was first confirmed using a BRE-luciferase reporter assay to document induction of Smad activation after exposure to rhMIS (3.2 relative light units increase after 20nM MIS). This model was then assessed for cell cycle progression in the presence of MIS. We observed a strong G1 arrest (62% vs. 43% untreated) after 15h exposure to 25nM MIS in cells expressing the receptor with no change in the MIS- parental cell line. These in vitro data are consistent with our survival results in EOC demonstrating a significantly improved overall survival (p=0.04) in MISRII expressing cancers. Conclusions: The majority of gynecologic cancers express MISRII. Our in vitro studies demonstrate that receptor activation results in cell cycle arrest, reduced colony formation, and sensitization to cisplatin. Confirming this in vitro data is the observation that EOC expressing MISRII have improved response to therapy and longer survival. Together, these results support further targeting of the MISRII pathway as an anticancer strategy in gynecologic malignancy. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 1586.

Studies of patient satisfaction are continually needed to provide feedback to the medical community about rapidly changing telemedicine technology. We accumulated data during 1998 from geriatric patients living in a retirement community based on their experience with telemedicine (one encounter a week for eight weeks). Responses to the items on a Likert scale were generally positive. A similar study was conducted with random patients at the same site two and a half years later. The results were once again positive and appeared to show an even better response than those obtained in the previous study. Thus, although the pilot study was small (20 patients, 18 reporting), this trend may reflect an increased acceptance of telemedicine applications among geriatric patients. Larger studies are needed to substantiate this claim.