Nanoparticles increase the efficacy of cancer chemopreventive agents in cells exposed to cigarette smoke condensate.

Lung cancer is a leading cause of death in developed countries. Although smoking cessation is a primary strategy for preventing lung cancer, former smokers remain at high risk of cancer. Accordingly, there is a need to increase the efficacy of lung cancer prevention. Poor bioavailability is the main factor limiting the efficacy of chemopreventive agents. The aim of this study was to increase the efficacy of cancer chemopreventive agents by using lipid nanoparticles (NPs) as a carrier. This study evaluated the ability of lipid NPs to modify the pharmacodynamics of chemopreventive agents including N-acetyl-L-cysteine, phenethyl isothiocyanate and resveratrol (RES). The chemopreventive efficacy of these drugs was determined by evaluating their abilities to counteract cytotoxic damage (DNA fragmentation) induced by cigarette smoke condensate (CSC) and to activate protective apoptosis (annexin-V cytofluorimetric staining) in bronchial epithelial cells both in vitro and in ex vivo experiment in mice. NPs decreased the toxicity of RES and increased its ability to counteract CSC cytotoxicity. NPs significantly increased the ability of phenethyl isothiocyanate to attenuate CSC-induced DNA fragmentation at the highest tested dose. In contrast, this potentiating effect was observed at all tested doses of RES, NPs dramatically increasing RES-induced apoptosis in CSC-treated cells. These results provide evidence that NPs are highly effective at increasing the efficacy of lipophilic drugs (RES) but are not effective towards hydrophilic agents (N-acetyl-L-cysteine), which already possess remarkable bioavailability. Intermediate effects were observed for phenethyl isothiocyanate. These findings are relevant to the identification of cancer chemopreventive agents that would benefit from lipid NP delivery.

Readmission after pancreatic resection is not an appropriate measure of quality.

BACKGROUND: Hospital readmission has been proposed as a metric for quality of medical and surgical care. We examined our institutional experience with readmission after pancreatic resection, and assessed factors predictive of readmission. METHODS: We reviewed 787 pancreatic resections performed at a single institution between 2006 and 2010. Univariate and multivariate logistic regression models were used to assess the relationships between preoperative and postoperative characteristics and readmission. Reasons for hospital readmission were examined in detail. RESULTS: We found the 30-day readmission rate after pancreatic resection to be 11.6 %. In univariate analysis, young age, pancreaticoduodenectomy versus other operations, open versus laparoscopic technique, fistula formation, the need for reoperation, and any complication during the index hospitalization were predictive of readmission. In multivariate analysis, only young age and postoperative complication were predictive of readmission. Vascular resection, postoperative ICU care, length of stay, and discharge disposition were not associated with readmission. The most common reasons for readmission were leaks, fistulas, abscesses, and wound infections (45.1 %), delayed gastric emptying (12.1 %), venous thrombosis (7.7 %), and GI bleeding (7.7 %). CONCLUSIONS: We found the vast majority of readmissions after pancreatic resection were to manage complications related to the operation and were not due to poor coordination of care or poor discharge planning. Because evidence-based measures to prevent these surgical complications do not exist, we cannot support the use of readmission rates themselves as a quality indicator after pancreatic surgery.

An oral delivery device based on self-folding hydrogels.

A self-folding miniature device has been developed to provide enhanced mucoadhesion, drug protection, and targeted unidirectional delivery. The main part of the device is a finger like bilayered structure composed of two bonded layers. One is a pH-sensitive hydrogel based on crosslinked poly(methyacrylic acid) (PMAA) that swells significantly when in contact with body fluids, while the other is a non-swelling layer based on poly(hydroxyethyl methacrylate) (PHEMA). A mucoadhesive drug layer is attached on the bilayer. Thus, the self-folding device first attaches to the mucus and then curls into the mucus due to the different swelling of the bilayered structure, leading to enhanced mucoadhesion. The non-swelling PHEMA layer can also serve as a diffusion barrier, minimizing any drug leakage in the intestine. The resulting unidirectional release provides improved drug transport through the mucosal epithelium. The functionality of this device is successfully demonstrated in vitro using a porcine small intestine.

Short-term but not long-term loss of patency of venous reconstruction during pancreatic resection is associated with decreased survival.

BACKGROUND: Pancreatic surgery with vascular reconstruction is increasingly performed to offer the benefits of surgical resection to patients with locally advanced disease. The short- and long-term patency rates and the clinical significance of thrombosis of such reconstructions are unknown. METHODS: We reviewed pancreatectomies requiring venous reconstruction from 1994 to 2011. We sought to identify predictors of acute (within 30 days) and late thrombosis. We compared survival of patients with thrombosis to patients with patent reconstructions. RESULTS: Of 203 pancreatectomies requiring venous reconstruction, acute thrombosis occurred in nine (4.4 %) cases and was associated with increased perioperative mortality (22.2 versus 4.6 %, p = 0.023). Even when nonfatal, acute thrombosis was associated with decreased median survival (7.1 versus 15.9 months, p = 0.011) and increased hazard of death (hazard ratio 8.6, confidence interval 3.7-19.9, p < 0.001). A late loss of patency was seen in 31.2 % of cases at a median of 9.5 months. Later loss of patency was not associated with decreased median survival or increased hazard of death. CONCLUSIONS: Acute thrombosis of the portal venous reconstructions after pancreatectomy is associated with increased perioperative mortality and, even when nonfatal, is associated with decreased survival. Late loss of patency occurs in one-third of patients but does not affect survival.

Predictors of recurrence in intraductal papillary mucinous neoplasm: experience with 183 pancreatic resections.

OBJECTIVES: We examined long-term outcomes in patients with surgically treated intraductal papillary mucinous neoplasm (IPMN) to determine if any clinical or histologic features could predict risk of recurrent disease. METHODS: We reviewed 183 margin-negative surgical resections performed for IPMN between 1994 and 2011 with documented postoperative abdominal imaging. We calculated time to recurrent disease as indicated by radiographic change and created a multivariable Cox proportional hazards model to assess the relationship between patient characteristics and histopathologic tumor features and disease recurrence. RESULTS: Among patients with margin-negative resections and adequate imaging follow-up, we observed a recurrence rate of 13% over a median follow-up of 32.0 months. Individuals with invasive tumors on original pathology were more likely to recur (HR 5.2, 95% CI 2.2-12.2); however, original pathology did not predict disease severity on recurrence. Controlling for invasive pathology, no other histologic feature of the original tumor, including dysplasia at the surgical margin, predicted recurrence. Among non-invasive IPMN, pancreatitis was associated with disease recurrence (HR 3.6, 95% CI 1.2-10.7). CONCLUSIONS: The frequency of recurrent disease in this population and the inability to predict recurrence argues for universal and continuous surveillance after resection for IPMN. The relationship between pancreatitis and disease recurrence should be investigated further.

Delivery of calf thymus DNA to tumor by folate receptor targeted cationic liposomes.

Calf thymus DNA (ctDNA) has been shown to stimulate macrophages to produce cytokines both in vitro and in vivo when complexed with cationic liposomes. In addition, direct cytotoxicity of ctDNA has been found in tissue culture and in mice. In this study, ctDNA and folate receptor targeted cationic liposome complexes (ctDNA-F-CLs) were prepared and evaluated in FR (+) tumors. In addition, the underlying mechanism for the anti-cancer activity of ctDNA-F-CLs was investigated. Selective uptake of ctDNA-F-CLs was observed in FR (+) KB and L1210JF cells using flow cytometry. In RAW264.7 cells and DBA/2 mice, ctDNA-F-CLs and ctDNA-N-CLs significantly induced TNF-α and IL-6 production compared to free ctDNA. However, no significant difference in cytokine production was observed between ctDNA-N-CLs and ctDNA-F-CLs. In tumor bearing DBA/2 mice, ctDNA-F-CLs significantly increased INF-γ and IL-6 production compared to ctDNA-N-CLs. Furthermore in L1210JF cells, ctDNA-F-CLs had significantly increased cytotoxicity compared to ctDNA-N-CLs. Tumor cell apoptosis was also found in co-culture of RAW264.7 cells and ctDNA-F-CLs treated L1210JF cells. In L1210JF tumor bearing mice, ctDNA-F-CLs were found to significantly inhibit tumor growth and prolong the median survival time (MeST). In contrast, ctDNA-N-CLs and free ctDNA showed similar activities for tumor inhibition and animal survival. Moreover, the anti-cancer effect of ctDNA-F-CL was further enhanced by combination with anti-cancer drug doxorubicin. These results suggest that ctDNA-F-CLs are a promising agent for treatment of FR-positive tumors.