Circadian gene expression and clinicopathologic correlates in pancreatic cancer.

INTRODUCTION: The circadian rhythm is responsible for physiologic homeostasis, behavior, and components of multiple metabolic processes. Disruption of the circadian rhythm is associated with cancer development, and several circadian clock genes have been implicated in loss of cell cycle control, impaired DNA damage repair, and subsequent tumor formation. Here, we investigated the expression profiles of several circadian clock genes in pancreatic ductal adenocarcinoma (PDA). METHODS: Quantitative real-time polymerase chain reaction was used to examine the circadian clock genes (brain-muscle-like (Bmal)-ARNTL, circadian locomotor output cycles kaput (Clock), cryptochrome 1 (Cry1), cryptochrome 2 (Cry2), casein kinase 1ε (CK1ε), period 1 (Per1), period 2 (Per2), period 3 (Per3), timeless (Tim), and timeless-interacting protein (Tipin)) in PDA, as well as matching adjacent and benign tissue. Logistic regression models with robust variance were used to analyze the gene expression levels, and Kaplan-Meier survival curves were generated based on gene expression. RESULTS: In the tumor tissue of PDA patients, compared to their matched adjacent tissue, expression levels of all circadian genes were lower, with statistical significance for Per1, Per2, Per3, Cry1, Cry2, Tipin, Tim, CK1ε, Bmal-ARNTL, and Clock (p \u3c 0.025). PDA tumors also expressed significantly lower levels of the circadian genes when compared to benign lesions for Per1, Per2, Per3, Cry2, Tipin, and CK1ε. A significant association between low levels of expression in the tumors and reduced survival was found with Per1, Per2, Per3, Cry2, Tipin, CK1ε, Clock, and Bmal-ARNTL. CONCLUSIONS: Our results reveal for the first time a dysregulated transcription of several circadian genes in PDA. Elevation of the gene levels in the benign and matched adjacent tissues may be indicative of their role during the process of tumorigenesis. The potential of using circadian genes as predictive markers of the outcomes and survival and distinguishing PDA from benign pancreas must be studied in larger populations to validate and demonstrate their eventual clinical utility

Does resident experience affect outcomes in complex abdominal surgery? Pancreaticoduodenectomy as an example.

OBJECTIVES: Understanding the factors contributing to improved postoperative patient outcomes remains paramount. For complex abdominal operations such as pancreaticoduodenectomy (PD), the influence of provider and hospital volume on surgical outcomes has been described. The impact of resident experience is less well understood. METHODS: We reviewed perioperative outcomes after PD at a single high-volume center between 2006 and 2012. Resident participation and outcomes were collected in a prospectively maintained database. Resident experience was defined as postgraduate year (PGY) and number of PDs performed. RESULTS: Forty-three residents and four attending surgeons completed 686 PDs. The overall complication rate was 44 %; PD-specific complications (defined as pancreatic fistula, delayed gastric emptying, intraabdominal abscess, wound infection, and bile leak) occurred in 28 % of patients. The overall complication rates were similar when comparing PGY 4 to PGY 5 residents (55.3 vs. 43.0 %; p \u3e 0.05). On univariate analysis, there was a difference in PD-specific complications seen between a PGY 4 as compared to a PGY 5 resident (44 vs. 27 %, respectively; p = 0.016). However, this was not statistically significant when adjusted for attending surgeon. Logistic regression demonstrated that as residents perform more cases, PD-specific complications decrease (OR = 0.97; p \u3c 0.01). For a resident\u27s first PD case, the predicted probability of a PD-specific complication is 27 %; this rate decreases to 19 % by resident case number 15. CONCLUSIONS: Complex cases, such as PD, provide unparalleled learning opportunities and remain an important component of surgical training. We highlight the impact of resident involvement in complex abdominal operations, demonstrating for the first time that as residents build experience with PD, patient outcomes improve. This is consistent with volume-outcome relationships for attending physicians and high-volume hospitals. Maximizing resident repetitive exposure to complex procedures benefits both the patient and the trainee

Differential expression of cytochrome P450 omega-hydroxylase isoforms and their association with clinicopathological features in pancreatic ductal adenocarcinoma.

BACKGROUND: The cytochrome P450 (CYP) superfamily consists of enzymes that catalyze the oxidation of lipids, steroids, and drugs. In particular, the CYP4 family plays an essential role in lipid metabolism by the ω-hydroxylation of terminal ends of fatty acids. Disturbance of this system has been associated with increased angiogenesis, proliferation, and metastasis of several cancers. This study aimed to detect the expression of CYP4 isoforms (CYP4A11, CYP4F2, CYP4F3) in pancreatic ductal adenocarcinoma (PDA) and their association with clinicopathological features. METHODS: Pancreatic specimens were collected from 73 patients who underwent surgical resection at the Thomas Jefferson University Hospital. Quantitative polymerase chain reaction was used to examine the cytochrome P450 isoforms in PDA (n = 62), adjacent-normal (n = 30), and benign tissues (n = 11). Logistic regression models were used to analyze gene expression among tissue types. Spearman rank correlations were calculated for isoform expression and for age. Differences in expression by gender were assessed via t test. Other clinicopathological variables (diabetes, smoking, obesity, T stage, perineural invasion, nodal status) were analyzed by Wilcoxon rank sum. RESULTS: CYP4 expression for isoforms was significantly higher in PDA tissues versus matched-adjacent tissues (p \u3c 0.01). PDA tumors expressed significantly higher levels of CYP4F2 and CYP4F3 when compared to benign lesions (p \u3c 0.01). Significant associations were found between low levels of CYP4F2 and CYP4F3 and increased age of PDA patients. Interestingly, all isoforms were expressed at higher levels in male patients. CONCLUSIONS: Transcriptional upregulation of cytochrome P450 ω-hydroxylase suggests that these enzymes have the potential to be used as distinguishing markers in pancreatic pathology

Does Resident Experience Affect Outcomes in Complex Abdominal Surgery?

Background: For complex abdominal operations, the influence of provider and hospital volume on surgical outcomes has been described. The impact of resident experience is less well understood.Methods: We reviewed perioperative outcomes after pancreaticoduodenectomy (PD) at a single high-volume center between 2006 and 2012. Resident participation and outcomes were collected in a prospectively maintained database. Resident experience was defined as post-graduate year (PGY) and number of PDs performed.Results: Twenty-nine residents and four attending surgeons completed 681 PDs. The overall complication rate was 44%; PD-specific complications (defined as pancreatic fistula, delayed gastric emptying, bile leak, abscess, and wound infection) occurred in 28% and were significantly more common when the first assistant was a PGY 4 rather than a PGY 5 or 6 (44% vs. 27%, p=0.016). Logistic regression demonstrated that as residents perform more cases, PD-specific complications decrease (OR=0.97, pConclusions: We highlight the impact of resident involvement in complex abdominal operations, demonstrating that as residents build experience with PD, patient outcomes improve. This is consistent with volume-outcome relationships for attending physicians and high-volume hospitals. Complex cases provide unparalleled learning opportunities and remain an important component of surgical training. Maximizing resident repetitive exposure to complex surgical procedures benefits both the patient and the trainee

RAN GTPase and Osteopontin in Pancreatic Cancer.

INTRODUCTION: Pancreatic ductal adenocarcinoma (PDA) has the worst prognosis among cancers, mainly due to the high incidence of early metastases. RAN small GTPase (RAN) is a protein that plays physiological roles in the regulation of nuclear transport and microtubule spindle assembly. RAN was recently shown to mediate the invasive functions of the prometastatic protein osteopontin (OPN) in breast cancer cells. We and others have shown previously that high levels of OPN are present in PDA. In this study, we analyzed the expression and correlation of RAN with OPN in human pancreatic lesions, and explored their regulation in PDA cell lines. METHODS: Real time PCR was used to analyze RAN and OPN mRNA levels in PDA, adjacent non-malignant, and benign pancreatic tissues. Expression levels were correlated with survival and different clinicopathological parameters using different statistical methods. Transient transfection studies using OPN and RAN plasmids, and knockdown experiments using siRNA were used to examine their mutual regulation. RESULTS: OPN and RAN levels highly correlated with each other (p CONCLUSIONS: The high levels of RAN in PDA and its correlation with OPN and with perineural invasion suggest that RAN may contribute to PDA metastasis and progression through the induction of OPN. RAN\u27s role in the regulation of OPN in PDA is unique and could provide potential novel therapeutic strategies to combat PDA aggressiveness