Prostaglandin E2: A Pancreatic Fluid Biomarker of Intraductal Papillary Mucinous Neoplasm Dysplasi

Background With the increased frequency of diagnostic imaging, pancreatic cysts are now detected in >3% of American adults. Most of these are intraductal papillary mucinous neoplasms (IPMNs) with well-established but variable malignant potential. A biomarker that predicts malignant potential or dysplastic grade would help determine which IPMNs require removal and which can be observed safely. We previously reported that pancreatic fluid prostaglandin E2 (PGE2) levels might have promise as a predictor of IPMN dysplasia and we seek to validate those results in the current study. Study Design Pancreatic cyst/duct fluid was prospectively collected from 100 patients with IPMN undergoing pancreatic resection. Surgical pathology revealed 47 low-/moderate-grade, 34 high-grade, and 20 invasive IPMNs. The PGE2 levels were assessed by ELISA and correlated with IPMN dysplasia grade, demographics, clinical radiologic/pathologic variables, acute/chronic pancreatitis, and NSAID use. Results Mean pancreatic cyst fluid PGE2 levels in high-grade and invasive IPMNs were significantly higher than low-/moderate-grade IPMNs (3.5 and 4.4 pg/μL, respectively, vs 1.2 pg/μL; p 192 ng/mL, PGE2 at a threshold of 0.5 pg/μL demonstrated 78% sensitivity, 100% specificity, and 86% accuracy for detection of high-grade/invasive IPMN. Conclusions Our results validate pancreatic cyst fluid PGE2 as an indicator of IPMN dysplasia, especially in select patients with preoperative pancreatic cyst fluid CEA >192 ng/mL. The inclusion of PGE2/CEA in a diagnostic biomarker panel can facilitate more optimal treatment stratification of IPMN patients

Urologic surgery and COVID-19: How the pandemic is changing the way we operate

The coronavirus disease 2019 (COVID-19) pandemic has had a global impact on all aspects of healthcare, including surgical procedures. For urologists, it has affected and will continue to influence how we approach the care of patients pre-operatively, intra-operatively, and post-operatively. A risk-benefit assessment of each patient undergoing surgery should be performed during the COVID-19 pandemic based on the urgency of the surgery and the risk of viral illness and transmission. Patients with advanced age and comorbidities have a higher incidence of mortality. Routine preoperative testing and symptom screening is recommended to identify those with COVID-19. Adequate personal protective equipment (PPE) for the surgical team is essential to protect healthcare workers and ensure an adequate workforce. For COVID-19 positive or suspected patients, the use of N95 respirators is recommended if available. The anesthesia method chosen should attempt to minimize aerosolization of the virus. Negative pressure rooms are strongly preferred for intubation/extubation and other aerosolizing procedures. Although transmission has not yet been shown during laparoscopic and robotic procedures, efforts should be made to minimize the risk of aerosolization. Ultra low particulate air filters are recommended for use during minimally invasive procedures to decrease the risk of viral transmission. Thorough cleaning and sterilization should be performed post-operatively with adequate time allowed for the operating room air to be cycled after procedures. COVID-19 patients should be separated from non-infected patients at all levels of care including recovery to decrease the risk of infection. Future directions will be guided by outcomes and infection rates as social distancing guidelines are relaxed and more surgical procedures are reintroduced. Recommendations should be adapted to the local environment and will continue to evolve as more data becomes available, the shortage of testing and PPE is resolved, and a vaccine and therapeutics for COVID-19 are developed

Post-Pancreatoduodenectomy Outcomes and Epidural Analgesia: A 5-Year Single Institution Experience

Introduction Optimal pain control post-pancreatoduodenectomy is a challenge. Epidural analgesia (EDA) is increasingly utilized despite inherent risks and unclear effects on outcomes. Methods All pancreatoduodenectomies (PD) performed from 1/2013-12/2017 were included. Clinical parameters were obtained from retrospective review of a prospective clinical database, the ACS NSQIP prospective institutional database and medical record review. Chi-Square/Fisher’s Exact and Independent-Samples t-Tests were used for univariable analyses; multivariable regression (MVR) was performed. Results 671 consecutive PD from a single institution were included (429 EDA, 242 non-EDA). On univariable analysis, EDA patients experienced significantly less wound disruption (0.2% vs. 2.1%), unplanned intubation (3.0% vs. 7.9%), pulmonary embolism (0.5% vs. 2.5%), mechanical-ventilation >48hrs (2.1% vs. 7.9%), septic shock (2.6% vs. 5.8%), and lower pain scores. On MVR accounting for baseline group differences (gender, hypertension, pre-operative transfusion, labs, approach, pancreatic duct size), EDA was associated with less superficial wound infections (OR 0.34; CI 0.14-0.83; P=0.017), unplanned intubations (OR 0.36; CI 0.14-0.88; P=0.024), mechanical ventilation >48 hrs (OR 0.22; CI 0.08-0.62; P=0.004), and septic shock (OR 0.39; CI 0.15-1.00; P=0.050). EDA improved pain scores post-PD days 1-3 (P<0.001). No differences were seen in cardiac or renal complications; pancreatic fistula (B+C) or delayed gastric emptying; 30/90-day mortality; length of stay, readmission, discharge destination, or unplanned reoperation. Conclusion Based on the largest single institution series published to date, our data support the use of EDA for optimization of pain control. More importantly, our data document that EDA significantly improved infectious and pulmonary complications

“Show me the Data”: A Recipe for Quality Improvement Success in an Academic Surgical Department

Background Surgeons in academic medical centers have traditionally taken a siloed approach to reducing postoperative complications. We initiated a project focusing on transparency and sharing of data in order to engage surgeons in collaborative quality improvement. Its key features were the development of a comprehensive Department Quality Dashboard and the creation of a Clinical Operations Council that oversaw quality. The purpose of this study was to assess the impact of those efforts. Study Design We compared inpatient outcomes before and after our intervention, allowing one quarter as the diffusion period. The outcomes analyzed were: risk-adjusted length of stay (LOS), mortality and direct cost and unadjusted incidence of complications and 30-day all-cause readmissions, as determined by the Vizient Clinical Database. We examined the outcomes of three groups: Group 1 (Surgery), Group 2 - all other surgical departments (Other Surgery) and Group 3 - all other patients (Non-Surgery). Two-tailed Students’s t-test was used for analysis and a p value of <0.05 considered statistically significant. Results Group 1 demonstrated statistically significant improvements in mortality (p=0.01), LOS (p=0.002), cost (p=0.0001) and complications (p=0.02) while the all-cause readmission rate was unchanged, resulting in mean decrease of 0.55 LOS days and direct cost savings of $2300 per surgical admission. The comparison groups had only modest decreases in some of the analyzed outcomes and an increase in complication rates. Conclusions These data suggest that a collaborative, data-driven and transparent approach to assessing the quality of surgical care can yield significant improvements in patient outcomes

Ocean warming and acidification may drag down the commercial Arctic cod fishery by 2100

The Arctic Ocean is an early warning system for indicators and effects of climate change. We use a novel combination of experimental and time-series data on effects of ocean warming and acidification on the commercially important Northeast Arctic cod (Gadus morhua) to incorporate these physiological processes into the recruitment model of the fish population. By running an ecological-economic optimization model, we investigate how the interaction of ocean warming, acidification and fishing pressure affects the sustainability of the fishery in terms of ecological, economic, social and consumer-related indicators, ranging from present day conditions up to future climate change scenarios. We find that near-term climate change will benefit the fishery, but under likely future warming and acidification this large fishery is at risk of collapse by the end of the century, even with the best adaptation effort in terms of reduced fishing pressure.publishedVersio

DEEPEN: A negation detection system for clinical text incorporating dependency relation into NegEx

In Electronic Health Records (EHRs), much of valuable information regarding patients’ conditions is embedded in free text format. Natural language processing (NLP) techniques have been developed to extract clinical information from free text. One challenge faced in clinical NLP is that the meaning of clinical entities is heavily affected by modifiers such as negation. A negation detection algorithm, NegEx, applies a simplistic approach that has been shown to be powerful in clinical NLP. However, due to the failure to consider the contextual relationship between words within a sentence, NegEx fails to correctly capture the negation status of concepts in complex sentences. Incorrect negation assignment could cause inaccurate diagnosis of patients’ condition or contaminated study cohorts. We developed a negation algorithm called DEEPEN to decrease NegEx’s false positives by taking into account the dependency relationship between negation words and concepts within a sentence using Stanford dependency parser. The system was developed and tested using EHR data from Indiana University (IU) and it was further evaluated on Mayo Clinic dataset to assess its generalizability. The evaluation results demonstrate DEEPEN, which incorporates dependency parsing into NegEx, can reduce the number of incorrect negation assignment for patients with positive findings, and therefore improve the identification of patients with the target clinical findings in EHRs

Management of Branch‐duct Intraductal Papillary Mucinous Neoplasms: A Large Single Center Study to Assess Predictors of Malignancy and Long Term Outcomes

Background and Aims Management of branch-duct intraductal papillary mucinous neoplasms (BD-IPMNs) remains challenging. We determined factors associated with malignancy in BD-IPMNs and long-term outcomes. Methods This retrospective cohort study included all patients with established BD-IPMNs by the International Consensus Guidelines (ICG) 2012 and/or pathologically confirmed BD-IPMNs in a tertiary care referral center between 2001 and 2013. Main outcome measures were the association between high-risk stigmata (HRS)/worrisome features (WFs) of the ICG 2012 and malignant BD-IPMNs, performance characteristics of EUS-FNA for the diagnosis of malignant BD-IPMNs, and recurrence and long-term outcomes of BD-IPMN patients undergoing surgery or imaging surveillance. Results Of 364 BD-IPMN patients, 229 underwent imaging surveillance and 135 underwent surgery. Among the 135 resected BD-IPMNs, HRS/WFs on CT/magnetic resonance imaging (MRI) were similar between the benign and malignant groups, but main pancreatic duct (MPD) dilation (5-9 mm) was more frequently identified in malignant lesions. On EUS-FNA, mural nodules, MPD features suspicious for involvement, and suspicious/positive malignant cytology were more frequently detected in the malignant group with a sensitivity, specificity, and accuracy of 33%, 94%, and 86%; 42%, 91%, and 83%; and 33% 91%, and 82%, respectively. Mural nodules identified by EUS were missed by CT/MRI in 28% in the malignant group. Patients with malignant lesions had a higher risk of any IPMN recurrence during a mean follow-up period of 131 months (P = .01). Conclusions Among HRS and WFs of the ICG 2012, an MPD size of 5 to 9 mm on CT/MRI was associated with malignant BD-IPMNs. EUS features including mural nodules, MPD features suspicious for involvement, and suspicious/malignant cytology were accurate and highly specific for malignant BD-IPMNs. Our study highlights the incremental value of EUS-FNA over imaging in identifying malignant BD-IPMNs, particularly in patients without WFs and those with smaller cysts. Benign IPMN recurrence was observed in some patients up to 8 years after resection

Pancreatic Cyst Fluid Vascular Endothelial Growth Factor A and Carcinoembryonic Antigen: A Highly Accurate Test for the Diagnosis of Serous Cystic Neoplasm

Background Accurate differentiation of pancreatic cystic lesions is important for early detection and prevention of pancreatic cancer, as well as avoidance of unnecessary surgical intervention. Serous cystic neoplasms (SCNs) have no malignant potential, but can mimic the following premalignant mucinous cystic lesions: mucinous cystic neoplasm and intraductal papillary mucinous neoplasm (IPMN). We recently identified vascular endothelial growth factor (VEGF)-A as a novel pancreatic fluid biomarker for SCN. We hypothesize that combining cyst fluid CEA with VEGF-A will improve the diagnostic accuracy of VEGF-A. Methods Pancreatic cyst/duct fluid was collected from consenting patients undergoing surgical cyst resection with corresponding pathologic diagnoses. Pancreatic fluid VEGF-A and CEA levels were detected by ELISA. Results One hundred and forty-nine patients with pancreatic cystic lesions met inclusion criteria. Pathologic diagnoses included pseudocyst (n = 14), SCN (n = 26), mucinous cystic neoplasm (n = 40), low-/moderate-grade IPMN (n = 34), high-grade IPMN (n = 20), invasive IPMN (n = 10), and solid pseudopapillary neoplasm (n = 5). Vascular endothelial growth factor A was significantly elevated in SCN cyst fluid compared with all other diagnoses (p 5,000 pg/mL, VEGF-A alone has 100% sensitivity and 83.7% specificity to distinguish SCNs from other cystic lesions. With a threshold of ≤10 ng/mL, CEA alone identifies SCN with 95.5% sensitivity and 81.5% specificity. Sensitivity and specificity of the VEGF-A/CEA combination are 95.5% and 100%, respectively. The c-statistic increased from 0.98 to 0.99 in the receiver operating characteristic analysis when CEA was added to VEGF-A alone. Conclusions Although VEGF-A alone is a highly accurate test for SCN, the combination of VEGF-A with CEA approaches the gold standard for pathologic diagnosis, importantly avoiding false positives. Patients with a positive test indicating benign SCN can be spared a high-risk surgical pancreatic resection

Role of 14-3-3σ in poor prognosis and in radiation and drug resistance of human pancreatic cancers

<p>Abstract</p> <p>Background</p> <p>Pancreatic cancer is the fourth leading cause of death in the US. Unlike other solid tumors such as testicular cancer which are now curable, more than 90% of pancreatic cancer patients die due to lack of response to therapy. Recently, the level of 14-3-3σ mRNA was found to be increased in pancreatic cancers and this increased expression may contribute to the failure in treatment of pancreatic cancers. In the present study, we tested this hypothesis.</p> <p>Methods</p> <p>Western blot analysis was used to determine 14-3-3σ protein level in fresh frozen tissues and was correlated to clinical outcome. A stable cell line expressing 14-3-3σ was established and the effect of 14-3-3σ over-expression on cellular response to radiation and anticancer drugs were tested using SRB assay and clonogenic assays. Cell cycle distribution and apoptosis analyses were performed using propidium iodide staining and PARP cleavage assays.</p> <p>Results</p> <p>We found that 14-3-3σ protein level was increased significantly in about 71% (17 of 24) of human pancreatic cancer tissues and that the 14-3-3σ protein level in cancers correlated with lymph node metastasis and poor prognosis. Furthermore, we demonstrated that over-expression of 14-3-3σ in a pancreatic cancer cell line caused resistance to γ-irradiation as well as anticancer drugs by causing resistance to treatment-induced apoptosis and G2/M arrest.</p> <p>Conclusion</p> <p>The increased level of 14-3-3σ protein likely contributes to the poor clinical outcome of human pancreatic cancers by causing resistance to radiation and anticancer drugs. Thus, 14-3-3σ may serve as a prognosis marker predicting survival of pancreatic cancer patients and guide the clinical treatment of these patients.</p

Circulating Thrombospondin-2 enhances prediction of malignant intraductal papillary mucinous neoplasm

Background IPMNs are cystic pancreatic lesions with variable malignant potential. Thrombospondin-2 (THBS2)—an endogenous, anti-angiogenic matrix glycoprotein—may modulate tumor progression. We hypothesized that circulating levels of THBS2 could aid in preoperative prediction of malignant IPMN. Methods Preoperative serum/plasma samples were procured from patients undergoing surgery. Circulating levels of THBS2 were measured (enzyme-linked immunosorbent assay) and compared to surgical pathology IPMN dysplastic grade. Results 164 patients underwent THBS2 testing (100 Low/Moderate-IPMN; 64 High-Grade/Invasive-IPMN). Circulating THBS2 (mean ± SD) was greater in High-Grade/Invasive-IPMN than Low/Moderate-grade IPMN (26.6 ± 12.7 ng/mL vs. 20.4 ± 8.2 ng/mL; P < 0.001). THBS2 (AUC = 0.65) out-performed CA19-9 (n = 144; AUC = 0.59) in predicting IPMN grade. The combination of THBS2, CA19-9, radiographic main-duct involvement, main-duct diameter, age, sex, and BMI (AUC 0.82; n = 137) provided a good prediction model for IPMN grade. Conclusion Circulating THBS2 is correlated with IPMN dysplasia grade. THBS2 alone did not strongly predict IPMN grade but rather strengthened prediction models for High-Grade/Invasive IPMN when combined with other clinical/biomarker data