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OBJECTIVES: Pancreatic cystic lesions (PCLs) may be precancerous. Those likely to harbor high-grade dysplasia (HGD) or pancreatic cancer (PC) are targets for surgical resection. Current algorithms to predict advanced neoplasia (HGD/PC) in PCLs lack diagnostic accuracy. In pancreatic tissue and cystfluid (CF) from PCLs, we sought to identify and validate novel methylated DNA markers (MDMs) that discriminate HGD/PC from low-grade dysplasia (LGD) or no dysplasia (ND). METHODS: From an unbiased whole-methylome discovery approach using predefined selection criteria followed by multistep validation on case (HGD or PC) and control (ND or LGD) tissues, we identified discriminant MDMs. Top candidate MDMs were then assayed by quantitative methylation-specific polymerase chain reaction on archival CF from surgically resected PCLs. RESULTS: Of 25 discriminant MDMs identified in tissue, 13 were selected for validation in 134 CF samples (21 cases [8 HGD, 13 PC], 113 controls [45 ND, 68 LGD]). A tree-based algorithm using 2 CF-MDMs (TBX15, BMP3) achieved sensitivity and specificity above 90%. Discrimination was significantly better by this CF-MDM panel than by mutant KRAS or carcinoembryonic antigen, with areas under the receiver operating characteristic curve of 0.93 (95% confidence interval: 0.86–0.99), 0.71 (0.57–0.85), and 0.72(0.60–0.84), respectively. Cutoffs for the MDM panel applied to an independent CF validation set (31 cases, 56 controls) yielded similarly high discrimination, areas under the receiver operating characteristic curve 5 0.86 (95% confidence interval: 0.77–0.94, P = 0.2). DISCUSSION: Novel MDMs discovered and validated in tissue accurately identify PCLs harboring HGD/PC. A panel of 2 MDMs assayed in CF yielded results with potential to enhance current risk prediction algorithms. Prospective studies are indicated to optimize and further evaluate CF-MDMs for clinical use.

Definitive chemoradiotherapy for unresectable pancreatic cancer has traditionally involved 5-fluorouracil-based chemotherapy. Our institution has a long history of combining gemcitabine and radiotherapy (RT), and performed a retrospective review of all patients treated in this manner. We reviewed the records of 180 patients treated from 1999 to 2012. Mean RT dose was 40.9 Gy in 2.2-Gy fractions, and targeted only radiographically apparent disease. Ninety-six percent of patients received full-dose gemcitabine-based chemotherapy with RT. Kaplan-Meier was used to analyze time-to-event endpoints, and Cox regression models were used to assess significant prognostic variables. Eighty-nine percent of patients completed RT without a toxicity-related treatment break. Median follow-up was 10.2 months. Twenty-nine percent of patients had a radiographic decrease in primary tumor size following treatment. Median overall survival was 11.8 months, time to distant metastasis (TDM) was 6.7 months, and time to local recurrence (TLR) was 8.3 months. On multivariate analysis, male sex, lower performance status, and higher posttreatment CA 19-9 level predicted for worse overall survival. Posttreatment, CA 19-9 was also associated with TDM and TLR, and radiographic tumor response was associated with better TLR. Definitive chemoradiation using full-dose gemcitabine is well tolerated and achieves survival outcomes comparable to reported trials in the literature.

To appraise the recent literature dealing with important advances in the field of pancreatic surgery.Surgical care for pancreatic cancer patients remains fractured, with imperfect patient selection and ongoing bias in referral patterns based on socioeconomic factors. Analysis of readmissions after pancreatectomy reveals it to be a poor quality of care metric. More extensive pancreatic resections lead to higher morbidity. Intraductal papillary mucinous neoplasm and pancreatic neuroendocrine tumor biology affect patient outcomes and suggest the need for better diagnostic approaches for these entities. Perioperative drainage still has a role during Whipple pancreaticoduodenectomy on the basis of the results of a randomized controlled trial. Laparoscopic and robotic approaches married with new emerging technologies have the potential to transform the practice of pancreatic surgery.Pancreatic surgery is a rapidly evolving field with the promise to significantly improve outcomes for patients with a variety of pancreatic diseases in the future.

Purpose of review This review intends to describe recent studies on pancreatic tumor-associated stroma and potential opportunities and limitations to its targeting. Recent findings One of the defining features of pancreatic cancer is extensive desmoplasia, or an inflammatory, fibrotic reaction. Carcinoma cells live in this complex microenvironment which is comprised of extracellular matrix (ECM), diffusible growth factors, cytokines and a variety of nonepithelial cell types including endothelial cells, immune cells, fibroblasts, myofibroblasts and stellate cells. In addition to the heterogeneity noted in the nonneoplastic cells within the tumor microenvironment, it has also been recognized that neoplastic cancer cells themselves are heterogeneous, and include a subpopulation of stem-cell like cells within tumors termed cancer stem cells. Due to the failure of current therapeutics to improve outcomes in patients with pancreatic cancer, new therapeutic avenues targeting different components of the tumor microenvironment are being investigated. In this review article, we will focus on recent studies regarding the function of the tumor stroma in pancreatic cancer and therapeutic treatments that are being advanced to target the stroma as a critical part of tumor management. Summary Recent studies have shed new light on the contribution of the pancreatic cancer fibroinflammatory stroma to pancreatic cancer biology. Additional studies are needed to better define its full contribution to tumor behavior and how to best understand the optimal ways to develop therapies that counteract its pro-neoplastic properties.

OBJECTIVES Normally, sonic hedgehog (Shh) is expressed in the pancreas during fetal development and transiently after tissue injury. Although pancreatic cancers express Shh, it is not known if the protein is secreted into the blood and whether its plasma levels change with pancreatic transformation. The goal of this study was to develop an enzyme-linked immunosorbent assay to detect human Shh in blood and determine its levels in subjects with and without pancreatic cancer. METHODS A human Shh enzyme-linked immunosorbent assay was developed, and plasma Shh levels were measured in blood samples from healthy subjects and patients with pancreatitis or pancreatic cancer. The biological activity of plasma Shh was tested using NIH-3T3 cells. RESULTS The mean levels of Shh in human blood were lower in patients with pancreatitis and pancreatic cancer than in healthy subjects. Hematopoietic cells did not express Shh, suggesting that Shh is secreted into the bloodstream. Plasma fractions enriched with Shh did not induce Gli-1 messenger RNA, suggesting that the protein was not biologically active. CONCLUSIONS Shh is secreted from tissues and organs into the circulation, but its activity is blocked by plasma proteins. Reduced plasma levels were found in pancreatic cancer patients, but alone were not sufficient to predict pancreatic cancer.

We review recent literature with a view to forge an integrative understanding of the molecular, cellular and extracellular milieu of pancreatic cancer, and discuss them in the context of development of novel, personalized therapeutic options.Pancreatic tumorigenesis, examined using genetically engineered mouse models, appears to be driven by local inflammation, in concert with the 'big four' mutations involving oncogenic KRAS, SMAD4, CDKN2A, and TP53, through induction of epithelial-to-mesenchymal transition (EMT) and cancer stem cells, and accompanied by metastasis. High-throughput sequencing of pancreatic ductal adenocarcinoma as well as neuroendocrine tumors and rarer subtypes of cancers of the pancreas has revealed several novel mutations in genes like PALB2, guanine nucleotide-binding protein, alpha stimulating, death-domain-associated protein, α thalassemia/mental retardation syndrome X linked, switch/sucrose nonfermentable pathway related, and in genes in the ubiquitin-dependent pathways such as USP9X. Therapeutic targeting of the tumor-stroma axis by cytokines and immune response modulators and the role of autophagy in pancreatic cancer are some other salient themes explored in the recent publications.Recent publications shed new light on the mutational landscape of pancreatic cancer and further delineate the distinctive pancreatic cancer-stroma ecosystem as determined by the dynamic interplay of inflammation, hallmark mutations, EMT, and cancer stem cells.

Despite the dramatically increased entry of women into general surgery and surgical subspecialties, traditionally male-dominated fields, there remains a gross under-representation of women in the leadership positions of these departments. Women begin their careers with fewer academic resources and tend to progress through the ranks slower than men. Female surgeons also receive significantly lower salaries than their male counterparts and are more vulnerable to discrimination, both obvious and covert. Although some argue that female surgeons tend to choose their families over careers, studies have actually shown that women are as eager as men to assume leadership positions, are equally qualified for these positions as men, and are as good as men at leadership tasks.Three major constraints contribute to the glass-ceiling phenomenon: traditional gender roles, manifestations of sexism in the medical environment, and lack of effective mentors. Gender roles contribute to unconscious assumptions that have little to do with actual knowledge and abilities of an individuals and they negatively influence decision-making when it comes to promotions. Sexism has many forms, from subtle to explicit forms, and some studies show that far more women report being discriminately against than do men. There is a lack of same-sex mentors and role models for women in academic surgery, thereby isolating female academicians further. This review summarizes the manifestation of the glass-ceiling phenomenon, identifies some causes of these inequalities, and proposes different strategies for continuing the advancement of women in academic surgery and to shatter the glass ceiling.

Cystic lesions of the pancreas are increasingly being recognized due to the widespread use of high resolution abdominal imaging. Since certain cyst types are precursors to invasive cancer, this situation presents an opportunity to intervene prior to malignant progression. Effective implementation of that strategy has been hampered by difficulties in clearly distinguishing cystic lesions with no malignant potential from those with malignant potential. Here we explored whether glycosylation variants on specific proteins in cyst fluid samples could serve as biomarkers to aid in this diagnosis.We used a novel antibody-lectin sandwich microarray method to measure the protein expression and glycosylation of mucin (MUC)1, MUC5AC, MUC16, carcinoembryonic antigen, and other proteins implicated in pancreatic neoplasia in cyst fluid samples. Fifty-three cyst fluid samples were obtained from patients with mucinous cystic neoplasms (n=17), intraductal papillary mucinous neoplasms (n=15), serous cystadenomas (n=12), or pseudocysts (n=9), with confirmation of histologic diagnosis at surgical resection.The detection of a glycan variant on MUC5AC using the lectin wheat-germ agglutinin discriminated mucin-producing cystic tumors (mucinous cystic neoplasms+intraductal papillary mucinous neoplasms) from benign cystic lesions (serous cystadenomas+pseudocysts) with a 78% sensitivity at 80% specificity, and when used in combination with cyst fluid CA 19-9 gave a sensitivity of 87% at 86% specificity. These biomarkers performed better than cyst fluid carcinoembryonic antigen (37%/80% sensitivity/specificity).These results demonstrate the value of glycan variants for biomarker discovery and suggest that these biomarkers could greatly enhance the accuracy of differentiating pancreatic cystic tumors. Validation studies will be required to determine the clinical value of these markers.

Serum biomarkers for early diagnosis of pancreatic adenocarcinoma are not currently available. We recently observed elevated expression of CEACAM1 in pancreatic adenocarcinomas and sought to determine whether serum CEACAM1 levels were elevated in pancreatic cancer patients.CEACAM1 messenger RNA levels were measured in pancreatic tissue samples using quantitative reverse transcription-polymerase chain reaction. CEACAM1 was localized by immunohistochemistry in adenocarcinomas and in pancreatic intraductal neoplasia lesions. CEACAM1 serum levels were assessed by a double determinant enzyme-linked immunosorbent assay and compared with serum levels of CA19-9.CEACAM1 had higher expression levels in pancreatic adenocarcinomas compared with noncancerous pancreas (P0.0001) and was localized to neoplastic cells (95% (45/47) of adenocarcinomas and 85% (17/20) of pancreatic intraductal neoplasia 3 lesions. CEACAM1 was expressed in the sera of 91% (74/81) of pancreatic cancer patients, 24% (15/61) of normal patients, and 66% (35/53) of patients with chronic pancreatitis, with a sensitivity and specificity superior to CA19-9. The combination of CEACAM1 and CA19-9 had significantly higher diagnostic accuracy than CA19-9.CEACAM1 is expressed in pancreatic adenocarcinoma, and serum levels of CEACAM1 serve as a useful indicator for the presence of pancreatic cancer. Additional validation studies on the use of serum CEACAM1 as a diagnostic marker in pancreatic cancer are warranted.

The recent terrorist attacks in New York City and Washington D.C. and the subsequent cases of anthrax exposure and infection throughout the United States make the once-theoretical risk of a bioterrorist attack with aerosolized anthrax very real. It is estimated that 100 kg of anthrax spores released upwind of Washington D.C. would result in 130,000 to 3 million deaths; many of these patients would die undiagnosed and untreated. 1 In a covert, large-scale release of anthrax, the initial deaths would result from a delay in recognizing the clinical manifestations of cutaneous, inhalation, or gastrointestinal disease and instituting appropriate treatment. To reduce the death rate, knowledge of the clinical manifestations, disease course, and medical as well as surgical treatment of anthrax infection is imperative. 2 Data regarding the diagnosis and management of anthrax comes from human case reports, mostly from foreign countries in which the disease is endemic, and experimental animal studies. The closest incident to a large-scale bioterrorist attack with aerosolized anthrax was the accidental release of the agent from a military microbiology facility at Sverdlovsk in 1979, from which limited information is available. There were at least 79 cases of anthrax infection, resulting in 68 deaths. 3,4 With such limited data and individual clinical experience, not all recommendations are rigorously evidence-based but rather have been clinically derived, as well as based on established surgical and medical practices. The Centers for Disease Control and Prevention (CDC) has begun a process of physician education to increase familiarity with the clinical manifestations and treatment, but there has been little discussion of the surgical aspects of anthrax infection. Although the primary treatment of anthrax infection is medical, surgical complications can occur, particularly if a large number of individuals are infected. Awareness of these complications and knowledge of their treatment are critical if the deaths and complications are to be limited. Aside from the surgical indications, it is likely that in the case of a large-scale anthrax exposure, all physicians, including surgeons, would play a pivotal role in diagnosing and treating these patients. As such, a review of intentional infection with aerosolized anthrax, emphasizing surgical management, seems timely.

BACKGROUND: Education is a major function of academic medical centers. At these teaching institutions residents provide a substantial amount of care on medical and surgical services. The attitudes of patients about the training of surgical residents and the impact of residents on patients' perceptions of care in a surgical setting are unknown. STUDY DESIGN: Patients admitted to the gastrointestinal surgery service completed a 30-item survey designed for this study. Patients included in the study underwent operations and had a postoperative inpatient hospital stay. We analyzed patients' answers to determine frequency and correlations among answers. RESULTS: Two hundred patients participated in the study during a 7-month period between July 1999 and January 2000. A majority of patients were comfortable having residents involved in their care (86%) and felt it was important to help educate future surgeons (91%). Most did not feel inconvenienced by being at a teaching hospital (71%) and felt they received extra attention there (74%). Patients were more willing to participate in resident education if they expected to have several physicians involved in their care, felt that they received extra attention, or if the teaching atmosphere did not inconvenience them. Despite the stated willingness of patients to help with surgical resident education, 32% answered that they would not want residents doing any of their operation. CONCLUSIONS: Surgical resident education is well received and considered important by patients. Patient orientation to the resident education process is vital to patients' perceptions of care and may render patients more willing to participate in educational activities.

Congenital heart defects (CHDs) are the most common type of birth defect, affecting ≈1% of births per year.[1][1] Although survival has been improving over time, there remain numerous gaps in the understanding of the public health impact of CHDs across the lifespan. Recognizing that there was “a

This study was designed to determine the intra-operative incidence of right-sided ventricular ischaemia and any association with left ventricular ischaemia. In 60 patients, undergoing coronary artery bypass grafting surgery, a right-sided precordial lead V5R was used. ST segment deviation of more than 1 mm in V5R was considered significant for myocardial ischaemia. Right ventricular ischaemia occurred in 14 patients (23.3%) but was not associated with left ventricular inferior wall ischaemia. In 4 patients (6.6%) presenting with right ventricular ischaemia, ischaemia of the left inferior wall also developed but in all cases was transient and disappeared by the end of surgery. No myocardial infarction was detected in the post-operative period. The present study showed that the use of a right-sided lead may improve intra-operative electro?ƒ?cardio?ƒ?graphic monitoring, by revealing ischaemia in those patients in whom ECG abnormalities were not detected by conventional leads. The transient right ventricular ischaemia recorded in this study was probably related to a reduced hypothermic protection of the right ventricle during aortic cross clamping.

Author(s): Freeman, M; Pandol, SJ; Liddle, RA; Saluja, AK; Fernandez-Del Castillo, C; Maitra, A; Sahin-Toth, M; Go, VL

RESULTS: Snail over-expression in KrasG12D mice significantly increased mast cell and granulocyte infiltration to the pancreatic tumor microenvironment. Snail over-expression in KrasG12D mice did not increase T-regulatory cell or macrophage infiltration to the pancreatic tumor microenvironment. Cerulein-induced pancreatitis in KrasG12D mice increased mast cell infiltration, and Snail over-expression appears to potentiate the effect of cerulein in these mice.

Myocardial tolerance to total ischemia was compared in animals anesthetized with halothane or isoflurane by measuring the time required for development of cardiac rigor in the absence of coronary circulation or wall stress. Sixteen dogs, eight in each group, were anesthetized with equally potent inspired concentrations of either halothane (2 MAC) or isoflurane (2 MAC), intubated, and ventilated. Thirty minutes later, the heart was rapidly excised. A left ventricular slab was prepared and maintained at 37 degrees C. A portion of each slab was placed in a compressibility gauge that detects rigor onset by an abrupt increase in resistance to tissue deformation. Subendocardial tissue pressure was continuously measured in a second slab using needle-tipped Millar pressure transducers. A third slab was used for intermittent tissue sampling and HPLC assay of high-energy nucleotide levels. There were no differences in pre-ischemic heart rate, mean arterial pressure, glucose, lactate, PO2, PCO2, pH, plasma epinephrine, or norepinephrine levels between the two groups. The onset of rigor as measured by the compressibility gauge was delayed in the halothane group (68 +/- 7.2 vs. 60 +/- 5.0 min; P less than .05). Tissue ATP and ADP levels declined throughout the period of ischemia, with a trend towards preservation in the halothane group. The data show that myocardial tolerance to total normothermic ischemia is improved in animals anesthetized with halothane compared to isoflurane, independent of the effects on hemodynamics or collateral coronary circulation.