Serial EUS-Guided FNA for the Surveillance of Pancreatic Cysts: A Study of Long-Term Performance of Tumor Markers.

BACKGROUND AND AIM: The natural history of KRAS mutations in mucinous pancreatic cysts (MPCs) over time remains to be fully understood. The aim of this study was to examine the performance of DNA markers and assess changes of KRAS mutations over time. METHODS: Patients who underwent EUS-FNA of pancreatic cysts with at least two separate molecular analysis results were included in the study. We assessed the baseline patient and cyst characteristics, and DNA fluid analysis. The presence of either a KRAS mutation, or a CEA > 192 ng/ml was used as the diagnostic standard for mucinous cysts when surgical pathology was not available. RESULTS: A total of 933 pancreatic cyst fluid samples were collected, including 117 with ≥ 2 FNAs. Examinations were performed over a median of 30 months (range 1-115 months). Forty-three (36%) had a mutant KRAS on the index analysis out of which 26 had a change in their KRAS status to the wild-type. Eighty-one (64%) had a wild-type KRAS on the index analysis out of which 18 had change in their KRAS status to mutant type. There was no significant difference in the index cyst characteristics, presence of symptoms, or main duct involvement based on KRAS status change. Increasing age was associated with a changing KRAS mutation status (p = 0.023). CONCLUSION: KRAS mutations gain and loss in pancreatic cyst fluid appears to occur frequently during long-term surveillance of MPCs. Age appears to be the only predictor for KRAS change over time.

Is resident assistance equivalent to fellows during hepatectomy?

OBJECTIVE: Hepatectomy is a complex operative procedure frequently performed at academic institutions with trainee participation. The aim of this study was to determine the effect of assistant's training level on outcomes following hepatectomy. METHODS: A retrospective review of a prospective, single-institution ACS-NSQIP database was performed for patients that underwent hepatectomy (2013-2016). Patients were divided by trainee assistant level: hepatopancreatobiliary (HPB) fellow versus general surgery resident (PGY 4-5). Demographic, perioperative, and 30-day outcome variables were compared using Chi-Square/Fisher's exact, Mann-Whitney U test, and multivariable regression. Cases involving a senior-level general surgery resident or HPB fellow as first assistant were included (n = 352). Those with a second attending, junior-level resident, or no documented assistant were excluded (n = 39). RESULTS: Patients undergoing hepatectomy with an HPB fellow as primary assistant had more frequent preoperative biliary stenting, longer operative time, and more concomitant procedures including biliary reconstruction, resulting in a higher rate of post-hepatectomy liver failure (PHLF) (15% vs. 8%, P = 0.044). However, trainee level did not impact PHLF on multivariable analysis (OR 0.60, 95% CI [0.29-1.25], P = 0.173). Fellows assisted with proportionally more major hepatectomies (45% vs. 31%; P = 0.010) and resections for hepatobiliary cancers (31% vs. 19%, P = 0.014). On stratified analysis of major and minor hepatectomies, outcomes were similar between trainee groups. CONCLUSION: Fellows performed higher complexity cases with longer operative time. Despite these differences, outcomes were similar regardless of assistant training level. Resident and HPB fellow participation in operations requiring liver resection provide comparable quality of care.

Travel distance affects rates and reasons for inpatient visits after pancreatectomy.

BACKGROUND: Centralization of complex surgical care leads to increased travel distances for patients. We sought to determine if increased travel distance to the index hospital altered inpatient Visit rates following pancreatectomy. METHODS: Pancreatectomies from 2013-2016 were reviewed retrospectively from a single high-volume institution. Travel distance for 936 patients was determined, and patients were grouped by 50-mile increments. Visits (Observations or Readmissions) and corresponding reasons were gathered. RESULTS: 222 patients (23.7%) had a Visit to any hospital (AH) within 90 days postoperative; 195 (87.8%) were to the index hospital (IH). The <50 miles group had the highest Visit rate to AH (28.6% vs. 17.8% vs. 24.6%; P = 0.008) and the IH (26.9% vs. 15.2% vs. 20.6%; P = 0.002) compared to 50-100 and > 100 miles. This trend was statistically significant for Observations, but not Readmissions. Gastrointestinal (GI) complaints alone led to 20.7% patients requiring Visits to AH at 90-days, mostly in <50miles group for Visits and Observations at AH and IH. CONCLUSIONS: Patients closest to the IH had the highest Visit and Observation rate following pancreatectomy without affecting Readmission rate, with GI complaints as a driving factor. Inpatient education and outpatient symptom management may reduce repeat hospitalization.

Clinical criteria for integrated molecular pathology in intraductal papillary mucinous neoplasm: less is more.

BACKGROUND: For pancreatic cysts with negative cytology, Integrated Molecular Pathology (IMP) is a malignancy risk score integrating clinical criteria with pancreatic cyst fluid DNA profiling. Aside from main pancreatic duct (MPD) diameter, integrated clinical criteria are not International Consensus Guidelines High-Risk Stigmata. We predicted exclusion of clinical criteria except MPD diameter could simplify the IMP and better distinguish invasive/malignant disease. METHODS: Records of >1100 patients with IPMN were reviewed retrospectively. Sensitivity, specificity, and accuracy of conventional IMP for invasive/malignant disease was compared to DNA profile including only MPD ≥10mm (IMP-10.) Invasive outcomes were invasive-IPMN/adenocarcinoma on surgical pathology, pathologic or radiographic evidence of invasive/metastatic disease during surveillance. Malignant outcomes included high grade dysplastic IPMN (HGD-IPMN). RESULTS: 225 patients who met study criteria underwent 283 IMP evaluations: 98 followed by surgery, 185 followed by ≥ 23 months surveillance. IMP-10 had greater specificity (90.1% vs. 73.7%) and accuracy (89.8% vs. 74.2%) for invasive disease compared to IMP in surgery + surveillance patients, but lower sensitivity (77.8% vs. 88.9%). Trends were similar in surgery patients alone and malignant outcome analyses. CONCLUSION: IMP-10 excludes less-reliable clinical factors resulting in greater accuracy in predicting invasive/malignant disease and fewer patients with benign disease being recommended for surgery.

Transient Biliary Fistula After Pancreatoduodenectomy Increases Risk of Biliary Anastomotic Stricture.

BACKGROUND: Biliary fistula after pancreatoduodenectomy (PD) is associated with significant morbidity and mortality. The aim of this study was to determine the risk of early postoperative biliary fistula for developing biliary anastomotic stricture after PD. METHODS: Retrospective review of all PD performed for various indications at a single institution between 2013 and 2018. Postoperative biliary fistulae were graded according to the International Study Group of Liver Surgery (ISGLS) as grade A-C. Multivariable analysis was performed for all comparative patient subgroups. RESULTS: A total of 843 patients underwent PD for malignant (68%) and benign (32%) indications. Postoperative biliary fistula developed in 66 (8%) patients; ISGLS grade A in 29 (3%), grade B in 32 (4%), and grade C in 5 (0.6%). Ninety-day mortality was 3% (25 patients). The remaining 818 patients were evaluated with a median follow-up of 16 months (IQR, 5-32 months). Biliary anastomotic stricture developed in 41 (5%) patients at a median of 10 months (IQR, 6-18 months) postoperatively. Strictures were managed with percutaneous (27 patients, 66%) or endoscopic (14 patients, 34%) stenting. No biliary stricture required operative anastomotic revision. Postoperative biliary fistula (HR, 4.4; 95% CI, 2.0-9.9; P = 0.0002) was associated with biliary anastomotic stricture; an increased risk for biliary anastomotic stricture was seen in patients with grade A (HR, 6.4; 95% CI, 2.4-16.9; P = 0.0002) and grade B (HR, 3.6; 95% CI, 1.2-10.9; P = 0.02) postoperative biliary fistula. CONCLUSION: Postoperative biliary fistula after pancreatoduodenectomy, including clinically insignificant, transient biliary fistula, is associated with an increased risk of a late biliary anastomotic stricture requiring stenting.

Two open whipples a day: Excessive or efficient.

BACKGROUND: Demand for pancreatic surgery is rising, occasionally necessitating consecutive PDs to be performed by a single surgeon in the same workday. The safety of this practice is unknown. METHODS: Institutional prospective ACS-NSQIP data were reviewed for PDs (2013-2017). Instances where a single surgeon performed two PDs in the same day were a PD pair (PD1, PD2) and compared with univariable analysis. Paired vs. unpaired-PD matched analyses were performed. RESULTS: 661 PDs (25-PD pairs) were performed. PD1 and PD2 revealed similar infectious (12% vs16%), pulmonary (8% vs8%), cardiovascular (12% vs4%), and aggregate (24% vs24%) morbidity (P>0.05). Pancreatic fistula (B + C 0%), delayed gastric emptying (4% vs12%), hospital stay (9.3 vs8.8 days), and 30-day mortality (4% vs4%) were similar (P > 0.05). Matched outcomes were similar except higher cardiovascular morbidity for paired vs. unpaired PD (7% vs0%; P = 0.015). CONCLUSION: With proper patient selection, and in experienced hands at high-volume centers, two consecutive open PDs may be safely performed.

Secretin-induced Duodenal Aspirate of Pancreatic Juice (SIDA): Utility of Commercial Genetic Analysis.

BACKGROUND: Secretin-induced duodenal aspiration (SIDA) of pancreatic duct fluid has been proposed for pancreatic neoplasm screening in very high-risk patients. We sought to determine the clinical yield and safety of commercially-analyzed SIDA samples in patients at moderately elevated risk. PATIENTS AND METHODS: A prospectively maintained institutional database of pancreatic fluid DNA profiles was retrospectively reviewed. RESULTS: Fifty-seven patients underwent SIDA testing, most commonly for intraductal papillary mucinous neoplasms (n=43) and not otherwise specified solitary cysts (n=9). SIDA mutation yield was low compared to 37 concomitant endoscopic ultrasound-guided fine needle aspiration (EUS-FNA) samples of pancreatic fluid: KRAS (2.5% vs. 40.0%), GNAS (2.6% vs. 11.1%) and allelic loss of heterozygosity (3.1% vs. 0%). Patients undergoing SIDA alone experienced no complications while 3 patients with concomitant EUS-FNA had post-procedural pancreatitis. CONCLUSION: The genetic yield of commercially-analyzed SIDA samples was relatively low in a moderately elevated risk cohort. SIDA testing may have a better safety profile than EUS-FNA.

Utility of DNA Profiling From Main Pancreatic Duct Fluid by Endoscopic Ultrasound and Endoscopic Retrograde Cholangiopancreatography to Screen for Malignant Potential.

OBJECTIVES: The yield of genetic testing of main pancreatic duct (MPD) fluid collected during endoscopic retrograde cholangiopancreatography (ERCP) versus endoscopic ultrasound-guided fine-needle aspiration is unclear. METHODS: Consecutive MPD fluid samples obtained by endoscopic ultrasound/ERCP with DNA profiling were reviewed, excluding specimens designated "no amplification." Invasive disease included invasive cancer or malignant cytology. RESULTS: One hundred ten samples from 109 patients who underwent ERCP (n = 32) or endoscopic ultrasound-guided fine-needle aspiration (n = 78) were analyzed (2007-2018). Leading indications were dilated MPD and suspected intraductal papillary mucinous neoplasm. Elevated DNA quantity, KRAS, loss of heterozygosity (LOH), and GNAS mutations occurred in 61.5%, 25.5%, 16.4%, and 8.7% of samples, respectively. Elevated DNA quantity occurred more frequently in ERCP samples (84.4% vs 51.9%, P = 0.002); other mutation yields were similar (P > 0.05). Invasive pathology (P = 0.032) was associated with LOH in the subset of patients who underwent surgery (n = 44). Adverse events occurred more frequently after ERCP (28.1% vs 9.0%, P = 0.016). CONCLUSIONS: Endoscopic MPD fluid sampling may yield genetic data to improve diagnosis and risk stratification. In our surgical cohort, LOH was the sole predictor of invasive pathology. Endoscopic ultrasound-guided fine-needle aspiration of MPD fluid, when possible, is preferred because of superior safety profile.

A Quantitative Global Proteomics Approach Identifies Candidate Urinary Biomarkers That Correlate With Intraductal Papillary Mucinous Neoplasm Dysplasia.

OBJECTIVES: A proteomic discovery study was performed to determine if urine possesses a unique biosignature that could form the basis for a noninvasive test able to predict intraductal papillary mucinous neoplasm (IPMN) dysplasia. METHODS: Urine was collected from patients undergoing surgery for IPMN (72 low/moderate, 27 high-grade/invasive). Quantitative mass spectrometry-based proteomics was performed. Proteins of interest were identified by differential expression analysis followed by principal component analysis. RESULTS: Proteomics identified greater than 4800 urinary proteins. Low/moderate and high-grade/invasive IPMN were distinguished by 188 proteins (P < 0.05). Following principal component analysis and heatmap visualization, vitamin D binding protein (DBP), apolipoprotein A1 (APOA1), and alpha-1 antitrypsin (A1AT) were selected. The proteomic abundance of DBP (median [interquartile range]) was significantly higher for high-grade/invasive than for low/moderate IPMN (219,735 [128,882-269,943] vs. 112,295 [77,905-180,773] normalized reporter ion intensity units; P = 0.001). Similarly, APOA1 was more abundant in the high-grade/invasive than low/moderate groups (235,420 [144,933-371,247] vs 150,095 [103,419-236,591]; P = 0.0007) as was A1AT (567,514 [358,544-774,801] vs 358,393 [260,850-477,882]; P = 0.0006). CONCLUSIONS: Urinary DBP, APOA1, and A1AT represent potential biomarker candidates that may provide a noninvasive means of predicting IPMN dysplastic grade.

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 ±â€¯SD) was greater in High-Grade/Invasive-IPMN than Low/Moderate-grade IPMN (26.6 ±â€¯12.7 ng/mL vs. 20.4 ±â€¯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.

Pancreatic Fluid Interleukin-1ß Complements Prostaglandin E2 and Serum Carbohydrate Antigen 19-9 in Prediction of Intraductal Papillary Mucinous Neoplasm Dysplasia.

OBJECTIVES: We sought to determine if interleukin (IL)-1ß and prostaglandin E2 (PGE2) (inflammatory mediators in pancreatic fluid) together with serum carbohydrate antigen (CA) 19-9 could better predict intraductal papillary mucinous neoplasm (IPMN) dysplasia than individual biomarkers alone. METHODS: Pancreatic cyst fluid (n = 92) collected via endoscopy or surgery (2003-2016) was analyzed for PGE2 and IL-1ß (enzyme-linked immunosorbent assay). Patients had surgical pathology-proven IPMN. Threshold values (PGE2 [>1100 pg/mL], IL-1ß [>20 pg/mL], and serum CA 19-9 [>36 U/mL]) were determined. RESULTS: Levels of IL-1ß were higher in high-grade dysplasia (HGD)/invasive-IPMN (n = 42) compared with low/moderate IPMN (n = 37) (median [range], 54.6 [0-2671] vs 5.9 [0-797] pg/mL; P < 0.001; area under curve [AUC], 0.766). Similarly, PGE2 was higher in HGD/invasive IPMN (n = 45) compared with low/moderate IPMN (n = 47) (median [range], 1790 [20-15,180] vs. 140 [10-14,630] pg/mL; P < 0.001; AUC, 0.748). Presence of elevated PGE2 and IL-1ß (AUC, 0.789) provided 89% specificity and 82% positive predictive value (PPV) for HGD/invasive IPMN. Elevated levels of all 3 provided 100% specificity and PPV for HGD/invasive IPMN. CONCLUSIONS: Cyst fluid PGE2, IL-1ß, and serum CA 19-9 in combination optimize specificity and PPV for HGD/invasive IPMN and may help build a panel of markers to predict IPMN dysplasia.

Post-Pancreaticoduodenectomy Outcomes and Epidural Analgesia: A 5-year Single-Institution Experience.

BACKGROUND: Optimal pain control post pancreaticoduodenectomy is a challenge. Epidural analgesia (EDA) is used increasingly, despite inherent risks and unclear effects on outcomes. METHODS: All pancreaticoduodenectomies (PDs) performed from January 2013 through December 2017 were included. Clinical parameters were obtained from a retrospective review of a prospective clinical database, the American College of Surgeons NSQIP prospective institutional database, and medical record review. Chi-square, Fisher's exact test, and independent-samples t-tests were used for univariable analyses. Multivariable regression was performed. RESULTS: Six hundred and seventy-one consecutive PDs 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 longer than 48 hours (2.1% vs 7.9%), septic shock (2.6% vs 5.8%), and lower pain scores. On multivariable regression (accounting for baseline group differences (ie sex, hypertension, preoperative transfusion, laboratory results, approach, and pancreatic duct size), EDA was associated with less superficial wound infections (odds ratio [OR] 0.34; 95% CI 0.14 to 0.83; p = 0.017), unplanned intubations (OR 0.36; 95% CI 0.14 to 0.88; p = 0.024), mechanical ventilation longer than 48 hours (OR 0.22; 95% CI 0.08 to 0.62; p = 0.004), and septic shock (OR 0.39; 95% CI 0.15 to 1.00; p = 0.050). Epidural analgesia improved pain scores post-PD days 1 to 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. CONCLUSIONS: 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 improved infectious and pulmonary complications significantly.

The Dilemma of the Dilated Main Pancreatic Duct in the Distal Pancreatic Remnant After Proximal Pancreatectomy for IPMN.

OBJECTIVE(S): A dilated main pancreatic duct in the distal remnant after proximal pancreatectomy for intraductal papillary mucinous neoplasms (IPMN) poses a diagnostic dilemma. We sought to determine parameters predictive of remnant main-duct IPMN and malignancy during surveillance. METHODS: Three hundred seventeen patients underwent proximal pancreatectomy for IPMN (Indiana University, 1991-2016). Main-duct dilation included those ≥ 5 mm or "dilated" on radiographic reports. Statistics compared groups using Student's T/Mann-Whitney U tests for continuous variables or chi-square/Fisher's exact test for categorical variables with P < 0.05 considered significant. RESULTS: High-grade/invasive IPMN or adenocarcinoma at proximal pancreatectomy predicted malignant outcomes (100.0% malignant outcomes; P < 0.001) in remnant surveillance. Low/moderate-grade lesions revealed benign outcomes at last surveillance regardless of duct diameter. Twenty of 21 patients undergoing distal remnant reoperation had a dilated main duct. Seven had main-duct IPMN on remnant pathology; these patients had greater mean maximum main-duct diameter prior to reoperation (9.5 vs 6.2 mm, P = 0.072), but this did not reach statistical significance. Several features showed high sensitivity/specificity for remnant main-duct IPMN. CONCLUSIONS: Remnant main-duct dilation after proximal pancreatectomy for IPMN remains a diagnostic dilemma. Several parameters show a promise in accurately diagnosing main-duct IPMN in the remnant.

A multimodality test to guide the management of patients with a pancreatic cyst.

Pancreatic cysts are common and often pose a management dilemma, because some cysts are precancerous, whereas others have little risk of developing into invasive cancers. We used supervised machine learning techniques to develop a comprehensive test, CompCyst, to guide the management of patients with pancreatic cysts. The test is based on selected clinical features, imaging characteristics, and cyst fluid genetic and biochemical markers. Using data from 436 patients with pancreatic cysts, we trained CompCyst to classify patients as those who required surgery, those who should be routinely monitored, and those who did not require further surveillance. We then tested CompCyst in an independent cohort of 426 patients, with histopathology used as the gold standard. We found that clinical management informed by the CompCyst test was more accurate than the management dictated by conventional clinical and imaging criteria alone. Application of the CompCyst test would have spared surgery in more than half of the patients who underwent unnecessary resection of their cysts. CompCyst therefore has the potential to reduce the patient morbidity and economic costs associated with current standard-of-care pancreatic cyst management practices.

DNA profile components predict malignant outcomes in select cases of intraductal papillary mucinous neoplasm with negative cytology.

BACKGROUND: Predicting malignancy in intraductal papillary mucinous neoplasm remains challenging. Integrated molecular pathology combines pancreatic fluid DNA and clinical factors into a malignant potential score. We sought to determine the utility of DNA components alone in predicting high-grade dysplasia/invasive disease. METHODS: We reviewed prospectively the records from 1,106 patients with intraductal papillary mucinous neoplasm. We excluded non-intraductal papillary mucinous neoplasm cases and cases with definitive malignant cytology. A total 225 patients had 283 DNA profiles (98 followed by surgery, 185 followed by ≥23-month surveillance). High-grade dysplasia/invasive outcomes were high-grade dysplasia, intraductal papillary mucinous neoplasm-invasive, and adenocarcinoma on surgical pathology or mesenteric or vascular invasion, metastases, or biopsy with high-grade dysplasia or adenocarcinoma during surveillance. RESULTS: High-quantity DNA predicted (P = .004) high-grade dysplasia/invasive disease outcomes with sensitivity of 78.3%, but 52.7% specificity, indicating benign cases may exhibit high-quantity DNA. High clonality loss of heterozygosity of tumor suppressor genes was 98.0% specific, strongly predicted high-grade dysplasia/invasive disease but lacked sensitivity (20.0%). High-quantity DNA + high clonality loss of heterozygosity had 99.0% specificity for high-grade dysplasia/invasive disease. KRAS mutation alone did not predict high-grade dysplasia/invasive disease, but, when combined with high-quantity DNA (specificity 84.7%) and high clonality loss of heterozygosity (specificity 99.0%) strongly predicted high-grade dysplasia/invasive outcomes. CONCLUSION: Certain DNA components are highly specific for high-grade dysplasia/invasive disease and may indicate aggressive lesions, requiring resection when cytology fails.

Pancreatic cyst fluid glucose: rapid, inexpensive, and accurate diagnosis of mucinous pancreatic cysts.

BACKGROUND: The most widely accepted biochemical test for preoperative differentiation of mucinous from benign, nonmucinous pancreatic cysts is cyst fluid carcinoembryonic antigen. However, the diagnostic accuracy of carcinoembryonic antigen ranges from 70% to 86%. Based on previous work, we hypothesize that pancreatic cyst fluid glucose may be an attractive alternative to carcinoembryonic antigen. METHODS: Pancreatic cyst fluid was collected during endoscopic or operative intervention. Diagnoses were pathologically confirmed. Glucose and carcinoembryonic antigen were measured using a patient glucometer and automated analyzer/enzyme-linked immunosorbent assay. Sensitivity, specificity, accuracy, and receiver operator characteristic analyses were performed. RESULTS: Cyst fluid samples from 153 patients were evaluated (mucinous: 25 mucinous cystic neoplasms, 77 intraductal papillary mucinous neoplasms, 4 ductal adenocarcinomas; nonmucinous: 21 serous cystic neoplasms, 9 cystic neuroendocrine tumors, 14 pseudocysts, 3 solid pseudopapillary neoplasms). Median cyst fluid glucose was lower in mucinous versus nonmucinous cysts (19 vs 96 mg/dL; P < .0001). With a threshold of ≤ 50 mg/dL, cyst fluid glucose was 92% sensitive, 87% specific, and 90% accurate in diagnosing mucinous pancreatic cysts. In comparison, cyst fluid carcinoembryonic antigen with a threshold of >192 ng/mL was 58% sensitive, 96% specific, and 69% accurate. Area under the curve for glucose and CEA were similar at 0.91 and 0.92. CONCLUSION: Cyst fluid glucose has significant advantages over carcinoembryonic antigen and should be considered for use as a routine diagnostic test for pancreatic mucinous cysts.

The role of calmodulin recruitment in Ca2+ stimulation of adenylyl cyclase type 8.

Ca2+ stimulation of adenylyl cyclase type 8 (AC8) is mediated by calmodulin (CaM). An earlier study identified two CaM binding sites in AC8; one that was apparently not essential for AC8 activity, located at the N terminus, and a second site that was critical for Ca2+ stimulation, found at the C terminus (Gu, C., and Cooper, D. M. F. (1999) J. Biol. Chem. 274, 8012-8021). This study explores the role of these two CaM binding domains and their interaction in regulating AC8 activity, employing binding and functional studies with mutant CaM and modified AC8 species. We report that the N-terminal CaM binding domain of AC8 has a role in recruiting CaM and that this recruitment is essential to permit stimulation by Ca2+ in vivo. Using Ca2+-insensitive mutants of CaM, we found that partially liganded CaM can bind to AC8, but only fully liganded Ca2+/CaM can stimulate AC8 activity. Moreover, partially liganded CaM inhibited AC8 activity in vivo. The results indicate that CaM pre-associates with the N terminus of AC8, and we suggest that this recruited CaM is used by the C terminus of AC8 to mediate Ca2+ stimulation.