Nuzhat A. Ahmad

Pancreatic cyst fluid DNA analysis in evaluating pancreatic cysts: a report of the PANDA study

BACKGROUND The role of pancreatic cyst fluid DNA analysis in evaluating pancreatic cysts remains unclear. OBJECTIVE Our purpose was to evaluate the utility of a detailed DNA analysis of pancreatic cyst fluid to diagnose mucinous and malignant cysts. DESIGN Prospective, multicenter study. PATIENTS Patients with pancreatic cysts presenting for EUS evaluation. INTERVENTION EUS-guided pancreatic cyst aspirates cytology evaluation, carcinoembryonic antigen (CEA) level determination, and a detailed DNA analysis; incorporating DNA quantification, k-ras mutation and multiple allelic loss analysis, mutational amplitude, and sequence determination. MAIN OUTCOME MEASUREMENTS Cyst fluid analysis compared with surgical pathologic or malignant cytologic examination. RESULTS The study cohort consisted of 113 patients with 40 malignant, 48 premalignant, and 25 benign cysts. Cyst fluid k-ras mutation was helpful in the diagnosis of mucinous cysts (odds ratio 20.9, specificity 96%), whereas receiver-operator characteristic curve analysis indicated optimal cutoff points for allelic loss amplitude (area under the curve [AUC] 0.79; optimal value > 65%) and CEA (AUC 0.74; optimal value >148 ng/mL). Components of DNA analysis detecting malignant cysts included allelic loss amplitude over 82% (AUC 0.9) and high DNA amount (optical density ratio >10, AUC 0.79). The criteria of a high amplitude k-ras mutation followed by allelic loss showed maximum specificity (96%) for malignancy. All malignant cysts with negative cytologic evaluation (10/40) could be diagnosed as malignant by using DNA analysis. LIMITATIONS Limited follow-up, selection bias. CONCLUSIONS Elevated amounts of pancreatic cyst fluid DNA, high-amplitude mutations, and specific mutation acquisition sequences are indicators of malignancy. The presence of a k-ras mutation is also indicative of a mucinous cyst. DNA analysis should be considered when cyst cytologic examination is negative for malignancy.

Can EUS alone differentiate between malignant and benign cystic lesions of the pancreas

OBJECTIVE:The aim of this study was to evaluate the ability of endoscopic ultrasound (EUS) alone to predict and differentiate malignant from benign cystic lesions of the pancreas.METHODS:From January, 1995, to August, 1999, 98 cases of pancreatic cystic lesions were evaluated by EUS; all of these were originally imaged by cross-sectional modalities that were not diagnostic. Among these, surgical/pathological correlation was available in 48 patients. The original endosonographic images were reviewed by two endosonographers who were blinded to each others interpretation and to the surgical and pathological interpretation. The EUS images were assessed for the presence or absence of the following characteristics: 1) wall, 2) solid component, 3) septae, 4) lymphadenopathy, and 5) number of cysts. These characteristics were then correlated with the surgical and pathological findings and were assessed to determine if any were predictors of the lesion being benign or malignant.RESULTS:For reviewer A, the presence of a solid component by EUS was the only statistically significant predictor of malignancy (odds ratio = 4.73, 95% CI = 1.13–19.68, p = 0.03). However, 61% of patients with benign lesions were also interpreted by EUS to have a solid component. For reviewer B, none of the features were found to be significant predictors of a malignant lesion. When the results of both reviewers were combined, the presence of a solid component was not found to be a statistically significant predictor of malignancy (odds ratio = 1.046, 95% CI = 0.99–1.09, p = 0.07).CONCLUSION:Endosonographic features cannot reliably differentiate between benign and malignant cystic lesions of the pancreas after a nondiagnostic cross-sectional modality.

Acute pancreatitis after EUS-guided FNA of solid pancreatic masses: a pooled analysis from EUS centers in the United States

BACKGROUND The aim of this study was to determine the frequency and the severity of pancreatitis after EUS-guided FNA of solid pancreatic masses. A survey of centers that offer training in EUS in the United States was conducted. METHODS A list of centers in which training in EUS is offered was obtained from the Web site of the American Society for Gastrointestinal Endoscopy. Designated program directors were contacted via e-mail. The information requested included the number of EUS-guided FNA procedures performed for solid pancreatic masses, the number of cases of post-procedure pancreatitis, and the method for tracking complications. For each episode of pancreatitis, technical details were obtained about the procedure, including the location of the mass, the type of fine needle used, the number of needle passes, and the nature of the lesion. RESULTS Nineteen of the 27 programs contacted returned the questionnaire (70%). In total, 4909 EUS-guided FNAs of solid pancreatic masses were performed in these 19 centers over a mean of 4 years (range 11 months to 9 years). Pancreatitis occurred after 14 (0.29%): 95% CI[0.16, 0.48] procedures. At two centers in which data on complications were prospectively collected, the frequency of acute pancreatitis was 0.64%, suggesting that the frequency of pancreatitis in the retrospective cohort (0.26%) was under-reported (p=0.22). The odds that cases of pancreatitis would be reported were 2.45 greater for the prospective compared with the retrospective cohort (95% CI[0.55, 10.98]). The median duration of hospitalization for treatment of pancreatitis was 3 days (range 1-21 days). The pancreatitis was classified as mild in 10 cases, moderate in 3, and severe in one; one death (proximate cause, pulmonary embolism) occurred after the development of pancreatitis in a patient with multiple comorbid conditions. CONCLUSIONS EUS-guided FNA of solid pancreatic masses is infrequently associated with acute pancreatitis. The procedure appears to be safe when performed by experienced endosonographers. The frequency of post EUS-guided FNA pancreatitis may be underestimated by retrospective analysis.

Detection of Circulating Pancreas Epithelial Cells in Patients With Pancreatic Cystic Lesions

Hematogenous dissemination is thought to be a late event in cancer progression. We recently showed in a genetic model of pancreatic ductal adenocarcinoma that pancreas cells can be detected in the bloodstream before tumor formation. To confirm these findings in humans, we used microfluidic geometrically enhanced differential immunocapture to detect circulating pancreas epithelial cells in patient blood samples. We captured more than 3 circulating pancreas epithelial cells/mL in 7 of 21 (33%) patients with cystic lesions and no clinical diagnosis of cancer (Sendai criteria negative), 8 of 11 (73%) with pancreatic ductal adenocarcinoma, and in 0 of 19 patients without cysts or cancer (controls). These findings indicate that cancer cells are present in the circulation of patients before tumors are detected, which might be used in risk assessment.

Long term survival after pancreatic resection for pancreatic adenocarcinoma

OBJECTIVE:The aim of this study was to determine the long term survival of patients with pancreatic adenocarcinoma who underwent surgical resection and to assess the association of clinical, pathological, and treatment features with survival.METHODS:Between January, 1990, and December, 1998, 125 patients underwent a pancreaticoduodenal or partial pancreatic resection for pancreatic ductal adenocarcinoma at our institution. The records of these patients were reviewed for demographics, tumor characteristics including size, histological grade, margin status, lymph node status, surgical TNM staging, and postoperative adjuvant therapy. The primary outcome variable analyzed was survival.RESULTS:A total of 116 patients had complete follow-up and were included in the final analysis. The median survival after surgery was 16 months. The 1-, 3-, 5-, and 7-yr survival rates for all 116 patients were 60%, 23%, 19%, and 11%, respectively. The 1-, 3-, 5-, and 7-yr survival rates for patients who received adjuvant therapy were 69%, 28%, 23%, and 18% compared with 20% and 0% in patients who did not receive adjuvant therapy (p < 0.0001). The 1-, 3-, 5-, and 7-yr survival rates for patients with negative lymph nodes were 73%, 38%, 26%, and 22% compared with survival rates of 52%, 14%, 14%, and 9% in patients with positive lymph nodes (p = 0.01). In multivariate analyses, adjuvant therapy was the only feature found to be strongly associated with survival (hazards ratio = 0.26, 95% CI = 0.15–0.44).CONCLUSIONS:The overall 5- and 7-yr survival rates of 19% and 11% in our study further validate that surgical resection in patients with pancreatic adenocarcinoma can result in long term survival, particularly when performed in association with adjuvant chemoradiation.

Endoscopic management of biliary complications after adult living donor liver transplantation.

OBJECTIVES:Biliary complications and their treatment in adult cadaveric liver transplantation (CLT) are well described. However, biliary complications and their management in living donor liver transplantation (LDLT) are not well characterized. We assessed the role of endoscopic retrograde cholangiopancreatography (ERCP) in the diagnosis and management of biliary complications following LDLT.METHODS:We performed a retrospective cohort analysis of all LDLT recipients with duct-to-duct anastomoses (n = 15). Specific data included referral for ERCP, diagnosis, and therapy. Comparisons were made to a 260 CLT recipient cohort.RESULTS:Greater percentage of LDLT recipients underwent ERCP (73%) compared to CLT recipients (25%; p = 0.001). Biliary complications diagnosed by ERCP in LDLT recipients consisted of bile leaks and strictures, and were more frequent than in CLT recipients (leaks: 53% vs 12%; p = 0.001; strictures: 27% vs 5%; p = 0.01). Most leaks occurred at T-tube sites (LDLT: 87%; CLT: 65%). Diagnosis and therapy of leaks required a median of 2 ERCP procedures in both groups. Bile leaks were successfully treated endoscopically in 100% and 84% of LDLT and CLT recipients, respectively (p = 0.56). Most biliary strictures were anastomotic (LDLT: 100%; CLT: 64%). Strictures were diagnosed and treated with a median of 1.5 and 2 ERCP procedures in the LDLT and CLT groups, respectively. The duration of endoscopic therapy was a median of 10 and 14 wk, and success rates were 75% and 62% (p = 1.0) in LDLT and CLT groups, respectively.CONCLUSIONS:LDLT is associated with increased biliary complications as compared to CLT. ERCP is useful for diagnosis, can successfully treat most LDLT-related biliary complications, and should be attempted prior to more invasive interventions.

Endosonography is superior to angiography in the preoperative assessment of vascular involvement among patients with pancreatic carcinoma.

Surgical exploration in patients with pancreatic carcinoma without adequate preoperative attempts to determine resectability results in resection in only a minority of patients. Besides distant metastases, involvement of the major vessels is the most important parameter for determining resectability in patients with pancreatic adenocarcinoma. Angiography has been an integral part of pancreatic cancer staging. Lately, endoscopic ultrasound (EUS) has emerged as a more accurate tool in the diagnosis and staging of pancreatic cancer. We hypothesize that EUS is more accurate than selective venous angiography (SVA) for assessing resectability of pancreatic adenocarcinoma based on preoperative evaluation of vascular involvement. Twenty-one patients who met the inclusion criteria were prospectively evaluated with both EUS and SVA before undergoing surgical exploration for attempted curative resection. Vascular involvement was determined by EUS and SVA using previously described criteria. The sensitivity, specificity, and overall accuracy of EUS and SVA in assessing vascular involvement were compared, using surgical exploration as the gold standard. Endoscopic ultrasound had a higher sensitivity than SVA for detecting vascular involvement (86% vs. 21%, respectively;p = 0.0018). The specificity and accuracy of EUS for detecting vascular involvement was 71% and 81%, respectively. In contrast, the specificity and accuracy of SVA for detecting vascular involvement was 71% and 38%, respectively. Endoscopic ultrasound is significantly more sensitive than angiography for detecting vascu lar involvement in patients with pancreatic adenocarcinoma and, thus, may improve patient selection for attempted curative resection.

Role of endoscopic ultrasound and magnetic resonance imaging in the preoperative staging of pancreatic adenocarcinoma.

OBJECTIVE:Endoscopic ultrasound (EUS) and magnetic resonance imaging (MRI) have both been assessed individually as staging modalities for pancreatic cancer. The aim of our study was to assess whether tumor staging by both EUS and MRI in the same cohort of patients could predict resectability and unresectability in patients with pancreatic cancer.METHODS:A review of 63 patients evaluated preoperatively with both EUS and MRI for pancreatic adenocarcinoma between January 1995 and December 1998 was done. Patients were staged as resectable or unresectable by predefined criteria. Preoperative staging by both modalities was compared to surgical outcome and the sensitivity and predictive values of each modality for determining resectability and unresectability was determined.RESULTS:EUS did not allow for complete T- and N-staging in 10 patients; therefore, for EUS, the final analysis was done on 63 of 73 patients (86%). EUS correctly staged 22 of 36 patients with resectable tumors. The sensitivity of EUS for resectability was 61%, with a positive predictive value of 69%. All 73 patients had complete MRI examinations; therefore, the final analysis was done on all 73 patients. MRI correctly staged 30 of 41 patients with resectable tumors. The sensitivity of MRI for predicting resectability was 73% with a positive predictive value of 77%. MRI and EUS both predicted resectability in 18 patients, of whom 16 (89%) were found to be resectable on surgical exploration. MRI and EUS both predicted unresectability in 17 (27%) patients, of whom 4 (24%) were found to be resectable on surgical exploration. When both MRI and EUS agreed on resectability, the positive predictive value for resectability was 89%. When both MRI and EUS agreed on unresectability, the positive predictive value for unresectability was 76%.CONCLUSIONS:Neither MRI nor EUS alone were highly sensitive or predictive of resectability. However, when both tests agreed on resectability, nearly all patients were found to be resectable on surgical exploration.

The effect of lidocaine sprayed on the major duodenal papilla on the frequency of post-ERCP pancreatitis

BACKGROUND Acute pancreatitis remains a serious cause of ERCP-related morbidity. Topical application of lidocaine reportedly blunts cholecystokinin release from intestinal mucosa and reduces sphincter of Oddi spasm. A randomized trial was conducted to evaluate the effect of lidocaine sprayed on the major duodenal papilla on the frequency of post-ERCP pancreatitis. Secondary outcomes evaluated were ease of cannulation and severity of post-ERCP pancreatitis. METHODS Patients undergoing ERCP were randomized in blocks of 6 to have 10 mL of either 1% lidocaine or normal saline solution sprayed on the major papilla before cannulation. Patients were observed for the development of post-ERCP pancreatitis. Patient history- and procedure-related variables were recorded. RESULTS A total of 326 patients were enrolled, of whom 32 were excluded after randomization but before analysis. Of patients analyzed, 145 were randomized to treatment with lidocaine and 149 to placebo. No patient was lost to follow-up. There was no significant difference noted in patient history- or procedure-related variables. Seven patients in the lidocaine group and 5 in the placebo group developed post-ERCP pancreatitis (p=0.73). Ease of cannulation did not differ between the two groups. CONCLUSIONS Lidocaine sprayed on the major papilla does not decrease the frequency of post-ERCP pancreatitis.

Use of antimicrobials for EUS-guided FNA of pancreatic cysts: a retrospective, comparative analysis

BACKGROUND Pancreatic cystic lesions present a challenge for patients and physicians alike. Morphology alone is inaccurate in discriminating lesion pathology, and use of EUS-guided FNA (EUS-FNA) improves accuracy. Current American Society for Gastrointestinal Endoscopy guidelines recommend prophylactic antibiotics during FNA of cystic lesions to minimize infection risk. However, evidence pertaining to infection risk has been conflicting. The use of prophylactic antibiotics might not be free of other adverse events and might not prevent infection. OBJECTIVE To assess the impact of antimicrobial therapy for prophylaxis during EUS-FNA of pancreatic cysts. DESIGN Retrospective cohort study. PATIENTS This study involved all patients who underwent EUS-FNA of pancreatic cysts at one institution from May 2007 to April 2010. INTERVENTION Antibiotic prophylaxis for EUS-FNA. MAIN OUTCOME MEASUREMENTS Infection of a pancreatic cyst, fever, or bacteremia after EUS-FNA. Secondary variables included other complications of the procedure related to the use of prophylaxis (ie, allergic reactions, secondary infections). RESULTS EUS-FNA was performed on 253 patients in 266 procedures. Antibiotics were used in 88 endoscopy cases (ATB group), whereas no antibiotics were used in 178 cases (NATB group). There were no differences in patient or cyst characteristics between groups. There were 4 major complications in the NATB group (localized bleeding, 2; pancreatitis, 1; bile leakage, 1) and 2 in the ATB group (possible cyst infection, 1; bile leakage, 1) (P = 1.0). Eight mild adverse events were observed in the NATB group and 6 in the ATB group (P = .56). Infections and antibiotic-related complications occurred in 1 (0.6%) (transient fever) in the NATB group and 4 (4.5%) in the ATB group (local allergic reaction, 2; possible cyst infection, 1; Clostridium difficile diarrhea, 1) (P = .04). LIMITATIONS Retrospective analysis. CONCLUSION The incidence of infectious complications after EUS-FNA of pancreatic cystic lesions, with or without antibiotic prophylaxis, appears very low. We have not observed a protective effect from periprocedural prophylactic antibiotic administration.