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1.
Br J Surg ; 108(6): 709-716, 2021 06 22.
Article in English | MEDLINE | ID: mdl-34157083

ABSTRACT

BACKGROUND: An increasing body of evidence suggests that microbiota may promote progression of pancreatic ductal adenocarcinoma (PDAC). It was hypothesized that gammaproteobacteria (such as Klebsiella pneumoniae) influence survival in PDAC, and that quinolone treatment may attenuate this effect. METHODS: This was a retrospective study of patients from the Massachusetts General Hospital (USA) and Ludwig-Maximilians-University (Germany) who underwent preoperative treatment and pancreatoduodenectomy for locally advanced or borderline resectable PDAC between January 2007 and December 2017, and for whom a bile culture was available. Associations between tumour characteristics, survival data, antibiotic use and results of intraoperative bile cultures were investigated. Survival was analysed using Kaplan-Meier curves and Cox regression analysis. RESULTS: Analysis of a total of 211 patients revealed that an increasing number of pathogen species found in intraoperative bile cultures was associated with a decrease in progression-free survival (PFS) (-1·9 (95 per cent c.i. -3·3 to -0·5) months per species; P = 0·009). Adjuvant treatment with gemcitabine improved PFS in patients who were negative for K. pneumoniae (26·2 versus 15·3 months; P = 0·039), but not in those who tested positive (19·5 versus 13·2 months; P = 0·137). Quinolone treatment was associated with improved median overall survival (OS) independent of K. pneumoniae status (48·8 versus 26·2 months; P = 0·006) and among those who tested positive for K. pneumoniae (median not reached versus 18·8 months; P = 0·028). Patients with quinolone-resistant K. pneumoniae had shorter PFS than those with quinolone-sensitive K. pneumoniae (9·1 versus 18·8 months; P = 0·001). CONCLUSION: K. pneumoniae may promote chemoresistance to adjuvant gemcitabine, and quinolone treatment is associated with improved survival.


Subject(s)
Anti-Bacterial Agents/therapeutic use , Bile/microbiology , Klebsiella Infections/complications , Klebsiella pneumoniae , Pancreatic Neoplasms/microbiology , Quinolones/therapeutic use , Aged , Female , Humans , Kaplan-Meier Estimate , Klebsiella Infections/drug therapy , Male , Pancreatic Neoplasms/mortality , Pancreatic Neoplasms/surgery , Pancreaticoduodenectomy , Prognosis , Retrospective Studies , Survival Analysis
2.
Am J Surg ; 221(1): 134-140, 2021 01.
Article in English | MEDLINE | ID: mdl-32847686

ABSTRACT

OBJECTIVES: Preoperative biliary stenting is required for patients with obstructive jaundice from pancreatic adenocarcinoma who are receiving neoadjuvant chemotherapy. While in most patients this approach results in durable biliary drainage, some patients develop cholangitis during neoadjuvant treatment. Further, several studies have shown that preoperative cholangitis in patients with hepatobiliary malignancies can result in substantially unfavorable outcomes. The aim of this study was to evaluate the impact of preoperative cholangitis in patients who underwent pancreaticoduodenectomy after completing neoadjuvant chemotherapy. METHODS: Participants: all adult patients (n = 449) diagnosed with pancreatic adenocarcinoma from January 1st, 2013 to March 31st, 2018 who pursued treatment at the Massachusetts General Hospital were screened. Of these 449 patients, 97 met final inclusion criteria of receiving neoadjuvant chemotherapy with intent to pursue curative surgery. Data were collected via retrospective chart review including baseline characteristics, survival, episodes of preoperative cholangitis, and surgical complications. RESULTS: In patients completing successful pancreaticoduodenectomy surgery, preoperative cholangitis is associated with increased mortality (HR 2.67, 95% CI:1.16-6.13). This finding is independent of postoperative outcomes or tumor recurrence rate. The presence of cholangitis did not impact completion of neoadjuvant chemotherapy (92% vs 85%, p = 0.5) or ability to proceed to surgery (76% vs 75%, p = 1.0). Preoperative cholangitis was not associated with postoperative morbidity (42.1% vs 45.1%, p = 1.0). CONCLUSIONS: One episode of cholangitis during neoadjuvant chemotherapy is associated with increased mortality following successful pancreaticoduodenectomy, independent of immediate postoperative outcomes or tumor recurrence. Preoperative cholangitis does not affect ability to pursue neoadjuvant chemotherapy or complete successful surgery. Patients who develop cholangitis during the neoadjuvant chemotherapy treatment phase may reflect a distinct phenotype of patients with PDAC with a complex and more challenging clinical course.


Subject(s)
Adenocarcinoma/complications , Adenocarcinoma/mortality , Cholangitis/complications , Pancreatic Neoplasms/complications , Pancreatic Neoplasms/mortality , Pancreaticoduodenectomy , Adenocarcinoma/surgery , Aged , Female , Humans , Male , Middle Aged , Pancreatic Neoplasms/surgery , Retrospective Studies , Risk Factors
3.
Pancreatology ; 20(6): 1213-1217, 2020 Sep.
Article in English | MEDLINE | ID: mdl-32819844

ABSTRACT

BACKGROUND: Pancreatic cysts <15 mm without worrisome features have practically no risk of malignancy at the time of diagnosis but this can change over time. Optimal duration of follow-up is a matter of debate. We evaluated predictors of malignancy and attempted to identify a time to safely discontinue surveillance. METHODS: Bi-centric study utilizing prospectively collected databases of patients with pancreatic cysts measuring <15 mm and without worrisome features who underwent surveillance at the Massachusetts General Hospital (1988-2017) and at the University of Verona Hospital Trust (2000-2016). The risk of malignant transformation was assessed using the Kaplan-Meier method and parametric survival models, and predictors of malignancy were evaluated using Cox regression. RESULTS: 806 patients were identified. Median follow-up was 58 months (6-347). Over time, 58 (7.2%) cysts were resected and of those, 11 had high grade dysplasia (HGD) or invasive cancer. Three additional patients had unresectable cancer for a total rate of malignancy of 1.7%. Predictors of development of malignancy included an increase in size ≥2.5 mm/year (HR = 29.54, 95% CI: 9.39-92.91, P < 0.001) and the development of worrisome features (HR = 9.17, 95% CI: 2.99-28.10, P = 0.001). Comparison of parametric survival models suggested that the risk of malignancy decreased after three years of surveillance and was lower than 0.2% after five years. CONCLUSIONS: Pancreatic cysts <15  mm at the time of diagnosis have a very low risk of malignant transformation. Our findings indicate the risk decreases over time. Size increase of ≥2.5 mm/year is the strongest predictor of malignancy.


Subject(s)
Cell Transformation, Neoplastic/pathology , Pancreatic Cyst/complications , Pancreatic Neoplasms/etiology , Adolescent , Adult , Aged , Aged, 80 and over , Databases, Factual , Disease Progression , Female , Follow-Up Studies , Humans , Kaplan-Meier Estimate , Male , Middle Aged , Pancreatic Cyst/pathology , Pancreatic Neoplasms/pathology , Predictive Value of Tests , Retrospective Studies , Risk Factors , Survival Analysis , Young Adult
4.
Pancreatology ; 20(4): 729-735, 2020 Jun.
Article in English | MEDLINE | ID: mdl-32332003

ABSTRACT

BACKGROUND: Current guidelines for IPMN include an elevated serum carbohydrate antigen (CA) 19-9 among the worrisome features. However, the correlation of CA 19-9 with histological malignant features and survival is unclear. Serum CEA is also currently used for preoperative management of IPMN, although its measurement is not evidence-based. Accordingly, we aimed to assess the role of these tumor markers as predictors of malignancy in IPMN. METHODS: IPMN resected between 1998 and 2018 at Massachusetts General Hospital were analyzed. Clinical, pathological and survival data were collected and compared to preoperative levels of CA 19-9 and CEA. Receiver operating characteristic (ROC) and Cox regression analyses were performed considering cut-offs of 37 U/ml (CA 19-9) and 5 µg/l (CEA). RESULTS: Analysis of 594 patients showed that preoperative CA 19-9 levels > 37 U/ml (n = 128) were associated with an increased likelihood of invasive carcinoma when compared to normal levels (45.3% vs. 18.0%, P < 0.001), while there was no difference with respect to high-grade dysplasia (32.9% vs 31.9%, P = 0.88). The proportion of concurrent pancreatic cancer was higher in patients with CA 19-9 > 37 U/ml (17.2% vs 4.9%, P < 0.001). An elevated CA 19-9 was also associated with worse overall and disease-free survival (HR = 1.943, P = 0.007 and HR = 2.484, P < 0.001 respectively). CEA levels did not correlate with malignancy. CONCLUSION: In patients with IPMN, serum CA19-9 > 37 U/ml is associated with invasive IPMN and concurrent pancreatic cancer as well as worse survival, but not with high-grade dysplasia. Serum CEA appears to have minimal utility in the management of these patients.


Subject(s)
CA-19-9 Antigen/blood , Pancreatic Intraductal Neoplasms/blood , Pancreatic Intraductal Neoplasms/pathology , Adenocarcinoma, Mucinous , Adult , Aged , Aged, 80 and over , Biomarkers, Tumor/blood , Female , Humans , Male , Middle Aged , Pancreatic Intraductal Neoplasms/therapy , Pancreatic Neoplasms/blood , Pancreatic Neoplasms/pathology , Pancreatic Neoplasms/therapy , Sensitivity and Specificity , Pancreatic Neoplasms
5.
Pancreatology ; 20(2): 149-157, 2020 Mar.
Article in English | MEDLINE | ID: mdl-31870802

ABSTRACT

BACKGROUND/OBJECTIVES: Chronic pancreatitis (CP) is a complex inflammatory disease with pain as the predominant symptom. Pain relief can be achieved using invasive interventions such as endoscopy and surgery. This paper is part of the international consensus guidelines on CP and presents the consensus guideline for surgery and timing of intervention in CP. METHODS: An international working group with 15 experts on CP surgery from the major pancreas societies (IAP, APA, JPS, and EPC) evaluated 20 statements generated from evidence on 5 questions deemed to be the most clinically relevant in CP. The Grading of Recommendations Assessment, Development, and Evaluation (GRADE) approach was used to evaluate the level of evidence available for each statement. To determine the level of agreement, the working group voted on the 20 statements for strength of agreement, using a nine-point Likert scale in order to calculate Cronbach's alpha reliability coefficient. RESULTS: Strong consensus was obtained for the following statements: Surgery in CP is indicated as treatment of intractable pain and local complications of adjacent organs, and in case of suspicion of malignant (cystic) lesion; Early surgery is favored over surgery in a more advanced stage of disease to achieve optimal long-term pain relief; In patients with an enlarged pancreatic head, a combined drainage and resection procedure, such as the Frey, Beger, and Berne procedure, may be the treatment of choice; Pancreaticoduodenectomy is the most suitable surgical option for patients with groove pancreatitis; The risk of pancreatic carcinoma in patients with CP is too low (2% in 10 year) to recommend active screening or prophylactic surgery; Patients with hereditary CP have such a high risk of pancreatic cancer that prophylactic resection can be considered (lifetime risk of 40-55%). Weak agreement for procedure choice in patients with dilated duct and normal size pancreatic head: both the extended lateral pancreaticojejunostomy and Frey procedure seems to provide equivalent pain control in patients. CONCLUSIONS: This international expert consensus guideline provides evidenced-based statements concerning key aspects in surgery and timing of intervention in CP. It is meant to guide clinical practitioners and surgeons in the treatment of patients with CP.


Subject(s)
Pancreatitis, Chronic/surgery , Pancreatitis, Chronic/therapy , Consensus , Humans , Pain, Intractable/etiology , Pain, Intractable/therapy , Pancreatectomy , Pancreatic Cyst/complications , Pancreatic Cyst/surgery , Pancreaticoduodenectomy , Pancreaticojejunostomy , Pancreatitis, Chronic/complications , Risk Factors , Time-to-Treatment
6.
World J Surg ; 43(3): 929-936, 2019 Mar.
Article in English | MEDLINE | ID: mdl-30377724

ABSTRACT

BACKGROUND: While intraoperative fluid overload is associated with higher complication rates following surgery, data for pancreaticoduodenectomy are scarce and heterogeneous. We evaluated multiple prior definitions of restrictive and liberal fluid regimens and analyzed whether these affected surgical outcomes at our tertiary referral center. METHODS: Studies evaluating different intraoperative fluid regimens on outcomes after pancreatic resections were retrieved. After application of all prior definitions of restrictive and liberal fluid regimens to our patient cohort, relative risks of each outcome were calculated using all reported infusion regimens. RESULTS: Five hundred and seven pancreaticoduodenectomies were included. Nine different fluid regimens were evaluated. Two regimens utilized absolute volume cutoffs, and the remaining evaluated various infusion rates, ranging from 5 to 15 mL/kg/h. Total volume administration of >5000 mL and >6000 mL was associated with increased complications (RR 1.25 and RR 1.17, respectively) and >6000 mL with increased sepsis (RR 2.14). Conversely, a rate of <5 mL/kg/h was associated with increased risk of postoperative pancreatic fistula (POPF, RR 3.16) and sepsis (RR 3.20), <6.8 mL/kg/h with increased major morbidity (RR 1.64) and sepsis (RR 2.27), and <8.2 mL/kg/h with increased POPF (RR 2.16). No effects were observed on pulmonary complications, surgical site infections, length of stay, or mortality. CONCLUSIONS: In an uncontrolled setting with no standard intraoperative or postoperative care map, the volume of intraoperative fluid administration appears to have limited impact on early postoperative outcomes following pancreaticoduodenectomy, with adverse outcomes only seen at extreme values.


Subject(s)
Fluid Therapy , Intraoperative Care , Pancreaticoduodenectomy/statistics & numerical data , Postoperative Complications/etiology , Aged , Cohort Studies , Female , Fluid Therapy/adverse effects , Fluid Therapy/methods , Hospital Mortality , Humans , Intraoperative Care/adverse effects , Intraoperative Care/methods , Male , Middle Aged , Pancreatic Fistula/etiology , Pancreaticoduodenectomy/mortality , Sepsis/etiology , Tertiary Care Centers/statistics & numerical data
7.
Eur J Surg Oncol ; 42(2): 197-204, 2016 Feb.
Article in English | MEDLINE | ID: mdl-26687069

ABSTRACT

BACKGROUND: Intraductal papillary mucinous neoplasms (IPMN) have been reported to be associated with concurrent, distinct pancreatic ductal adenocarcinoma (con-PDAC) in about 8% (range, 4-10%) of resected branch duct (BD) lesions. In addition, other pancreatic and ampullary tumors are occasionally diagnosed with IPMN in patients undergoing pancreatic surgery. The objective of this study is to describe the prevalence, clinicopathologic characteristics and prognosis of IPMN with concurrent pancreatic and ampullary neoplasms, especially con-PDAC. METHODS: The combined databases of pancreatic resections from the Massachusetts General Hospital and the Negrar Hospital, Italy, were analyzed for patients who had been diagnosed with IPMN and concurrent pancreatic or ampullary neoplasms. RESULTS: 2762 patients underwent pancreatic surgery from January 2000 to December 2012. Sixteen percent (n = 441) had pathologically confirmed IPMN and 11% of these (n = 50) had a different distinct synchronous pancreatic neoplasm. The majority of these, 62%, were con-PDAC, followed by neuroendocrine neoplasms (10%) and ampullary carcinoma (10%). Less frequently, mucinous (6%) as well as serous cystic neoplasms (6%), adenosquamous carcinoma (4%) and distal bile duct cancer (2%) were diagnosed. Among all patients with synchronous neoplasms, 66% harbored BD-IPMN, 28% combined IPMN and 6% main duct IPMN. Abdominal pain and/or jaundice were the leading symptoms in half of patients. CONCLUSION: IPMN, mainly BD-IPMN, are associated with con-PDAC in about 7% of patients and account for 62% of all concurrent pancreatic/ampullary neoplasms. Other synchronous neoplasms may be found sporadically with IPMN without a suspected association.


Subject(s)
Adenocarcinoma, Mucinous/pathology , Ampulla of Vater , Carcinoma, Adenosquamous/pathology , Carcinoma, Pancreatic Ductal/pathology , Common Bile Duct Neoplasms/pathology , Neoplasms, Multiple Primary/pathology , Neuroendocrine Tumors/pathology , Pancreatic Neoplasms/pathology , Abdominal Pain/etiology , Adenocarcinoma, Mucinous/epidemiology , Adenocarcinoma, Mucinous/surgery , Aged , Aged, 80 and over , Carcinoma, Adenosquamous/epidemiology , Carcinoma, Adenosquamous/surgery , Carcinoma, Pancreatic Ductal/epidemiology , Carcinoma, Pancreatic Ductal/surgery , Chemotherapy, Adjuvant , Common Bile Duct Neoplasms/epidemiology , Common Bile Duct Neoplasms/surgery , Female , Humans , Incidental Findings , Jaundice/etiology , Male , Middle Aged , Neoplasms, Multiple Primary/epidemiology , Neoplasms, Multiple Primary/surgery , Neuroendocrine Tumors/epidemiology , Neuroendocrine Tumors/surgery , Pancreatic Neoplasms/epidemiology , Pancreatic Neoplasms/surgery , Prevalence , Prognosis , Survival Rate
8.
Gut ; 65(2): 305-12, 2016 Feb.
Article in English | MEDLINE | ID: mdl-26045140

ABSTRACT

OBJECTIVES: Serous cystic neoplasm (SCN) is a cystic neoplasm of the pancreas whose natural history is poorly known. The purpose of the study was to attempt to describe the natural history of SCN, including the specific mortality. DESIGN: Retrospective multinational study including SCN diagnosed between 1990 and 2014. RESULTS: 2622 patients were included. Seventy-four per cent were women, and median age at diagnosis was 58 years (16-99). Patients presented with non-specific abdominal pain (27%), pancreaticobiliary symptoms (9%), diabetes mellitus (5%), other symptoms (4%) and/or were asymptomatic (61%). Fifty-two per cent of patients were operated on during the first year after diagnosis (median size: 40 mm (2-200)), 9% had resection beyond 1 year of follow-up (3 years (1-20), size at diagnosis: 25 mm (4-140)) and 39% had no surgery (3.6 years (1-23), 25.5 mm (1-200)). Surgical indications were (not exclusive) uncertain diagnosis (60%), symptoms (23%), size increase (12%), large size (6%) and adjacent organ compression (5%). In patients followed beyond 1 year (n=1271), size increased in 37% (growth rate: 4 mm/year), was stable in 57% and decreased in 6%. Three serous cystadenocarcinomas were recorded. Postoperative mortality was 0.6% (n=10), and SCN's related mortality was 0.1% (n=1). CONCLUSIONS: After a 3-year follow-up, clinical relevant symptoms occurred in a very small proportion of patients and size slowly increased in less than half. Surgical treatment should be proposed only for diagnosis remaining uncertain after complete workup, significant and related symptoms or exceptionally when exists concern with malignancy. This study supports an initial conservative management in the majority of patients with SCN. TRIAL REGISTRATION NUMBER: IRB 00006477.


Subject(s)
Cystadenoma, Serous , Pancreatic Neoplasms , Adolescent , Adult , Aged , Aged, 80 and over , Cystadenoma, Serous/diagnosis , Cystadenoma, Serous/mortality , Cystadenoma, Serous/pathology , Cystadenoma, Serous/therapy , Europe , Female , Humans , Internationality , Male , Middle Aged , Pancreatic Neoplasms/diagnosis , Pancreatic Neoplasms/mortality , Pancreatic Neoplasms/pathology , Pancreatic Neoplasms/therapy , Retrospective Studies , Societies, Medical , Young Adult
9.
Pancreatology ; 13(1): 43-7, 2013.
Article in English | MEDLINE | ID: mdl-23395569

ABSTRACT

UNLABELLED: The frequency and significance of calcification in intraductal papillary mucinous neoplasms (IPMN) are unknown. We examined calcifications by computed tomography (CT) in a large cohort of IPMNs and correlated them with clinicopathologic characteristics. METHODS: Preoperative contrast-enhanced CT imaging studies of 164 patients with surgically resected IPMN were retrospectively reviewed. Morphologic characteristics of IPMN, presence and type of calcifications, their location, the degree of dysplasia and the epithelial subtype were recorded. Symptoms at the time of diagnosis, history of smoking, and alcohol consumption were obtained from medical records. RESULTS: Of the 164 IPMNs, 68 were branch duct type (Br-IPMN) and 96 main duct (MD-IPMN) or combined type (CT-IPMN); 78 (48%) had a malignant component (CIS and Invasive). Calcifications were present in 33 cases (20%). By type, 16 calcifications were punctate, 11 coarse and 9 eggshell, and by location, 15 were mural, 3 septal, 2 ductal, 1 in the solid component, and 13 in multiple locations. Calcifications were seen more frequently in larger lesions (44 mm vs 32 mm p = 0.002), and when MPD dilation was noted (70% vs 45%, p = 0.023). There was no association between presence of calcification and malignancy, epithelial subtype, or other clinical data. However, malignancy was present in 9/11 IPMN with coarse calcification (p = 0.04), suggesting this may be a worrisome feature. CONCLUSION: Calcification is found in 20% of IPMNs, and is more common in larger lesions. Although its overall presence has no correlation with malignancy, coarse calcification, when combined with other morphologic features, may be a radiologic sign of malignancy.


Subject(s)
Carcinoma, Pancreatic Ductal/pathology , Neoplasms, Glandular and Epithelial/pathology , Pancreatic Neoplasms/pathology , Adenocarcinoma, Mucinous/diagnostic imaging , Adenocarcinoma, Mucinous/pathology , Aged , Calcinosis/diagnostic imaging , Carcinoma, Pancreatic Ductal/diagnostic imaging , Carcinoma, Papillary/diagnostic imaging , Carcinoma, Papillary/pathology , Female , Humans , Male , Middle Aged , Neoplasms, Glandular and Epithelial/diagnostic imaging , Pancreatic Neoplasms/diagnostic imaging , Retrospective Studies , Tomography, X-Ray Computed
10.
Aliment Pharmacol Ther ; 31(2): 285-94, 2010 Jan 15.
Article in English | MEDLINE | ID: mdl-19845568

ABSTRACT

BACKGROUND: Despite advances in cross-sectional imaging and the use of molecular markers, distinguishing between benign and malignant cysts remains a clinical challenge. AIMS: To identify both preoperative clinical and cyst characteristics at the time of EUS that predict malignancy. METHODS: A retrospective analysis was performed on consecutive patients with pancreatic cysts who underwent endoscopic ultrasound (EUS) and surgical resection from May 1996 to December 2007 at a tertiary centre. Clinical history, EUS characteristics, cytology, tumour markers and surgical histology were collected. Predictors of malignancy were determined by univariate and multivariate analysis using logistic regression. RESULTS: A total of 153 patients underwent a EUS and subsequent surgical intervention.Of the 153 patients, 57 (37%) had a histological diagnosis of malignancy. On univariate analysis, older age (P < 0.001), male gender (P = 0.010), jaundice (P = 0.039), history of other malignancy (P = 0.036), associated mass in cyst (P = 0.004) and malignant cytology (P < 0.001) were found to be associated with malignancy. History of pancreatitis (P = 0.008) and endoscopist impression of pseudocyst (P = 0.001) were found to be associated with benign cysts. Multivariate analysis found that only older age [Odds ratio (OR), 1.04; 95% confidence interval (CI), 1.01-1.08], male gender (OR, 2.26; 95% CI, 1.08-4.73) and malignant cytology (OR, 6.60; 95% CI, 2.02-21.58) were independent predictors of malignancy. CONCLUSIONS: Older age, male gender and malignant cytology from EUS predict malignancy at surgical resection. These characteristics may be used to estimate the probability of malignancy in a cyst and aid in management.


Subject(s)
Pancreatic Cyst/pathology , Pancreatic Neoplasms/pathology , Preoperative Care/methods , Adult , Aged , Aged, 80 and over , Confidence Intervals , Endosonography , Female , Humans , Male , Middle Aged , Neoplasm Staging/methods , Odds Ratio , Pancreatic Cyst/surgery , Pancreatic Neoplasms/surgery , Predictive Value of Tests , Retrospective Studies , Risk Assessment/methods , Young Adult
11.
Pancreatology ; 5(1): 37-43; discussion 43, 2005.
Article in English | MEDLINE | ID: mdl-15775698

ABSTRACT

BACKGROUND: Release of TNFalpha is thought to play an important role in mediating systemic effects in acute pancreatitis (AP). We have been unable to find an elevation of plasma TNFalpha in AP and hypothesize that it is susceptible to catabolism by circulating pancreatic proteases. METHODS: (1) AP was induced in Sprague-Dawley rats by cerulein hyperstimulation preceded by intraductal infusion of saline (mild) or glycodeoxycholic acid (severe). Healthy and sham-operated animals served as controls. Severity of pancreatitis was confirmed by histology. Plasma TNFalpha levels were measured at various time points after induction of AP with competitive ELISA. (2) Recombinant rat TNFalpha (rrTNFalpha) was incubated with trypsin, elastase, chymotrypsin and pepsin. Western Blot was performed to visualize TNF degradation. (3) RrTNFalpha was incubated in a concentration and time-dependant manner with proteases and TNF bioactivity was evaluated with a cytotoxicity assay. RESULTS: (1) Plasma TNFalpha levels in severe pancreatitis were significantly lower than in sham-operated controls after 0.5 and 6 h. (2) Incubation with proteases showed degradation in the presence of trypsin, elastase and chymotrypsin and no effect of pepsin. (3) There was a concentration dependent inactivation of rrTNFalpha in the presence of pancreatic proteases and a complete time-dependent inactivation in the presence of trypsin. CONCLUSION: Plasma TNFalpha does not rise in experimental AP, and levels are significantly lower in severe pancreatitis compared to sham-operated controls. Our study demonstrates degradation and inactivation of TNFalpha by pancreatic proteases, suggesting that it is unlikely it plays an important role in the development of distant organ failure.


Subject(s)
Pancreatitis/blood , Pancreatitis/enzymology , Peptide Hydrolases/metabolism , Tumor Necrosis Factor-alpha/metabolism , Acute Disease , Animals , Male , Pancreas/enzymology , Rats , Rats, Sprague-Dawley
12.
Abdom Imaging ; 28(3): 357-65, 2003.
Article in English | MEDLINE | ID: mdl-12719906

ABSTRACT

Intraductal papillary mucinous tumor (IPMT) is an uncommon pancreatic neoplasm with characteristic histology and distinctive clinicobiologic behavior. It is characterized by proliferation of ductal epithelium associated with ductal dilatation and variable mucin production. Due to indolent nature of these tumors, IPMTs are frequently missed or misdiagnosed. Prompt recognition and differentiation from other tumors are essential because IPMT has a better prognosis than other pancreatic malignancies. The purpose of this article is to display the radiologic spectrum of IPMT.


Subject(s)
Carcinoma, Pancreatic Ductal/diagnosis , Cystadenoma, Mucinous/diagnosis , Pancreatic Neoplasms/diagnosis , Aged , Carcinoma, Pancreatic Ductal/diagnostic imaging , Cholangiopancreatography, Endoscopic Retrograde , Cystadenoma, Mucinous/diagnostic imaging , Female , Humans , Magnetic Resonance Imaging , Male , Middle Aged , Pancreatic Neoplasms/diagnostic imaging , Tomography, X-Ray Computed , Ultrasonography
13.
Radiology ; 221(1): 93-106, 2001 Oct.
Article in English | MEDLINE | ID: mdl-11568326

ABSTRACT

PURPOSE: To evaluate the cost-effectiveness of imaging strategies for the assessment of resectability in patients with pancreatic cancer. MATERIALS AND METHODS: A decision model was developed to calculate costs and benefits (survival) accruing to hypothetical cohorts of patients with known or suspected pancreatic cancer. Results are presented as cost per life-year gained under various scenarios and assumptions of diagnostic test characteristics, surgical mortality, disease characteristics, and costs. RESULTS: With best estimates for all data inputs, the strategy of computed tomography (CT) followed by laparoscopy and laparoscopic ultrasonography (US) had an incremental cost-effectiveness ratio of $87,502 per life-year gained, compared with best supportive care. This strategy was significantly more cost-effective than CT followed by magnetic resonance (MR) imaging and was significantly less expensive than other imaging strategies while providing a statistically and clinically insignificant difference in life-year gains. A strategy involving no imaging (immediate surgery) was more expensive but less effective than all imaging strategies. A hypothetical perfect test with cost equal to that of CT followed by MR had an incremental cost-effectiveness ratio of $64,401 per life-year gained, compared to best supportive care. CONCLUSION: Most available imaging tests for assessing resectability of pancreatic cancer do not differ in effectiveness, but a strategy of CT, laparoscopy, and laparoscopic US would consistently result in significantly lower costs than other imaging tests under a wide range of scenarios.


Subject(s)
Decision Support Techniques , Pancreatic Neoplasms/diagnosis , Pancreatic Neoplasms/economics , Cost-Benefit Analysis , Humans , Pancreatic Neoplasms/diagnostic imaging , Pancreatic Neoplasms/mortality , Pancreatic Neoplasms/surgery , Sensitivity and Specificity , Survival Rate , Tomography, X-Ray Computed/economics , Ultrasonography
14.
Ann Surg ; 234(3): 344-50; discussion 350-1, 2001 Sep.
Article in English | MEDLINE | ID: mdl-11524587

ABSTRACT

OBJECTIVE: To determine the presence of telomerase activity in a variety of periampullary malignancies and pancreatic diseases and quantify its activity to establish any association with the stage or aggressiveness of malignancy. SUMMARY BACKGROUND DATA: Progressive shortening of telomeres, repetitive DNA sequences at the ends of chromosomes, plays a role in cell senescence. Telomerase catalyzes conservation of telomeric repeats and may promote cell immortality and hence malignancy. It is absent in normal tissues but upregulated in more than 80% of cancers. METHODS: Fresh specimens of 62 periampullary tumors were snap-frozen in liquid nitrogen and adjacent tissue was formalin-fixed for histopathology. The telomerase repeat amplification protocol (TRAP) was used to obtain telomerase DNA products. These were separated with gel electrophoresis, stained with SYBR green, and quantified by densitometry. Findings were confirmed with a fluorometric TRAP assay in which fluorescent primers specific for telomerase were selectively amplified in its presence. RESULTS: Telomerase activity was upregulated in 26 of 33 periampullary malignancies (79%): 17 of 21 pancreatic adenocarcinomas (81%), 2 of 2 cholangiocarcinomas, 2 of 2 duodenal carcinomas, and 5 of 8 ampullary carcinomas (63%). Poorly differentiated periampullary tumors had significantly higher telomerase activity than well-differentiated tumors, and tumors larger than 2 cm had significantly higher telomerase activity than those 2 cm or smaller. Pancreatic ductal adenocarcinomas with lymph node metastases had significantly greater activity than node-negative cancers. Two of 11 intraductal papillary mucinous tumors were positive for telomerase activity, but only in foci of invasive carcinoma. Chronic pancreatitis (n = 7), serous cystadenomas (n = 5), benign mucinous cystic neoplasms (n = 4), neuroendocrine cancer (n = 1), and acinar cell carcinoma (n = 1) had no detectable telomerase activity. CONCLUSION: Telomerase activity is common in periampullary carcinomas. The magnitude of activity correlates with aggressiveness in pancreatic adenocarcinoma and may prove useful as a molecular index for biologic staging.


Subject(s)
Pancreatic Neoplasms/pathology , Telomerase/analysis , Adenocarcinoma/enzymology , Adenocarcinoma, Mucinous/enzymology , Ampulla of Vater , Biomarkers, Tumor/analysis , Carcinoma, Papillary/enzymology , Cholangiocarcinoma/enzymology , Duodenal Neoplasms/enzymology , Fluorometry , Humans , Lymphatic Metastasis , Pancreatic Neoplasms/enzymology , Pancreatitis/enzymology , Polymerase Chain Reaction , Sensitivity and Specificity
15.
Surgery ; 130(2): 175-81, 2001 Aug.
Article in English | MEDLINE | ID: mdl-11490346

ABSTRACT

BACKGROUND: We evaluated the effect of the novel protease inhibitor nafamostat on rat necrotizing pancreatitis through different routes of administration. METHODS: Three hours after the induction of severe pancreatitis, the rats received intravenous gabexate or intravenous or local mesenteric intra-arterial nafamostat. At 9 hours, ascites and bronchoalveolar lavage fluid were collected for the evaluation of capillary leakage (Evans blue extravasation). Pancreas and lung were excised for histologic features, myeloperoxidase, and trypsinogen activation peptide. Twenty-four hour survival was evaluated. RESULTS: Only the intravenous infusion of nafamostat significantly reduced myeloperoxidase (11.7 +/- 2.3 vs 18.3 +/- 1.8 mU/mg; P <.05) and capillary leakage in lungs (Evans blue dye, 1.6 +/- 0.3 vs 2.6 +/- 0.3; P <.05). Only intra-arterial infusion of nafamostat significantly diminished capillary peritoneal leakage (Evans blue dye, 3.6 +/- 0.9 vs 9.4 +/- 0.4; P <.01). Typsinogen activation peptide levels were significantly reduced in all groups, but only intra-arterial infusion did so to baseline. Histologic inflammation in the pancreas was most significantly reduced after intra-arterial infusion (0.92 +/- 0.08 vs 2.91 +/- 0.06; P <.05). No form of protease inhibition reduced mortality rates. CONCLUSIONS: The effects of protease inhibition depend on the route of administration. Nafamostat has maximal effects on the pancreas and peritoneal capillary leakage when delivered by way of local intra-arterial infusion, and shows a greater reduction of lung leukocyte infiltration and capillary leakage by the intravenous route. Nafamostat is more effective than gabexate.


Subject(s)
Complement Inactivator Proteins/pharmacology , Guanidines/pharmacology , Pancreatitis, Acute Necrotizing/drug therapy , Protease Inhibitors/pharmacology , Animals , Benzamidines , Capillary Permeability/drug effects , Evans Blue/pharmacokinetics , Gabexate/pharmacology , Injections, Intra-Arterial , Injections, Intravenous , Lung/enzymology , Male , Oligopeptides/metabolism , Pancreas/pathology , Pancreatitis, Acute Necrotizing/mortality , Pancreatitis, Acute Necrotizing/pathology , Peritoneum/metabolism , Peroxidase/metabolism , Rats , Rats, Sprague-Dawley , Serine Proteinase Inhibitors/pharmacology , Survival Rate
16.
Surgery ; 129(6): 736-44, 2001 Jun.
Article in English | MEDLINE | ID: mdl-11391373

ABSTRACT

BACKGROUND: Alcohol abuse is a major cause of pancreatic damage. Recent experimental evidence suggests that fatty acid ethyl esters (FAEE), nonoxidative ethanol metabolites, injure pancreatic acinar cells. Linkage between oxidative and nonoxidative metabolism of ethanol in the pancreas may contribute to increased FAEE levels. METHODS: To study the association between oxidative and nonoxidative ethanol metabolism, FAEE concentration and FAEE synthase activity in rat pancreatic and liver homogenates incubated with ethanol were evaluated with and without inhibitors of oxidative ethanol metabolism. For toxicity studies, trypsinogen activation peptide synthesis as a measure of pancreatic cell injury was quantitated in unstimulated and cerulein-stimulated isolated pancreatic acinar cells incubated with ethanol or FAEE. RESULTS: Inhibition of oxidative ethanol metabolism results in a 2- to 3-fold increase in nonoxidative ethanol metabolism to FAEE in pancreas and in liver. Both ethanol and FAEE induce increased intracellular trypsinogen activation by more than 50% in the presence of physiologic concentrations of cerulein in vitro. CONCLUSIONS: These findings demonstrate that the inhibition of oxidative ethanol metabolism results in an increase in flux through the nonoxidative pathway and support the proposition that alcohol-induced pancreatic injury is mediated at least in part by FAEE, which are important products of pancreatic ethanol metabolism.


Subject(s)
Ethanol/metabolism , Pancreas/metabolism , Acyltransferases/metabolism , Animals , Cholecystokinin/pharmacology , Ethanol/toxicity , Male , Oxidation-Reduction , Pancreas/drug effects , Rats , Rats, Sprague-Dawley
17.
Radiographics ; 21(3): 673-90, 2001.
Article in English | MEDLINE | ID: mdl-11353115

ABSTRACT

Over the past decade, performance of the Whipple procedure, or pancreatoduodenectomy, to treat both malignant and benign disease has increased. This increase is in large part due to the decreasing perioperative mortality rate, which is down from historic highs of 25% to the 1.0%--1.5% now achieved in large centers. Although advances in surgical management have improved the outlook for patients undergoing pancreatoduodenectomy, the improving mortality rate is also in part attributed to improvements over the past 2 decades in cross-sectional imaging and imaging-guided interventional procedures. Although the mortality rates have improved, the morbidity, or rate of complications, has remained relatively constant. Contributions by radiologists in both diagnosis and treatment of complications are crucial in certain patients with postpancreatoduodenectomy abdominal abscesses, bilomas, liver abscess, and biliary obstruction. Familiarity with normal variations in the postoperative appearance of the upper abdomen, awareness of pitfalls in interpretation, and knowledge of the available imaging-guided interventions will facilitate recognition of postpancreatoduodenectomy complications and allow prompt triage of patients to imaging-guided interventions.


Subject(s)
Pancreaticoduodenectomy , Postoperative Complications/diagnostic imaging , Radiography, Interventional , Tomography, X-Ray Computed , Humans , Postoperative Complications/therapy
18.
Surgery ; 129(5): 537-46, 2001 May.
Article in English | MEDLINE | ID: mdl-11331445

ABSTRACT

BACKGROUND: Patients with pancreatic cancer often have tumor recurrence despite curative resection. Cancer cells detected in blood or bone marrow at the time of diagnosis may relate to tumor stage and to prognosis. Recent research emphasis has centered on tumor cells in bone marrow aspirates, but whether these represent early micrometastases or blood-borne cells in transit is unknown. PATIENTS AND METHODS: We developed a specific immunocytochemical assay that evaluated more than 5.3 x 10(6) extracted mononuclear cells per sample of blood and bone marrow and that could identify a single tumor cell in that population. The assay was applied to samples of blood and bone marrow from 105 patients with pancreatic cancer and 66 controls. The prevalence of isolated tumor cells was compared with Union Internationale Contre le Cancer (UICC) stage. A multivariate Cox regression analysis for survival was performed. RESULTS: Pancreatic cancer cells were detected in 26% of blood samples and in 24% of bone marrow specimens. Specificity for cancer was 96%. The prevalence of isolated tumor cells in patients with proven resectable cancer was 9% in blood and 13% in bone marrow. The prevalence increased with UICC tumor stage in blood (P =.04) but not in bone marrow (P =.52) and correlated in blood with resectability (P =.02), progression of disease (P=.08), and peritoneal dissemination (P =.003). While survival correlated significantly with tumor stage (P <.001) and isolated tumor cells in blood correlated with tumor stage, the finding of cancer cells in blood or bone marrow, or both, was not independently associated with survival in patients with pancreatic cancer. CONCLUSIONS: Isolated tumor cells in blood but not bone marrow reflect the stage of growth and spread of pancreatic cancer, particularly in the peritoneal cavity. The findings are consistent with cells in bone marrow aspirates being in transit, not implanted. These disseminated cancer cells may be the consequence, rather than the cause, of progression.


Subject(s)
Bone Marrow/pathology , Carcinoma, Pancreatic Ductal/surgery , Neoplastic Cells, Circulating/pathology , Pancreatic Neoplasms/pathology , Pancreatic Neoplasms/surgery , Aged , Biomarkers, Tumor , Carcinoma, Pancreatic Ductal/mortality , Carcinoma, Pancreatic Ductal/secondary , Female , Humans , Male , Middle Aged , Pancreatic Neoplasms/mortality , Preoperative Care/methods , Prevalence , Prognosis , Proportional Hazards Models
19.
Arch Surg ; 136(4): 391-8, 2001 Apr.
Article in English | MEDLINE | ID: mdl-11296108

ABSTRACT

HYPOTHESIS: Experience with pancreatic resection for the last 10 years has resulted in new trends in patient characteristics and, for pancreaticoduodenectomy (PD), a decrease in the length of stay (LOS). This decrease is due in part to the implementation of case management and clinical pathways. DESIGN: Retrospective case series of patients undergoing pancreatic resection. SETTING: A university-affiliated, tertiary care referral center. PATIENTS: The study comprised 733 consecutive patients undergoing pancreatic resection for benign or malignant disease at the Massachusetts General Hospital in Boston from April 1990 to March 2000. INTERVENTIONS: Of the 733 pancreatic resections, 489 were PD; 190, distal pancreatectomy; 40, total pancreatectomy; and 14, middle-segment pancreatectomy. MAIN OUTCOME MEASURES: Length of stay; occurrence of delayed gastric emptying, pancreatic fistula, reoperation, readmission, or other complications; mortality; and comparison of patients in 3 periods according to the implementation of case management (July 1995) and clinical pathways (September 1998). RESULTS: For PD, patients in group 1 (April 1990 to June 1995) were significantly younger (mean +/- SD, 57 +/- 15 years) than those in group 2 (July 1995 to August 1998; mean +/- SD, 62 +/- 13 years) and group 3 (September 1998 to October 2000; mean +/- SD, 65 +/- 13 years)(P <.01). Over time, the proportion of PD for cystic tumors increased from 9.9% to 20% (P =.01), and the proportion of PD for chronic pancreatitis decreased from 23% to 10% (P <.01). Use of pylorus-preserving PD decreased from 45% to 0% (P <.001). Delayed gastric emptying decreased from 17% to 6.1% (P <.01). Pancreatic fistula, reoperation, and mortality were unchanged. Length of stay for PD decreased from 16.1 +/- 0.6 to 9.5 +/- 0.4 days (mean +/- SE) (P <.001). Multivariate analysis showed that period, case volume, pylorus-preserving PD, and presence of complications are all independent predictors of LOS (P <.05 for all). For distal pancreatectomy, patients in groups 2 and 3 were older than those in group 1 (mean +/- SD, 57 +/-14 vs 52 +/- 17 years) (P <.05). Resections for cystic tumors increased from 26% to 52% (P <.05), and resections for chronic pancreatitis decreased from 32% to 14% (P =.06). Median LOS decreased from 9 days to 6. For total pancreatectomy, resections for cystic tumors increased from 18% to 43%. Median LOS decreased from 14.5 days to 11. For all resections, case volume increased from 4 resections per month in 1990 to 5.8 in 1995 and 12 in 2000 (r = 0.83; P <.001). CONCLUSIONS: Older patients are increasingly being selected for pancreatic resection. This reflects an increasing frequency of operations performed for cystic tumors and fewer for chronic pancreatitis. With the exception of delayed gastric emptying, complications and mortality have remained the same or decreased slightly during the past 10 years. However, there has been a significant decrease in LOS; this is the result of implementation of case management and clinical pathways, increasing case volume, decreasing incidence of delayed gastric emptying, and decreasing use of pylorus-preserving PD.


Subject(s)
Adenocarcinoma/surgery , Pancreatectomy , Pancreatic Neoplasms/surgery , Pancreatitis/surgery , Aged , Chronic Disease , Gastric Emptying , Humans , Length of Stay , Middle Aged , Pancreatectomy/adverse effects , Pancreaticoduodenectomy , Retrospective Studies
20.
Ann Surg ; 233(5): 688-95, 2001 May.
Article in English | MEDLINE | ID: mdl-11323507

ABSTRACT

OBJECTIVE: To investigate whether a high-fat/high-protein diet (HFPD) acts as a promoter of the natural course of cancer growth in the 7,12-dimethylbenzanthracene (DMBA)-induced ductal pancreatic cancer model in rats. SUMMARY BACKGROUND DATA: DMBA implantation to the rat pancreas induces ductal adenocarcinoma. Information regarding the effects of diet and the presence of K-ras mutation in this model is not available. METHODS: Rats were randomly assigned to regular rat chow or a diet with a 30% content in fat and protein (HFPD). The presentation of cancer, the histologic spectrum of neoplasia at 1 and 9 months, and the prevalence of cancer in relation to diet were assessed. Histologic specimens comprising normal ducts, hyperplasia, dysplasia/carcinoma in situ, or carcinoma were designated by a pathologist and microdissected. Genomic DNA was extracted, and K-ras and H-ras gene mutations were determined by a mutant-enriched polymerase chain reaction assay and direct sequencing. RESULTS: Rats fed HFPD increased their weight significantly compared with controls. DMBA induced characteristic stages of neoplasia at the implant site but not elsewhere. Macroscopic cancers of the pancreatic head presented regularly with common bile duct and gastric outlet obstruction. The prevalence of K-ras mutations was proportional to the degree of epithelial abnormality. K-ras mutations were significantly more frequent in cancer than in normal and hyperplastic ducts. H-ras mutations were not found. At 1 month in the HFPD-fed rats, the prevalence of cancer (16%) and dysplasia (16%) was not significantly different from the prevalence of cancer (29%) and dysplasia (8%) in the chow-fed rats. At 9 months the prevalence of cancer in the HFPD-fed rats increased to 29%, whereas that in the chow-fed rats decreased to 17%. The combined prevalence of cancer and dysplasia at 9 months in the HFPD-fed rats (34%) significantly exceeded that in the chow-fed rats. CONCLUSIONS: DMBA induces characteristic stages of neoplasia in the evolution of ductal pancreatic cancer in rats. K-ras mutations occur progressively in the ladder of oncogenesis, as in human pancreatic neoplasms. The addition of a diet with a high fat and protein content acts as a promoter of carcinogenesis, possibly by interfering with repair mechanisms and natural regression of early lesions.


Subject(s)
Carcinoma, Pancreatic Ductal/etiology , Dietary Fats/adverse effects , Dietary Proteins/adverse effects , Pancreatic Neoplasms/etiology , 9,10-Dimethyl-1,2-benzanthracene , Animals , Genes, ras/genetics , Male , Mutation , Random Allocation , Rats , Rats, Sprague-Dawley
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