Giuseppe Malleo

Early Versus Late Drain Removal After Standard Pancreatic Resections Results of a Prospective Randomized Trial

Summary of Background Data:The role of surgically placed intra-abdominal drainages after pancreatic resections has not been clearly established. In particular, their effect on morbidity rates and the optimal timing for their removal remains controversial. Methods:A total of 114 eligible patients who underwent standard pancreatic resections and at low risk of postoperative pancreatic fistula according to our institutional protocol (amylase value in drains ≤5000 U/L on postoperative day [POD] 1) were randomized on POD 3 to receive either early (POD 3) or standard drain removal (POD 5 or beyond). The primary end point of the study was the incidence of pancreatic fistula. Secondary endpoints included abdominal complications, pulmonary complications, in-hospital stay, and perioperative mortality. Cost-analysis between the 2 groups was also made. Results:Early drain removal was associated with a decreased rate of pancreatic fistula (P = 0.0001), abdominal complications (P = 0.002), and pulmonary complications (P = 0.007). Median in-hospital stay was shorter (P = 0.018), and hospital costs decreased (P = 0.02). Mortality was nil. A significant association with pancreatic fistula was found for timing of drain removal (P < 0.001), unintentional weight decrease before surgery (P = 0.022), type of pancreas texture (P = 0.015), serum amylase levels on POD 1 (P = 0.001), and albumin levels on POD 1 (P = 0.039). Multivariate analysis showed that timing of drain removal (P = 0.0003) and unintentional weight decrease before surgery (P = 0.02) were independent risk factors of pancreatic fistula. Conclusions:In patients at low risk of pancreatic fistula, intra-abdominal drains can be safely removed on POD 3 after standard pancreatic resections. A prolonged period of drain insertion is associated with a higher rate of postoperative complications with increased hospital stay and costs. The manuscript is a randomized trial, registered in the NLM database as NCT00931554.

Targeted next‐generation sequencing of cancer genes dissects the molecular profiles of intraductal papillary neoplasms of the pancreas

Intraductal neoplasms are important precursors to invasive pancreatic cancer and provide an opportunity to detect and treat pancreatic neoplasia before an invasive carcinoma develops. The diagnostic evaluation of these lesions is challenging, as diagnostic imaging and cytological sampling do not provide accurate information on lesion classification, the grade of dysplasia or the presence of invasion. Moreover, the molecular driver gene mutations of these precursor lesions have yet to be fully characterized. Fifty‐two intraductal papillary neoplasms, including 48 intraductal papillary mucinous neoplasms (IPMNs) and four intraductal tubulopapillary neoplasms (ITPNs), were subjected to the mutation assessment in 51 cancer‐associated genes, using ion torrent semiconductor‐based next‐generation sequencing. P16 and Smad4 immunohistochemistry was performed on 34 IPMNs and 17 IPMN‐associated carcinomas. At least one somatic mutation was observed in 46/48 (96%) IPMNs; 29 (60%) had multiple gene alterations. GNAS and/or KRAS mutations were found in 44/48 (92%) of IPMNs. GNAS was mutated in 38/48 (79%) IPMNs, KRAS in 24/48 (50%) and these mutations coexisted in 18/48 (37.5%) of IPMNs. RNF43 was the third most commonly mutated gene and was always associated with GNAS and/or KRAS mutations, as were virtually all the low‐frequency mutations found in other genes. Mutations in TP53 and BRAF genes (10% and 6%) were only observed in high‐grade IPMNs. P16 was lost in 7/34 IPMNs and 9/17 IPMN‐associated carcinomas; Smad4 was lost in 1/34 IPMNs and 5/17 IPMN‐associated carcinomas. In contrast to IPMNs, only one of four ITPNs had detectable driver gene (GNAS and NRAS) mutations. Deep sequencing DNA from seven cyst fluid aspirates identified 10 of the 13 mutations detected in their associated IPMN. Using next‐generation sequencing to detect cyst fluid mutations has the potential to improve the diagnostic and prognostic stratification of pancreatic cystic neoplasms.

A Combination of Molecular Markers and Clinical Features Improve the Classification of Pancreatic Cysts

BACKGROUND & AIMS The management of pancreatic cysts poses challenges to both patients and their physicians. We investigated whether a combination of molecular markers and clinical information could improve the classification of pancreatic cysts and management of patients. METHODS We performed a multi-center, retrospective study of 130 patients with resected pancreatic cystic neoplasms (12 serous cystadenomas, 10 solid pseudopapillary neoplasms, 12 mucinous cystic neoplasms, and 96 intraductal papillary mucinous neoplasms). Cyst fluid was analyzed to identify subtle mutations in genes known to be mutated in pancreatic cysts (BRAF, CDKN2A, CTNNB1, GNAS, KRAS, NRAS, PIK3CA, RNF43, SMAD4, TP53, and VHL); to identify loss of heterozygozity at CDKN2A, RNF43, SMAD4, TP53, and VHL tumor suppressor loci; and to identify aneuploidy. The analyses were performed using specialized technologies for implementing and interpreting massively parallel sequencing data acquisition. An algorithm was used to select markers that could classify cyst type and grade. The accuracy of the molecular markers was compared with that of clinical markers and a combination of molecular and clinical markers. RESULTS We identified molecular markers and clinical features that classified cyst type with 90%-100% sensitivity and 92%-98% specificity. The molecular marker panel correctly identified 67 of the 74 patients who did not require surgery and could, therefore, reduce the number of unnecessary operations by 91%. CONCLUSIONS We identified a panel of molecular markers and clinical features that show promise for the accurate classification of cystic neoplasms of the pancreas and identification of cysts that require surgery.

Role of tumor necrosis factor-alpha in acute pancreatitis: from biological basis to clinical evidence.

Tumor necrosis factor (TNF)-&agr; is a pleiotropic cytokine that exerts host-damaging effects in different autoimmune and inflammatory diseases. It is a key regulator of other proinflammatory cytokines and of leukocyte adhesion molecules, and it is a priming activator of immune cells. In recent years, several research lines-mostly derived from animal models and in vitro studies-suggested that TNF-&agr; plays a pivotal role in the pathogenesis of acute pancreatitis. In particular, it contributes to the systemic progression of the inflammatory response and to the end-organ dysfunction often observed in severe disease. Current clinical applications of TNF-&agr; in acute pancreatitis include the assessment of blood concentrations to predict disease severity and to identify individuals prone to develop complications such as multiple organ failure and septic shock. However, TNF-&agr; is rapidly cleared from the bloodstream, and sensitivity and overall accuracy of its measurement seem strictly time dependent, thereby being of potential prognostic value only in the first days after the onset of the disease. In parallel, TNF-&agr; has been evaluated as a novel pharmacologic target for treating pancreatitis. Although promising results have been observed in the laboratory, transition to clinical practice seems problematic, in particular, in the light of divergent results obtained in sepsis trials. Therefore, in future clinical trials pertaining to TNF-&agr; neutralization in acute pancreatitis, timing of intervention should be related to changes in TNF-&agr; serum levels, and inclusion and exclusion criteria should be accurately selected to better define the population most likely to benefit.

Serous cystic neoplasm of the pancreas: a multinational study of 2622 patients under the auspices of the International Association of Pancreatology and European Pancreatic Club (European Study Group on Cystic Tumors of the Pancreas)

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 SCNs 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.

Pancreatic resections for cystic neoplasms: From the surgeon's presumption to the pathologist's reality

BACKGROUND Current guidelines for the management of pancreatic cystic neoplasms are based on the assumption that these lesions can be classified correctly on the basis of features of cross-sectional imaging. However, a certain degree of overlap between different lesions exists, and little is known about the rate of inaccurate preoperative diagnoses. To address this issue, preoperative and final pathologic diagnoses of patients resected for a presumed pancreatic cystic neoplasm were compared. METHODS Retrospective analysis was undertaken of patients managed operatively between 2000 and 2010. Preoperative workup was reviewed to identify diagnostic pitfalls and potential risk factors for incorrect preoperative characterization of cystic lesions presumed to be neoplastic. RESULTS We analyzed 476 patients. Final pathologic diagnosis matched the preoperative diagnosis in 78% of cases. The highest accuracy was reached for solid pseudopapillary neoplasms (95%) and for main duct/mixed duct intraductal papillary mucinous neoplasms (81%). Surprisingly, 23 cysts (5%) were found to be ductal adenocarcinoma, whereas 45 patients (9%) underwent a pancreatic resection for a non-neoplastic condition. The use of a routine radiologic workup, including contrast-enhanced ultrasonography and magnetic resonance imaging, was associated with a favorably correct characterization of the cystic lesion. Endoscopic ultrasonography did not seem to improve diagnostic accuracy. Increased levels of serum carbohydrate antigen (CA)19-9 resulted as risk factors for an incorrect diagnosis as well as for a final diagnosis of a ductal adenocarcinoma. CONCLUSION The overall rate of inaccurate preoperative diagnoses in a tertiary care center with a broad experience in pancreatology approached 22%. Serum CA19-9 is an important complementary tool within the context of preoperative investigation of cystic neoplasms of the pancreas.

Low progression of intraductal papillary mucinous neoplasms with worrisome features and high-risk stigmata undergoing non-operative management: a mid-term follow-up analysis

Objective To evaluate mid-term outcomes and predictors of survival in non-operated patients with pancreatic intraductal papillary mucinous neoplasms (IPMNs) with worrisome features or high-risk stigmata as defined by International Consensus Guidelines for IPMN. Reasons for non-surgical options were physicians’ recommendation, patient personal choice or comorbidities precluding surgery. Methods In this retrospective, multicentre analysis, IPMNs were classified as branch duct (BD) and main duct (MD), the latter including mixed IPMNs. Univariate and multivariate analysis for overall survival (OS) and disease-specific survival (DSS) were obtained. Results Of 281 patients identified, 159 (57%) had BD-IPMNs and 122 (43%) had MD-IPMNs; 50 (18%) had high-risk stigmata and 231 (82%) had worrisome features. Median follow-up was 51 months. The 5-year OS and DSS for the entire cohort were 81% and 89.9%. An invasive pancreatic malignancy developed in 34 patients (12%); 31 had invasive IPMNs (11%) and 3 had IPMN-distinct pancreatic ductal adenocarcinoma (1%). Independent predictors of poor DSS in the entire cohort were age >70 years, atypical/malignant cyst fluid cytology, jaundice and MD >15 mm. Compared with MD-IPMNs, BD-IPMNs had significantly better 5-year OS (86% vs 74.1%, p=0.002) and DSS (97% vs 81.2%, p<0.0001). Patients with worrisome features had better 5-year DSS compared with those with high-risk stigmata (96.2% vs 60.2%, p<0.0001). Conclusions In elderly patients with IPMNs that have worrisome features, the 5-year DSS is 96%, suggesting that conservative management is appropriate. By contrast, presence of high-risk stigmata is associated with a 40% risk of IPMN-related death, reinforcing that surgical resection should be offered to fit patients.

Delayed gastric emptying after pylorus-preserving pancreaticoduodenectomy: validation of International Study Group of Pancreatic Surgery classification and analysis of risk factors

OBJECTIVES This study evaluates the incidence and clinical features and associated risk factors of delayed gastric emptying (DGE) after pancreaticoduodenectomy, employing the International Study Group of Pancreatic Surgery (ISGPS) consensus definition. METHODS Demographic, pathological and surgical details for 260 consecutive patients who underwent pylorus-preserving pancreaticoduodenectomy at a single institution were analysed using univariate and multivariate models. RESULTS Postoperative complications occurred in 108 (41.5%) and DGE was diagnosed in 36 (13.8%) of 260 patients. Among the 36 DGE patients, 16 had grade A, 18 grade B and two grade C DGE. Resumption of a solid diet (P < 0.001), time to passage of stool (P= 0.002) and hospital discharge (P < 0.001) occurred later in DGE patients. The need for total parenteral nutrition was significantly higher in DGE grade B/C patients (P < 0.001). In the univariate analysis, abdominal collections (P≤ 0.001), pancreatic fistula (PF) grades B and C (P < 0.001), biliary fistula (P= 0.002), pulmonary complications (P < 0.001) and sepsis (P= 0.002) were associated with DGE. Only abdominal collections (P= 0.009), PF grade B/C (P < 0.001) and sepsis (P= 0.024) were associated with clinically relevant DGE. In the multivariate analysis, PF grade B/C (P= 0.004) and biliary fistula (P= 0.039) were independent risk factors for DGE. CONCLUSIONS The ISGPS classification and grading systems correlate well with the clinical course of DGE and are feasible for patient management. The principal risk factors for DGE seem to be pancreatic and biliary fistulas.

Perioperative and long-term results of laparoscopic spleen-preserving distal pancreatectomy with or without splenic vessels conservation: a retrospective analysis.

Laparoscopic spleen‐preserving distal pancreatectomy can be performed with or without splenic vessels conservation. The formation of perigastric varices is the main long‐term complication and represents the area of major concern among surgeons. Aim of this paper was to evaluate the outcomes of patients who underwent spleen‐preserving distal pancreatectomy (with or without splenic vessels conservation) at our institution.

TNF-α as a Therapeutic Target in Acute Pancreatitis — Lessons from Experimental Models

A considerable body of experimental evidence suggests that tumor necrosis factor (TNF)-α plays a major role in several aspects of inflammation and shock. In particular, it is pivotal in many detrimental effects of acute pancreatitis, and it represents a major determinant of the systemic progression and end-organ damage (such as acute lung injury and liver failure) of this pathologic condition. Given the importance of TNF-α in the pathogenesis of acute pancreatitis, investigators have regarded blocking the action of this mediator as an attractive treatment option. Different specific and nonspecific inhibitors have been developed with promising results in animal models, but, on the other hand, no clinical trials have been designed so far. Difficulties in clinical applications may be multifactorial; experimental models are not fully reliable and reproduce at least some aspects of human disease, timing of intervention should be related to changes in TNF-α serum levels, and inclusion criteria should be accurately selected to better define the population most likely to benefit.