Surgical Treatment of Pancreatic Cancer: Currently Debated Topics on Vascular Resection.

Vascular resections involving the superior mesenteric and portal veins (SMV-PV), celiac axis (CA), superior mesenteric artery (SMA) and hepatic artery (HA) have multiplied in recent years, raising the resection rate for pancreatic cancer (PDAC) and the related morbidity and mortality rates. While resection is generally accepted for resectable SMV-PV, the usefulness of associated arterial resection in borderline resectable (BRPC) and locally-advanced PDAC (LAPC) is much debated. Careful selection of splenic vein reconstruction is very important to prevent left-sided portal hypertension (LSPH). During distal pancreatectomy (DP), CA and common HA resection is largely accepted, while there is debate on the value of SMA and proper HA resection and reconstruction. Their resection is useless according to several reviews and meta-analyses, and some international societies, although some high-volume centers have reported good results. Short- and long-term reconstructed vessel patency varies with the type of reconstruction, the material used, and the surgeon's experience. Laparoscopic and robotic pancreaticoduodenectomy and DP are generally accepted if done by surgeons performing at least 10 such procedures annually. The usefulness of associated vascular resection remains highly controversial. Surgeons need to complete numerous minimally-invasive procedures to overcome the learning curve, and prevent an increase in complications and surgical mortality. Higher resectability rates and satisfactory long-term results have been reported after neoadjuvant therapy (NAT) for BRPC and LAPC requiring vascular resection. It is essential to select the most appropriate NAT for a given patient and to assess PDAC resectability preoperatively.

Systematic review and meta-analysis of surgical drain management after the diagnosis of postoperative pancreatic fistula after pancreaticoduodenectomy: draining-tract-targeted works better than standard management.

PURPOSE: Drains' role after pancreaticoduodenectomy (PD) is debated by proponents of no drain, draining selected cases, and early drain removal. The aim of the study was to assess the effect of "standard" and "draining-tract-targeted" management of abdominal drains still in situ after diagnosing a postoperative pancreatic fistula (POPF). METHODS: PubMed and Scopus were searched for "pancreaticoduodenectomy or pancreatoduodenectomy or duodenopancreatectomy," "Whipple," "proximal pancreatectomy," "pylorus-preserving pancreatectomy," and "postoperative pancreatic fistula or POPF.". Main outcomes included clinically relevant (CR) POPF, grade-C POPF, overall mortality, POPF-related mortality, and CR-POPF-related mortality. Secondary outcomes were incidence of radiological and/or endoscopic interventions, reoperations, and completion pancreatectomies. RESULTS: Overall, 12,089 studies were retrieved by the search of the English literature (01/01/1990-31/12/2018). Three hundred and twenty-six studies (90,321 patients) reporting ≥ 100 PDs and ≥ 10 PD/year were finally included into the study. Average incidences were obtained by averaging the incidence rates reported in the single articles. Pooled incidences were calculated by combining the number of events and the total number of patients considered in the various studies. These were then meta-analyzed using DerSimonian and Laird's (1986) method. Pearson's chi-squared test was used to compare pooled incidences between groups. Post hoc testing was used to see which groups differed. The meta-analyzed incidences were compared using a fixed effect for moderators. "Draining-tract-targeted" management showed a significant advantage over "standard" management in four clinically relevant outcomes out of eight according to pool analysis and in one of them according to meta-analysis. CONCLUSION: Clinically, "draining-targeted" management of POPF should be preferred to "standard" management.

TERT gene harbors multiple variants associated with pancreatic cancer susceptibility.

A small number of common susceptibility loci have been identified for pancreatic cancer, one of which is marked by rs401681 in the TERT-CLPTM1L gene region on chromosome 5p15.33. Because this region is characterized by low linkage disequilibrium, we sought to identify whether additional single nucleotide polymorphisms (SNPs) could be related to pancreatic cancer risk, independently of rs401681. We performed an in-depth analysis of genetic variability of the telomerase reverse transcriptase (TERT) and the telomerase RNA component (TERC) genes, in 5,550 subjects with pancreatic cancer and 7,585 controls from the PANcreatic Disease ReseArch (PANDoRA) and the PanScan consortia. We identified a significant association between a variant in TERT and pancreatic cancer risk (rs2853677, odds ratio = 0.85; 95% confidence interval = 0.80-0.90, p = 8.3 × 10(-8)). Additional analysis adjusting rs2853677 for rs401681 indicated that the two SNPs are independently associated with pancreatic cancer risk, as suggested by the low linkage disequilibrium between them (r(2) = 0.07, D' = 0.28). Three additional SNPs in TERT reached statistical significance after correction for multiple testing: rs2736100 (p = 3.0 × 10(-5) ), rs4583925 (p = 4.0 × 10(-5) ) and rs2735948 (p = 5.0 × 10(-5) ). In conclusion, we confirmed that the TERT locus is associated with pancreatic cancer risk, possibly through several independent variants.

Inflammation and pancreatic cancer: molecular and functional interactions between S100A8, S100A9, NT-S100A8 and TGFß1.

BACKGROUND: In order to gain further insight on the crosstalk between pancreatic cancer (PDAC) and stromal cells, we investigated interactions occurring between TGFß1 and the inflammatory proteins S100A8, S100A9 and NT-S100A8, a PDAC-associated S100A8 derived peptide, in cell signaling, intracellular calcium (Cai2+) and epithelial to mesenchymal transition (EMT). NF-κB, Akt and mTOR pathways, Cai2+ and EMT were studied in well (Capan1 and BxPC3) and poorly differentiated (Panc1 and MiaPaCa2) cell lines. RESULTS: NT-S100A8, one of the low molecular weight N-terminal peptides from S100A8 to be released by PDAC-derived proteases, shared many effects on NF-κB, Akt and mTOR signaling with S100A8, but mainly with TGFß1. The chief effects of S100A8, S100A9 and NT-S100A8 were to inhibit NF-κB and stimulate mTOR; the molecules inhibited Akt in Smad4-expressing, while stimulated Akt in Smad4 negative cells. By restoring Smad4 expression in BxPC3 and silencing it in MiaPaCa2, S100A8 and NT-S100A8 were shown to inhibit NF-κB and Akt in the presence of an intact TGFß1 canonical signaling pathway. TGFß1 counteracted S100A8, S100A9 and NT-S100A8 effects in Smad4 expressing, not in Smad4 negative cells, while it synergized with NT-S100A8 in altering Cai2+ and stimulating PDAC cell growth. The effects of TGFß1 on both EMT (increased Twist and decreased N-Cadherin expression) and Cai2+ were antagonized by S100A9, which formed heterodimers with TGFß1 (MALDI-TOF/MS and co-immuno-precipitation). CONCLUSIONS: The effects of S100A8 and S100A9 on PDAC cell signaling appear to be cell-type and context dependent. NT-S100A8 mimics the effects of TGFß1 on cell signaling, and the formation of complexes between TGFß1 with S100A9 appears to be the molecular mechanism underlying the reciprocal antagonism of these molecules on cell signaling, Cai2+ and EMT.

Pancreatic secondary lesions from renal cell carcinoma.

BACKGROUND: Metastatic lesions to the pancreas are uncommon. The most frequent metastases are from renal cell carcinoma (RCC). We analyzed the clinical features and survival of patients with pancreatic metastasis from renal cell carcinoma. METHODS: We retrospectively reviewed the clinical records of patients with pancreatic metastases from RCC, observed in our department from January 2004 to March 2010. Follow-up continued to September 2013. RESULTS: In the study period 13 patients with a diagnosis of metastasis from RCC were observed in our clinic, and among them 9 pancreatic resections were performed (2 pancreaticoduodenectomy, 1 duodenum-preserving pancreatic head resection, 1 central pancreatectomy, and 5 distal pancreatectomy). Four patients did not undergo a pancreatic resection: two refused surgery, one had an endoscopic biliary stent for jaundice placed and then underwent a surgical biliary bypass, and the fourth patient was too advanced and had only an endoscopic biliary stent. The mean follow-up was 56 months (range 5-115, median 53), with one nonresected patient lost in follow-up after 38 months. Among the other 12 patients, 4 died: two for progression of disease 5 and 20 months respectively after our observation. The mean (±SEM) disease-free survival of seven resected patients with curative intent was 40 ± 11 months (median 34). CONCLUSIONS: Pancreatic metastases from RCC are often asymptomatic. They generally present slow growth and an indolent behavior. Surgery is the treatment of choice in those patients with only pancreatic involvement, achieving long-term survival and disease-free survival.

Squamoid cyst of pancreatic ducts: a challenging differential diagnosis among benign pancreatic cysts.

CONTEXT: In the last years, cystic pancreatic lesions are often detected when clinically silent, because of the wider use of diagnostic imaging techniques. First described by Othman in 2007, "squamoid cyst of pancreatic ducts" represents a cystic dilation of ducts, lined by non-keratinized squamous epithelium. We report the first case of squamoid cyst of pancreatic ducts in Italy. CASE REPORT: A 68-year-old woman presented a cystic lesion (4 cm) of the pancreatic tail as incidental finding at MRI. It had a thickened wall, no internal septa and no communication with the Wirsung duct were detected. A CT scan showed a lamellar calcification on its posterior wall. A ¹8F-FDG-PET was negative. Blood tests were normal, including CEA and CA 19-9. We performed a spleen-preserving distal pancreatectomy. Histology showed a unilocular cyst, with serous fluid and a fibrous wall, with multilayered epithelium without cytological atypias. Immunohistochemistry showed CK 7 positive and CK 5 negative. The patient is still alive and without disease after 42 months of follow-up. CONCLUSIONS: In the English literature only seven cases resected for this cyst type have been reported. No preoperative test can achieve a definitive diagnosis, so surgical resection remains the treatment of choice in order to exclude malignancy. However, after intraoperative frozen section, a limited pancreatic resection can be performed.

Currently Debated Topics on Surgical Treatment of Pancreatic Ductal Adenocarcinoma: A Narrative Review on Surgical Treatment of Borderline Resectable, Locally Advanced, and Synchronous or Metachronous Oligometastatic Tumor.

BACKGROUND: Previously considered inoperable patients (borderline resectable, locally advanced, synchronous oligometastatic or metachronous pancreatic adenocarcinoma (PDAC)) are starting to become resectable thanks to advances in chemo/radiotherapy and the reduction in operative mortality. METHODS: This narrative review presents a chosen literature selection, giving a picture of the current state of treatment of these patients. RESULTS: Neoadjuvant therapy (NAT) is generally recognized as the treatment of choice before surgery. However, despite the increased efficacy, the best pathological response is still limited to 10.9-27.9% of patients. There are still limited data on the selection of possible NAT responders and how to diagnose non-responders early. Multidetector computed tomography has high sensitivity and low specificity in evaluating resectability after NAT, limiting the resection rate of resectable patients. Ca 19-9 and Positron emission tomography are giving promising results. The prediction of early recurrence after a radical resection of synchronous or metachronous metastatic PDAC, thus identifying patients with poor prognosis and saving them from a resection of little benefit, is still ongoing, although some promising data are available. CONCLUSION: In conclusion, high-level evidence demonstrating the benefit of the surgical treatment of such patients is still lacking and should not be performed outside of high-volume centers with interdisciplinary teams of surgeons and oncologists.

Surgical treatment of pancreatic cancer: Currently debated topics on morbidity, mortality, and lymphadenectomy.

This review will examine several aspects of pancreatic surgery. Over the past twenty years, the need for a standardized postoperative complication report after resective pancreatic surgery has led to the definition both of a postoperative complication severity score, a postoperative pancreatic fistula (POPF) severity grading, a fistula risk score (FRS) and a postoperative morbidity index to establish the burden of complications. Unfortunately, three problems have hindered the success of standardization: first, the failure to define a minimum postoperative follow-up period that needs to be reported; second, the lack of a clear definition of POPF-related morbidity and mortality; third, the often-incomplete reporting of postoperative complications. The debate on the extent of lymphadenectomy to associate to pancreaticoduodenectomy started in the late 1980s when, based on retrospective studies, Japanese surgeons reported better survival after extended" than after "standard" lymphadenectomy. Subsequently, eight prospective randomized controlled trials showed that "extended" lymphadenectomy offers no advantage over "standard" lymphadenectomy. Several consensus conference and reviews tried to define the optimal extent of lymphadenectomy to be associated to pancreaticoduodenectomy and distal pancreatectomy (DP). At least nineteen lymph nodes (LN) are required for optimal tumor staging, but eleven LN are considered the minimum to prevent under staging. There is no general agreement about aborting PD in LN16-positive patients; some authors perform PD in fit patients. Based on retrospective studies, a significant increase of R0 resections, a decrease of recurrence rate, a decrease of local recurrence rate and an increase of median or overall disease-free survival were reported after mesopancreas excision.

Altered intracellular calcium fluxes in pancreatic cancer induced diabetes mellitus: Relevance of the S100A8 N-terminal peptide (NT-S100A8).

After isolating NT-S100A8 from pancreatic cancer (PC) tissue of diabetic patients, we verified whether this peptide alters PC cell growth and invasion and/or insulin release and [Ca(2+)](i) oscillations of insulin secreting cells and/or insulin signaling. BxPC3, Capan1, MiaPaCa2, Panc1 (PC cell lines) cell growth, and invasion were assessed in the absence or presence of 50, 200, and 500 nM NT-S100A8. In NT-S100A8 stimulated ß-TC6 (insulinoma cell line) culture medium, insulin and [Ca(2+)] were measured at 2, 3, 5, 10, 15, 30, and 60 min, and [Ca(2+)](i) oscillations were monitored (epifluorescence) for 3 min. Five hundred nanomolars NT-S100A8 stimulated BxPC3 cell growth only and dose dependently reduced MiaPaCa2 and Panc1 invasion. Five hundred nanomolars NT-S100A8 induced a rapid insulin release and enhanced ß-TC6 [Ca(2+)](i) oscillations after both one (F = 6.05, P < 0.01) and 2 min (F = 7.42, P < 0.01). In the presence of NT-S100A8, [Ca(2+)] in ß-TC6 culture medium significantly decreased with respect to control cells (F = 6.3, P < 0.01). NT-S100A8 did not counteract insulin induced phosphorylation of the insulin receptor, Akt and IκB-α, but it independently activated Akt and NF-κB signaling in PC cells. In conclusion, NT-S100A8 exerts a mild effect on PC cell growth, while it reduces PC cell invasion, possibly by Akt and NF-κB signaling, NT-S100A8 enhances [Ca(2+)](i) oscillations and insulin release, probably by inducing Ca(2+) influx from the extracellular space, but it does not interfere with insulin signaling.

Comparison of International Consensus Guidelines versus 18-FDG PET in detecting malignancy of intraductal papillary mucinous neoplasms of the pancreas.

OBJECTIVE: To assess the reliability of the International Consensus Guidelines (ICG) and 18-fluorodeoxyglucose positron emission tomography (PET) in distinguishing benign from malignant intraductal papillary mucinous neoplasms (IPMNs) of the pancreas. BACKGROUND: Since 2006 the ICG have been used to choose immediate surgery or surveillance for IPMN patients, but their low specificity increases the number of benign IPMNs that undergo resective surgery. PET has proved highly sensitive and specific in detecting malignancy in cystic neoplasms of the pancreas, including IPMNs. METHODS: Patients suspected with IPMNs of the pancreas seen at our Department from January 1989 to July 2010 were identified and classified as cases of main duct, mixed type and branch type IPMN. The indication for resection or surveillance was verified a posteriori for all patients according to the ICG. PET was considered positive for a Standardized Uptake Value ≥2.5. Surveillance included clinical examination, laboratory tests, CA 19-9 serum levels, and computed tomography and/or magnetic resonance and magnetic resonance cholangiopancreatography every 6 months for 2 years and yearly thereafter. Endoscopic ultrasound was rarely performed. PET was repeated in clinically or radiologically suspect cases, or if tumor markers increased. RESULTS: Sixty-one main duct or mixed type and 101-branch type IPMNs were included in the study. A histological diagnosis was available for 81 of 162 patients, missing for 1 locally advanced IPMN, whereas 62 patients are under surveillance and it proved impossible to contact 18. Conservative surgery was performed in 16 of 68 patients with benign IPMNs. The sensitivity, specificity, positive and negative predictive value, and accuracy of the ICG in detecting malignancy were 93.2, 22.2, 59.4, 72.7, and 61.2, whereas for PET they were 83.3, 100, 100, 84.6, and 91.3. CONCLUSIONS: PET is more accurate than the ICG in distinguishing benign from malignant (invasive and noninvasive) IPMNs. Prophylactic IPMN resection in young patients fit for surgery should be guided by the ICG, whereas PET should be performed in older patients, cases at increased surgical risk, or when the feasibility of parenchyma-sparing surgery demands a reliable preoperative exclusion of malignancy.

Distal pancreatectomy for body-tail pancreatic cancer: is there a role for celiac axis resection?

BACKGROUND/AIMS: Body-tail pancreatic cancer is an aggressive disease with a low resectability rate and a poor prognosis. Celiac axis invasion usually contraindicates resection. The aim of this study was to analyze the feasibility of distal pancreatectomy (DP) with celiac axis resection (DP-CAR) for locally advanced body-tail pancreatic cancer. METHODS: All DPs performed between January 1989 and December 2007 were considered. DP and DP-CAR were reviewed for pre-, intra- and postoperative data. An extensive, detailed literature review on DP and DP-CAR was also performed. RESULTS: DP was performed in 49 of our patients, and 745 cases were retrieved from the literature. The overall morbidity and mortality rates were 32.0 and 3.0%, respectively. We performed DP-CAR in 5 patients with no mortality but 80% morbidity. A further 90 patients were retrieved from the literature. Arterial reconstruction was needed in 1/5 of our patients and in 13/90 of patients in the literature. Collaterals from superior mesenteric artery maintained adequate hepatic artery blood flow in the remaining 81 patients. The overall morbidity and mortality rates were 40.6 and 2.1%, respectively. The median survival ranged between 4.5 and 25 months after DP and was 13 months after DP-CAR. CONCLUSIONS: DP-CAR improves resectability without increasing the mortality rate. The complication rate after DP-CAR was higher than after DP, but still within the range of extended DP. DP-CAR should be considered for the inclusion among the 'extended' procedures for the treatment of body-tail pancreatic cancers invading the celiac axis. and IAP.

Middle-preserving pancreatectomy: an interesting procedure for pancreas-sparing resection.

CONTEXT: Total pancreatectomy is the treatment of choice for multicentric diseases involving the head and the body-tail of the pancreas. Middle-preserving pancreatectomy is a recently reported alternative procedure when the pancreatic body is spared from disease. We report on the successful preservation of the pancreatic body in a patient harboring a multicentric intraductal papillary mucinous neoplasia (IPMN). CASE REPORT: A multicentric IPMN was diagnosed in a 59-year-old man. A standard pylorus preserving pancreaticoduodenectomy was performed, followed by a spleen-preserving distal pancreatectomy. The splenic vessels were carefully preserved. The residual 5 cm of the pancreatic body were anastomosed to the jejunum after verifying that the resection line on both sides was negative at frozen section examination. The postoperative course was complicated by transient peritoneal bleeding managed with angiographic embolization of the splenic artery. A borderline mixed type IPMN of the head and chronic pancreatitis of the tail were found at pathological examination. Eleven months after surgery, the patient is well and disease free; glycemic control is achieved by diet. CONCLUSION: A middle-preserving pancreatectomy can be performed safely for multicentric IPMNs involving the head and the body-tail of the gland. It can prevent problems with the glycemic control that usually follows total pancreatectomy.

Decreased expression and promoter methylation of the menin tumor suppressor in pancreatic ductal adenocarcinoma.

Loss of menin, a tumor suppressor coded by the MEN1 gene, is a key factor in the pathogenesis of multiple endocrine neoplasia type I and in a percentage of sporadic endocrine tumors of the pancreas and parathyroid glands. This study investigated expression of the menin protein in the normal exocrine pancreas and in pancreatic ductal adenocarcinoma (PDAC), the most common pancreatic tumor. Immunofluorescence (IF) analyses showed that menin is expressed at high levels in normal acinar and duct cells. Examination of 24 clinical samples of PDAC revealed a pronounced decrease in menin expression in all tumors examined. To identify alterations underlying this defect, we searched for disruption and epigenetic silencing of the MEN1 gene. Analysis of nine laser-microdissected tumors revealed loss of heterozygosity of intragenic (one tumor) or adjacent (three tumors) MEN1 microsatellite markers. Methylation of CpG sites in the MEN1 promoter was documented in five of 24 tumors. IF analyses also revealed low to undetectable menin expression in the PDAC cell lines MiaPaCa-2 and Panc-1. Ectopic expression of menin in these cells resulted in a marked alteration of the cell cycle, with an increase in the G1/S+G2 ratio. These findings represent the first evidence that the MEN1 gene is a target of mutation and methylation in PDAC and that menin influences the cell cycle profile of duct cells.

Postoperative pancreatic fistulas: preventing severe complications and reducing reoperation and mortality rate.

BACKGROUND: Postoperative pancreatic fistula (POPF) is responsible for severe complications and death in patients who underwent pancreatic surgery. The reported success rate of conservative treatment is around 80%. Therefore up to 20% of patients usually need surgical treatment that can be repeated in some. Uncontrolled sepsis and massive hemorrhage are the main causes for mortality in this setting. METHOD: Four hundred forty-five patients underwent surgery for pancreatic diseases (January 1993-August 2007); 70 of them developed a POPF. An early aggressive treatment based on interventional radiology was applied to all patients. The drain's track and/or percutaneous approach was used to insert catheters into the peripancreatic fluid collection/s or abscess/es. The position of catheters was verified at least once a week. Surgery was performed in case of failure of conservative approach. RESULTS: Conservative treatment (approach by drain's track in 49, percutaneous in 16, mixed in 2) was successful in 67 patients. A patient under dialysis had the drains inserted during an emergency surgery for peritonitis 6 days after surgery; a second patient underwent repeated surgical debridement, and a third patient underwent a procedure on the abdominal wall to separate a POPF from a colonic fistula. No patient with diagnosed POPF died. CONCLUSIONS: Early aggressive interventional radiology allowed managing conservatively 95.7% of POPF preventing severe complications and avoiding death.

Metastasis to the pancreas from colorectal cancer: is there a place for pancreatic resection?

PURPOSE: Pancreatic metastases from colorectal cancer are very rare, and the possible benefit of surgical treatment is not clearly defined. This study was designed to evaluate the outcome of patients undergoing pancreatic resection for metastatic colorectal cancer to the pancreas. METHODS: Nine patients underwent pancreatic resection for metastatic colorectal cancer between January 1980 and December 2006. The primary cancers were colon (n = 7) and rectal carcinoma (n = 2). The median interval between primary treatment and detection of pancreatic metastases was 32.5 months. In three cases pancreatic metastases were synchronous with the primary tumor. RESULTS: Five patients underwent pancreaticoduodenectomy, and four underwent distal pancreatectomy. A left lateral liver section and three colon resections were simultaneously performed in four patients. There was no postoperative mortality, and only two patients experienced complications. Survival averaged 19.8 (median, 17.0; range, 5-30) months: seven patients died of metastatic disease, one for unrelated disease after five months, and one is alive with liver metastases 30 months after surgery. CONCLUSION: Surgical resection can be performed safely in patients with isolated pancreatic metastases from colorectal cancer and in selected patients with associated extrapancreatic disease. Although long-term survival is rare, surgery should be included, whenever possible, in the multimodality approach to this disease.

Aggressive behaviour of solid-pseudopapillary tumor of the pancreas in adults: a case report and review of the literature.

Solid-pseudopapillary tumor (SPT) is a rare neoplasm of the pancreas that usually occurs in young females. It is generally considered a low-grade malignant tumor that can remain asymptomatic for several years. The occurrence of infiltrating varieties of SPT is around 10%-15%. Between 1986 and 2006, 282 cystic tumors of the pancreas were observed. Among them a SPT was diagnosed in 8 patients (2.8%) with only one infiltrating variety. This was diagnosed in a 49-year-old female 13 years after the sonographic evidence of a small pancreatic cystic lesion interpreted as a pseudocyst. The tumor invaded a long segment of the portal-mesenteric vein confluence, and was removed with a total pancreatectomy, resection of the portal vein and reconstruction with the internal jugular vein. Histological examination confirmed the R-0 resection of the primary SPT, although a vascular invasion was demonstrated. The postoperative course was uneventful, but 32 mo after surgery the patient experienced diffuse liver metastases. Chemotherapy with different drugs was started. The patient is alive and symptom-free, with stable disease, 75 mo after surgery. Twenty-five patients with invasion of the portal vein and/or of mesenteric vessels were retrieved from the literature, 16 recent patients with tumor relapse after potentially curative resection were also retrieved. The best treatment remains a radical resection whenever possible, even in locally advanced or metastatic disease. The role of chemotherapy, and/or radiotherapy, is still to be defined.