The short- and long-term outcomes of pancreaticoduodenectomy for cancer in Child A patients are acceptable: a patient-control study from the Surgical French Association report for pancreatic surgery.

BACKGROUND: On the basis of now dated studies, cirrhosis is usually considered to be a contraindication in pancreatoduodenectomy (PD) for adenocarcinoma of the pancreatic head (APH). OBJECTIVE: Examine the outcomes of PD for APH in the presence of cirrhosis. METHODS: Retrospective, multicenter study of cirrhotic patients with APH having undergone PD between January 2004 and March 2012. Cirrhotic patients were matched 1:2 for demographic, surgical and histologic criteria with non-cirrhotic patients. Primary endpoint was morbidity and mortality. Secondary endpoints were surgical parameters, morbidity related to pancreatic surgery and cirrhosis, and follow-up. RESULTS: We included 35 patients with cirrhosis. Twenty-four patients (69%) were Child A and none were Child C. The Child A cirrhotic patients and non-cirrhotic patients respectively had complication rates of 79% vs. 43% (P = 0.002), major complication rates of 33% vs. 21% (P = 0.26), pancreatic fistula rates of 13% vs. 9% (P = 0.57), post-operative mortality of 4% vs. 5% (P = 0.94), 3-year overall survival rates of 44% vs. 50% (P = 0.46). All Child B cirrhotic patients experienced post-operative complications. CONCLUSION: Pancreatoduodenectomy for APH was possible in Child A cirrhotic patients with a mortality and long-term outcomes equivalent to non-cirrhotic patients. Child B cirrhosis remains a clear contraindication to surgery.

Value of preoperative biliary drainage in a consecutive series of resectable periampullary lesions. From randomized studies to real medical practice.

BACKGROUND: In cases with periampullary tumors, the practice of preoperative biliary drainage (PBD) is still debated without clear uniform indications. Our study focused on resectable cases with an obstructive jaundice candidate for curative surgery. Main endpoints were overall complication and mortality rates between patients treated with and without PBD. METHODS: From January 2008 to November 2010, 100 consecutive patients with periampullary lesion underwent pancreatectomy. The rates of postoperative complications and mortality were compared between PBD and non-PBD patients. RESULTS: The two groups were well matched for demographics, clinical, and operative characteristics. In patients who completed preoperative PBD protocol, biliary stent was placed systematically in 45 % of these cases without any clear indication. Post-PBD complication delayed surgery in 24 % of cases. Postoperative complications did not differ significantly between the two groups except for a significantly higher positive bile culture in PBD group (p = 0.001). There were seven cases of hospital mortality, four in PBD and three in non-PBD group. DFS was equal (32 months) in both groups (p = 0.55), and OS was 43 vs 32 months (p = 0.45). CONCLUSION: PBD did not significantly increase the risk of overall postoperative complications, although it was associated to higher rate of biliary infections. PBD was not associated with any advantages in patients with a resectable periampullary lesion by reducing operative morbidity. PBD should be considered in selected patients when surgery has to be delayed.

Complete regression of locally advanced hepatocellular carcinoma induced by sorafenib allowing curative resection.

We report two cases of locally advanced hepatocellular carcinoma (HCC) with portal vein tumour thrombosis (PVTT) who complete regression by sorafenib treatment allowed curative resection. Two male adult (59 and 57 years) cirrhotic patients with HCC associated with PVTT including one with lymph node involvement had elevated α-fetoprotein level (AFP) (867 and 17 000) and were treated with standard sorafenib treatment during 10 and 12 months respectively. Size decrease of the main tumour, disappearance of PVTT and normalization of AFP allowed curative surgical resection. No viable tumour cells were found in the specimen and the two patients are currently alive without recurrence 12 and 16 months after surgery. These first two cases of complete tumour necrosis after sorafenib treatment allow us to reconsider surgical treatment in patients with unresectable HCC responding to this medical treatment.

An onco-geriatric approach to select older patients for optimal treatments of pancreatic adenocarcinoma.

INTRODUCTION: Pancreatic adenocarcinoma affects mainly older patients. Surgery is indicated for localized tumors while chemotherapy alone is proposed in advanced or metastatic tumors. OBJECTIVE: To evaluate the feasibility of standard of care oncologic treatments in this population, the accuracy of the geriatric evaluation to predict the ability of patients to tolerate the recommended treatments and to identify specific geriatric prognosis factors. METHODS: We included, between 2007 and 2014, all consecutive patients over 70 years of age with a pathologically diagnosed pancreatic cancer. The patients underwent a comprehensive geriatric assessment before therapeutic decision in a multidisciplinary team meeting. We analyzed factors independently associated with all-cause mortality with Cox survival analysis. RESULTS: Seventy-three patients (median age = 77.9 years) were prospectively included. Among them, 42 patients underwent surgery whereas the 31 other patients not eligible for surgical treatment received chemotherapy (n = 22) or best supportive care alone (n = 9). Almost 62% of operated patients received adjuvant chemotherapy. In the non-surgical group, a mean of 9 cycles of palliative chemotherapy per patients were administrated. Median overall survival was 21.3 months in the surgical group and 6.1 months in the palliative group (p = 0.0001). Most of oncologic parameters were found to be independent survival predictors. Age was not associated with the survival, but a significant impact of Lawton's Instrumental Activities of Daily Living (IADL) impairment (IADL<4) (HR = 5.0, p = 0.047), Cumulative Index Rating Scale-Geriatric (CIRS-G) ≥2 (HR = 19, p = 0.035) and weight loss >10% (HR = 4.6, p = 0.03) on survival was detected. Surgery was the only factor independently predictive of survival in multivariate analysis (p < 0.001). CONCLUSION: Almost 90% of selected older pancreatic patients with cancer (64 out of 73 patients) may benefit from the same standard treatments as younger patients. IADL impairment of patients, CIRS-G ≥2, and weight loss >10% constitute survival prognostic factors which should be added to the oncological criteria in the therapeutic decision-making process.

Extracellular lumican inhibits pancreatic cancer cell growth and is associated with prolonged survival after surgery.

PURPOSE: To evaluate the relevance between lumican expression patterns and the clinical course of patients with pancreatic ductal adenocarcinoma (PDAC), and to investigate the role of lumican in PDAC progression. EXPERIMENTAL DESIGN: One hundred thirty-one patient tumors were chosen for tissue microarray staining, and Cox regression analysis was used to test the associations between lumican expression and clinical, pathologic, and oncologic outcomes in all patients. Primary PDAC cells and recombinant human lumican protein were used to establish a working model to mimic the in vivo interactions between stromal lumican and PDAC cells. Using this model, we tested the effects of lumican on EGFR signaling via Akt and hypoxia-inducible factor-1α (HIF1α) and its subsequent influence on glucose consumption, lactate production, intracellular ATP, and apoptotic cell death. RESULTS: Lumican was present in the stroma surrounding PDAC cells in roughly one-half of primary tumors and the direct xenografts. Patients with stromal lumican were associated with a profound reduction in metastatic recurrence after surgery and 3-fold longer survival than patients without stromal lumican. In PDAC cells, extracellular lumican reduced EGFR expression and phosphorylation through enhanced dimerization and internalization of EGFR and the resultant inhibition of Akt kinase activity. Lumican also reduced HIF1α expression and activity via Akt. PDAC cells with enhanced HIF1α activity were resistant to lumican-induced inhibition of glucose consumption, lactate production, intracellular ATP, and apoptosis. CONCLUSIONS: There is a positive association between stromal lumican in primary PDAC tumors and prolonged survival after tumor resection. Lumican plays a restrictive role in EGFR-expressing pancreatic cancer progression.

SMAD4 regulates cell motility through transcription of N-cadherin in human pancreatic ductal epithelium.

Expression of the cellular adhesion protein N-cadherin is a critical event during epithelial-mesenchymal transition (EMT). The SMAD4 protein has been identified as a mediator of transforming growth factor-ß (TGF-ß) superfamily signaling, which regulates EMT, but the mechanisms linking TGF-ß signaling to N-cadherin expression remain unclear. When the TGF-ß pathway is activated, SMAD proteins, including the common mediator SMAD4, are subsequently translocated into the nucleus, where they influence gene transcription via SMAD binding elements (SBEs). Here we describe a mechanism for control of CDH2, the gene encoding N-cadherin, through the canonical TGFß-SMAD4 pathway. We first identified four previously undescribed SBEs within the CDH2 promoter. Using telomerase immortalized human pancreatic ductal epithelium, we found that TGF-ß stimulation prompted specific SMAD4 binding to all four SBEs. Luciferase reporter and SMAD4-knockdown experiments demonstrated that specific SMAD4 binding to the SBE located at -3790 bp to -3795 bp within the promoter region of CDH2 was necessary for TGF-ß-stimulated transcription. Expression of N-cadherin on the surface of epithelial cells facilitates motility and invasion, and we demonstrated that knockdown of SMAD4 causes decreased N-cadherin expression, which results in diminished migration and invasion of human pancreatic ductal epithelial cells. Similar reduction of cell motility was produced after CDH2 knockdown. Together, these findings suggest that SMAD4 is critical for the TGF-ß-driven upregulation of N-cadherin and the resultant invasive phenotype of human pancreatic ductal epithelial cells during EMT.

Pancreatic resection: drain or no drain?

BACKGROUND: Despite reports of randomized, control trials and cohort studies that do not support the use of drains, most surgeons routinely place prophylactic, intraperitoneal drains at the time of pancreatic resections. We sought to evaluate the outcome of elective pancreatic resection with or without prophylactic peripancreatic drainage. The primary outcome was the rate of postoperative complications. Total pancreatectomy and pancreatectomy for chronic pancreatitis were excluded. METHODS: From September 2005 to February 2012, of the 375 patients who had pancreatic surgery, 242 were eligible for the study. A drain was used in 130 and no drain was used in 112 patients. The data for the 2 groups were recorded in a prospective database. The statistical analysis compared variables using Chi-square and Fisher's exact tests for categorical variables and the independent-samples t-test for continuous variables. RESULTS: The demographic, operative, and pathologic data were similar between the 2 groups. There was no increase in the frequency or severity of the overall complications in the no drain group. In the drain and no drain groups, postoperative complications occurred in 64% and 67% of patients, respectively (P = .11); post-pancreatectomy hemorrhage occurred in 19% and 23% (P = .33); and pancreatic fistula occurred in 16% and 13% (P = .34). The requirement for an interventional procedure was equivalent for both of the groups (14.6% and 20.5%; P = .15). The median hospital stay was 16 days (range, 2-98) and 18 (range, 7-131; P = .18), and the 90-day hospital mortality was 5.4% and 4.5% (P = .49) in the drain and the no drain groups, respectively. CONCLUSION: In a tertiary, high-volume, Hepatobiliary and pancreatic (HBP) surgery center, the routine prophylactic draining of the abdominal cavity after pancreatic resection did not decrease the frequency or severity of postoperative complications. Prophylactic peripancreatic drainage also did not decrease the requirement for interventional procedures. Interventional radiology and transgastric endoscopic drainage of the post-pancreatectomy collection are feasible and improve patients' outcomes. Malnutrition and the type of operation were independent factors for postoperative complications.

Neuroendocrine neoplasms of the jejunum: a heterogeneous group with distinctive proximal and distal subsets.

Neuroendocrine tumors (NETs) of the jejunum are rare and usually grouped with either duodenal or ileal NETs. We aimed at better evaluating their characteristics by studying 116 cases of small-bowel NETs for which a precise anatomical location was available. Thirty-four cases were duodenal. Eighty-two were located after the duodenojejunal ligament, including ten cases in the first 50 cm, four cases between 50 and 100 cm, and six cases between 100 and 250 cm. All tumors located after 50 cm from the duodenojejunal ligament were enterochromaffin neoplasms. In contrast, the ten tumors located before this point formed a heterogeneous group. They included two cases of gastrin-expressing tumors in the first 10 cm and one case of enterochromaffin tumor located at 45 cm. The seven remaining cases were large tumors, located between 10 and 50 cm, of intermediate or high histological grade (four out of seven G2 or G3), locally invasive and usually metastatic (five out of seven with liver metastases); their survival was comparable to that of duodenal NETs. Patients with tumors located in the duodenum or the first 50 cm of the jejunum had longer survivals than those with lower jejunal and ileal tumors (p = 0.024). In conclusion, our study underlines the heterogeneity of jejunal NETs and supports the distinction between "upper" and "lower" jejunal tumors, which, for prognostic purposes, might be grouped with, respectively, duodenal and ileal NETs. Our data suggest that the arbitrary limit between upper and lower jejunal tumors might be fixed at 50 cm from the duodenojejunal ligament.

Is the combination of chromogranin A and pancreatic polypeptide serum determinations of interest in the diagnosis and follow-up of gastro-entero-pancreatic neuroendocrine tumours?

INTRODUCTION: Chromogranin A (CgA) is the principal tumour marker for gastroenteropancreatic neuroendocrine tumours (GEPNET). Combining serum CgA and pancreatic polypeptide (PP) levels may increase the sensitivity of tumour markers in the diagnosis of GEPNET. OBJECTIVES: (1) To evaluate the sensitivity of PP and CgA in GEPNET. (2) To compare changes in serum CgA and PP levels with the morphological evolution of the tumours. PATIENTS AND METHODS: Sixty-six pancreatic and 49 gastrointestinal NET, with at least one serum determination of CgA and PP at the same time were retrieved from an institutional data base. Secondly, the variations in serum CgA or PP at successive determinations were compared to Response Evaluation Criteria in Solid Tumours (RECIST) criteria in 57 patients (112 follow-up visits) with high serum CgA levels and in 21 patients (37 follow-up visits) with high serum PP levels. RESULTS: Among the 115 patients included in the study group, an increase in serum CgA (normal <98 µg/L) or PP (normal <100 pmol/L) was found in respectively 79 (69%) and 36 (31%) cases. Seven patients had normal CgA and elevated PP levels. Both markers were significantly more elevated in metastatic disease (74% versus 51% for CgA and 37% versus 18% for PP). The concordance rates between serum markers and RECIST criteria were 51% for CgA and 54% for PP. CONCLUSIONS: Serum PP determination identify few false-negative results of serum CgA determination in GEPNET. Our study does not validate the use of CgA or PP as surrogate markers for detecting changes in tumour burden.

Effect of neoadjuvant chemoradiation and surgical technique on recurrence of localized pancreatic cancer.

OBJECTIVES: To determine the influence of neoadjuvant chemoradiation and standardized dissection of the superior mesenteric artery upon the oncologic outcome of patients with localized pancreatic adenocarcinoma. METHODS: One hundred ninety-four patients with pancreatic adenocarcinoma who underwent pancreaticoduodenectomy between 2004 and 2008 were evaluated. The retroperitoneal dissection was performed directly along the superior mesenteric artery in all cases. A standard histopathologic protocol that measured the "superior mesenteric artery (SMA) margin distance" between cancer cells and the superior mesenteric artery was employed. RESULTS: Seventy-six percent of patients received neoadjuvant chemoradiation. The SMA margin was positive in 4% of patients but an additional 22% of patients with a negative margin had a SMA margin distance of ≤1 mm. Preoperative CT images overestimated the SMA margin distance in 73% of cases. Patients who received chemoradiation had longer SMA margin distances than those who did not. Patients who received chemoradiation and had a SMA margin of >1 mm had the lowest recurrence rates. Administration of neoadjuvant chemoradiation and lower estimated blood loss were independently associated with longer progression-free survival on multivariate analysis. CONCLUSIONS: Preoperative chemoradiation and meticulous dissection of the superior mesenteric artery maximize the distance between cancer cells and the SMA margin and may influence locoregional control.