Olivier Turrini

Effect of Hospital Volume, Surgeon Experience, and Surgeon Volume on Patient Outcomes After Pancreaticoduodenectomy: A Single-Institution Experience

OBJECTIVE To determine the importance of hospital volume, surgeon experience, and surgeon volume in performing pancreaticoduodenectomy (PD). DESIGN, SETTING, AND PATIENTS From 1980 through 2007, 1003 patients underwent PD by 19 surgeons at a university hospital. MAIN OUTCOME MEASURES Patient morbidity and mortality, quality of resection, and learning curve were examined according to hospital volume (period 1: 1980-2003 vs period 2: 2004-2007), surgeon experience (total number of PDs), and surgeon volume (number of PDs per year). RESULTS Perioperative morbidity and mortality for all 1003 PDs were 41% and 3%, respectively. Differences existed between period 1 and period 2 in percentage of PDs performed in elderly patients (7% vs 17%), mortality (4% vs 2%), estimated blood loss (1817 mL vs 780 mL), length of stay (18 days vs 12 days), and proportion of International Study Group on Pancreatic Fistula grade C pancreatic fistulae (29% vs 12%). Surgeons with less experience (<50 PDs) performed PD with higher morbidity (53% vs 39%), pancreatic fistula rate (20% vs 10%), estimated blood loss (1918 mL vs 1101 mL), and operative time (458 minutes vs 335 minutes) compared with surgeons with more experience (> or =50 PDs). Experienced surgeons had comparable outcomes irrespective of annual volume. Mortality, margins, and number of lymph nodes resected were not affected by surgeon experience or surgeon volume. Learning curves projected that less experienced surgeons would achieve morbidity and mortality rates equivalent to those of experienced surgeons when they reached 20 and 60 PDs, respectively. CONCLUSIONS Improvement in PD outcomes, including mortality, occurred with increased PD volume at a pancreatic center. Surgeon experience remained an important determinant of overall morbidity. Experienced surgeons, however, had comparable outcomes irrespective of annual volume.

Strengthened glycolysis under hypoxia supports tumor symbiosis and hexosamine biosynthesis in pancreatic adenocarcinoma

Pancreatic ductal adenocarcinoma is one of the most intractable and fatal cancer. The decreased blood vessel density displayed by this tumor not only favors its resistance to chemotherapy but also participates in its aggressiveness due to the consequent high degree of hypoxia. It is indeed clear that hypoxia promotes selective pressure on malignant cells that must develop adaptive metabolic responses to reach their energetic and biosynthetic demands. Here, using a well-defined mouse model of pancreatic cancer, we report that hypoxic areas from pancreatic ductal adenocarcinoma are mainly composed of epithelial cells harboring epithelial-mesenchymal transition features and expressing glycolytic markers, two characteristics associated with tumor aggressiveness. We also show that hypoxia increases the “glycolytic” switch of pancreatic cancer cells from oxydative phosphorylation to lactate production and we demonstrate that increased lactate efflux from hypoxic cancer cells favors the growth of normoxic cancer cells. In addition, we show that glutamine metabolization by hypoxic pancreatic tumor cells is necessary for their survival. Metabolized glucose and glutamine converge toward a common pathway, termed hexosamine biosynthetic pathway, which allows O-linked N-acetylglucosamine modifications of proteins. Here, we report that hypoxia increases transcription of hexosamine biosynthetic pathway genes as well as levels of O-glycosylated proteins and that O-linked N-acetylglucosaminylation of proteins is a process required for hypoxic pancreatic cancer cell survival. Our results demonstrate that hypoxia-driven metabolic adaptive processes, such as high glycolytic rate and hexosamine biosynthetic pathway activation, favor hypoxic and normoxic cancer cell survival and correlate with pancreatic ductal adenocarcinoma aggressiveness.

Genome profiling of pancreatic adenocarcinoma

Pancreatic adenocarcinoma is one of the most aggressive human cancers. It displays many different chromosomal abnormalities and mutations. By using 244 K high‐resolution array‐comparative genomic hybridization (aCGH) we studied the genome alterations of 39 fine‐needle aspirations from pancreatic adenocarcinoma and eight human adenocarcinoma pancreatic cell lines. Using both visual inspection and GISTIC analysis, recurrent losses were observed on 1p, 3p, 4p, 6, 8p, 9, 10, 11q, 15q, 17, 18, 19p, 20p, 21, and 22 and comprised several known or suspected tumor suppressor genes such as ARHGEF10, ARID1A, CDKN2A/B, FHIT, PTEN, RB1, RUNX1‐3, SMAD4, STK11/LKB1, TP53, and TUSC3. Heterozygous deletion of the 1p35‐p36 chromosomal region was identified in one‐third of the tumors and three of the cell lines. This region, commonly deleted in human cancers, contains several tumor suppressor genes including ARID1A and RUNX3. We identified frequent genetic gains on chromosome arms 1q, 3q, 5p, 6p, 7q, 8q, 12q, 15q, 18q, 19q, and 20q. Amplifications were observed in 16 tumors. AKT2, CCND3, CDK4, FOXA2, GATA6, MDM2, MYC, and SMURF1 genes were gained or amplified. The most obvious amplification was located at 18q11.2 and targeted the GATA6 gene, which plays a predominant role in the initial specification of the pancreas and in pancreatic cell type differentiation. In conclusion, we have identified novel biomarkers and potential therapeutic targets in pancreatic adenocarcinoma.

A polymorphism of EGFR extracellular domain is associated with progression free-survival in metastatic colorectal cancer patients receiving cetuximab-based treatment

BackgroundCetuximab, a monoclonal antibody targeting Epidermal Growth Factor Receptor (EGFR), is currently used in metastatic colorectal cancer (mCRC), but predictive factors for therapeutic response are lacking. Mutational status of KRAS and EGFR, and EGFR copy number are potential determinants of cetuximab activity.MethodsWe analyzed tumor tissues from 32 EGFR-positive mCRC patients receiving cetuximab/irinotecan combination and evaluable for treatment response. EGFR copy number was quantified by fluorescence in situ hybridization (FISH). KRAS exon 1 and EGFR exons coding for extracellular regions were sequenced.ResultsNine patients experienced an objective response (partial response) and 23 were considered as nonresponders (12 with stable disease and 11 with progressive disease). There was no EGFR amplification found, but high polysomy was noted in 2 patients, both of which were cetuximab responders. No EGFR mutations were found but a variant of exon 13 (R521K) was observed in 12 patients, 11 of which achieved objective response or stable disease. Progression-free and overall survivals were significantly better in patients with this EGFR exon 13 variant. KRAS mutations were found in 14 cases. While there was a trend for an increased KRAS mutation frequency in nonresponder patients (12 mutations out of 23, 52%) as compared to responder patients (2 out of 9, 22%), authentic tumor response or long-term disease stabilization was found in KRAS mutated patients.ConclusionThis preliminary study suggests that: an increase in EGFR copy number may be associated with cetuximab response but is a rare event in CRC, KRAS mutations are associated with low response rate but do not preclude any cetuximab-based combination efficacy and EGFR exon 13 variant (R521K) may predict for cetuximab benefit.

Should the portal vein be routinely resected during pancreaticoduodenectomy for adenocarcinoma

Introduction:In pancreatic adenocarcinoma (PA), a margin negative resection (R0) is critical for long-term survival. Background:Although pancreaticoduodenectomy (PD) with en-bloc portal vein/superior mesenteric vein (PV/SMV) resection is used in patients with venous involvement by tumor, its utility in patients with no venous involvement is unknown. This study examines survival in patients with no venous involvement who had PD with PV/SMV resection. Methods:From 2000 to 2010, 34 patients had PD with PV/SMV resection for resectable PA on preoperative staging. Fifteen patients (44%) had histological venous involvement and 19 (56%) had no histological involvement (–PV/SMV group). We matched 1:1 the –PV/SMV group (n = 19) with 19 contemporaneous PA patients who had a standard PD (control group) for age, tumor stage, tumor size, lymph node invasion, lymph node ratio, perineural invasion, margins status, and carbohydrate antigen 19-9 (CA 19-9) levels. Results:No differences were noted between the –PV/SMV group (n = 19) and the matched control group (n = 19) in morbidity, mortality, reoperation rate, or length of hospital stay. Median survival (42 months vs. 22 months, P = 0.02) and overall 3-year survival (60% vs. 31%, P = 0.03) were significantly longer in the –PV/SMV group compared with the control group. Conclusions:Patients with PA and no venous involvement who had PD with PV/SMV resection had a significantly longer overall survival than patients in a matched control group who had PD without venous resection.

Neoadjuvant 5 fluorouracil-cisplatin chemoradiation effect on survival in patients with resectable pancreatic head adenocarcinoma: a ten-year single institution experience.

Objectives: It is the aim of this study to assess the outcome of patients who received neoadjuvant 5-fluorouracil-cisplatin chemoradiation (CRT) for stage I/III pancreatic adenocarcinoma. Methods: Eligible patients (n = 101) received radiation therapy (45 Gy) associated with continuous infusion of 5-fluorouracil accompanied by a cisplatin bolus. Results: Of the 102 patients enrolled in the study, 26 patients had progression of cancer during treatment and were deemed unresectable; 1 patient died during CRT of septic shock. Sixty-two of 75 remaining patients underwent pancreaticoduodenectomy. The overall median survival of all 102 patients in the study was 17 months, with a 5-year survival of 10%. For patients who underwent resection, the median survival was 23 months. Correspondingly, the median survival was 11 months for the 40 unresected patients (p = 0.002). The 5-year survivals for resected and unresected patients were 18 and 0% (p = 0.01), respectively. A complete pathological response to neoadjuvant CRT was noted for 8 patients (13%). Margin and lymph node positivity was present in 5 (8%) and 15 (24%) patients, respectively. There was documented local recurrence in 8 (13%) and distant recurrence in 36 (58%) patients, with the liver being the most common site. Conclusion: Neoadjuvant 5-fluorouracil-based CRT had a limited impact on survival but appeared to be associated with improved local control.

Predictive Factors of Tumor Response After Neoadjuvant Chemoradiation for Locally Advanced Rectal Cancer

PURPOSE Neoadjuvant chemoradiation followed by surgery is the standard of care for locally advanced rectal cancer. The aim of this study was to correlate tumor response to survival and to identify predictive factors for tumor response after chemoradiation. METHODS AND MATERIALS From 1998 to 2008, 168 patients with histologically proven locally advanced adenocarcinoma treated by preoperative chemoradiation before total mesorectal excision were retrospectively studied. They received a radiation dose of 45 Gy with a concomitant 5-fluorouracil (5-FU)-based chemotherapy. Analysis of tumor response was based on lowering of the T stage between pretreatment endorectal ultrasound and pathologic specimens. Overall and progression-free survival rates were correlated with tumor response. Tumor response was analyzed with predictive factors. RESULTS The median follow-up was 34 months. Five-year disease-free survival and overall survival rates were, of 44.4% and 74.5% in the whole population, 83.4% and 83.4%, respectively, in patients with pathological complete response, 38.6% and 71.9%, respectively, in patients with tumor downstaging, and 29.1 and 58.9% respectively, in patients with absence of response. A pretreatment carcinoembryonic antigen (CEA) level of <5 ng/ml was significantly independently associated with pathologic complete tumor response (p = 0.019). Pretreatment small tumor size (p = 0.04), pretreatment CEA level of <5 ng/ml (p = 0.008), and chemotherapy with capecitabine (vs. 5-FU) (p = 0.04) were significantly associated with tumor downstaging. CONCLUSIONS Downstaging and complete response after CRT improved progression-free survival and overall survival of locally advanced rectal adenocarcinoma. In multivariate analysis, a pretreatment CEA level of <5 ng/ml was associated with complete tumor response. Thus, small tumor size, a pretreatment CEA level of < 5 ng/ml, and use of capecitabine were associated with tumor downstaging.

Side-branch intraductal papillary mucinous neoplasms of the pancreatic head/uncinate: resection or enucleation?

INTRODUCTION Side-branch intraductal papillary mucinous neoplasms (IPMN) of the pancreatic head/uncinate are an increasingly common indication for pancreaticoduodenectomy (PD). However, enucleation (EN) may be an alternative to PD in selected patients to improve outcomes and preserve pancreatic parenchyma. AIM To determine peri-operative outcomes in patients with side-branch IPMN of the pancreatic head/uncinate undergoing EN or PD compared with a cohort of patients with pancreatic adenocarcinoma (PA) undergoing PD. METHODS Retrospective review of a prospectively collected, combined, academic institutional series from 2005 to 2008. Of 107 pancreatic head/uncinate IPMN, enucleation was performed in 7 (IPMN EN) and PD was performed in 100 (IPMN PD) with 17 of these radiographically amenable to EN (IPMN PD(en) ). During the same time period, 281 patients underwent PD for PA (Control PD). RESULTS Operative time was shorter (p<0.05) and blood loss (p<0.05) was less in the IPMN EN group compared with all other groups. Peri-operative mortality and morbidity of all IPMN groups (IPMN EN, IPMN PD(en) ) were similar to the Control PD group. Overall pancreatic fistulae rate in the IPMN EN group was higher than in the IPMN PD(en) and Control PD groups; however, the rate of grade C pancreatic fistulae was the same in all groups. CONCLUSIONS Pancreaticoduodenectomy for side-branch IPMNs can be performed safely. Compared with PD, enucleation for IPMN has less blood loss, shorter operative time and similar morbidity, mortality, hospital length of stay (LOS) and readmission rate. Enucleation should be considered more frequently as an option for patients with unifocal side-branch IPMN.

Pancreatectomy for adenocarcinoma in elderly patients: postoperative outcomes and long term results: a study of the French Surgical Association.

AIM To determine the benefit of surgery for resectable pancreatic adenocarcinomas (PAs) in elderly patients. METHODS From 2004 to 2009, 932 patients with resectable PAs underwent pancreatectomies without neoadjuvant treatment in 37 institutions. The patients were divided into three groups according to age: <70 years (control group; n = 580); 70-79 years (70s group, n = 288), and ≥ 80 years (80s group; n = 64). Preoperative, intraoperative, postoperative, and histological data were recorded to assess the postoperative course and survival. RESULTS Preoperative or intraoperative characteristics, and the histological findings were comparable in the three groups. Postoperative mortality and morbidity rates did not differ in the three groups. Adjuvant therapies were more frequently used in younger patients than in elderly patients (p < 0.01). The overall 1-year, 3-year, and 5-year survival rates of control group/70s group/80s group were 82.2%/75.7%/75.7%, 49.9%/41.8%/31%, and 38.7%/33.2%/0%, respectively (p = 0.16). The median survival of the control, 70s, and 80s groups was 24 months, 35.3 months, and 30 months, respectively. Four independent prognostic indicators were identified by multivariate analysis: venous invasion (hazard ratio (HR) = 2.12), arterial invasion (HR = 2.96), positive lymph nodes (HR = 2.25), and adjuvant treatment (HR = 0.65). CONCLUSIONS Fit elderly patients with resectable PAs should not be excluded from surgical resection of PA solely because of their real age. Moreover, elderly patients seem to obtain similar advantages from pancreatectomies than younger patients.

Current knowledge on pancreatic cancer

Pancreatic cancer is the fourth leading cause of cancer death with a median survival of 6 months and a dismal 5-year survival rate of 3–5%. The development and progression of pancreatic cancer are caused by the activation of oncogenes, the inactivation of tumor suppressor genes, and the deregulation of many signaling pathways. Therefore, the strategies targeting these molecules as well as their downstream signaling could be promising for the prevention and treatment of pancreatic cancer. However, although targeted therapies for pancreatic cancer have yielded encouraging results in vitro and in animal models, these findings have not been translated into improved outcomes in clinical trials. This failure is due to an incomplete understanding of the biology of pancreatic cancer and to the selection of poorly efficient or imperfectly targeted agents. In this review, we will critically present the current knowledge regarding the molecular, biochemical, clinical, and therapeutic aspects of pancreatic cancer.