Consensus in determining the resectability of locally progressed pancreatic ductal adenocarcinoma - results of the Conko-007 multicenter trial.

BACKGROUND: One critical step in the therapy of patients with localized pancreatic cancer is the determination of local resectability. The decision between primary surgery versus upfront local or systemic cancer therapy seems especially to differ between pancreatic cancer centers. In our cohort study, we analyzed the independent judgement of resectability of five experienced high volume pancreatic surgeons in 200 consecutive patients with borderline resectable or locally advanced pancreatic cancer. METHODS: Pretherapeutic CT or MRI scans of 200 consecutive patients with borderline resectable or locally advanced pancreatic cancer were evaluated by 5 independent pancreatic surgeons. Resectability and the degree of abutment of the tumor to the venous and arterial structures adjacent to the pancreas were reported. Interrater reliability and dispersion indices were compared. RESULTS: One hundred ninety-four CT scans and 6 MRI scans were evaluated and all parameters were evaluated by all surgeons in 133 (66.5%) cases. Low agreement was observed for tumor infiltration of venous structures (κ = 0.265 and κ = 0.285) while good agreement was achieved for the abutment of the tumor to arterial structures (interrater reliability celiac trunk κ = 0.708 P < 0.001). In patients with vascular tumor contact indicating locally advanced disease, surgeons highly agreed on unresectability, but in patients with vascular tumor abutment consistent with borderline resectable disease, the judgement of resectability was less uniform (dispersion index locally advanced vs. borderline resectable p < 0.05). CONCLUSION: Excellent agreement between surgeons exists in determining the presence of arterial abutment and locally advanced pancreatic cancer. The determination of resectability in borderline resectable patients is influenced by additional subjective factors. TRIAL REGISTRATION: EudraCT:2009-014476-21 (2013-02-22) and NCT01827553 (2013-04-09).

[Relevance of MRSA on a Visceral Surgical Intensive Care Unit]. / Relevanz von MRSA auf einer viszeralchirurgischen Intensivstation.

Background: Resistance to antibiotics is a worldwide increasing problem. A well-known example is methicillin resistant Staphylococcus aureus, MRSA. What is the relevance of MRSA on a surgical ICU? Patients/Material and Methods: On a 20 bed academic SICU/intermediate care ward 14,976 patients were treated in a seven-year period. We identified only 98 MRSA-positive patients. 56 (57 %) of them were merely colonised, 42 (43 %) suffered from an MRSA infection. A control group comprised 56 similar patients without MRSA detection. Results: Patients with MRSA infection had a higher mortality rate (OR 4.18; p = 0.002), but only 4 out of 20 patients died due to the MRSA infection. APACHE 2 score of more than 20 was predictive for being colonised with MRSA (OR 3.08; p = 0.04), but it was not a risk factor for developing an MRSA infection (OR 1.03; p = 0.95). Patients with MRSA colonisation did not have a higher mortality rate than patients without. Conclusion: Outcome depended on severity of the disease, but not on the MRSA colonisation status. Patients with MRSA infection were more likely to die, but the reason of death rarely was MRSA.

Pancreatogastrostomy Versus Pancreatojejunostomy for RECOnstruction After PANCreatoduodenectomy (RECOPANC, DRKS 00000767): Perioperative and Long-term Results of a Multicenter Randomized Controlled Trial.

OBJECTIVES: To assess pancreatic fistula rate and secondary endpoints after pancreatogastrostomy (PG) versus pancreatojejunostomy (PJ) for reconstruction in pancreatoduodenectomy in the setting of a multicenter randomized controlled trial. BACKGROUND: PJ and PG are established methods for reconstruction in pancreatoduodenectomy. Recent prospective trials suggest superiority of the PG regarding perioperative complications. METHODS: A multicenter prospective randomized controlled trial comparing PG with PJ was conducted involving 14 German high-volume academic centers for pancreatic surgery. The primary endpoint was clinically relevant postoperative pancreatic fistula. Secondary endpoints comprised perioperative outcome and pancreatic function and quality of life measured at 6 and 12 months of follow-up. RESULTS: From May 2011 to December 2012, 440 patients were randomized, and 320 were included in the intention-to-treat analysis. There was no significant difference in the rate of grade B/C fistula after PG versus PJ (20% vs 22%, P = 0.617). The overall incidence of grade B/C fistula was 21%, and the in-hospital mortality was 6%. Multivariate analysis of the primary endpoint disclosed soft pancreatic texture (odds ratio: 2.1, P = 0.016) as the only independent risk factor. Compared with PJ, PG was associated with an increased rate of grade A/B bleeding events, perioperative stroke, less enzyme supplementation at 6 months, and improved results in some quality of life parameters. CONCLUSIONS: The rate of grade B/C fistula after PG versus PJ was not different. There were more postoperative bleeding events with PG. Perioperative morbidity and mortality of pancreatoduodenectomy seem to be underestimated, even in the high-volume center setting.

Cancer cell invasion and EMT marker expression: a three-dimensional study of the human cancer-host interface.

Cancer cell invasion takes place at the cancer-host interface and is a prerequisite for distant metastasis. The relationships between current biological and clinical concepts such as cell migration modes, tumour budding and epithelial-mesenchymal transition (EMT) remains unclear in several aspects, especially for the 'real' situation in human cancer. We developed a novel method that provides exact three-dimensional (3D) information on both microscopic morphology and gene expression, over a virtually unlimited spatial range, by reconstruction from serial immunostained tissue slices. Quantitative 3D assessment of tumour budding at the cancer-host interface in human pancreatic, colorectal, lung and breast adenocarcinoma suggests collective cell migration as the mechanism of cancer cell invasion, while single cancer cell migration seems to be virtually absent. Budding tumour cells display a shift towards spindle-like as well as a rounded morphology. This is associated with decreased E-cadherin staining intensity and a shift from membranous to cytoplasmic staining, as well as increased nuclear ZEB1 expression.

[Fusion of Continuously Moving Table MRI and PET Improves Lesion Detection in Recurrent Rectal Cancer]. / Kombination von MRT und PET erlaubt genauere Rezidivdiagnostik des Rektumkarzinoms durch Bildfusion.

PURPOSE: It was the aim of this study to investigate the complementary diagnostic performance of a combined pelvic and thoracoabdominal magnetic resonance imaging (MRI) examination and positron emission tomography (PET) enhanced by image fusion in patients with suspected rectal cancer recurrence. PATIENTS AND METHODS: Thirty-one patients with clinically suspected recurrence from rectal cancer were retrospectively included, who had received MRI (high resolution pelvic MRI combined with thoracoabdominal MRI performed during continuous table translation) and (18)F-FDG-PET within 30 days. MRI alone, PET alone, and MRI and PET combined including fusion images were analysed by two observers in consensus. The likelihood of malignancy of all detectable lesions was rated on a 5-point Likert scale. The standard of reference consisted of histopathology and follow-up imaging. Confidence ratings were analysed with a jackknife free response receiver-operator characteristic paradigm (JAFROC). Further test characteristics were derived by considering "probably malignant" and "definitely malignant" lesions as positive test results. RESULTS: The reference standard comprised 150 malignant lesions (48 local, 102 distant). JAFROC analysis revealed overall figures-of-merit of 0.73 for MRI, 0.63 for PET, and 0.83 for the combined approach (differences significant). The sensitivities of MRI, PET and the combined approach were 85.4, 52.1, and 95.8 % for local recurrence and 61.8, 47.1, and 81.4 % for distant recurrence, respectively. CONCLUSION: The combination of local high-resolution MRI, thoracoabdominal continuously moving table MRI and FDG-PET supported by image fusion improves lesion detection in recurrent rectal cancer.

[Laparoscopic total gastrectomy with extended lymphadenectomy and intracorporal circular stapled esophagojejunostomy]. / Die total-laparoskopische Gastrektomie mit D2-Lymphadenektomie und intrakorporaler Ösophagojejunostomie in zirkulärer Staplertechnik.

Laparoscopic total gastrectomy for early and advanced gastric cancer is an exacting procedure which is increasingly performed in specialised institutions. Not only gastric resection and extended lymphadenectomy but especially the reconstruction by oesophagojejunostomy is a technically demanding and vulnerable operative step. In this article we present our laparoscopic technique of total gastrectomy with extended lymphadenectomy and complete intracorporal reconstruction by end-to-side circular stapled oesophagojejunostomy. The operative technique of the gastric resection, the extended lymphadenectomy and the reconstruction are described in detail in a step-by-step approach and demonstrated in a supplemental video.

[The abdominal compartment syndrome - relevance and therapeutic consequences]. / Das abdominale Kompartmentsyndrom - Relevanz und therapeutische Konsequenzen.

BACKGROUND: Intra-abdominal hypertension (IAH) has a high prevalence among critically ill patients. It is increasingly recognised as a risk factor for poor outcome. PATIENTS / MATERIAL AND METHODS: A review of the literature including explicit management instructions was performed. We report the standardised techniques for intra-abdominal pressure (IAP) measurement as well as consensus definitions and treatment recommendations ranging from conservative measures to decompression laparotomy. RESULTS: The abdominal compartment syndrome (ACS) is defined as a sustained IAH > 20 mmHg accompanied by new organ dysfunctions. It occurs predominantly in surgical patients and is associated with a poor outcome. Organ dysfunctions related to IAH mainly concern the kidneys and -respiratory system. The mechanism of action essentially is a perfusion deficit. Clinical judgement alone does not allow a valid estimate of intra-abdominal pressure. CONCLUSION: In patients at risk the IAP should be measured. In case of IAH conservative options for lowering the pressure are mandatory. Decompression laparotomy should be considered if conservative measures fail.

Reinforcement of colonic anastomoses with a collagenous double-layer matrix extracted from porcine dermis.

BACKGROUND: Anastomotic leakage is a major factor for morbidity in colorectal surgery. Anastomotic reinforcement with biological or synthetic materials has been claimed to be useful in preventing anastomotic leakage. METHODS: We evaluated a non-cross-linked collagenous matrix Bio-Gide (BG) for sealing colonic anastomoses in a rodent model. The animals were investigated for 4, 30 and 90 days. Macroscopic examination, histological examination and measurement of bursting pressure were performed. The anastomotic stricture rate was evaluated by radiographic contrast enema. RESULTS: Microscopically anastomoses sealed by BG showed impaired anastomotic healing. Blood vessel ingrowth and collagen deposition were decreased without reaching significance after 4 days. The anastomotic bursting pressure was significantly decreased (p = 0.0454) in the early phase of healing. Anastomotic neovascularization was significantly decreased compared to the control group after 30 (p = 0.0058) and 90 days (p = 0.0275). Although no difference in anastomotic stricture rate was evident, the rate of intra-abdominal adhesions was significantly increased after 30 (p = 0.0124) and 90 days (p = 0.0281). CONCLUSION: BG failed to improve colonic anastomotic healing. Early anastomotic healing was impaired if anastomoses were reinforced with BG. BG did not affect the anastomotic stricture rate for up to 3 months; nevertheless, intra-abdominal adhesions were increased.

Pitfalls and technical aspects during the research of intestinal anastomotic healing in rats.

BACKGROUND: Fundamental experimental research into intestinal anastomotic healing in rodent models will gain increasing interest in the future. METHODS: The aim of this study was to describe our 5-year experience with a standardized experimental setup of small and large bowel anastomoses in a rodent model and present a basic set of assessment tools investigating anastomotic healing. Anastomotic technique, perioperative complications such as anastomotic insufficiency (AI) and obstructive ileus were in the focus. RESULTS: During different studies with varying study patterns, 167 rat small bowel anastomoses and 120 colonic anastomoses were performed. Overall mortality was 3.6% in small bowel and 2.5% in colonic anastomoses, AI occurred in 2.9 and 4%, respectively. A postoperative obstructive ileus was seen in 3/167 small bowel anastomoses and none in the colonic group. CONCLUSION: When performing experimental intestinal anastomoses in a standardized operative setting and critically considering special perioperative issues, the incidence of relevant complications can be maintained at an adequately low level.

[Tumour stem cells and metastasis]. / Tumorstammzellen und Metastasierung.

The underlying mechanisms of cancer development, invasion and metastasis are still only partly unraveled. Cancer stem cells (CSC) and the so-called epithelial-mesenchymal transition (EMT) seem to contribute to these oncological phenomena. Cancer stem cells which, according to our present knowledge, play an important role in tumour development and persistence, are operationally defined. The embryonic programme of EMT is activated aberrantly in cancer cells at the invasive front and seems to contribute to tumour invasion and metastasis. Recent observations suggest that the EMT and CSC traits are closely related. This provides new explanatory models for cancer development and metastasis.

[Postoperative sepsis: diagnosis, special features, management]. / Die postoperative Sepsis: Diagnose, Besonderheiten, Management.

A high level of suspicion is necessary to detect postoperative sepsis in good time. It may be difficult to differentiate sepsis from normal SIRS in the postoperative setting. Early signs and symptoms include delirium and respiratory compromise. These should trigger the search for a septic focus aggressively with special attention to the original site of surgery. Key recommendations include early goal-directed resuscitation of the septic patient, administration of broad-spectrum antibiotic therapy within 1 hour of diagnosis, and source control with attention to the balance of risks and benefits of the chosen method. In cases of severe abdominal sepsis the concept of relaparotomy on-demand has become most popular.

[Patient assignment to a surgical intensive care unit - plea for a preoperative risk stratification]. / Belegungsdynamik einer chirurgischen Intensivstation - Plädoyer für eine präoperative Stratifizierung von elektiven chirurgischen Patienten.

BACKGROUND: Surgical intensive care units (ICUs) have to meet the demands of caring for elective surgical patients, for surgical emergencies, and for trauma patients. To achieve this a high flexibility and a high rate of admissions and discharges are needed. ICU beds are scant and expensive, so who is to be admitted? PATIENTS AND METHODS: All admissions and dis-charges of a 20-bed surgical ICU in a university hospital within one year have been analysed. RESULTS: During the analysed year 2524 patients were admitted to the surgical ICU (6.9 + or - 3.1 per day). Of 1886 planned admissions (elective surgery) only 1234 were eventually admitted, but there were 1290 additional patients admitted as emergencies. Of all realised admissions only 49 % were planned. In 653 requested but refused elective admissions, the surgery was performed with-out intensive care admission in 432 patients (64.9 %). CONCLUSIONS: Half of the patients of the surgical ICU are electively surgical, half of them are emergencies. The limited number of ICU beds requires strict indications for admission. It turns out to be useful to create a category of patients in whom postoperative intensive care is desirable but not mandatory.

The rate of postoperative pancreatic fistula after distal pancreatectomy is independent of the pancreatic stump closure technique - A retrospective analysis of 284 cases.

BACKGROUND: Many techniques have been developed to prevent postoperative pancreatic fistula (POPF) after distal pancreatectomy, but POPF rates remain high. The aim of our study was to analyze POPF occurrence after closure of the pancreatic remnant by different operative techniques. METHODS: Between 2006 and 2017, 284 patients underwent distal pancreatectomy in our institution. For subgroup analysis the patients were divided into hand-sewn (n = 201) and stapler closure (n = 52) groups. The hand-sewn closure was performed in three different ways (fishmouth-technique, n = 27; interrupted transpancreatic U-suture technique, n = 77; common interrupted suture, n = 97). All other techniques were summarized in a separate group (n = 31). Results were gained by analysis of our prospective pancreatic database. RESULTS: The median age was 63 (range 23-88) years. 74 of 284 patients (26%) were operated with spleen preservation (similar rates in subgroups). ASA-classes, median BMI as well as frequencies of malignant diseases, chronic pancreatitis, alcohol and nicotine abuse were also comparable in the subgroups. Neither the rates of overall POPF (fishmouth-technique 30%, common interrupted suture 40%, stapler closure 33% and interrupted U-suture 38%) nor the rates of POPF grades B and C showed significant differences in the subgroups. However is shown to be associated with pancreatic function and parenchymal texture. CONCLUSION: In our experience the technique of pancreatic stump closure after distal resection did not influence postoperative pancreatic fistula rate. As a consequence patient specific reasons rather than surgical techniques may be responsible for POPF formation after distal pancreatectomy.

Clinical course and pancreas parenchyma sparing surgical treatment of severe pancreatic trauma.

INTRODUCTION: Pancreatic trauma (PT) involving the main pancreatic duct is rare, but represents a challenging clinical problem with relevant morbidity and mortality. It is generally classified according to the American Association for the Surgery of Trauma (AAST) and often presents as concomitant injury in blunt or penetrating abdominal trauma. Diagnosis may be delayed because of a lack of clinical or radiological manifestation. Treatment options for main pancreatic duct injuries comprise highly complex surgical procedures. PATIENTS AND METHODS: We retrospectively analyzed clinical data from 12 patients who underwent surgery in two tertiary centers in Germany during 2003-2016 for grade III-V PT with affection of the main pancreatic duct, according to the AAST classification. RESULTS: The median age was 23 (range: 7-44) years. In nine patients blunt abdominal trauma was the reason for PT, whereas penetrating trauma only occurred in three patients. MRI outperformed classical trauma CT imaging with regard to detection of duct involvement. Complex procedures as i.e. an emergency pancreatic head resection, distal pancreatectomy or parenchyma sparing pancreatogastrostomy were performed. Compared to elective pancreatic surgery the complication rate in the emergency setting was higher. Yet, parenchyma-sparing procedures demonstrated safety. CONCLUSIONS: Often extension of diagnostics including MRI and/or ERP at an early stage is necessary to guide clinical decision-making. If, due to main duct injuries, surgical therapy for PT is required, we suggest consideration of an organ preservative pancreatogastrostomy in grade III/IV trauma of the pancreatic body or tail.

3D-MSCT gastric pouch volumetry in bariatric surgery-preliminary clinical results.

BACKGROUND: Insufficient weight loss or persistent abdominal complaints are reasons for revisionary operations in bariatric surgery. The selection of the secondary procedure is influenced by clinical and by patho-anatomical factors like the size of the gastric pouch. The purpose of this study was to evaluate multi-slice computed tomography (MSCT)-based volumetric assessment of gastric pouches, gastric sleeves, and anastomoses in patients after bariatric surgery. METHODS: Twenty-six patients after bariatric surgery received abdominal MSCT immediately after oral administration of an ionic contrast agent solution and intravenous administration of buthylscopalamine. Indications were insufficient weight loss after primary operation, persistent upper abdominal complaints, and decline of bariatric analysis and reporting outcomes system (BAROS) score. The gastric volumes, diameter of the gastrojejunostomy, and the proximal part of the Roux limb were measured on volume rendering images and freely angulated reformations. RESULTS: Evaluation of gastric volumes was successful in 25 examinations (96%). The diameters of gastrojejunostomy as well as the dimensions of the Roux limb were evaluable in all cases. After gastric bypass surgery, a pouch volume >30 ml was found in ten, a widening of the gastrojejunostomy in eight, and a dilated Roux limb in six cases. Two patients presented a combination of a wide anastomosis and a strongly dilated Roux limb. Patients after biliopancreatic diversion had gastric volumes between 210 and 840 ml. Other findings were a fistula, an intragastral stenosis, and internal hernias. CONCLUSIONS: MSCT allows crucial patho-anatomical measurements and provides helpful information for selecting the appropriate revisionary operation after bariatric surgery.

[Of what relevance is the diagnosis of "pneumatosis intestinalis" and portal gas for the surgeon?]. / Welche Bedeutung hat die Diagnose "Pneumatosis intestinalis" und "Portal Gas" für den Chirurgen?

Pneumatosis intestinalis (PI) describes the existence of gas in the wall of the gastrointestinal tract; portal gas (PG) describes gas in the portovenous system. Both are predominantly diagnosed radiologically (computed tomography as the most sensitive method) and do not represent per se self-contained syndromes, but PI and PG are possible symptoms of a variety of diseases. Possible sources of gas are bacterial gas (e. g., bowel wall invasion by aerogenic bacteria), intraluminal and extraluminal enteric gas (e. g., increased intraluminal pressure e.g. endoscopy), and pulmonary gas (e. g., COPD). The treatment of PI /PG depends on the underlying disease. The decision for laparotomy/ laparoscopy should be a conclusion of clinical and possibly radiological signs. Since in many cases, the simultaneous detection of PI and PG, is caused by mesenterial ischemia and has a poor prognosis, in these cases, the decision for operation (laparotomy/ laparoscopy) should be made liberally. A symptomatic therapy with metronidazole and oxygen should be considered, if despite the adequate treatment of the underlying disease, PI continues with abdominal symptoms (such as intestinal pseudo-obstruction or nonspecific abdominal pain).

[Timing of resection in patients with colorectal carcinoma and synchronous liver metastases]. / Zeitlicher Ablauf von Leber- und Darmresektion bei Patienten mit kolorektalem Karzinom und synchronen Lebermetastasen.

Timing of surgical therapy in patients with synchronous colorectal liver metastases is becoming more complex. The standard therapy for most of the patients remains resection of the colorectal cancer first followed 6 weeks later by liver resection. Simultaneous colon and liver resection is safe and advisable in cases of minor liver resections and right-sided colon tumours. Major liver resections in combination with resection of the colorectal cancer carry the risk of increased postoperative morbidity and mortality. They should be considered for selected patients only. A pre-requisite is, in addition, special expertise of the operating surgeon in colorectal as well as in hepatobiliary surgery. If the synchronous liver metastases are near to essential anatomic structures, the liver resection should be performed before the bowel resection. The same holds if the metastases are technically resectable, but the future liver remnant seems to be too small. Using well known techniques, the future liver remnant should be increased and the liver metastases resected before treatment of the colonic primary tumour. The risk for local complications is very low when leaving the colorectal tumour in situ during treatment of liver metastases. When synchronous liver metastases are technically not resectable or carry a high risk of an R1 resection, patients should be treated first with systemic neo-adjuvant chemotherapy. If sufficient down-sizing of the metastases can be achieved, liver resection should be performed before bowel resection. A close cooperation between the oncologist and the hepatobiliary surgeon is most important, since the window for curative surgery is rather limited in these patients. In patients with resectable synchronous liver metastases, the advantage of a neoadjuvant chemotherapy has not been proven yet.

[Diagnosis of and therapy for gastric cancer--work-flow]. / Diagnostik und Therapie des Magenkarzinoms--Workflow.

AIM: This review comments on the diagnosis and treatment of gastric cancer in the classical meaning--excluding adenocarcinoma of the -oesophagogastric junction. Algorithms of diagnosis and care with respect to tumour stage are presented. PREOPERATIVE DIAGNOSIS: Besides oesophagogastroduodenoscopy, endoscopic ultrasonography is necessary for the accurate diagnosis of T categories and as a selection criterion for neoadjuvant chemotherapy. Computed tomography is recommended for preoperative evaluation of tumours > T1, laparoscopy has become an effective stag-ing tool in T3 and T4 tumours avoiding unnecessary laparotomies and improving the detection of small -liver and peritoneal metastases. TREATMENT: Endoscopic mucosal resection and submucosal dissection are indicated in superficial cancer confined to the mucosa with special characteristics (T1 a / no ulcer / G1, 2 / Laurén intestinal / L0 / V0 / tumour size < 2 cm). In all other cases total gastrectomy or distal subtotal gastric resection are indicated, the latter in cases of tumours located in the distal two-thirds of the stomach. Standard lymphadenectomy (LAD) is the D2 LAD without distal pancreatectomy and splenectomy. The Roux-en-Y oesophagojejunostomy is still the preferred type of reconstruction. An additional pouch reconstruction should be considered in -patients with favourable prognosis, this also -applies for the preservation of the duodenal passage by jejunum interposition. Extended organ resections are only indicated in cases where a R0-resection is possible. Hepatic resection for metachronous or synchronous liver metastases is rarely advised since 50 % of patients with liver metastases show concomitant peritoneal dissemination of the disease. DISCUSSION AND CONCLUSIONS: Undergoing gastrectomy at a high-volume centre is associated with lower in-hospital mortality and a better prognosis, however, clear thresholds for case load cannot be given. Perioperative chemotherapy and postoperative chemoradiotherapy are based on the MAGIC and MacDonald trials. Perioperative chemotherapy should be performed in patients with T3 and T4 tumours with the aim to increase the likelihood of curative R0-resection by downsizing the tumour. Adjuvant postoperative chemotherapy cannot be recommended since its benefit has so far not been proven in randomised trials. In selected patients with incomplete lymph-node dissection and questionable R0-resection postoperative chemoradiotherapy may be debated.

Management and outcomes of intraductal papillary mucinous neoplasms.

Background: This study evaluated the outcome and survival of patients with radiologically suspected intraductal papillary mucinous neoplasms (IPMNs). Methods: IPMN management was reviewed according to Fukuoka risk factors and IPMN localization, differentiating main-duct (MD), mixed-type (MT) and branch-duct (BD) IPMNs. Perioperative results were compared with those of patients undergoing resection of pancreatic ductal adenocarcinoma (PDAC) over the same interval (2010-2014). Overall (OS) and disease-specific (DSS) survival rates were calculated and subgroups compared. Results: Of 142 patients with IPMNs, 26 had MD-IPMN, eight had MT-IPMN and 108 had BD-IPMN. Some 74 per cent of patients with MD- and MT-IPMN were managed by primary resection, whereas this was used in only 27·8 per cent of those with BD-IPMN. The risk of secondary resection and malignant transformation for BD-IPMNs smaller than 20 mm was 8 and 2 per cent respectively during follow-up. Pancreatic head resection of IPMNs was associated with an increased risk of postoperative pancreatic fistula grade B/C compared with resection of PDAC (12 of 33 (36 per cent) versus 41 of 221 (18·6 per cent) respectively; P = 0·010), and greater morbidity and mortality (Clavien-Dindo grade III: 15 of 33 (45 per cent) versus 56 of 221 (25·3 per cent) respectively; grade IV: 1 (3 per cent) versus 7 (3·2 per cent); grade V: 2 (6 per cent) versus 2 (0·9 per cent); P = 0·008). Five-year OS and DSS rates in patients with MD-IPMN were worse than those for MT- and BD-IPMN (OS: 44, 86 and 97·4 per cent respectively, P < 0·001; DSS: 60, 100 and 98·6 per cent; P < 0·001). Patients with invasive IPMN had worse OS and DSS rates than those with non-invasive dysplasia (OS: IPMN-carcinoma (10 patients) 33 per cent, high-grade dysplasia 100 per cent, intermediate-grade dysplasia 63 per cent, low grade-dysplasia 100 per cent, P < 0·001; DSS: IPMN-carcinoma 43 per cent, all grades of dysplasia 100 per cent, P < 0·001). Patients with high-risk stigmata had poorer survival than those without risk factors (OS: high-risk stigmata (35 patients) 55 per cent, worrisome features (31) 95 per cent, no risk factors (76) 100 per cent, P < 0·001; DSS: 71, 100 and 100 per cent respectively, P < 0·001). Conclusion: The risk of malignant transformation was very low for BD-IPMNs, but the development of high-risk stigmata was associated with disease-specific mortality. Patients with IPMN had greater morbidity after resection than those having resection of PDAC.

A new liposomal formulation of Gemcitabine is active in an orthotopic mouse model of pancreatic cancer accessible to bioluminescence imaging.

Despite its rapid enzymatic inactivation and therefore limited activity in vivo, Gemcitabine is the standard drug for pancreatic cancer treatment. To protect the drug, and achieve passive tumor targeting, we developed a liposomal formulation of Gemcitabine, GemLip (Ø: 36 nm: 47% entrapment). Its anti-tumoral activity was tested on MIA PaCa-2 cells growing orthotopically in nude mice. Bioluminescence measurement mediated by the stable integration of the luciferase gene was employed to randomize the mice, and monitor tumor growth. GemLip (4 and 8 mg/kg), Gemcitabine (240 mg/kg), and empty liposomes (equivalent to 8 mg/kg GemLip) were injected intravenously once weekly for 5 weeks. GemLip (8 mg/kg) stopped tumor growth, as measured via in vivo bioluminescence, reducing the primary tumor size by 68% (SD +/- 8%; p < 0.02), whereas Gemcitabine hardly affected tumor size (-7%; +/- 1.5%). In 80% of animals, luciferase activity in the liver indicated the presence of metastases. All treatments, including the empty liposomes, reduced the metastatic burden. Thus, GemLip shows promising antitumoral activity in this model. Surprisingly, empty liposomes attenuate the spread of metastases similar to Gemcitabine and GemLip. Further, luciferase marked tumor cells are a powerful tool to observe tumor growth in vivo, and to detect and quantify metastases.