Independent Validation and Assay Standardization of Improved Metabolic Biomarker Signature to Differentiate Pancreatic Ductal Adenocarcinoma From Chronic Pancreatitis.

BACKGROUND & AIMS: Pancreatic ductal adenocarcinoma cancer (PDAC) is a highly lethal malignancy requiring efficient detection when the primary tumor is still resectable. We previously developed the MxPancreasScore comprising 9 analytes and serum carbohydrate antigen 19-9 (CA19-9), achieving an accuracy of 90.6%. The necessity for 5 different analytical platforms and multiple analytical runs, however, hindered clinical applicability. We therefore aimed to develop a simpler single-analytical run, single-platform diagnostic signature. METHODS: We evaluated 941 patients (PDAC, 356; chronic pancreatitis [CP], 304; nonpancreatic disease, 281) in 3 multicenter independent tests, and identification (ID) and validation cohort 1 (VD1) and 2 (VD2) were evaluated. Targeted quantitative plasma metabolite analysis was performed on a liquid chromatography-tandem mass spectrometry platform. A machine learning-aided algorithm identified an improved (i-Metabolic) and minimalistic metabolic (m-Metabolic) signatures, and compared them for performance. RESULTS: The i-Metabolic Signature, (12 analytes plus CA19-9) distinguished PDAC from CP with area under the curve (95% confidence interval) of 97.2% (97.1%-97.3%), 93.5% (93.4%-93.7%), and 92.2% (92.1%-92.3%) in the ID, VD1, and VD2 cohorts, respectively. In the VD2 cohort, the m-Metabolic signature (4 analytes plus CA19-9) discriminated PDAC from CP with a sensitivity of 77.3% and specificity of 89.6%, with an overall accuracy of 82.4%. For the subset of 45 patients with PDAC with resectable stages IA-IIB tumors, the sensitivity, specificity, and accuracy were 73.2%, 89.6%, and 82.7%, respectively; for those with detectable CA19-9 >2 U/mL, 81.6%, 88.7%, and 84.5%, respectively; and for those with CA19-9 <37 U/mL, 39.7%, 94.1%, and 76.3%, respectively. CONCLUSIONS: The single-platform, single-run, m-Metabolic signature of just 4 metabolites used in combination with serum CA19-9 levels is an innovative accurate diagnostic tool for PDAC at the time of clinical presentation, warranting further large-scale evaluation.

Plasma Metabolome Profiling Identifies Metabolic Subtypes of Pancreatic Ductal Adenocarcinoma.

Pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest cancers. Developing biomarkers for early detection and chemotherapeutic response prediction is crucial to improve the dismal prognosis of PDAC patients. However, molecular cancer signatures based on transcriptome analysis do not reflect intratumoral heterogeneity. To explore a more accurate stratification of PDAC phenotypes in an easily accessible matrix, plasma metabolome analysis using MxP® Global Profiling and MxP® Lipidomics was performed in 361 PDAC patients. We identified three metabolic PDAC subtypes associated with distinct complex lipid patterns. Subtype 1 was associated with reduced ceramide levels and a strong enrichment of triacylglycerols. Subtype 2 demonstrated increased abundance of ceramides, sphingomyelin and other complex sphingolipids, whereas subtype 3 showed decreased levels of sphingolipid metabolites in plasma. Pathway enrichment analysis revealed that sphingolipid-related pathways differ most among subtypes. Weighted correlation network analysis (WGCNA) implied PDAC subtypes differed in their metabolic programs. Interestingly, a reduced expression among related pathway genes in tumor tissue was associated with the lowest survival rate. However, our metabolic PDAC subtypes did not show any correlation to the described molecular PDAC subtypes. Our findings pave the way for further studies investigating sphingolipids metabolisms in PDAC.

Identification and validation of a multivariable prediction model based on blood plasma and serum metabolomics for the distinction of chronic pancreatitis subjects from non-pancreas disease control subjects.

OBJECTIVE: Chronic pancreatitis (CP) is a fibroinflammatory syndrome leading to organ dysfunction, chronic pain, an increased risk for pancreatic cancer and considerable morbidity. Due to a lack of specific biomarkers, diagnosis is based on symptoms and specific but insensitive imaging features, preventing an early diagnosis and appropriate management. DESIGN: We conducted a type 3 study for multivariable prediction for individual prognosis according to the TRIPOD guidelines. A signature to distinguish CP from controls (n=160) was identified using gas chromatography-mass spectrometry and liquid chromatography-tandem mass spectrometry on ethylenediaminetetraacetic acid (EDTA)-plasma and validated in independent cohorts. RESULTS: A Naive Bayes algorithm identified eight metabolites of six ontology classes. After algorithm training and computation of optimal cut-offs, classification according to the metabolic signature detected CP with an area under the curve (AUC) of 0.85 ((95% CI 0.79 to 0.91). External validation in two independent cohorts (total n=502) resulted in similar accuracy for detection of CP compared with non-pancreatic controls in EDTA-plasma (AUC 0.85 (95% CI 0.81 to 0.89)) and serum (AUC 0.87 (95% CI 0.81 to 0.95)). CONCLUSIONS: This is the first study that identifies and independently validates a metabolomic signature in plasma and serum for the diagnosis of CP in large, prospective cohorts. The results could provide the basis for the development of the first routine laboratory test for CP.

Induction Chemotherapy for Primarily Unresectable Locally Advanced Pancreatic Adenocarcinoma-Who Will Benefit from a Secondary Resection?

Background and Objectives: An increasing number of patients (pts) with locally advanced pancreatic cancer (LAPC) are treated with an intensive neoadjuvant therapy to obtain a secondary curative resection. Only a certain number of patients benefit from this intention. The aim of this investigation was to identify prognostic factors which may predict a benefit for secondary resection. Materials and Methods: Survival time and clinicopathological data of pts with pancreatic cancer were prospective and consecutively collected in our Comprehensive Cancer Center Database. For this investigation, we screened for pts with primarily unresectable pancreatic cancer who underwent a secondary resection after receiving induction therapy in the time between March 2017 and May 2019. Results: 40 pts had a sufficient database to carry out a reliable analysis. The carbohydrate-antigen 19-9 (CA 19-9) level of the pts treated with induction therapy decreased by 44.7% from 4358.3 U/mL to 138.5 U/mL (p = 0.001). The local cancer extension was significantly reduced (p < 0.001), and the Eastern Cooperative Oncology Group (ECOG) performance status was lowered (p = 0.03). The median overall survival (mOS) was 20 months (95% CI: 17.2-22.9). Pts who showed a normal CA 19-9 level (<37 U/mL) at diagnosis and after neoadjuvant therapy or had a Body Mass Index (BMI) below 25 kg/m2 after chemotherapy had a significant prolonged overall survival (29 vs. 19 months, p = 0.02; 26 vs. 18 months, p = 0.04; 15 vs. 24 months, p = 0.01). Pts who still presented elevated CA 19-9 levels >400 U/mL after induction therapy did not profit from a secondary resection (24 vs. 7 months, p < 0.001). Nodal negativity as well as the performance of an adjuvant therapy lead to better mOS (25 vs. 15 months, p = 0.003; 10 vs. 25 months, p < 0.001). Conclusion: The pts in our investigation had different benefits from the multimodal treatment. We identified the CA 19-9 level at time of diagnosis and after neoadjuvant therapy as well as the preoperative BMI as predictive factors for overall survival. Furthermore, diagnostics of presurgical nodal status should gain more importance as nodal negativity is associated with better outcome.

Is there a Role for the Appleby Procedure in 2020? Results from a Matched-Pair-Analysis.

BACKGROUND/AIM: Locally advanced pancreatic cancer (LAPC) of the pancreatic body involving the celiac axis requires specialized treatment, including a subtotal distal pancreatectomy (SDP) with resection of the celiac axis (Appleby procedure). This study aimed to examine the value of the Appleby procedure, in current individualized treatment approaches, and to define its possible therapeutic impact for patients with LAPC. PATIENTS AND METHODS: 20 consecutive patients who underwent SDP with resection of the celiac axis between January 2005 and December 2018 were identified from a prospectively collected database and were matched with 20 patients experiencing SDP without resection of the celiac axis. Both perioperative parameters, as well as the overall postoperative course, were evaluated. RESULTS: The rate of perioperative complications in both groups was comparable (p=0.744). The rate of severe type C postoperative pancreatic haemorrhages (PPH) was significantly lower in patients with resection of the celiac axis compared to those without (p=0.035). CONCLUSION: The Appleby procedure may be considered as a safe and feasible treatment option with favorably fewer postoperative severe bleeding complications. Besides surgical expertise, such procedures, however, require an experienced interventional radiologist and should thus only be performed in high-volume centers.

Postoperative acute necrotizing pancreatitis of the pancreatic remnant (POANP): a new definition of severe pancreatitis following pancreaticoduodenectomy.

BACKGROUND: Recent studies have suggested acute pancreatitis as a separate pancreatic-specific complication following pancreaticoduodenectomy. However, data on necrotizing pancreatitis of the pancreatic remnant is limited. This study aimed to evaluate parameters of patients undergoing completion pancreatectomy (CP) after initial pancreaticoduodenectomy (PD) and compare those with or without necrosis of the pancreatic remanent. METHODS: Patients who underwent CP following PD between January 2005 and December 2017 were identified from a prospectively collected database. Perioperative parameters were recorded, and patients were divided into those with or without histological evidence of necrosis of the pancreatic remnant. RESULTS: Postoperative acute necrotizing pancreatitis (POANP) was histologically detected in 33 (41%) of 79 patients after CP. Serum CRP levels on POD 2 and the day of revision were significantly higher in the POANP group (p < 0.001 for each). POANP was reflected by higher APACHE II and SOFA scores after PD (P < 0.001 for each). Although patients with POANP had an earlier revision, length of ICU and total hospital stay was prolonged (p < 0.001 for each). POANP was associated with more major complications (Clavien-Dindo ≥ 3) and more often necessitated reoperations within 30 days (p < 0.001 for each). CONCLUSION: Patients requiring CP following PD for POANP have an increased risk of major complications, and longer hospital stay. CRP levels, APACHE II and SOFA score, seem to correlate with the severity and might predict POANP. Universally accepted definitions with a clinically validated grading system of severity for POAP and POANP are needed to facilitate appropriate treatment strategies and enable comparison of future studies.

Neoadjuvant Chemotherapy Enhances Local Postoperative Histopathological Tumour Stage in Borderline Resectable Pancreatic Cancer - A Matched-Pair Analysis.

BACKGROUND: Neoadjuvant chemotherapy (NAC) is established in the treatment of ductal pancreatic adenocarcinoma for downsizing borderline-resectable pancreatic cancer (BRPC) and may affect nodal positivity and rates of R0 resection. This study aimed to identify the impact of NAC on postoperative histopathological parameters with a prognostic relevance. PATIENTS AND METHODS: A one-to-three matched-pair analysis, including an overall total of 132 patients (25% treated with NAC and subsequent resection and 75% undergoing upfront surgery) was performed. Influence of NAC on nodal positivity, lymphatic, vascular and perineural invasion, as well as resection stage and grading, was examined. Furthermore, perioperative complications, in-hospital stay, re-admission rates, mortality, as well as preoperative body mass index and American Association of Anesthesiologist classification scores, were evaluated. RESULTS: Patients treated with NAC significantly less frequently had lymphatic tissue invasion (lymph node invasion: 51.5% vs. 72.7%; p=0.032, and lymphatic vessel invasion 9.4% vs. 55.3%; p=0.0004), whereas vascular and perineural invasion, as well as grading and resection state were not significantly different. Carbohydrate antigen 19-9 regression in correlation with nodal positivity also did not differ, and both groups showed comparable perioperative complication rates. Occurrence and severity of postoperative pancreatic fistula (18.2% vs. 24.3%; p=0.034) were significantly lower in patients who had undergone NAC. CONCLUSION: NAC significantly affects postoperative histopathological tumour stage in BRPC and appears to be a safe treatment option without increased perioperative complications, re-admission, in-hospital stay, or mortality. Further studies are mandatory to underline the suitability of NAC for ductal pancreatic adenocarcinoma subgroups in order to guide clinicians in their daily decision-making comprehensively.

Influence of the body mass index on postoperative outcome and long-term survival after pancreatic resections in patients with underlying malignancy.

BACKGROUND: While the long-term survival rate among patients with pancreatic and periampullary carcinomas remains low, it can be influenced by various factors. The purpose of this retrospective study was to investigate the effects of body mass index (BMI) on postoperative complications and patient survival after pancreatic resections for underlying malignancy over a 20-year observation period. METHODS: We analyzed 1,384 patients, 918 patients with pancreatic ductal adenocarcinoma (PDAC) (66.3%), 229 patients with distal cholangiocarcinoma (16.5%), 206 ampullary carcinoma patients (14.8%), and 31 duodenal carcinoma patients (2.2%). Patients were classified into four groups (group 1 <18.5; group 2, 18.5-25.0; group 3, 25.1-30.0; group 4 >30.0) according to their BMI (kg/m2). We analyzed differences in postoperative complications, postoperative length of hospital stays, reoperations, postoperative mortality and survival rate among the groups. RESULTS: Within a mean observation period of 687.7 [2-8,500] days, 735 (53.1%) patients died. There were important differences in postoperative complications (group 1, 16.2%; group 2, 20.3%; group 3, 27.2%, group 4, 41.6%) with the type of postoperative complications also varying between the groups. Overall 1-, 5-, 10- and 15-year survival rates were 66.4%, 25.5%, 17.9%, and 12.1%, respectively, with survival rates varying amongst the four groups. CONCLUSIONS: Patients with a BMI between 18.5 and 30 show better postoperative outcomes, regarding complications, hospitalization duration, and reoperation rates than underweight or obese patients. Short-term survival depends strongly on postoperative complications while patients with a higher BMI show better long-term survival rates.

Analysis of outcomes and predictors of long-term survival following resection for retroperitoneal sarcoma.

BACKGROUND: Retroperitoneal sarcomas (RPS) include a heterogeneous group of rare malignant tumours, and various treatment algorithms are still controversially discussed until today. The present study aimed to examine postoperative and long-term outcomes after resection of primary RPS. PATIENTS AND METHODS: Clinicopathological data of patients who underwent resection of primary RPS between 2005 and 2015 were assessed, and predictors for overall survival (OS) and disease-free survival (DFS) were identified. RESULTS: Sixty-one patients underwent resection for primary RPS. Postoperative morbidity and mortality rates were 31 and 3%, respectively. After a median follow-up time of 74 months, 5-year OS and DFS rates were 58 and 34%, respectively. Histologic high grade (5-year OS: G1: 92% vs. G2: 54% vs. G3: 43%, P = 0.030) was significantly associated with diminished OS in univariate and multivariate analyses. When assessing DFS, histologic high grade (5-year DFS: G1: 63% vs. G2: 24% vs. G3: 22%, P = 0.013), positive surgical resection margins (5-year DFS: R0: 53% vs. R1: 10% vs. R2: 0%, P = 0.014), and vascular involvement (5-year DFS: yes: 33% vs no: 39%, P = 0.001), were significantly associated with inferior DFS in univariate and multivariate analyses. CONCLUSIONS: High-grade tumours indicated poor OS, while vascular involvement, positive surgical resection margins, and histologic grade are the most important predictors of DFS. Although multimodal treatment strategies are progressively established, surgical resection remains the mainstay in the majority of patients with RPS, even in cases with vascular involvement.

EUS-guided drainage in the management of postoperative pancreatic leaks and fistulas (with video).

BACKGROUND AND AIMS: Postoperative pancreatic leakage and fistulae (POPF) are a leading adverse event after partial pancreatic resection. Treatment algorithms are currently not standardized. Evidence regarding the role of endoscopy is scarce. METHODS: One hundred ninety-six POPF patients with (n = 132) and without (n = 64) concomitant pancreatic fluid collections (PFCs) from centers in Berlin, Kiel, and Dresden were analyzed retrospectively. Clinical resolution was used as the primary endpoint of analysis. RESULTS: Analysis was stratified by the presence or absence of a PFC because these patients differed in treatment pathway and the presence of systemic inflammation with a median C-reactive protein of 30.7 mg/dL in patients without a PFC versus 131.0 mg/dL in patients with a PFC (P = 3.4 × 10-4). In patients with PFCs, EUS-guided intervention led to resolution in a median of 8 days as compared with 25 days for percutaneous drainage and 248 days for surgery (P = 3.75 × 10-14). There was a trend toward a higher success rate of EUS-guided intervention as a primary treatment modality with 85% (P = .034), followed by percutaneous drainage (64%) and surgery (41%). When applied as a rescue intervention (n = 24), EUS led to clinical resolution in 96% of cases. In patients without PFCs, EUS-guided internalization in a novel endoscopic technique led to resolution after a median of 4 days as compared with 51 days for a remaining surgical drainage (P = 9.3 × 10-9). CONCLUSIONS: In this retrospective analysis, EUS-guided drainage of POPF led to a more rapid resolution. EUS may be considered as a viable option in the management of PFCs and POPF and should be evaluated in prospective studies.

Strengths, Weaknesses, Opportunities, and Threats of Centralized Pancreatic Surgery: a Single-Center Analysis of 3000 Consecutive Pancreatic Resections.

BACKGROUND: Pancreatic surgery at high-volume centers has undergone major changes over the last decades. However, the quality of surgery remains to be considered as one important factor for achieving long-term survival especially in patients at advanced stages of disease. METHODS: Between January 1990 and June 2017, 3000 consecutive patients have undergone pancreatic resections at our institution. Relevant postoperative data and histopathological findings as well as overall survival were analyzed. In addition, a SWOT (strengths, weaknesses, opportunities, threats) analysis of pancreatic surgery at high-volume centers was performed. RESULTS: A total of 2218 pancreatic head resections (74%), 494 distal pancreatectomies (16%), 200 total pancreatectomies (7%), and 88 other resections (3%) were performed within our study period. Despite additional vascular resections in 265 patients (9%) and additional liver resections in 167 patients (6%), overall perioperative mortality did not exceed 3%. Overall survival strongly depended on the underlying disease, as well as on lymph node stage (p = < 0.001) and surgical radicality (p = < 0.001). CONCLUSIONS: The decentralization of pancreatic surgery over the last decades has led to a focus on high-volume centers to perform extended procedures in complex patients. The present SWOT analysis underlines the significance of a centralization of pancreatic surgery for patient safety and to increase the chance of long-term survival.

The role of hepatectomy for synchronous liver metastases from pancreatic adenocarcinoma.

BACKGROUND: The role of hepatectomy for patients with liver metastases from ductal adenocarcinoma of the pancreas (PLM) remains controversial. Therefore, the aim of our study was to examine the postoperative morbidity, mortality, and long-term survivals after liver resection for synchronous PLM. METHODS: Clinicopathological data of patients who underwent hepatectomy for PLM between 1993 and 2015 were assessed. Major endpoint of this study was to identify predictors of overall survival (OS). RESULTS: During the study period, 76 patients underwent resection for pancreatic cancer and concomitant hepatectomy for synchronous PLM. Pancreatoduodenectomy, distal pancreatectomy, and total pancreatectomy were performed in 67%, 25%, and 8% of the patients, respectively. The median PLM size was 1 (1-13) cm and 36% of patients had multiple PLM. The majority of patients (96%) underwent a minor liver resection. After a median follow-up time of 130 months, 1-, 3-, and 5-year OS rates were 41%, 13%, and 7%, respectively. Postoperative morbidity and mortality rates were 50% and 5%, respectively. Preoperative and postoperative chemotherapy was administered to 5% and 72% of patients, respectively. In univariate analysis, type of pancreatic procedure (P = .020), resection and reconstruction of the superior mesenteric artery (P = .016), T4 stage (P = .086), R1 margin status at liver resection (P = .001), lymph node metastases (P = .016), poorly differentiated cancer (G3) (P = .037), no preoperative chemotherapy (P = .013), and no postoperative chemotherapy (P = .005) were significantly associated with worse OS. In the multivariate analysis, poorly differentiated cancer (G3) (hazard ratio [HR] = 1.87; 95% confidence interval [CI] = 1.08-3.24; P = .026), R1 margin status at liver resection (HR = 4.97; 95% CI = 1.46-16.86; P = .010), no preoperative chemotherapy (HR = 4.07; 95% CI = 1.40-11.83; P = .010), and no postoperative chemotherapy (HR = 1.88; 95% CI = 1.06-3.29; P = .030) independently predicted worse OS. CONCLUSIONS: Liver resection for PLM is feasible and safe and may be recommended within the framework of an individualized cancer therapy. Multimodal treatment strategy including perioperative chemotherapy and hepatectomy may provide prolonged survival in selected patients with metastatic pancreatic cancer.

Clinicopathological Stratification and Long-term Follow-up of Patients with Periampullary Carcinomas.

BACKGROUND: Periampullary carcinomas generally confer a poor outcome. Choosing the most effective treatment regimen for each sub-entity proves challenging and is usually based on experience from pancreatic adenocarcinoma (PDAC). PATIENTS AND METHODS: The long-term follow-up is presented of 472 patients with periampullary tumors [PDAC, distal cholangiocarcinoma (dCC) and ampullary carcinomas (AC)] who underwent radical resection considering clinical characteristics, paraclinical findings and histopathological features in order to define factors of prognostic relevance. RESULTS: Patients with PDACs presented with larger tumor sizes, more frequent R1 resection, higher rate of nodal and perineural invasion, higher tumor stage according to the classification of tumors of the Union Internationale contre le Cancer when compared to those with dCCs and ACs. In a multivariate analysis, age >65 years, postoperative complications and higher grading of the tumor proved to be independent prognostic factors for survival. CONCLUSION: Patients suffering from PDAC have the worst prognosis and greatest benefit from radical resection of all patients with periampullary tumors. More detailed studies are warranted to better distinguish between the different entities.

A Bi-national Analysis of 252 Pancreatic Resections for Chronic Pancreatitis with Regard to Incidental Carcinoma Sequence and Overall Postoperative Outcome.

BACKGROUND/AIM: Numerous treatment algorithms for patients with chronic pancreatitis are still debated. In particular, surgical therapy is often only considered after long-term conservative treatment. The aim of this study was the bi-national analysis of patients who underwent pancreatic resection for suspected chronic pancreatitis at an Austrian and a German high-volume center with regard to overall postoperative outcome and incidental carcinoma sequence. PATIENTS AND METHODS: Overall, 252 consecutive pancreatic resections for suspected chronic pancreatitis were performed at the two institutions between 2005 and 2015. In a bi-national retrospective analysis, postoperative results as well as histopathological findings were analyzed. RESULTS: Pancreatic resections were performed in 193 male (76.6%) and 59 female patients (23.4%), with a median age of 53.2 years. A total of 175 resections of the pancreatic head (69.4%), 37 distal pancreatectomies (14.7%), 23 total pancreatectomies (9.1%) and 18 other pancreatic resections (7.1%) were performed within our study period. Postoperative complications Clavien-Dindo grade II or greater occurred in 94 patients (37.3%). Twenty-one patients (8.3%) developed clinically relevant postoperative pancreatic fistula (grade B and C), while postoperative mortality occurred in four patients (1.6%). Final histological examination of the operative specimen revealed incidental pancreatic adenocarcinoma in 18 out of the 252 patients (7.1%). CONCLUSION: The results of our study demonstrate that pancreatic resections for chronic pancreatitis may nowadays be considered technically feasible and safe. The high incidence of incidental pancreatic adenocarcinoma especially underlines the necessity for an early surgical therapeutic approach for these patients.

Safety and efficacy of Nab-paclitaxel plus gemcitabine in patients with advanced pancreatic cancer suffering from cholestatic hyperbilirubinaemia-A retrospective analysis.

INTRODUCTION: Treatment of patients with advanced pancreatic carcinoma (APC) and hyperbilirubinaemia is problematic because these patients were regularly excluded from clinical studies. Nanoparticle albumin-bound paclitaxel and gemcitabine (nab-P/G) is an evidence-based treatment for patients with APC. This retrospective study investigated the safety and efficacy of nab-P/G in patients with APC and cholestatic hyperbilirubinaemia. METHODS: We screened our prospective database for patients with APC treated with nab-P/G at total bilirubin levels of ≥1.2 mg/dl. Patients were assigned into three groups according to their bilirubin level (A: 1.2-3 mg/dl, B: >3-5 mg/dl, C: >5 mg/dl). Analyses with regard to safety and survival were performed. RESULTS: Twenty-nine of 168 patients screened between Dec 2013 and Dec 2015 fulfilled the inclusion criteria. Most patients (83%) were male; median age was 63 [41-79] years. Nab-P/G administrations in patients with an elevated bilirubin level (median, range) did not result in unexpected toxicities assessed by predefined (non-)haematological parameters. Median overall survival (mOS) for the whole group was 11.7 (95% confidence interval [CI]: 6.8-14.0) months; for A: 11.8 (95% CI: 6.5-16.5), B: 9.2 (95% CI: 1.1 - NA) months and C 11.8 (95% CI: 5.9-20.0] months (p = 0.843). Again, mOS from the first application of nab-P/G did not differ between the groups (p = 0.13). CONCLUSION: Nab-P/G administrations in our pts with cholestatic hyperbilirubinaemia suffering from APC were feasible and safe with respect to individualised dose administrations. A multicenter phase 1 trial in pts with hyperbilirubinaemia is started (AIO-PAK-0117) to confirm these findings in a prospective setting.

Routine portal vein resection for pancreatic adenocarcinoma shows no benefit in overall survival.

BACKGROUND: Extended pancreatic resections including resections of the portal (PV) may nowadays be performed safely. Limitations in distinguishing tumor involvement from inflammatory adhesions however lead to portal vein resections (PVR) without evidence of tumor infiltration in the final histopathological examination. The aim of this study was to analyze the impact of these "false negative" resections on operative outcome and long-term survival. METHODS: 40 patients who underwent pancreatic resection with PVR for pancreatic adenocarcinoma (PA) without tumor infiltration of the PV (PVR-group) were identified. In a 1:3 match these patients were compared to 120 patients after standard pancreatic resection without PVR (SPR-group) with regard to operative outcome and overall survival. RESULTS: Survival analysis revealed that median survival was significantly shorter in the PVR group (311 days) as compared to the SPR group (558 days), (p = 0.0011, hazard ratio 1.98, 95% CI: 1.31-2.98). Also postoperative complications ≥ Clavien III occurred significantly more often in the PVR group (37.5% vs. 20.8%). CONCLUSIONS: Radical resection affords the best chance for long-term survival in patients with PA. Based on the results of this study a routine resection of the PV as recently proposed may however not be recommended.

Distal Pancreatectomy Combined with Multivisceral Resection Is Associated with Postoperative Complication Rates and Survival Comparable to Those After Standard Procedures.

BACKGROUND: For pancreatic tumors located in the body or tail of the pancreas, distal pancreatectomy (DP) remains the surgical procedure of choice to achieve radical tumor removal. Purpose of this study was to evaluate outcome and overall survival of patients who underwent DP combined with multivisceral resection (MVR). METHODS: Retrospective single-center case-matched analysis. Between January 1994 and June 2014, 494 consecutive patients were entered into a prospective database, and 126 patients undergoing DP + MVR (cases) were matched with 126 patients undergoing DP (controls) for gender, age, and underlying final diagnosis. RESULTS: There were no significant differences in patient demographics. Rates of postoperative pancreatic fistula (POPF) (36 (28.6%) vs. 29 (23.0%); p = 0.388) and postpancreatectomy hemorrhage (PPH) (7 (5.5%) vs. 5 (3.9%); p = 0.769) did not reveal any significant differences. Although operative time (237.8 ± 57.9 vs. 203.5 ± 34.5; p < 0.001) and the necessity for intraoperative transfusions (18 (14.3%) vs. 5 (4.0%); p < 0.001) was significantly higher, the number of patients with major complications (the Clavien-Dindo ≥ 3) was not increased (27 (19.8%) vs. 20 (15.9%); p = 0.332) in the DP + MVR group. Midterm survival analysis indicated no significant difference for adenocarcinoma and neuroendocrine tumors for either group. CONCLUSION: DP + MVR is a feasible and safe surgical procedure to achieve radical tumor removal and can offer beneficial survival outcomes. Although operative time and intraoperative transfusions are enhanced, POPF, PPH, or major complications (the Clavien-Dindo ≥ 3) are not significantly increased after DP + MVR. DP + MVR can therefore be recommended in selected patients for resection of extended tumors within the concept of interdisciplinary strategies.

Tumour buds determine prognosis in resected pancreatic ductal adenocarcinoma.

BACKGROUND: The prognostic effect of tumour budding was retrospectively analysed in a cohort of 173 patients with resected pancreatic ductal adenocarcinomas (PDACs) of the prospective clinical multicentre CONKO-001 trial. METHODS: Haematoxylin and eosin (H&E)-stained whole tissue slides were evaluated. In two independent approaches, the mean number of tumour buds was analysed according to the consensus criteria in colorectal cancer, in one 0.785 mm2 field of view and additionally in 10 high-power fields (HPF) (HPF = 0.238 mm2). RESULTS: Tumour budding was significantly associated with a higher tumour grade (p < 0.001) but not with distant or lymph node metastasis. Regardless of the quantification approach, an increased number of tumour buds was significantly associated with reduced disease-free survival (DFS) and overall survival (OS) (10 HPF approach DFS: HR = 1.056 (95% CI 1.022-1.092), p = 0.001; OS: HR = 1.052 (95% CI 1.018-1.087), p = 0.002; consensus method DFS: HR = 1.037 (95% CI 1.017-1.058), p < 0.001; OS: HR = 1.040 (95% CI 1.019-1.061), p < 0.001). Recently published cut-offs for tumour budding in colorectal cancer were prognostic in PDAC as well. CONCLUSIONS: Tumour budding is prognostic in the CONKO-001 clinical cohort of patients. Further standardisation and validation in additional clinical cohorts are necessary.

Dose-escalated radiotherapy for unresectable or locally recurrent pancreatic cancer: Dose volume analysis, toxicity and outcome of 28 consecutive patients.

PURPOSE: The role of radiotherapy for unresectable pancreatic cancer is controversial. A benefit of additional radiotherapy is supported by some observations. A dose-effect relationship was recently found by dose escalation employing image guided and intensity modulated radiotherapy. METHODS: We retrospectively evaluated 28 consecutive patients, all with history of extensive prior therapies for unresectable locally advanced/ recurrent pancreatic cancer (LAPC/LRPC). Treatment was delivered by helical tomotherapy after daily position verification with computed tomography. Dose to the planned target volume (PTV) was 51 Gy, while the dose to the macroscopic tumor was escalated by a simultaneous integrated boost to a median cumulative dose of 66 Gy (60-66 Gy). Concomitant chemotherapy consisted mainly of capecitabine (n = 23). RESULTS: 10 of 28 patients presented acute toxicities > grade 2, one patient succumbed to gastrointestinal bleeding after treatment. No correlations of toxicities and dose volume histograms (DVH) of retrospectively delineated small bowel loops were observed, although average small bowel volume receiving ≥ 20 Gy was 374 ml. DVH analyses revealed a correlation of splenic parameters and acute toxicity: Vomiting, anorexia, dehydration, hematologic toxicity, fatigue, combined gastro-intestinal toxicity wit R-values between 0.392 and 0.561 (all p-values > 0.05). Only one patient developed late toxicities > grade 2. With an average follow-up time in surviving patients of 14 months median overall survival time was 19 months and median time to local recurrence 13 months. In 8 patients with available imaging of local recurrence: 5 in field recurrences, 2 marginal recurrences and one lymph node recurrence outside the high dose radiation field were observed. In univariate analysis only ΔCA-19-9 during radiotherapy was associated with local control (p = 0.029) and overall survival (p = 0.049). CONCLUSION: Dose escalated normo-fractionated radiotherapy for LAPC/LRPC seems feasible and suitable to prolong local control and in consequence long-term survival. However, in-field local progression is still frequently observed and possibilities to increase the local effectiveness should be evaluated. Exposure of the spleen was predictive for acute toxicity and should be further investigated.

Incidence and Oncological Implications of Previously Undetected Tumor Multicentricity Following Pancreaticoduodenectomy for Pancreatic Adenocarcinoma in Patients Undergoing Salvage Pancreatectomy.

BACKGROUND: The risk for multicentricity of pancreatic adenocarcinoma remains unclear and the question whether pancreaticoduodenectomy represents sufficient oncological treatment for patients with ductal adenocarcinoma of the head of the pancreas needs further investigation. PATIENTS AND METHODS: Clinicopathological data of patients who underwent pancreaticoduodenectomy for pancreatic adenocarcinoma between 2005 and 2015 were assessed and the incidence of tumor multicentricity among patients who required salvage pancreatectomy within 90 postoperative days was evaluated. RESULTS: Pancreaticoduodenectomy was performed in 1,005 patients. Sixty-two patients (6%) suffered a major postoperative complication (pancreatic fistula/anastomotic leak/bleeding) after resection of the head of the pancreas, requiring salvage pancreatectomy. Histological examination of the pancreatic remnant in patients with ductal adenocarcinoma (n=19) revealed multicentric carcinoma in two patients, resulting in an incidence of 11% for tumor multicentricity. Preoperative cross-sectional imaging failed to identify tumor multicentricity in these patients. Additionally, two patients with pancreatic intraepithelial neoplasia and two with neuroendocrine tumor were identified. CONCLUSION: The incidence of previously undetected multicentric adenocarcinoma among patients undergoing salvage pancreatectomy in our study was surprisingly high. This finding suggests that the role of total pancreatectomy for pancreatic head cancer, as well as the current strategies for postoperative tumor surveillance, should be re-evaluated in order to provide the best oncological approach and prolonged survival for patients with ductal adenocarcinoma.