Patient-reported outcomes at three months after pancreatic surgery for benign and malignant diseases - A prospective observational study.

BACKGROUND/OBJECTIVES: Pancreatic surgery may have a long-lasting effect on patients' health status and quality of life (QoL). We aim to evaluate patient-reported outcomes (PRO) 3 months after pancreatic surgery. METHODS: Patients scheduled for pancreatic surgery were enrolled in a prospective trial at five German centers. Patients completed PRO questionnaires (EQ-5D-5L, EORTC QLQ-PAN26, patient-reported happiness, and HADS-D), we report the first follow-up 3 months after surgery as an interim analysis. Statistical testing was performed using R software. RESULTS: From 2019 to 2022 203 patients were enrolled, a three-month follow-up questionnaire was available in 135 (65.5 %). 77 (57.9 %) underwent surgery for malignant disease. Patient-reported health status (EQ-5D-5L) was impaired in 4/5 dimensions (mobility, self-care, usual activities, pain, discomfort) for patients with malignant and 3/5 dimensions (mobility, self-care, usual activities) for patients with benign disease 3 months after surgery (p < 0.05). Patients with malignant disease reported an increase in depressive symptoms, patients with benign disease had a decrease in anxiety symptoms (HADS-D; depression: 5.00 vs 6.51, p = 0.002; anxiety: 8.04 vs. 6.34, p = 0.030). Regarding pancreatic-disease-specific symptoms (EORTC-QLQ-PAN26), patients with malignant disease reported increased problems with taste, weight loss, weakness in arms and legs, dry mouth, body image and troubling side effects at three months. Patients with benign disease indicated more weakness in arms and legs, troubling side effects but less future worries at three months. CONCLUSION: Patient-reported outcomes of patients undergoing pancreatic surgery for benign vs. malignant disease show important differences. Patients with malignant tumors report more severely decreased quality of life 3 months postoperatively than patients with benign tumors.

The Role of Adjuvant Therapy in Duodenal Adenocarcinoma and Intestinal Subtype Ampullary Carcinoma after Curative Resection.

OBJECTIVE: Defining the role of adjuvant therapy in duodenal adenocarcinoma (DAC) and intestinal subtype ampullary carcinoma (iAC). SUMMARY BACKGROUND DATA: DAC and iAC share a similar histological differentiation but the benefit of adjuvant therapy remains unclear. METHODS: Patients undergoing curative-intent surgical resection for DAC and iAC between 2010 and 2021 at five high-volume centers were included. Patient baseline, perioperative and long-term oncological outcomes were evaluated. Statistical testing was performed with SPSS 25 (IBM). RESULTS: A total of 136 patients with DAC and 171 with iAC were identified. Patients with DAC had more advanced tumors than those with iAC. Median overall survival (OS) in DAC patients was 101 months versus 155 months for iAC patients (P=0.098). DAC had a higher rate of local (14.1% vs. 1.2%, P<0.001) and systemic recurrence (30.4% vs. 3.5%, P<0.001). Adjuvant therapy failed to improve overall survival in all patients with DAC and iAC. For DAC, patients with perineural invasion, but not other negative prognostic factors had improved OS rates with adjuvant therapy (72 m vs. 44 m, P=0.044). IAC patients with N+ (190 m vs. 57 m, P=0.003), T3-4 (177 m vs. 59 m, P=0.050) and perineural invasion (150 m vs. 59 m, P=0.019) had improved OS rates with adjuvant therapy. CONCLUSION: While adjuvant therapy fails to improve OS in all patients with DAC and iAC in the current study, it improved overall survival in DAC patients with perineural invasion and in iAC patients with T3-4 tumors, positive lymph nodes, and perineural invasion.

Comparison of Tumour-Specific Phenotypes in Human Primary and Expandable Pancreatic Cancer Cell Lines.

There is an ongoing need for patient-specific chemotherapy for pancreatic cancer. Tumour cells isolated from human tissues can be used to predict patients' response to chemotherapy. However, the isolation and maintenance of pancreatic cancer cells is challenging because these cells become highly vulnerable after losing the tumour microenvironment. Therefore, we investigated whether the cells retained their original characteristics after lentiviral transfection and expansion. Three human primary pancreatic cancer cell lines were lentivirally transduced to create expandable (Ex) cells which were then compared with primary (Pri) cells. No obvious differences in the morphology or epithelial-mesenchymal transition (EMT) were observed between the primary and expandable cell lines. The two expandable cell lines showed higher proliferation rates in the 2D and 3D models. All three expandable cell lines showed attenuated migratory ability. Differences in gene expression between primary and expandable cell lines were then compared using RNA-Seq data. Potential target drugs were predicted by differentially expressed genes (DEGs), and differentially expressed pathways (DEPs) related to tumour-specific characteristics such as proliferation, migration, EMT, drug resistance, and reactive oxygen species (ROS) were investigated using the Kyoto Encyclopedia of Genes and Genomes (KEGG) database. We found that the two expandable cell lines expressed similar chemosensitivity and redox-regulatory capability to gemcitabine and oxaliplatin in the 2D model as compared to their counterparts. In conclusion, we successfully generated expandable primary pancreatic cancer cell lines using lentiviral transduction. These expandable cells not only retain some tumour-specific biological traits of primary cells but also show an ongoing proliferative capacity, thereby yielding sufficient material for drug response assays, which may provide a patient-specific platform for chemotherapy drug screening.

Impact of spleen preservation on the incidence of postoperative pancreatic fistula after distal pancreatectomy: Is less more?

BACKGROUND: Postoperative pancreatic fistula (POPF) remains a major complication after distal pancreatectomy (DP) with a significant impact on patients' quality of life. There is limited evidence that preservation of the spleen reduces the risk of POPF. Therefore, we aimed to investigate the impact of splenectomy on perioperative outcome. METHODS: Data from patients who underwent DP for malignant and benign disease at our institution between 2004 and 2021 were reviewed. Patients were grouped according to spleen preservation (SP-DP) and splenectomy (DPS). Intraoperative parameters and postoperative outcomes were compared between groups. Univariable and multivariable analyses were used to investigate factors that influence the occurrence of clinically relevant (cr)POPF. RESULTS: A total of 199 patients were included, of whom 61 (30.7%) patients underwent SP-DP. Patients who underwent SP-DP had a significantly lower rate of crPOPF (p = 0.022), shorter hospital stay (p = 0.003), and less readmissions (p = 0.012). On multivariate analysis, obesity (OR 2.88, p = 0.021), benign lesions (OR 2.35, p = 0.018), postoperative acute pancreatitis (OR 2.53, p = 0.028), and splenectomy (OR 2.83, p = 0.011) were independent risk factors associated with the onset of crPOPF. DISCUSSION: Preservation of the spleen reduces the risk of crPOPF in patients undergoing distal pancreatectomy for benign and malignant disease.

Repeated resection for recurrent intrahepatic cholangiocarcinoma: A retrospective German multicentre study.

BACKGROUND: Tumour recurrence is common after resection of intrahepatic cholangiocarcinoma (ICC). Repeated resection is a potential curative treatment, but outcomes are not well-defined thus far. The aim of this retrospective multicentre cohort study was to show the feasibility and survival of repeated resection of ICC recurrence. METHODS: Data were collected from 18 German hepato-pancreatico-biliary centres for patients who underwent repeated exploration of recurrent ICC between January 2008 and December 2017. Primary end points were overall (OS) and recurrence-free survival from the day of primary and repeated resection. RESULTS: Of 156 patients who underwent repeated exploration for recurrent ICC, 113 underwent re-resection. CA19-9 prior to primary resection, R status of first liver resection and median time to recurrence were significant determinants of repeated resectability. Median OS in the repeated resection group was 65.2 months, with consecutive 1-, 3- and 5-year OS of 98%, 78% and 57% respectively. After re-exploration, median OS from primary resection was 46.7 months, with a consecutive 1-, 3- and 5-year OS of 95%, 55% and 22% respectively. From the day of repeated resection, the median OS was 36.8 months, with a consecutive 1-, 3- and 5-year OS of 86%, 51% and 34% respectively. Minor morbidity (grade I+II) was present in 27%, grade IIIa-IVb morbidity in 20% and mortality in 3.5% of patients. CONCLUSION: Repeated resection of ICC has acceptable morbidity and mortality and seems to be associated with improved long-term survival. Structured follow-up after resection of ICC is necessary for early identification of these patients.

Adipose-Derived Biogenic Nanoparticles for Suppression of Inflammation.

Extracellular vesicles secreted from adipose-derived mesenchymal stem cells (ADSCs) have therapeutic effects in inflammatory diseases. However, production of extracellular vesicles (EVs) from ADSCs is costly, inefficient, and time consuming. The anti-inflammatory properties of adipose tissue-derived EVs and other biogenic nanoparticles have not been explored. In this study, biogenic nanoparticles are obtained directly from lipoaspirate, an easily accessible and abundant source of biological material. Compared to ADSC-EVs, lipoaspirate nanoparticles (Lipo-NPs) take less time to process (hours compared to months) and cost less to produce (clinical-grade cell culture facilities are not required). The physicochemical characteristics and anti-inflammatory properties of Lipo-NPs are evaluated and compared to those of patient-matched ADSC-EVs. Moreover, guanabenz loading in Lipo-NPs is evaluated for enhanced anti-inflammatory effects. Apolipoprotein E and glycerolipids are enriched in Lipo-NPs compared to ADSC-EVs. Additionally, the uptake of Lipo-NPs in hepatocytes and macrophages is higher. Lipo-NPs and ADSC-EVs have comparable protective and anti-inflammatory effects. Specifically, Lipo-NPs reduce toll-like receptor 4-induced secretion of inflammatory cytokines in macrophages. Guanabenz-loaded Lipo-NPs further suppress inflammatory pathways, suggesting that this combination therapy can have promising applications for inflammatory diseases.

The MEGNA Score and Preoperative Anemia are Major Prognostic Factors After Resection in the German Intrahepatic Cholangiocarcinoma Cohort.

BACKGROUND: Surgical resection is associated with the best long-term results for intrahepatic cholangiocarcinoma (ICC); however, long-term outcomes are still poor. OBJECTIVE: The primary aim of this study was to validate the recently proposed MEGNA score and to identify additional prognostic factors influencing short- and long-term survival. PATIENTS AND METHODS: This was a retrospective analysis of a German multicenter cohort operated at 10 tertiary centers from 2004 to 2013. Patients were clustered using the MEGNA score and overall survival was analyzed. Cox regression analysis was used to identify prognostic factors for both overall and 90-day survival. RESULTS: A total of 488 patients undergoing liver resection for ICC fulfilled the inclusion criteria and underwent analysis. Median age was 67 years, 72.5% of patients underwent major hepatic resection, and the lymphadenectomy rate was 86.9%. Median overall survival was 32.2 months. The MEGNA score significantly discriminated the long-term overall survival: 0 (68%), I (48%), II (32%), and III (19%) [p <0.001]. In addition, anemia was an independent prognostic factor for overall survival (hazard ratio 1.78, 95% confidence interval 1.29-2.45; p <0.01). CONCLUSION: Hepatic resection provides the best long-term survival in all risk groups (19-65% overall survival). The MEGNA score is a good discriminator using histopathologic items and age for stratification. Correction of anemia should be attempted in every patient who responds to treatment. Perioperative liver failure remains a clinical challenge and contributes to a relevant number of perioperative deaths.

Adjuvant therapy is associated with improved overall survival in patients with pancreatobiliary or mixed subtype ampullary cancer after pancreatoduodenectomy - A multicenter cohort study.

BACKGROUND/OBJECTIVE: The benefit of adjuvant therapy in ampullary cancer (AMPAC) patients following pancreatoduodenectomy (PD) is debated. The aim of this study was to determine the role of adjuvant therapy after pancreatoduodenectomy (PD) in histological subtypes of AMPAC. METHODS: Patients undergoing PD for AMPAC at 5 high-volume European surgical centers from 1996 to 2017 were identified. Patient baseline characteristics, surgical and histopathological parameters, and long-term overall survival (OS) after resection were evaluated. RESULTS: 214 patients undergoing PD for AMPAC were included. ASA score (ASA1-2 149 vs. ASA 3-4 82 months median OS, p = 0.002), preoperative serum CEA (CEA <0.5 ng/ml 128 vs. CEA >0.5 ng/ml 62 months, p = 0.013), preoperative serum CA19-9 (CA19-9 < 40 IU/ml 147 vs. CA19-9 > 40IU/ml 111 months, p = 0.042), T stage (T1-2 163 vs. T3-4 98 months, p < 0.001), N stage (N0 159 vs. N+ 110 months, p < 0.001), grading (G1-2 145 vs. G3-4 113 months, p = 0.026), R status (R0 136 vs. R+ 38 months, p = 0.031), and histological subtype (intestinal subtype 156 vs. PB/M subtype 118 months, p = 0.003) qualified as prognostic parameters. In multivariable analysis, ASA score (HR 1.784, 95%CI 0.997-3.193, p = 0.050) and N stage (HR 1.831, 95%CI 0.904-3.707, p = 0.033) remained independent prognostic factors. In PB/M subtype AMPAC, patients undergoing adjuvant therapy showed an improved median overall survival (adjuvant therapy 85 months vs. no adjuvant therapy 65 months, p = 0.005), and adjuvant therapy remained an independent prognostic parameter in multivariate analysis (HR 0.351, 95%CI 0.151-0.851, p = 0.015). There was no significant benefit of adjuvant therapy in intestinal subtype AMPAC patients. CONCLUSION: Adjuvant treatment seems indicated in pancreatobiliary or mixed type AMPAC.

Downregulation of SPARC Is Associated with Epithelial-Mesenchymal Transition and Low Differentiation State of Biliary Tract Cancer Cells.

BACKGROUND: Biliary tract cancers (BTCs) have a poor prognosis. BTCs are characterized by a prominent desmoplastic reaction which possibly contributes to the aggressive phenotype of this tumor. The desmoplastic reaction includes excessive production and deposition of extracellular matrix proteins such as periostin, secreted protein acidic and rich in cysteine (SPARC), thrombospondin-1, as well as accumulation of α-smooth muscle actin-positive cancer-associated fibroblasts and immune cells, secreting growth factors and cytokines including transforming growth factor (TGF)-ß. In the present study, we investigated the expression of SPARC in BTC as well as its possible regulation by TGF-ß. METHODS: Expression levels of Sparc, TGF-ß1 and its receptor ALK5 were evaluated by quantitative real-time PCR in 6 biliary tract cell lines as well as 1 immortalized cholangiocyte cell line (MMNK-1). RNAs from tumor samples of 7 biliary tract cancer patients were analyzed for expression of Sparc, TGF-ß type II receptor (TbRII) as well as Twist and ZO-1. MMNK-1 cells were stimulated with TGF-ß for 24 h, and Sparc, ZO-1 and E-Cadherin expressions were determined. The presence of SPARC protein was analyzed by immunohistochemistry in tumor specimens from 10 patients. RESULTS: When comparing basal Sparc transcript levels in diverse BTC cell lines to MMNK-1 cells, we found that it was strongly downregulated in all cancer cell lines. The remaining expression levels were higher in highly differentiated cell lines (CCSW1, MZChA1, MZChA2 and TFK-1) than in less differentiated and undifferentiated ones (BDC, SKChA1). Expression of Sparc in BTC patient samples showed a significant positive correlation with expression of the epithelial marker ZO-1. In contrast, the mesenchymal marker Twist and the TbRII showed a trend of negative correlation with expression of Sparc in these samples. TGF-ß exposure significantly downregulated Sparc expression in MMNK-1 cholangiocytes in vitro in parallel to downregulation of epithelial markers (E-Cadherin and ZO-1). Finally, SPARC immunostaining was performed in 10 patient samples, and the correlation between absence of SPARC and survival times was analyzed. CONCLUSIONS: These data imply that a decrease in SPARC expression is correlated with dedifferentiation of BTC cells resulting in enhanced EMT being possibly mediated by TGF-ß. Thereby SPARC levels might be a marker for individual prognosis of a patient, and strategies aiming at inhibition of SPARC downregulation might have potential for new future therapies.

Early postoperative pancreatitis following pancreaticoduodenectomy: what is clinically relevant postoperative pancreatitis?

BACKGROUND/OBJECTIVES: Postoperative pancreatitis (POP) has recently been shown to be the cause of pancreatic fistula (POPF) following pancreaticoduodenectomy (PD). The aim of the present study was to document the perioperative outcome associated with POP and determine potential risk factors for POP. METHODS: Patients undergoing PD between 2009 and 2015 were identified from the prospective data base at a single center. The previous suggested definition of POP by Connor was used. Complications were graded according to the Clavien-Dindo classification and by the grading proposed for POP. Risk factors for POP were analyzed by univariate and multivariate analysis. RESULTS: Of 190 patients, a total of 100 patients (53%) developed POP of whom 22 (12%) and 13 (7%) had grade B and grade C complications, respectively. Elevated serum CRP-levels on postoperative day (POD) 2 and elevated serum lipase on POD 1 were associated with onset of cr-POP. CONCLUSION: The proposed definition of POP constitutes a valuable tool to assess a serious pancreatic-surgery associated complication. Routine serum CRP and serum lipase levels on the first two postoperative days enable sufficient discrimination of clinically relevant POP.

Prognostic relevance of preoperative bilirubin-adjusted serum carbohydrate antigen 19-9 in a multicenter subset analysis of 179 patients with distal cholangiocarcinoma.

BACKGROUND: Distal cholangiocarcinoma (DCC) is a rare malignancy and validated prognostic markers remain scarce. We aimed to evaluate the role of serum CA19-9 as a potential biomarker in DCC. METHODS: Patients operated for DCC at 6 high-volume surgical centers from 1994 to 2015 were identified from prospectively maintained databases. Patient baseline characteristics, surgical and histopathological parameters, as well as overall survival after resection were assessed for correlation with preoperative bilirubin-adjusted serum carbohydrate antigen 19-9 (CA19-9). Preoperative CA19-9 to bilirubin ratio (CA19-9/BR) was classified as elevated (≥ 25 U/ml/mg/dl) according to the upper serum normal values of CA19-9 (37 U/ml) and bilirubin (1.5 mg/dl) giving a cut-off at ≥ 25 U/ml/mg/dl. RESULTS: In total 179 patients underwent resection for DCC during the study period. High preoperative CA19-9/BR was associated with advanced age and regional lymph node metastases. Median overall survival after resection was 27 months. Elevated preoperative serum CA19-9/bilirubin ratio (HR 1.6, p = 0.025), T3/4 stage (HR 1.8, p = 0.022), distant metastasis (HR 2.5, p = 0.007), tumor grade (HR 1.9, p = 0.001) and R status (HR 1.7, p = 0.023) were identified as independent negative prognostic factors following multivariable analysis. CONCLUSION: Elevated preoperative bilirubin-adjusted serum CA19-9 correlates with regional lymph node metastases and constitutes a negative independent prognostic factor after resection of DCC.

Chronic pancreatitis and resectable synchronous pancreatic carcinoma: A survival analysis.

BACKGROUND/OBJECTIVES: Chronic pancreatitis (CP) is a risk factor for pancreatic cancer (PDAC). CP and PDAC are characterized by an abundance of desmoplastic tissue. The effect of this pancreatic desmoplastic tissue on PDAC is poorly understood. In literature, negative and positive effects on the natural course of PDAC have been discussed. The present analysis aims to assess the impact of CP on patients with resectable synchronous PDAC regarding short- and long-term survival. METHODS: All patients who underwent pancreatic resection at our institution from January 2005 to January 2014 were retrospectively evaluated. Definition of CP was based on clinical and radiological aspects and histological confirmation as used previously. We identified patients with CP, CP and PDAC, and PDAC without CP and compared perioperative course and survival. Statistical analysis was performed by chi-square, Kruskal-Wallis/Mann-Whitney-U and Breslow survival analysis. P-values <0.05 were defined as statistically significant. RESULTS: 159 patients met our inclusion criteria for CP. 49 of them (30.8%) had synchronous PDAC. 145 patients had PDAC without a history of CP. There was a more advanced nodal involvement in PDAC patients with CP. Perioperative outcome and long-term survival of PDAC patients with and without CP did not differ significantly. CONCLUSION: In a large clinical series CP had no impact on survival of patients with PDAC after resection with curative intent.

Clinical evaluation of the M-ANNHEIM classification: Development of the M-ANNHEIM-Surgery-Score as a new tool to monitor patients with chronic pancreatitis.

OBJECTIVES: The M-ANNHEIM classification of chronic pancreatitis (CP) stratifies degrees of disease severity according to the M-ANNHEIM-Severity-Score. We aimed to demonstrate the clinical usefulness of the M-ANNHEIM-Severity-Score in quantifying and predicting the frequency of pancreatic surgery, and to establish the M-ANNHEIM-Surgery-Score as a simplified system for patient surveillance regarding the demand of pancreatic surgery. METHODS: We performed a retrospective, cross-sectional study with 741 CP patients (Mannheim/Germany, n = 537; Gießen/Germany, n = 100; Donetsk/Ukraine, n = 104) categorized according to the M-ANNHEIM classification. RESULTS: We observed a significantly higher M-ANNHEIM-Severity-Score in patients that were classified within 7 days preceding pancreatic surgery than in individuals that did not require surgery (p < 0.001, Mann-Whitney-U-test). Using a logistic regression analysis with all variables of the M-ANNHEIM-Severity-Score, we established the M-ANNHEIM-Surgery-Score as a simplified new tool to identify patients that may require surgery. A receiver operating characteristic-analysis revealed a cut-off-value of 9 points within the M-ANNHEIM-Surgery-Score to identify these individuals (sensitivity 78.7 %, specificity 91 %). Based on the M-ANNHEIM-Surgery-Score, we defined three categories for demand of surgery with frequencies of pancreatic operations of 1.6 % (n = 7/440) in the "Baseline-Demand"-category, 7 % (n = 12/172) in the "Low-Demand"-category (p < 0.0001, Chi-square-test, OR 4.6, Confidence Interval (CI) 1.8 - 12), and 54 % (n = 70/129) in the "High-Demand"-category (p < 0.0001, OR 73, CI 32 - 167). Patients that were categorized for the "High-Demand"-category, but were not operated on, had a significantly increased ratio of clinical features that hamper performance of surgery (p < 0.001, Chi-square-test). CONCLUSIONS: The M-ANNHEIM-Surgery-Score represents a useful tool to monitor patients with CP and to estimate the demand of surgery in CP.

Extracorporal Shock Wave Therapy Enhances Receptor for Advanced Glycated End-Product-Dependent Flap Survival and Angiogenesis.

BACKGROUND/OBJECTIVES: Loss of skin flaps due to deteriorated wound healing is a crucial clinical issue. Extracorporal shock wave therapy (ESWT) promotes flap healing by inducing angiogenesis and suppressing inflammation. The receptor for advanced glycation end-products (RAGEs) was identified to play a pivotal role in wound healing. However, to date, the role of RAGE in skin flaps and its interference with ESWT are unknown. METHODS: Caudally pedicled musculocutanous skin flaps in RAGE and wt mice were treated with low-dose extracorporal shock waves (s-RAGE, s-wt) and analyzed for flap survival, histomorphologic studies, and immunohistochemistry during a 10-day period. Animals without ESWT served in each genotype as a control group (c-RAGE, c-wt). Statistical analysis was carried out by repeated-measures analysis of variance. RESULTS: Flap necrosis was significantly reduced after ESWT in wt animals but increased in RAGE-deficient animals. Morphometric differences between the 4 groups were identified and showed a delayed wound healing with dysregulated inflammatory cells and deteriorated angiogenesis in RAGE animals. Furthermore, spatial and temporal differences were observed. CONCLUSIONS: The RAGE controls inflammation and angiogenesis in flap healing. The protective effects of ESWT are dependent on intact RAGE signaling, which enables temporary targeted infiltration of immune cells and neoangiogenesis.

Long-term results after endoscopic drainage of pancreatic pseudocysts: A single-center experience.

BACKGROUND: Pancreatic pseudocysts (PPC) are collections of fluid encapsulated within a well-defined inflammatory wall that develop during pancreatic inflammation. Internal drainage represents the standard of care in lesions that persist and lead to symptoms and complications. Only limited data are available on long-term results and recurrence of PPC after drainage procedures. Thus, the aim of the present study was to analyse the long-term outcome after endoscopic drainage of PPC. MATERIAL AND METHODS: Patient data were retrospectively collected by review of clinical records of the University Medical Center Mannheim. We assessed the clinical short-term outcome (results in the first 30 days after initial drainage procedure), medium-term outcome (results 6 months after initial drainage procedure) and long-term outcome (results after stent removal). We performed statistical analysis to identify possible risk factors for recurrence of PPC. RESULTS: We identified 51 patients with initially successful endoscopic drainage of the PPC (n = 51/53, 96%). Among this cohort, 43 patients were available for assessment of medium-term results. In 82.9% of these 43 patients the drainage could be removed after successful treatment of the PPC. Thirty patients were available for long term follow-up with a mean observation period of 42.2 months (SD 32.8 months). Among these patients, seven (n = 7/30, 23.3%) had recurrent PPC. Approximately half of the recurrent cysts arose in different anatomical regions and most patients with recurrence had chronic pancreatitis. CONCLUSION: Endoscopic drainage represents an effective treatment for PPC. Approximately one quarter of the patients developed recurrent PPC. Half of recurrent PPC developed in different pancreatic regions than the initial PPC.

Diagnosing autoimmune pancreatitis with the Unifying-Autoimmune-Pancreatitis-Criteria.

BACKGROUND/OBJECTIVES: We had developed the Unifying-Autoimmune-Pancreatitis-Criteria (U-AIP) to diagnose autoimmune pancreatitis (AiP) within the M-ANNHEIM classification of chronic pancreatitis. In 2011, International-Consensus-Diagnostic-Criteria (ICDC) to diagnose AiP have been published. We had applied the U-AIP long before the ICDC were available. The aims of the study were, first, to describe patients with AiP diagnosed by the U-AIP; second, to compare diagnostic accuracies of the U-AIP and other diagnostic systems; third, to evaluate the clinical applicability of the U-AIP. METHODS: From 1998 until 2008, we identified patients with AiP using U-AIP, Japanese-, Korean-, Asian-, Mayo-HISORt-, Revised-Mayo-HISORt- and Italian-criteria. We retrospectively verified the diagnosis by ICDC and Revised-Japanese-2011-criteria, compared diagnostic accuracies of all systems and evaluated all criteria in consecutive patients with pancreatitis (2009 until 2010, Pancreas-Outpatient-Clinic-Cohort, n = 84). We retrospectively validated our diagnostic approach in consecutive patients with a pancreatic lesion requiring surgery (Surgical-Cohort, n = 98). RESULTS: Overall, we identified 21 patients with AiP. Unifying-Autoimmune-Pancreatitis-Criteria and ICDC presented the highest diagnostic accuracies (each 98.8%), highest Youden indices (each 0.95238), and highest proportions of diagnosed patients (each n = 20/21, U-AIP/ICDC vs. other diagnostic systems, p < 0.05, McNemar test). In the Pancreas-Outpatient-Clinic-Cohort, seven patients were diagnosed with AiP (n = 6 by U-AIP, n = 1 by Asian-criteria). International-Consensus-Diagnostic-Criteria confirmed the diagnosis in these individuals. Based on partial fulfillment of U-AIP, AiP was initially suspected in 13% (n = 10/77) of remaining patients from the Pancreas-Outpatient-Clinic-Cohort. In the Surgical-cohort, we identified one patient with AiP by U-AIP and ICDC. CONCLUSIONS: Unifying-Autoimmune-Pancreatitis-Criteria revealed a satisfactory clinical applicability and offered an additional approach to diagnose AiP.

Prevalence and Incidence of Autoimmune Pancreatitis in the Population Living in the Southwest of Germany.

BACKGROUND/AIMS: The prevalence and incidence of autoimmune pancreatitis (AiP) in those living in western countries are largely unknown. We aimed to determine the prevalence of AiP among patients with pancreatitis presenting to our tertiary referral center in Mannheim, Germany; and to estimate the incidence of AiP in the Southwest of Germany. METHODS: We performed a retrospective cross-sectional analysis and determined the prevalence of AiP in patients with acute pancreatitis (AP) or chronic pancreatitis (CP). Patients (n = 704; alcoholic pancreatitis n = 373, nonalcoholic pancreatitis n = 331) were stratified into the Retrospective-Pancreas-Cohort (RPC, period 1998-2008, n = 534) and the Pancreas-Clinic-Cohort (PCC, periods 2008-2010 and 2013-2014, n = 170, with detailed investigation for features of AiP). Diagnosis of AiP was established by International-Consensus-Diagnostic-Criteria and Unifying-Autoimmune-Pancreatitis-Criteria. RESULTS: In the RPC, the prevalence of AiP was 5.9% (n = 13/221) among individuals with nonalcoholic pancreatitis (n = 1/61 with AP, 1.6%; n = 12/160 with CP, 7.5%). In the PCC, the prevalence of AiP was 9.1% (n = 10/110) among patients with nonalcoholic pancreatitis (n = 2/24 with AP, 8.3%; n = 8/86 with CP, 9.3%), and 1.7% (n = 1/60) among subjects with alcoholic pancreatitis. We estimated the incidence of AiP with 0.29 per 100,000 population each year. CONCLUSION: The prevalence rate of AiP may account for 9% of patients with nonalcoholic pancreatitis but is almost never observed in patients with alcoholic pancreatitis. The incidence of AiP in Germany appears lower than 1 per 100,000 population.

Survival outcome and prognostic factors after pancreatoduodenectomy for distal bile duct carcinoma: a retrospective multicenter study.

PURPOSE: Pancreatoduodenectomy is the most common operative procedure performed for distal bile duct carcinoma. Data on outcome after surgery for this rare malignancy is scarce, especially from western countries. The purpose of this study is to explore the prognostic factors and outcome after pancreatoduodenectomy for distal bile duct carcinoma. METHODS: Patients receiving pancreatoduodenectomy for distal bile duct carcinoma were identified from institutional databases of five German and one Russian academic centers for pancreatic surgery. Univariable and multivariable general linear model, Kaplan-Meier method, and Cox regression were used to identify prognostic factors for postoperative mortality and overall survival. RESULTS: N = 228 patients operated from 1994 to 2015 were included. Reoperation (OR 5.38, 95%CI 1.51-19.22, p = 0.010), grade B/C postpancreatectomy hemorrhage (OR 3.73, 95%CI 1.13-12.35, p = 0.031), grade B/C postoperative pancreatic fistula (OR 4.29, 95%CI 1.25-14.72, p = 0.038), and advanced age (OR 4.00, 95%CI 1.12-14.03, p = 0.033) were independent risk factors for in-hospital mortality in multivariable analysis. Median survival was 29 months, 5-year survival 27%. Positive resection margin (HR 2.07, 95%CI 1.29-3.33, p = 0.003), high tumor grade (HR 1.71, 95%CI 1.13-2.58, p = 0.010), lymph node (HR 1.68, 95%CI 1.13-2.51, p = 0.011), and distant metastases (HR 2.70, 95%CI 1.21-5.58, p = 0.014), as well as severe non-fatal postoperative complications (HR 1.64, 95%CI 1.04-2.58, p = 0.033) were independent negative prognostic factors for survival in multivariable analysis. CONCLUSION: Distant metastases and positive resection margin are the strongest negative prognostic factors for survival after pancreatoduodenectomy for distal bile duct carcinoma; thus, surgery with curative intent is only warranted in patients with local disease, where R0 resection is feasible.

Laminin, gamma 2 (LAMC2): a promising new putative pancreatic cancer biomarker identified by proteomic analysis of pancreatic adenocarcinoma tissues.

In pancreatic cancer, the incidence and mortality curves coincide. One major reason for this high mortality rate in pancreatic ductal adenocarcinoma (PDAC) patients is the dearth of effective diagnostic, prognostic, and disease-monitoring biomarkers. Unfortunately, existing tumor markers, as well as current imaging modalities, are not sufficiently sensitive and/or specific for early-stage diagnosis. There is, therefore, an urgent need for improved serum markers of the disease. Herein, we performed Orbitrap® mass spectrometry proteomic analysis of four PDAC tissues and their adjacent benign tissues and identified a total of 2190 nonredundant proteins. Sixteen promising candidates were selected for further scrutiny using a systematic scoring algorithm. Our preliminary serum verification of the top four candidates (DSP, LAMC2, GP73, and DSG2) in 20 patients diagnosed with pancreatic cancer and 20 with benign pancreatic cysts, showed a significant (p < 0.05) elevation of LAMC2 in pancreatic cancer serum. Extensive validation of LAMC2 in healthy, benign, and PDAC sera from geographically diverse cohorts (n = 425) (Japan, Europe, and USA) demonstrated a significant increase in levels in early-stage PDAC compared with benign diseases. The sensitivity of LAMC2 was comparable to CA19.9 in all data sets, with an AUC value greater than 0.85 in discriminating healthy patients from early-stage PDAC patients. LAMC2 exhibited diagnostic complementarity with CA19.9 by showing significant (p < 0.001 in two out of three cohorts) elevation in PDAC patients with clinically low CA19.9 levels.

Chronic pancreatitis of the pancreatic remnant is an independent risk factor for pancreatic fistula after distal pancreatectomy.

BACKGROUND: There is an ongoing debate about the best closure technique after distal pancreatectomy (DP). The aim of the closure is to prevent the formation of a clinically relevant post-operative pancreatic fistula (POPF). Stapler technique seems to be equal compared with hand-sewn closure of the remnant. For both techniques, a fistula rate of approximately 30% has been reported. METHODS: We retrospectively analyzed our DPs between 01/2000 and 12/2010. In all cases, the pancreatic duct was over sewn with a separately stitched ligation of the pancreatic duct (5*0 PDS) followed by a single-stitched hand-sewn closure of the residual pancreatic gland. The POPF was classified according to the criteria of the International Study Group for Pancreatic Fistula (ISGPF). Univariate and multivariate analyses of potential risk factors for the formation of POPF were performed. Indications for operations included cystic tumors (n = 53), neuroendocrine tumors (n = 27), adenocarcinoma (n = 22), chronic pancreatitis (n = 9), metastasis (n = 6), and others (n = 7). RESULTS: During the period, we performed 124 DPs (♀ = 74, ♂ = 50). The mean age was 57.5 years (18-82). The POPF rates according to the ISGPF criteria were: no fistula, 54.8% (n = 68); grade A, 24.2% (n = 30); grade B, 19.3% (n = 24); and grade C, 1.7% (n = 2). Therefore, in 21.0% (n = 26) of the cases, a clinically relevant pancreatic fistula occurred. The mean postoperative stay was significantly higher after grade B/C fistula (26.3 days) compared with no fistula/grade A fistula (13.7 days) (p < 0.05). The uni- and multivariate analyses showed chronic pancreatitis of the pancreatic remnant to be an independent risk factor for the development of POPF (p = 0.004 OR 7.09). CONCLUSION: By using a standardized hand-sewn closure technique of the pancreatic remnant after DP with separately stitched ligation of the pancreatic duct, a comparably low fistula rate can be achieved. Signs of chronic pancreatitis of the pancreatic remnant may represent a risk factor for the development of a pancreatic fistula after DP and therefore an anastomosis of the remnant to the intestine should be considered.