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.

Targeted and explorative profiling of kallikrein proteases and global proteome biology of pancreatic ductal adenocarcinoma, chronic pancreatitis, and normal pancreas highlights disease-specific proteome remodelling.

Pancreatic ductal adenocarcinoma (PDAC) represents one of the most aggressive and lethal malignancies worldwide with an urgent need for new diagnostic and therapeutic strategies. One major risk factor for PDAC is the pre-indication of chronic pancreatitis (CP), which represents highly inflammatory pancreatic tissue. Kallikreins (KLKs) are secreted serine proteases that play an important role in various cancers as components of the tumor microenvironment. Previous studies of KLKs in solid tumors largely relied on either transcriptomics or immunodetection. We present one of the first targeted mass spectrometry profiling of kallikrein proteases in PDAC, CP, and normal pancreas. We show that KLK6 and KLK10 are significantly upregulated in PDAC (n=14) but not in CP (n=7) when compared to normal pancreas (n=16), highlighting their specific intertwining with malignancy. Additional explorative proteome profiling identified 5936 proteins in our pancreatic cohort and observed disease-specific proteome rearrangements in PDAC and CP. As such, PDAC features an enriched proteome motif for extracellular matrix (ECM) and cell adhesion while there is depletion of mitochondrial energy metabolism proteins, reminiscent of the Warburg effect. Although often regarded as a PDAC hallmark, the ECM fingerprint was also observed in CP, alongside with a prototypical inflammatory proteome motif as well as with an increased wound healing process and proteolytic activity, thereby possibly illustrating tissue autolysis. Proteogenomic analysis based on publicly accessible data sources identified 112 PDAC-specific and 32 CP-specific single amino acid variants, which among others affect KRAS and ANKHD1. Our study emphasizes the diagnostic potential of kallikreins and provides novel insights into proteomic characteristics of PDAC and CP.

TissueGrinder, a novel technology for rapid generation of patient-derived single cell suspensions from solid tumors by mechanical tissue dissociation.

Introduction: Recent advances hold promise of making personalized medicine a step closer to implementation in clinical settings. However, traditional sample preparation methods are not robust and reproducible. In this study, the TissueGrinder, a novel mechanical semi-automated benchtop device, which can isolate cells from tissue in a very fast and enzyme-free way is tested for cell isolation from surgically resected tumor tissues. Methods: Thirty-three surgically resected tumor tissues from various but mainly pancreatic, liver or colorectal origins were processed by both novel TissueGrinder and explant method. An optimized processing program for tumors from pancreatic, liver or colorectal cancer was developed. The viability and morphological characteristics of the isolated cells were evaluated microscopically. Expression of pancreatic cancer markers was evaluated in cells isolated from pancreatic tumors. Finally, the effect of mechanical stress on the cells was evaluated by assessing apoptosis markers via western blotting. Results: TissueGinder was more efficient in isolating cells from tumor tissue with a success rate of 75% when compared to explant method 45% in terms of cell outgrowth six weeks after processing. Cells isolated with TissueGinder had a higher abundance and were more heterogeneous in composition as compared to explant method. Mechanical processing of the cells with TissueGrinder does not lead to apoptosis but causes slight stress to the cells. Discussion: Our results show that TissueGrinder can process solid tumor tissues more rapidly and efficiently and with higher success rate compared to the conventionally used explant method. The results of the study suggest that the TissueGrinder might be a suitable method for obtaining cells, which is important for its application in individualized therapy. Due to the great variance in different tumor entities and the associated individual tissue characteristics, a further development of the dissociation protocol for other types of tumors and normal tissue will be targeted.

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.

[Definition and treatment of superior mesenteric artery revascularization and dissection-associated diarrhea (SMARD syndrome) in Germany]. / Definition und Behandlung der A.-mesenterica-superior-Revaskularisations- und -Dissektions-assoziierten Diarrhö (SMARD-Syndrom) in Deutschland.

BACKGROUND: The superior mesenteric artery (SMA) is exposed and dissected during pancreatic resections (PR) and mesenteric vascular surgery (MVS). The resulting damage of the surrounding extrinsic and intrinsic vegetative nerve plexus can lead to a temporary or treatment refractory diarrhea. OBJECTIVE: This study aimed to provide an overview of the current status of SMA revascularization and dissection-associated diarrhea (SMARD syndrome) in Germany. MATERIAL AND METHODS: After a selective literature search (SLS) on the frequency of newly developed postoperative diarrhea after PR and MVS, an online survey was initiated. RESULTS: The SLS (n = 4) confirmed that newly developed postoperative diarrhea is a frequent complication after preparation for revascularization (RV) or dissection (DIS) of the SMA (incidence approximately 62%). Treatment refractive courses were relatively uncommon with 14%. Out of 159 centers 54 took part in the survey and 63% stated that they carried out an SMA RV/DIS during PR or MVS. The average PR per center was 47 in 2018 and 49 in 2019. The average MVS was 5 per center in both years and on average 3 patients suffered from SMARD syndrome. CONCLUSION: This survey recorded the current status of the SMARD syndrome in Germany for the first time. So far there are no recommendations for the treatment of such a diarrhea. The results show that initially a symptomatic treatment should be carried out. Due to the complexity of the pathophysiology, causal treatment approaches have not yet been developed.

Proposal of a Standardized Questionnaire to Structure Clinical Peer Reviews of Mortality and Failure of Rescue in Pancreatic Surgery.

Background: Quality management tools such as clinical peer reviews facilitate root cause analysis and may, ultimately, help to reduce surgery-related morbidity and mortality. This study aimed to evaluate the reliability of a standardized questionnaire for clinical peer reviews in pancreatic surgery. Methods: All cases of in-hospital-mortality following pancreatic surgery at two high-volume centers (n = 86) were reviewed by two pancreatic surgeons. A standardized mortality review questionnaire was developed and applied to all cases. In a second step, 20 cases were randomly assigned to an online re-review that was completed by seven pancreatic surgeons. The overall consistency of the results between the peer review and online re-review was determined by Cohen's kappa (κ). The inter-rater reliability of the online re-review was assessed by Fleiss' kappa (κ). Results: The clinical peer review showed that 80% of the patient mortality was related to surgery. Post-operative pancreatic fistula (POPF) (36%) followed by post-pancreatectomy hemorrhage (PPH) (22%) were the most common surgical underlying (index) complications leading to in-hospital mortality. Most of the index complications yielded in abdominal sepsis (62%); 60% of the cases exhibited potential of improvement, especially through timely diagnosis and therapy (42%). There was a moderate to substantial strength of agreement between the peer review and the online re-review in regard to the category of death (surgical vs. non-surgical; κ = 0.886), type of surgical index complication (κ = 0.714) as well as surgical and non-surgical index complications (κ = 0.492 and κ = 0.793). Fleiss' kappa showed a moderate to substantial inter-rater agreement of the online re-review in terms of category of death (κ = 0.724), category of common surgical index complications (κ = 0.455) and surgical index complication (κ = 0.424). Conclusion: The proposed questionnaire to structure clinical peer reviews is a reliable tool for root cause analyses of in-hospital mortality and may help to identify specific options to improve outcomes in pancreatic surgery. However, the reliability of the peer feedback decreases with an increasing specificity of the review questions.

First report on establishment and characterization of a carcinosarcoma tumour cell line model of the bladder.

Carcinosarcoma of the urinary bladder is a very rare and aggressive subtype of bladder cancer with poor prognosis. Characteristically carcinosarcomas exhibit biphasic nature with both epithelial and mesenchymal differentiation. Limited information is available regarding its clinical features and appropriate treatments due to its rarity. Development of tumour models can further our understanding of bladder carcinosarcoma. We report establishment and characterization of the first-ever bladder carcinosarcoma cell line MaS-3. It is established by the outgrow method from 86 year-old caucasian male who underwent a radical pelvic resection after neoadjuvant radiotherapy. MaS-3 showed carcinosarcoma profile with high conformity with to the original tumour in terms of immunocytochemistry. Proteome analysis also aligned the MaS-3 cell line with the carcinosarcoma specimen rather than corresponding non-malignant tissue. Chemotherapy sensitivity testing revealed a great sensitivity of MaS-3 growth to 5-Fluorouracil, Gemcitabine and Cisplatin, with almost no impact of Irinotecan. Additionally, the suitability of MaS-3 for 3D in vitro experiments was also demonstrated. The newly established cell line MaS-3 shows typical characteristics of the tumour and may thus be a useful in vitro model system for studying the tumour biology and developing future of treatments of this rare but very aggressive entity.

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.

Impact of intraoperative margin clearance on survival following pancreatoduodenectomy for pancreatic cancer: a systematic review and meta-analysis.

The use of intraoperative margin revision to achieve margin clearance in patients undergoing pancreatoduodenectomy for pancreatic cancer is controversial. We performed a systematic review and meta-analysis to summarize the evidence of intraoperative margin revisions of the pancreatic neck and its impact on overall survival (OS). Nine studies with 4501 patients were included. Patient cohort was stratified in an R0R0-group (negative margin on frozen and permanent section), R1R0-group (revised positive margin on frozen section which turned negative on permanent section), and R1R1-group (positive margin on frozen and permanent section despite margin revision). OS was higher in the R1R0-group (HR 0.83, 95% CI 0.72-0.96, P = 0.01) compared to the R1R1-group but lower compared to the R0R0-group (HR 1.20; 95% CI 1.05-1.37, P = 0.008), respectively. Subgroup analyses on the use of different margin clearance definitions confirmed an OS benefit in the R1R0-group compared to the R1R1-group (HR 0.81; 95% CI 0.65-0.99, P = 0.04). In conclusion, intraoperative margin clearance of the pancreatic neck margin is associated with improved OS while residual tumor indicates aggressive tumor biology. Consensus definitions on margin terminologies, clearance, and surgical techniques are required.

Obesity and Pancreatic Cancer: A Matched-Pair Survival Analysis.

BACKGROUND: Morbid obesity is a risk factor for pancreatic ductal adenocarcinoma (PDAC). However, the impact of obesity on postoperative outcomes and overall survival in patients with PDAC remains a controversial topic. METHODS: Patients who underwent pancreatic surgery for PDAC between 1997 and 2018 were included in this study. Matched pairs (1:1) were generated according to age, gender and American Society of Anesthesiologists status. Obesity was defined according to the WHO definition as BMI ≥ 30 kg/m2. The primary endpoint was the difference in overall survival between patients with and without obesity. RESULTS: Out of 553 patients, a total of 76 fully matched pairs were generated. Obese patients had a mean BMI-level of 33 compared to 25 kg/m2 in patients without obesity (p = 0.001). The frequency of arterial hypertension (p = 0.002), intraoperative blood loss (p = 0.039), and perineural invasion (p = 0.033) were also higher in obese patients. Clinically relevant postoperative complications (p = 0.163) and overall survival rates (p = 0.885) were comparable in both study groups. Grade II and III obesity resulted in an impaired overall survival, although this was not statistically significant. Subgroup survival analyses revealed no significant differences for completion of adjuvant chemotherapy and curative-intent surgery. CONCLUSIONS: Obesity did not affect overall survival and postoperative complications in these patients with PDAC. Therefore, pancreatic surgery should not be withheld from obese 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.

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.

Influence of Clinical pathways on treatment and outcome quality for patients undergoing pancreatoduodenectomy? A retrospective cohort study.

BACKGROUND: Pancreatic surgery demands complex multidisciplinary management. Clinical pathways (CPs) are a tool to facilitate this task, but evidence for their utility in pancreatic surgery is scarce. This study evaluated the effect of CPs on quality of care for pancreatoduodenectomy. METHODS: Data of all consecutive patients who underwent pancreatoduodenectomy before (n = 147) or after (n = 148) CP introduction were evaluated regarding catheter and drain management, postoperative mobilization, pancreatic enzyme substitution, resumption of diet and length of stay. Outcome quality was assessed using glycaemia management, morbidity, mortality, reoperation and readmission rates. RESULTS: Catheters and abdominal drainages were removed significantly earlier in patients treated with CP (p < 0.0001). First intake of liquids, nutritional supplement and solids was significantly earlier in the CP group (p < 0.0001). Exocrine insufficiency was significantly less common after CP implementation (47.3% vs. 69.7%, p < 0.0001). The number of patients receiving intraoperative transfusion dropped significantly after CP implementation (p = 0.0005) and transfusion rate was more frequent in the pre-CP group (p = 0.05). The median number of days with maximum pain level >3 was significantly higher in the CP group (p < 0.0001). There was no significant difference in mortality, morbidity, reoperation and readmission rates. CONCLUSIONS: Following implementation of a CP for pancreatoduodenectomy, several indicators of process and outcome quality improved, while others such as mortality and reoperation rates remained unchanged. CPs are a promising tool to improve quality of care in pancreatic surgery.

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.

Clinical Pathways For Pancreatic Surgery: Are They A Suitable Instrument For Process Standardization To Improve Process And Outcome Quality Of Patients Undergoing Distal And Total Pancreatectomy? - A Retrospective Cohort Study.

PURPOSE: Pancreatic surgery demands complex multidisciplinary management, which is often cumbersome to implement. Clinical pathways (CPs) are a tool to facilitate this task, but evidence for their utility in pancreatic surgery is scarce. This study evaluated if CPs are a suitable tool for process standardization in order to improve process and outcome quality in patients undergoing distal and total pancreatectomy. PATIENTS AND METHODS: Data of consecutive patients who underwent distal or total pancreatectomy before (n=67) or after (n=61) CP introduction were evaluated regarding catheter management, postoperative mobilization, pancreatic enzyme substitution, resumption of diet and length of stay. Outcome quality was assessed using glycaemia management, morbidity, mortality, reoperation and readmission rates. RESULTS: The usage of incentive spirometers for pneumonia prophylaxis increased. The median number of days with hyperglycemia decreased significantly from 2.5 to 0. For distal pancreatectomy, the incidence of postoperative diabetes dropped from 27.9% to 7.1% (p=0.012). The incidence of postoperative exocrine pancreatic insufficiency decreased from 37.2% to 11.9% (p=0.007). There was no significant difference in mortality, morbidity, reoperation and readmission rates between groups. CONCLUSION: Following implementation of a pancreatic surgery CP, several indicators of process and outcome quality improved, while others such as mortality and reoperation rates remained unchanged. CPs are a promising tool to improve quality of care in pancreatic surgery.

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.

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.

The Clavien-Dindo Classification in Pancreatic Surgery: A Clinical and Economic Validation.

Background/Aims: In 2004 P. A. Clavien and D. Dindo published the well-known grading system of postoperative complications. It is established in several surgical disciplines. The aim of this study was to assess its validity in pancreatic surgery. The impact of complication grade on economic resources was investigated as well. Methods: From a prospective database, we retrospectively evaluated all patients who underwent pancreatic resection between January 2009 and December 2014 at our department. 309 patients received pancreatic head resection (pylorus-preserving pancreatoduodenectomy (PPPD) or Kausch-Whipple), total pancreatectomy or left resection. We performed a univariate analysis of the correlation between the Clavien-Dindo classification-grade (CDC-grade) with length of postoperative stay (LOS) and DRG-related (diagnosis related groups) remuneration using Kruskal-Wallis test. Furthermore, we performed a subgroup analysis (chi-square test and Fishers-test) of demographic, clinical, and perioperative data. Results: American Society of Anesthesiologists (ASA) score (p = 0.0014), operation time (p = 0.0229) and intraoperative blood loss (p = 0.0016) showed significant correlation with CDC-grade. Increasing LOS and DRG-related remuneration correlated significantly with increasing CDC-grade (p < 0.0001). Conclusion: The CDC-grading system shows high correlation to clinical outcome and case-related remuneration in pancreatic surgery. Therefore, it is a valid tool for evaluation and comparison of surgical techniques and surgical centers.