Louisa Bolm

Mesopancreatic Stromal Clearance Defines Curative Resection of Pancreatic Head Cancer and Can Be Predicted Preoperatively by Radiologic Parameters: A Retrospective Study.

Abstract Pancreatic ductal adenocarcinoma (PDAC) is characterized by a strong fibrotic stromal reaction and diffuse growth pattern. Peritumoral fibrosis is often evident during surgery but only distinguishable from tumor by microscopic examination. The aim of this study was to investigate the role of clearance of fibrotic stromal reaction at the mesopancreatic resection margin as a criterion for radical resection and preoperative assessment of resectability. Mesopancreatic stromal clearance status (S-status) was defined as the presence or absence (S+/S0) of fibrotic stromal reaction at the mesopancreatic resection margin. Detailed retrospective clinicopathologic re-evaluation of margin status and preoperative cross-sectional imaging was performed in a cohort of 91 patients operated for pancreatic head PDAC from 2001 to 2011. Conventional margin positive resection (R+, tumor cells directly at the margin) was found in 36%. However, S-status further divided the margin negative (R0) group into patients with median survival of 14 months versus 31 months (S+ versus S0, P = 0.005). Overall rate of S+ was 53%. S-status and lymph node ratio constituted the only independent predictors of survival. Stranding of the superior mesenteric artery fat sheath was the only independent radiologic predictor of S+ resection, and achieved a 71% correct prediction of S-status. Mesopancreatic stromal clearance is a major determinant of curative resection in PDAC, and preoperative prediction by cross-sectional imaging is possible, setting the basis for a new definition of borderline resectability.

Histopathological tumor invasion of the mesenterico-portal vein is characterized by aggressive biology and stromal fibroblast activation

BACKGROUND Mesenterico-portal vein resection (PVR) during pancreatoduodenectomy for pancreatic head cancer was established in the 1990s and can be considered a routine procedure in specialized centers today. True histopathologic portal vein invasion is predictive of poor prognosis. The aim of this study was to examine the relationship between mesenterico-portal venous tumor infiltration (PVI) and features of aggressive tumor biology. METHODS Patients receiving PVR for pancreatic ductal adenocarcinoma of the pancreatic head were identified from a prospectively maintained database. Immunohistochemical staining of tumor tissue was performed for the markers of epithelial-mesenchymal transition (EMT) E-Cadherin, Vimentin and beta-Catenin. Morphology of cancer-associated fibroblasts (CAFs) was assessed as inactive or activated. Statistical calculations were performed with MedCalc software. RESULTS In total, 41 patients could be included. Median overall survival was 25 months. PVI was found in 17 patients (41%) and was significantly associated with loss of membranous E-Cadherin in tumor buds (p = 0.020), increased Vimentin expression (p = 0.03), activated CAF morphology (p = 0.046) and margin positive resection (p = 0.005). CONCLUSION Our findings suggest that PVI is associated with aggressive tumor biology and disseminated growth less amenable to margin-negative resection.

The Role of Fibroblasts in Pancreatic Cancer: Extracellular Matrix Versus Paracrine Factors

BACKGROUND AND AIM: Desmoplasia is a characteristic feature and a suspected mechanism of tumor progression in pancreatic ductal adenocarcinoma (PDAC). Main constituents of the stroma involve cancer-associated fibroblasts (CAFs) and extracellular matrix (ECM). The aim of this study was to dissect the interaction of CAFs, ECM, and PDAC cells in both an in vitro setting and a large-scale clinical cohort study. METHODS AND MATERIAL: Patients operated for PDAC were identified from our prospectively maintained clinical database. A standard pathology protocol was applied for pancreatoduodenectomy specimens also assessing CAF activation as either CAF grade 0 or CAF grade +. Interaction between a spectrum of pancreatic cancer cell lines (PCCs) and mouse embryonic fibroblasts (NIH 3T3) was assessed in a conditioned medium experimental setup. RESULTS: One hundred eleven patients operated for PDAC from 2001 to 2011 were identified. Univariate analysis disclosed CAF grade + (P = .030), positive M status (P < .001), and lymph node ratio (LNR) > 0.1 (P = .045) to impair overall survival. Independent prognostic factors were CAF grade (P = .050) and positive M status (P = .002). CAF grade correlated with N status (CC = 0.206, P = .030), LNR (CC = 0.187, P = .049), tumor size (CC = −0.275, P = .003), and M status (CC = 0.190, P = .045). In the in vitro setting, paracrine effects of pancreatic cancer cell resulted in morphological activation of fibroblasts and tumor cell differentiation–dependent increase of fibroblast growth. Paracrine effects of poorly differentiated PCCs led to an upregulation of Vimentin in NIH 3T3 fibroblasts. Paracrine effects of fibroblasts on their part promoted cancer cell motility in all PCCs. As the second stromal component, fibroblast-derived ECM resulted in significantly decreased proliferation depending on density and led to upregulation of ZEB1 in poorly differentiated PCCs. CONCLUSION: In PDAC patients, positive CAF grading was identified as a negative prognostic parameter correlating with positive N status, high LNR, positive M status, and smaller tumor size. Whereas bilateral interaction of PCCs and CAFs promotes tumor progression, ECM poses PCC growth restrictions. In summary, our study discloses differential effects of stromal components and may help to interpret heterogeneous results of former studies.

Proteome Profiling of Primary Pancreatic Ductal Adenocarcinomas Undergoing Additive Chemoradiation Link ALDH1A1 to Early Local Recurrence and Chemoradiation Resistance

Pancreatic ductal adenocarcinoma (PDAC) has a poor prognosis with frequent post-surgical local recurrence. The combination of adjuvant chemotherapy with radiotherapy is under consideration to achieve a prolonged progression-free survival (PFS). To date, few studies have determined the proteome profiles associated with response to adjuvant chemoradiation. We herein analyzed the proteomes of primary PDAC tumors subjected to additive chemoradiation after surgical resection and achieving short PFS (median 6 months) versus prolonged PFS (median 28 months). Proteomic analysis revealed the overexpression of Aldehyde Dehydrogenase 1 Family Member A1 (ALDH1A1) and Monoamine Oxidase A (MAOA) in the short PFS cohort, which were corroborated by immunohistochemistry. In vitro, specific inhibition of ALDH1A1 by A37 in combination with gemcitabine, radiation, and chemoradiation lowered cell viability and augmented cell death in MiaPaCa-2 and Panc 05.04 cells. ALDH1A1 silencing in both cell lines dampened cell proliferation, cell metabolism, and colony formation. In MiaPaCa-2 cells, ALDH1A1 silencing sensitized cells towards treatment with gemcitabine, radiation or chemoradiation. In Panc 05.04, increased cell death was observed upon gemcitabine treatment only. These findings are in line with previous studies that have suggested a role of ALDH1A1 chemoradiation resistance, e.g., in esophageal cancer. In summary, we present one of the first proteome studies to investigate the responsiveness of PDAC to chemoradiation and provide further evidence for a role of ALDH1A1 in therapy resistance.

Multimodal Anti-tumor Approaches Combined with Immunotherapy to Overcome Tumor Resistance in Esophageal and Gastric Cancer

Upper gastrointestinal malignancies are associated with a high disease burden worldwide, and esophageal and gastric cancers represent the most common entities. Given a lack of early characteristic symptoms and potent screening instruments, the majority of patients present with advanced disease at the time of diagnosis. Complete surgical resection is a first-line curative option, and multimodal approaches involving chemotherapy and radiotherapy further improve patient prognosis. However, response to standard adjuvant and neoadjuvant treatments remains low, and new strategies are warranted to increase tumor control rates. Immunotherapy is emerging in various cancer entities and may be successfully combined with standard therapeutic regimens to improve patient outcome. For the purpose of this review we aimed to assess combined approaches of immunotherapy and standard treatment options such as chemotherapy, radiotherapy and surgery. Current trials evaluating multimodal approaches with immunotherapy in esophageal and gastric cancer are evaluated.

Perioperative and Long-term Oncological Results of Minimally Invasive Pancreatoduodenectomy as Hybrid Technique – A Matched Pair Analysis of 120 Cases

Background Laparoscopic pancreatoduodenectomy is a highly challenging procedure. The aim of this study was to analyse post-operative morbidity and mortality as well as long term overall survival in patients undergoing hybrid LPD, as compared to open pancreaticoduodenecomy (OPD) in a single surgeon series. Methods Patients undergoing pancreatoduodenectomy (PD) in the period from 2000 to 2015 were identified from a prospectively maintained database. All LPD procedures were performed by one specialised pancreatic surgeon (TK). Patients were matched 1 : 1 for age, sex, BMI, ASA, histological diagnosis, pancreatic texture and portal venous resection (PVR). All LPD procedures were performed as hybrid LPD – combining laparoscopic resection and open reconstruction via mini laparotomy. Results A total of 549 patients were identified, including 489 patients in the OPD group and 60 patients in the LPD group. 60 patients were identified who underwent LPD between 2010 and 2015 versus 60 OPD patients operated in the same period. Median overall operation time was shorter in the LPD group than with OPD patients (LPD 352 vs. OPD 397 min; p = 0.002). Overall transfusion units were lower in the LPD group (LPD range 0 – 4 vs. OPD range 0 – 11; p = 0.032). Intensive care unit stay (LPD 1 vs. OPD 6 d; p = 0.008) and overall hospital stay (OHS: LPD 14 vs. OPD 18 d; p = 0.012) were shorter in the LPD groups than in the OPD group. As regards postoperative complications, LPD was associated with reduced rates of clinically relevant grade B/C postoperative pancreatic fistula (LPD 15 vs. OPD 36%; p = 0.036) and grade B/C delayed gastric emptying (LPD 8 vs. OPD 20%; p = 0.049). A total of 56 patients were diagnosed with malignant disease. The number of harvested lymph nodes and R0-resection rates were equal for LPD and OPD patients. LPD patients showed a trend to improved median overall survival (LPD mean 56 months vs. OPD mean 48 months; p = 0.056). Conclusion Hybrid LPD is a safe procedure associated with a reduction in clinically relevant postoperative complications and allows faster recovery. Long term oncological outcome of hybrid LPD for malignant disease is equal to that with the standard open approach.

Kidney Transplantation after Extended Multivisceral Resection for Pancreatic Ductal Adenocarcinoma

Long-term survival in patients with pancreatic ductal adenocarcinoma (PDAC) is limited. Consequently, solid organ transplantation in PDAC patients is usually not considered. This is the first case report of kidney transplantation (KT) in a 57-year-old female patient after extended multivisceral resection for PDAC of the distal pancreas who had developed end-stage renal disease (ESRD) due to toxic kidney damage by chemotherapy. 13,5 years after initial PDAC-operation and 3 years after KT the patient remains in a good general health condition with sufficient function of the kidney allograft without local tumor recurrence or distant metastasis.

Characterization of various cell lines from different ampullary cancer subtypes and cancer associated fibroblast-mediated responses

BackgroundAmpullary cancer is a relatively rare form of cancer and usually treated by pancreatoduodenectomy, followed by adjuvant therapy. The intestinal subtype is associated with markedly improved prognosis after resection. At present, only few cell lines are available for in vitro studies of ampullary cancer and they have not been collectively characterized.MethodsWe characterize five ampullary cancer cell lines by subtype maker expression, epithelial-mesenchymal transition (EMT) features, growth and invasion, drug sensitivity and response to cancer-associated fibroblast conditioned medium (CAF-CM).ResultsOn the basis of EMT features, subtype marker expression, growth, invasion and drug sensitivity three types of cell lines could be distinguished: mesenchymal-like, pancreatobiliary-like and intestinal-like. Heterogeneous effects from the cell lines in response to CAF-CM, such as different growth rates, induction of EMT markers as well as suppression of intestinal differentiation markers were observed. In addition, proteomic analysis showed a clear difference in intestinal-like cell line from other cell lines.ConclusionMost of the available AMPAC cell lines seem to reflect a poorly differentiated pancreatobiliary or mesenchymal-like phenotype, which is consistent to their origin. We suggest that the most appropriate cell line model for intestinal-like AMPAC is the SNU869, while others seem to reflect aggressive AMPAC subtypes.