organotypic-slice-cultures-as-preclinical-models-tumor

Organotypic Slice Cultures as Preclinical Models of Tumor Microenvironment in Primary Pancreatic Cancer and Metastasis

Realistic preclinical models of primary pancreatic cancer and metastasis are urgently needed to test the therapy response ex vivo and facilitate ...

University Medical Center Schleswig-Holstein

Pancreatic ductal adenocarcinoma (PDAC) is the fourth most common cause of death from cancer. Its 5-year survival rate is less than 5%. This poor prognosis is mostly due to the cancer's early invasion and metastasis formation, leading to an initial diagnosis at an advanced incurable stage in the majority of patients. The only potentially curative treatment is radical surgical resection. The effect of current chemotherapeutics or radiotherapy is limited. Novel therapeutic strategies are therefore much needed. One of the hallmarks of PDAC is its abundant desmoplastic (stromal) reaction. The Hedgehog (Hh) signaling pathway is critical for embryologic development of the pancreas. Aberrant Hh signaling promotes pancreatic carcinogenesis, the maintenance of the tumor microenvironment and stromal growth. The canonical Hh-pathway in the tumor stroma has been targeted widely but has not yet lead to hopeful clinical results. Targeting both the tumor and its surrounding stroma through Hh pathway inhibition by also targeting non-canonical pathways as apparent in the tumor cell may therefore be a novel treatment strategy for PDAC. 

Regulation mechanisms of the hedgehog pathway in pancreatic cancer: a review.

The purpose of this study was to retrospectively evaluate diagnostic accuracy of cystic lesions of the pancreas in order to determine if less aggressive surgical treatment might be safe and therefore warranted.

Cystic lesions of the pancreas-is radical surgery really warranted?

The quality of surgery is directly dependent on the quantity, more specifically, on the number of operations performed at a given hospital as well as on the designated surgeon. This fact is supported by numerous studies and meta-analyses that will be presented in the following text. Most of the convincing data for complex procedures can be obtained from visceral (upper and lower gastrointestinal) surgery studies. Mortality of large oncological procedures, such as esophageal or pancreatic surgery, can be reduced by 50% if a certain number of interventions are guaranteed per year. Centralizing these operations performed by specialized surgeons is the key to success. This also ensures that the minimum volume amounts within a given hospital are well above the required levels, thus enabling to teach the necessary expertise step by step. The obligatory 'learning curve' for complex interventions cannot be completed within the framework of reference figures during residency training. Together, surgeons and their respective societies have introduced a proposal for efficient case-oriented centralized surgery. Whether 'we are there yet' in surgery will depend in the end on how these efforts will be incorporated into administrative requirements and the guidelines that will then be implemented across the board.

Minimum Volume Standards in Surgery - Are We There Yet?

The incidence of cystic neoplasms of the pancreas (CNP) is steadily increasing, most likely due to the commonly increased use of cross-sectional abdominal imaging. Most of these lesions are benign at the time of initial presentation, but some harbor malignant potential that either requires constant surveillance or surgical resection. However, it is still unclear when resection is mandated and when observation is sufficient. Moreover, the extent of resection and the technique used are also a matter of debate since limited resection and minimally invasive procedures are becoming more popular. Therefore, the aim of this review was to assess the role of surgery for the management of CNPs with an emphasis on novel procedures.

The role of surgery in cystic lesions of the pancreas.

To analyze possible associations between the duration of stent placement before surgery and the occurrence and severity of postoperative complications after pancreatoduodenectomy (PD).

Preoperative Biliary Stenting and Major Morbidity After Pancreatoduodenectomy: Does Elapsed Time Matter?: The FRAGERITA Study Group.

Biliary stenting leads to antimicrobial-resistant (AMR) microorganism retrievement in bile cultures. However, the impact of intraoperative bile colonizations on post-pancreaticoduodenectomy complications remains unclear. Aims of our study were to characterize the bile flora of stented patients in comparison with postoperative cultures and to analyze whether patterns of drug resistance affected postoperative outcomes.

The Relative Role of Bile Bacterial Isolation on Outcome in Stent-Bearing Patients Undergoing Pancreatoduodenectomy.

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.

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

 Borderline resectability in pancreatic cancer (PDAC) is currently debated.  Patients undergoing pancreatic resections for PDAC were identified from a prospectively maintained database. As new borderline criteria, the presence of any superior mesenterico-portal vein alteration (SMPV) and perivascular stranding of the superior mesenteric artery (SMA) was evaluated in preoperative imaging. The accuracy of established radiological borderline criteria as compared to the new borderline criteria in predicting R status (sensitivity/negative predictive value) and overall survival was assessed. (3)  118 patients undergoing pancreatic resections for PDAC from 2013 to 2018 were identified. Forty-three (36.4%) had radiological perivascular SMA stranding and 55 (46.6%) had SMPV alterations. Interrater reliability was 90% for SMA stranding and 87% for SMPV alterations. The new borderline definition including SMPV alterations and perivascular SMA stranding was the best predictor of conventional R status ( = 0.040, sensitivity 53%, negative predictive value 81%) and Leeds/Wittekind circumferential margin status ( = 0.050, sensitivity 73%, negative predictive value 79%) as compared to established borderline resectability definition criteria. Perivascular SMA stranding qualified as an independent negative prognostic parameter (HR 3.066, 95% CI 1.078-5.716,  = 0.036). : The radiological evaluation of any SMPV alteration and perivascular SMA stranding predicts R status and overall survival in PDAC patients, and may serve to identify potential candidates for neoadjuvant therapy.

Systematic Analysis of Accuracy in Predicting Complete Oncological Resection in Pancreatic Cancer Patients-Proposal of a New Simplified Borderline Resectability Definition.

Our aim was to evaluate recurrence patterns of surgically resected PDAC patients with negative (pN0) or positive (pN1) lymph nodes.

Timing But Not Patterns of Recurrence Is Different Between Node-negative and Node-positive Resected Pancreatic Cancer.

Pancreatic ductal adenocarcinoma (PDAC) is characterized by a highly desmoplastic reaction, warranting intense cancer-stroma communication. In this study, we interrogated the contribution of the BET family of chromatin adaptors to the cross-talk between PDAC cells and the tumor stroma. Short-term treatment of orthotopic xenograft tumors with CPI203, a small-molecule inhibitor of BET proteins, resulted in broad changes in the expression of genes encoding components of the extracellular matrix (matrisome) in both cancer and stromal cells. Remarkably, more than half of matrisome genes were expressed by cancer cells.  cocultures of PDAC cells and cancer-associated fibroblasts (CAF) demonstrated that matrisome expression was regulated by BET-dependent cancer-CAF cross-talk. Disrupting this cross-talk  resulted in diminished growth of orthotopic patient-derived xenograft tumors, reduced proliferation of cancer cells, and changes in collagen structure consistent with that of patients who experienced better survival. Examination of matrisome gene expression in publicly available data sets of 573 PDAC tumors identified a 65-gene signature that was able to distinguish long- and short-term PDAC survivors. Importantly, the expression of genes predictive of short-term survival was diminished in the cancer cells of orthotopic xenograft tumors of mice treated with CPI203. Taken together, these results demonstrate that inhibiting the activity BET proteins results in transcriptional and structural differences in the matrisome are associated with better patient survival. IMPLICATIONS: These studies highlight the biological relevance of the matrisome program in PDAC and suggest targeting of epigenetically driven tumor-stroma cross-talk as a potential therapeutic avenue.

Neoplastic-Stromal Cell Cross-talk Regulates Matrisome Expression in Pancreatic Cancer.

In view of the limited capacities in intensive care units and the increasing economic burden, identification of risk factors could allow better and more efficient planning. Therefore, the aim of this study was to assess independent risk factors for the duration of intensive care unit stay after pancreatoduodenectomy (PD).

Risk Stratification for the Intensive Care Unit Following Pancreaticoduodenectomy.

Pancreatic ductal adenocarcinoma (PDAC) is an aggressive gastrointestinal malignancy characterized by early loco-regional invasion. Portal vein resection (PVR) during pancreatoduodenectomy (PD) for PDAC is performed if tumor cell invasion to the venous wall (PVI) is suspected. The aim of this study is to evaluate radiological criteria for predicting PVR and PVI.

Radiological prediction of portal vein infiltration in patients with pancreatic ductal adenocarcinoma.

Postoperative pancreatic fistula (POPF) after pancreatoduodenectomy (PD) can be associated with severe postoperative morbidity. This study aims to develop a preoperative POPF risk calculator that can be easily implemented in clinical routine.

A simple preoperative stratification tool predicting the risk of postoperative pancreatic fistula after pancreatoduodenectomy.

The postoperative quality of life (QoL) after pancreatic surgery is frequently impaired. The aim of this study was to evaluate the QoL after pancreatic surgery and its influencing risk factors. Furthermore, an age-adjusted comparison with the normal population of Germany was performed.

Evaluation of Postoperative Quality of Life After Pancreatic Surgery and Determination of Influencing Risk Factors.

Surgically assessed pancreatic texture has been identified as the strongest predictor of postoperative pancreatic fistula. However, texture is a subjective parameter with no proven reliability or validity. Therefore, a more objective parameter is needed. In this study, we evaluated the fibrosis level at the pancreatic neck resection margin and correlated fibrosis and all clinico-pathologic parameters collected over the course of the Pancreatogastrostomy vs Pancreatojejunostomy for RECOnstruction (RECOPANC) study.

Article	Year
Regulation mechanisms of the hedgehog pathway in pancreatic cancer: a review. JOP : Journal of the pancreas\| PubMed ID: 25640779	2015
Cystic lesions of the pancreas-is radical surgery really warranted? Langenbeck's archives of surgery\| PubMed ID: 27048403	2016
Minimum Volume Standards in Surgery - Are We There Yet? Visceral medicine\| PubMed ID: 28560225	2017
The role of surgery in cystic lesions of the pancreas. Minerva chirurgica\| PubMed ID: 28565891	2017
Preoperative Biliary Stenting and Major Morbidity After Pancreatoduodenectomy: Does Elapsed Time Matter?: The FRAGERITA Study Group. Annals of surgery\| PubMed ID: 30303874	2018
The Relative Role of Bile Bacterial Isolation on Outcome in Stent-Bearing Patients Undergoing Pancreatoduodenectomy. Journal of gastrointestinal surgery : official journal of the Society for Surgery of the Alimentary Tract\| PubMed ID: 31506893	2020
Adjuvant therapy is associated with improved overall survival in patients with pancreatobiliary or mixed subtype ampullary cancer after pancreatoduodenectomy - A multicenter cohort study. Pancreatology : official journal of the International Association of Pancreatology (IAP) ... [et al.]\| PubMed ID: 31987649	2020
Systematic Analysis of Accuracy in Predicting Complete Oncological Resection in Pancreatic Cancer Patients-Proposal of a New Simplified Borderline Resectability Definition. Cancers\| PubMed ID: 32260453	2020
Timing But Not Patterns of Recurrence Is Different Between Node-negative and Node-positive Resected Pancreatic Cancer. Annals of surgery\| PubMed ID: 32675550	2020
Neoplastic-Stromal Cell Cross-talk Regulates Matrisome Expression in Pancreatic Cancer. Molecular cancer research : MCR\| PubMed ID: 32873625	2020
Risk Stratification for the Intensive Care Unit Following Pancreaticoduodenectomy. Zentralblatt fur Chirurgie\| PubMed ID: 33045755	2020
Radiological prediction of portal vein infiltration in patients with pancreatic ductal adenocarcinoma. Pancreatology : official journal of the International Association of Pancreatology (IAP) ... [et al.]\| PubMed ID: 33309623	2021
A simple preoperative stratification tool predicting the risk of postoperative pancreatic fistula after pancreatoduodenectomy. Pancreatology : official journal of the International Association of Pancreatology (IAP) ... [et al.]\| PubMed ID: 33775565	2021
Evaluation of Postoperative Quality of Life After Pancreatic Surgery and Determination of Influencing Risk Factors. Pancreas\| PubMed ID: 33835967	2021
Surgeon vs Pathologist for Prediction of Pancreatic Fistula: Results from the Randomized Multicenter RECOPANC Study. Journal of the American College of Surgeons\| PubMed ID: 33887486	2021

Kim Honselmann

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