Publications by authors named "Jörg Kleeff"

280 Publications

AGR2-dependent nuclear import of RNA polymerase II constitutes a specific target of pancreatic ductal adenocarcinoma in the context of wild-type p53.

Gastroenterology 2021 Jul 22. Epub 2021 Jul 22.

Department of Gastroenterology, the Affiliated Drum Tower Hospital of Nanjing University, Medical School, Nanjing, China; Department of Surgery, Ulm University Hospital, Ulm University, Ulm, Germany. Electronic address:

Background And Aim: Promoted by pancreatitis, oncogenic Kras triggers acinar cells' neoplastic transformation through acinar-to-ductal metaplasia (ADM) and pancreatic intraepithelial neoplasia (PanIN). Agr2 (anterior gradient 2), a known inhibitor of p53, is detected at early stage of pancreatic ductal adenocarcinoma (PDAC) development. RNA polymerase II (RNAPII) is a key nuclear enzyme; regulation of its nuclear localization in mammalian cells represents a potential therapeutic target.

Methods: A mouse model of inflammation-accelerated Kras-driven ADM and PanIN development was used. Pancreas-specific Agr2 ablation was performed to access its role in pancreatic carcinogenesis. Hydrophobic hexapeptides loaded in liposomes were developed to disrupt Agr2-RNAPII complex.

Results: We found that Agr2 is upregulated in ADM-to-PanIN transition in inflammation and Kras-driven early pancreatic carcinogenesis. Genetic ablation of Agr2 specifically blocks this metaplastic-to-neoplastic process. Mechanistically, Agr2 directs the nuclear import of RNAPII via its C-terminal nuclear localization signal, undermining the ATR-dependent p53 activation in ADM lesions. Since Agr2 binds to the largest subunit of RNAPII in a peptide motif-dependent manner, we developed a hexapeptide to interfere with the nuclear import of RNAPII by competitively disrupting the Agr2-RNAPII complex. This novel hexapeptide leads to dysfunction of RNAPII with concomitant activation of DNA damage response in early neoplastic lesions; hence, it dramatically compromises PDAC initiation in vivo. Moreover, the hexapeptide sensitizes PDAC cells and patient-derived organoids harbouring wild-type p53 to RNAPII inhibitors and first-line chemotherapeutic agents in vivo. Of note, this therapeutic effect is efficient across various cancer types.

Conclusion: Agr2 is identified as a novel adaptor protein for nuclear import of RNAPII in mammalian cells. Also, we provide genetic evidence defining Agr2-dependent nuclear import of RNAPII as a pharmaceutically accessible target for prevention and treatment in PDAC in the context of wild-type p53.
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http://dx.doi.org/10.1053/j.gastro.2021.07.030DOI Listing
July 2021

The in situ near-total pancreatectomy (LIVOCADO procedure) for end-staged chronic pancreatitis.

Langenbecks Arch Surg 2021 Jun 25. Epub 2021 Jun 25.

Department of General, Visceral and Transplantation Surgery, University of Heidelberg, Im Neuenheimer Feld 420, 69120, Heidelberg, Baden-Württemberg, Germany.

Purpose: Total pancreatectomy for severe pain in end-stage chronic pancreatitis may be the only option, but with vascular involvement, this is usually too high risk and/or technically not feasible. The purpose of the study was to present the clinical outcomes of a novel procedure in severe chronic pancreatitis complicated by uncontrollable pain and vascular involvement.

Methods: We describe an in situ near-total pancreatectomy that avoids peripancreatic vascular dissection (Livocado procedure) and report on surgical and clinical outcomes.

Results: The Livocado procedure was carried out on 18 (3.9%) of 465 patients undergoing surgery for chronic pancreatitis. There were 13 men and 5 women with a median (IQR) age of 48.5 (42.4-57) years and weight of 60.7 (58.0-75.0) kg. All had severe pain and vascular involvement; 17 had pancreatic parenchymal calcification; the median (IQR) oral morphine equivalent dose requirement was 86 (33-195) mg/day. The median (IQR) maximal pain scores were 9 (9-10); the average pain score was 6 (IQR 4-7). There was no peri-operative or 90-day mortality. At a median (IQR) follow-up of 32.5 (21-45.75) months, both maximal and average pain scores were significantly improved post-operatively, and at 12 months, two-thirds of patients were completely pain free. Six (33%) patients had employment pre-operatively versus 13 (72%) post-operatively (p = 0.01).

Conclusions: The Livocado procedure was safe and carried out successfully in patients with chronic pancreatitis with vascular involvement where other procedures would be contraindicated. Perioperative outcomes, post-operative pain scores, and employment rehabilitation were comparable with other procedures carried out in patients without vascular involvement.
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http://dx.doi.org/10.1007/s00423-021-02107-xDOI Listing
June 2021

Early Drain Removal is Safe in Patients With Low or Intermediate Risk of Pancreatic Fistula After Pancreaticoduodenectomy: A Multicenter, Randomized Controlled Trial.

Ann Surg 2021 Jun 11. Epub 2021 Jun 11.

Department of General Surgery, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing 100730, P.R. China Department of General Surgery, Peking University First Hospital, Peking University, Beijing 100034, P.R China Department of General Surgery, Beijing Xuanwu Hospital, Capital Medical University, Beijing 100053, P.R China Department of Hepatobiliary & Pancreatic Surgical Oncology, Chinese People's Liberation Army, General Hospital, Beijing 100853, P.R China Department of Hepato-Biliary-Pancreatic Surgery, Beijing Chaoyang Hospital, Capital Medical University, Beijing 100020, P.R China Department of General Surgery, Beijing Tongren Hospital, Capital Medical University, Beijing 100730, P.R China Department of Visceral, Vascular and Endocrine Surgery, Martin-Luther-University Halle-Wittenberg, 06120, Halle (Saale), Germany.

Objective: This multi-center randomized controlled trial (RCT) was designed to test the hypothesis that early drain removal (EDR) could decrease the incidence of grade 2-4 complications for patients undoing pancreaticoduodenectomy (PD) with low or intermediate risk of postoperative fistula (POPF).

Background: The safety and effects of EDR on postoperative complications after PD are still controversial.

Methods: A multi-center RCT at six tertiary referral hospitals was carried out (NCT03055676). Patients who met the inclusion criteria, including drain amylase level less than 5000 U/L on postoperative day (POD) 1 and POD 3, and drain output less than 300 ml per day within 3 days after surgery, were enrolled. Patients were then randomized to the EDR group or the routine drain removal (RDR) group. In the EDR group, all drainage tubes were removed on POD3. In the RDR group, drainage tubes were removed on POD 5 or beyond. Primary outcome was the incidence of Clavien-Dindo grade 2-4 complications. Secondary outcomes were comprehensive complication index (CCI), grade B/C postoperative pancreatic fistula (POPF), total medical expenses and post-operative in-hospital stay etc., within 90 days after surgery.

Results: A total of 692 patients were screened, and 312 patients were eligible for randomization. Baseline characteristics were well balanced between the two groups and 96.8% of these 312 patients had low or intermediate risk of POPF, according to the 10-point fistula risk score. A total of 20.5% of the patients in the EDR group suffered at least one grade 2-4 complication, versus 26.3% in the RDR group (P = 0.229). Multi-variate analysis showed older age (> 65 years old) and blood transfusion were independent risk factors for grade 2-4 complications. The rate of grade B/C POPF was low in either group (3.8% vs 6.4%, P = 0.305). The CCI of the two groups was also comparable (20.9 vs 20.9, P = 0.253). Total medical expenses were not significantly different. Post-operative in-hospital stay was clinically similar (15 d vs 16 d, P = 0.010).

Conclusions: Nearly half of the patients undergoing PD met the inclusion criteria, predicting low incidence of grade B/C POPF and major complications. EDR was safe in these patients but did not significantly decrease major complications.
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http://dx.doi.org/10.1097/SLA.0000000000004992DOI Listing
June 2021

Identification of prognostic lipid droplet-associated genes in pancreatic cancer patients via bioinformatics analysis.

Lipids Health Dis 2021 Jun 2;20(1):58. Epub 2021 Jun 2.

Department of Visceral, Vascular and Endocrine Surgery, University Medical Center, Martin-Luther-University Halle-Wittenberg, Ernst-Grube-Strasse 40, 06120, Halle (Saale), Germany.

Background: Pancreatic cancer is the fourth leading cause of cancer deaths in the United States both in females and in males, and is projected to become the second deadliest cancer by 2030. The overall 5-year survival rate remains at around 10%. Cancer metabolism and specifically lipid metabolism plays an important role in pancreatic cancer progression and metastasis. Lipid droplets can not only store and transfer lipids, but also act as molecular messengers, and signaling factors. As lipid droplets are implicated in reprogramming tumor cell metabolism and in invasion and migration of pancreatic cancer cells, we aimed to identify lipid droplet-associated genes as prognostic markers in pancreatic cancer.

Methods: We performed a literature search on review articles related to lipid droplet-associated proteins. To select relevant lipid droplet-associated factors, bioinformatics analysis on the GEPIA platform (data are publicly available) was carried out for selected genes to identify differential expression in pancreatic cancer versus healthy pancreatic tissues. Differentially expressed genes were further analyzed regarding overall survival of pancreatic cancer patients.

Results: 65 factors were identified as lipid droplet-associated factors. Bioinformatics analysis of 179 pancreatic cancer samples and 171 normal pancreatic tissue samples on the GEPIA platform identified 39 deferentially expressed genes in pancreatic cancer with 36 up-regulated genes (ACSL3, ACSL4, AGPAT2, BSCL2, CAV1, CAV2, CAVIN1, CES1, CIDEC, DGAT1, DGAT2, FAF2, G0S2, HILPDA, HSD17B11, ICE2, LDAH, LIPE, LPCAT1, LPCAT2, LPIN1, MGLL, NAPA, NCEH1, PCYT1A, PLIN2, PLIN3, RAB5A, RAB7A, RAB8A, RAB18, SNAP23, SQLE, VAPA, VCP, VMP1) and 3 down-regulated genes (FITM1, PLIN4, PLIN5). Among 39 differentially expressed factors, seven up-regulated genes (CAV2, CIDEC, HILPDA, HSD17B11, NCEH1, RAB5A, and SQLE) and two down-regulation genes (BSCL2 and FITM1) were significantly associated with overall survival of pancreatic cancer patients. Multivariate Cox regression analysis identified CAV2 as the only independent prognostic factor.

Conclusions: Through bioinformatics analysis, we identified nine prognostic relevant differentially expressed genes highlighting the role of lipid droplet-associated factors in pancreatic cancer.
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http://dx.doi.org/10.1186/s12944-021-01476-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8171034PMC
June 2021

Management problems in patients with pancreatic cancer from a surgeon's perspective.

Semin Oncol 2021 Apr 21. Epub 2021 Apr 21.

Department of Visceral, Vascular and Endocrine Surgery, Martin-Luther-University, Halle-Wittenberg, Halle, Germany. Electronic address:

Pancreatic cancer is one of the most lethal gastrointestinal tumor entities. Surgery is the only chance for cure; however, only a minority of patients can be offered this option. Due to the anatomic location of the gland, tumor-related problems and complications affecting the surrounding structures are common, leading to biliary and gastric outlet obstruction as well as portal vein thrombosis. This review article summarizes the management of pancreatic cancer-related problems from a surgical point of view. We further describe surgical treatment options in unresectable, metastasized and recurring pancreatic cancer, highlighting potential resection of oligometastatic disease in selected settings.
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http://dx.doi.org/10.1053/j.seminoncol.2021.02.008DOI Listing
April 2021

Multimodal Therapy of Upper Gastrointestinal Malignancies.

Cancers (Basel) 2021 Feb 14;13(4). Epub 2021 Feb 14.

Department of Visceral, Vascular and Endocrine Surgery, Martin-Luther-University Halle-Wittenberg, University Medical Center Halle (Saale), Ernst-Grube-Str. 40, 06120 Halle (Saale), Germany.

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http://dx.doi.org/10.3390/cancers13040793DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7918428PMC
February 2021

Targeting and Reprograming Cancer-Associated Fibroblasts and the Tumor Microenvironment in Pancreatic Cancer.

Cancers (Basel) 2021 Feb 9;13(4). Epub 2021 Feb 9.

Department of Visceral, Vascular and Endocrine Surgery, Martin-Luther-University Halle-Wittenberg, University Medical Center Halle, 06120 Halle, Germany.

Pancreatic cancer is the fourth leading cause of cancer deaths in the United States both in female and male, and is projected to become the second deadliest cancer by 2030. The overall five-year survival rate remains at around 10%. Pancreatic cancer exhibits a remarkable resistance to established therapeutic options such as chemotherapy and radiotherapy, due to dense stromal tumor microenvironment. Cancer-associated fibroblasts are the major stromal cell type and source of extracellular matrix proteins shaping a physical and metabolic barrier thereby reducing therapeutic efficacy. Targeting cancer-associated fibroblasts has been considered a promising therapeutic strategy. However, depleting cancer-associated fibroblasts may also have tumor-promoting effects due to their functional heterogeneity. Several subtypes of cancer-associated fibroblasts have been suggested to exhibit tumor-restraining function. This review article summarizes recent preclinical and clinical investigations addressing pancreatic cancer therapy through targeting specific subtypes of cancer-associated fibroblasts, deprogramming activated fibroblasts, administration of mesenchymal stem cells, as well as reprogramming tumor-promoting cancer-associated fibroblasts to tumor-restraining cancer-associated fibroblasts. Further, inter-cellular mediators between cancer-associated fibroblasts and the surrounding tissue microenvironment are discussed. It is important to increase our understanding of cancer-associated fibroblast heterogeneity and the tumor microenvironment for more specific and personalized therapies for pancreatic cancer patients in the future.
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http://dx.doi.org/10.3390/cancers13040697DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7915918PMC
February 2021

A multilayered post-GWAS assessment on genetic susceptibility to pancreatic cancer.

Genome Med 2021 Feb 1;13(1):15. Epub 2021 Feb 1.

CIBERONC, Madrid, Spain.

Background: Pancreatic cancer (PC) is a complex disease in which both non-genetic and genetic factors interplay. To date, 40 GWAS hits have been associated with PC risk in individuals of European descent, explaining 4.1% of the phenotypic variance.

Methods: We complemented a new conventional PC GWAS (1D) with genome spatial autocorrelation analysis (2D) permitting to prioritize low frequency variants not detected by GWAS. These were further expanded via Hi-C map (3D) interactions to gain additional insight into the inherited basis of PC. In silico functional analysis of public genomic information allowed prioritization of potentially relevant candidate variants.

Results: We identified several new variants located in genes for which there is experimental evidence of their implication in the biology and function of pancreatic acinar cells. Among them is a novel independent variant in NR5A2 (rs3790840) with a meta-analysis p value = 5.91E-06 in 1D approach and a Local Moran's Index (LMI) = 7.76 in 2D approach. We also identified a multi-hit region in CASC8-a lncRNA associated with pancreatic carcinogenesis-with a lowest p value = 6.91E-05. Importantly, two new PC loci were identified both by 2D and 3D approaches: SIAH3 (LMI = 18.24), CTRB2/BCAR1 (LMI = 6.03), in addition to a chromatin interacting region in XBP1-a major regulator of the ER stress and unfolded protein responses in acinar cells-identified by 3D; all of them with a strong in silico functional support.

Conclusions: This multi-step strategy, combined with an in-depth in silico functional analysis, offers a comprehensive approach to advance the study of PC genetic susceptibility and could be applied to other diseases.
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http://dx.doi.org/10.1186/s13073-020-00816-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7849104PMC
February 2021

mTORC1 and mTORC2 Converge on the Arp2/3 Complex to Promote Kras-Induced Acinar-to-Ductal Metaplasia and Early Pancreatic Carcinogenesis.

Gastroenterology 2021 Apr 1;160(5):1755-1770.e17. Epub 2021 Jan 1.

Department of Surgery, Klinikum rechts der Isar, School of Medicine, Technical University of Munich, Munich, Germany; Department of Gastroenterology, the Affiliated Drum Tower Hospital of Nanjing University, Medical School, Nanjing, China; German Cancer Consortium at the partner site Munich, Munich, Germany. Electronic address:

Background & Aims: Oncogenic Kras induces neoplastic transformation of pancreatic acinar cells through acinar-to-ductal metaplasia (ADM), an actin-based morphogenetic process, and drives pancreatic ductal adenocarcinoma (PDAC). mTOR (mechanistic target of rapamycin kinase) complex 1 (mTORC1) and 2 (mTORC2) contain Rptor and Rictor, respectively, and are activated downstream of Kras, thereby contributing to PDAC. Yet, whether and how mTORC1 and mTORC2 impact on ADM and the identity of the actin nucleator(s) mediating such actin rearrangements remain unknown.

Methods: A mouse model of inflammation-accelerated Kras-driven early pancreatic carcinogenesis was used. Rptor, Rictor, and Arpc4 (actin-related protein 2/3 complex subunit 4) were conditionally ablated in acinar cells to deactivate the function of mTORC1, mTORC2 and the actin-related protein (Arp) 2/3 complex, respectively.

Results: We found that mTORC1 and mTORC2 are markedly activated in human and mouse ADM lesions, and cooperate to promote Kras-driven ADM in mice and in vitro. They use the Arp2/3 complex as a common downstream effector to induce the remodeling the actin cytoskeleton leading to ADM. In particular, mTORC1 regulates the translation of Rac1 (Rac family small GTPase 1) and the Arp2/3-complex subunit Arp3, whereas mTORC2 activates the Arp2/3 complex by promoting Akt/Rac1 signaling. Consistently, genetic ablation of the Arp2/3 complex prevents Kras-driven ADM in vivo. In acinar cells, the Arp2/3 complex and its actin-nucleation activity mediated the formation of a basolateral actin cortex, which is indispensable for ADM and pre-neoplastic transformation.

Conclusions: Here, we show that mTORC1 and mTORC2 attain a dual, yet nonredundant regulatory role in ADM and early pancreatic carcinogenesis by promoting Arp2/3 complex function. The role of Arp2/3 complex as a common effector of mTORC1 and mTORC2 fills the gap between oncogenic signals and actin dynamics underlying PDAC initiation.
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http://dx.doi.org/10.1053/j.gastro.2020.12.061DOI Listing
April 2021

Cellular Heterogeneity of Pancreatic Stellate Cells, Mesenchymal Stem Cells, and Cancer-Associated Fibroblasts in Pancreatic Cancer.

Cancers (Basel) 2020 Dec 15;12(12). Epub 2020 Dec 15.

Department of Visceral, Vascular and Endocrine Surgery, Martin-Luther-University Halle-Wittenberg, University Medical Center Halle, 06120 Halle, Germany.

Pancreatic cancer is projected to become the second deadliest cancer by 2030 in the United States, and the overall five-year survival rate stands still at around 9%. The stroma compartment can make up more than 90% of the pancreatic tumor mass, contributing to the hypoxic tumor microenvironment. The dense stroma with extracellular matrix proteins can be a physical and metabolic barrier reducing therapeutic efficacy. Cancer-associated fibroblasts are a source of extracellular matrix proteins. Therefore, targeting these cells, or extracellular matrix proteins, have been considered as therapeutic strategies. However, several studies show that deletion of cancer-associated fibroblasts may have tumor-promoting effects. Cancer-associated fibroblasts are derived from a variety of different cell types, such as pancreatic stellate cells and mesenchymal stem cells, and constitute a diverse cell population consisting of several functionally heterogeneous subtypes. Several subtypes of cancer-associated fibroblasts exhibit a tumor-restraining function. This review article summarizes recent findings regarding origin and functional heterogeneity of tumor-promoting as well as tumor-restraining cancer-associated fibroblasts. A better understanding of cancer-associated fibroblast heterogeneity could provide more specific and personalized therapies for pancreatic cancer patients in the future.
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http://dx.doi.org/10.3390/cancers12123770DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7765115PMC
December 2020

Clinical Outcomes after Total Pancreatectomy: A Prospective Multicenter Pan-European Snapshot Study.

Ann Surg 2020 Nov 9. Epub 2020 Nov 9.

Department of Abdominal Surgery, University Medical Centre Ljubljana, Ljubljana, Slovenia.

Objective: To assess outcomes among patients undergoing total pancreatectomy (TP) including predictors for complications and in-hospital mortality.

Background: Current studies on TP mostly originate from high-volume centers and span long time periods and therefore may not reflect daily practice.

Methods: This prospective pan-European snapshot study included patients who underwent elective (primary or completion) TP in 43 centers in 16 European countries (June 2018-June 2019). Subgroup analysis included cut-off values for annual volume of pancreatoduodenectomies (<60 vs. ≥60). Predictors for major complications and in-hospital mortality were assessed in multivariable logistic regression.

Results: In total, 277 patients underwent TP, mostly for malignant disease (73%). Major postoperative complications occurred in 70 patients (25%). Median hospital stay was 12 days (IQR 9-18) and 40 patients were readmitted (15%). In-hospital mortality was 5% and 90-day mortality 8%. In the subgroup analysis, in-hospital mortality was lower in patients operated in centers with ≥60 pancreatoduodenectomies compared < 60 (4% vs. 10%, p = 0.046). In multivariable analysis, annual volume < 60 pancreatoduodenectomies (OR 3.78, 95%CI 1.18-12.16, p = 0.026), age (OR 1.07, 95%CI 1.01-1.14, p = 0.046), and estimated blood loss ≥2L (OR 11.89, 95%CI 2.64-53.61, p = 0.001) were associated with in-hospital mortality. ASA ≥3 (OR 2.87, 95%CI 1.56-5.26, p = 0.001) and estimated blood loss ≥2L (OR 3.52, 95%CI 1.25-9.90, p = 0.017) were associated with major complications.

Conclusion: This pan-European prospective snapshot study found a 5% in-hospital after TP. The identified predictors for mortality, including low-volume centers, age, and increased blood loss, may be used to improve outcomes.
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http://dx.doi.org/10.1097/SLA.0000000000004551DOI Listing
November 2020

Patients with colorectal cancer and brain metastasis: The relevance of extracranial metastatic patterns predicting time intervals to first occurrence of intracranial metastasis and survival.

Int J Cancer 2021 04 2;148(8):1919-1927. Epub 2020 Dec 2.

Department of Medicine III, University Hospital, LMU Munich, Munich, Germany.

The aim of the study was to investigate the predictive impact of extracranial metastatic patterns on course of disease and survival in patients with colorectal cancer (CRC) and brain metastasis (BM). A total of 228 patients (134 male [59%], 94 female [41%]) with histologically proven CRC and BM were classified into different groups according to extracranial metastatic patterns. Time intervals to metastatic events and survival times from initial CRC diagnosis, extracranial and intracranial metastasis were analyzed. Extracranial organs mostly affected were liver (102 of 228 [44.7%]) and lung (96 of 228 [42.1%]). Liver and lung metastases were detected in 31 patients (13.6%). Calculated over the entire course of disease, patients with lung metastasis showed longer overall survival (OS) than patients with liver metastasis or patients without lung metastasis (43.9 vs 34.6 [P = .002] vs 35.0 months [P = .002]). From the date of initial CRC diagnosis, lung metastasis occurred later in CRC history than liver metastasis (24.3 vs 7.5 months). Once lung metastasis was diagnosed, BM occurred faster than in patients with liver metastasis (15.8 vs 26.0 months; Δ 10.2 months). Accordingly, OS from the diagnosis of liver metastasis was longer than from lung metastasis (27.1 vs 19.6 months [P = .08]). Once BM was present, patients with lung metastasis lived longer than patients with liver metastasis (3.8 vs 1.1 months [P = .028]). Shortest survival times in all survival categories analyzed revealed patients with concurrent liver and lung metastasis. Patients with CRC and BM form a heterogeneous cohort where extracranial metastasis to liver or lungs predicts survival.
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http://dx.doi.org/10.1002/ijc.33364DOI Listing
April 2021

Expression of the EWSR1-FLI1 fusion oncogene in pancreas cells drives pancreatic atrophy and lipomatosis.

Pancreatology 2020 Dec 10;20(8):1673-1681. Epub 2020 Oct 10.

Department of Visceral, Vascular and Endocrine Surgery, Martin-Luther-University Halle-Wittenberg, University Medical Center Halle, Halle, Germany. Electronic address:

Background: Pancreatic ductal adenocarcinoma (PDAC) harbors mutant KRAS as the most common driver mutation. Studies on mouse models have uncovered the tumorigenic characteristics of the Kras oncogene driving pancreatic carcinogenesis. Similarly, Ewing sarcoma predominantly depends on the occurrence of the EWSR1-FLI1 fusion oncogene. The expression of EWSR1-FLI1 affects pro-tumorigenic pathways and induces cell transformation. In this study, we investigated whether mutant Kras could be exchanged by another potent oncogene, such as EWSR1-FLI1, to initiate pancreatic cancer development.

Methods: We generated two conditional mouse models expressing mutant Kras (KC) or the EWSR1-FLI1 oncogene (E/F) in pancreas cells. Pancreatic tissue was collected from the mice at 4-6 weeks and 11-13 weeks of age as well as from survival cohorts to determine the development of spontaneous acinar-to-ductal metaplasia (ADM) and neoplastic lesions. Immunohistochemistry and immunofluorescence staining were performed to characterize and quantify changes in tissue morphology.

Results: The expression of the EWSR1-FLI1 fusion protein in pancreas cells was confirmed by positive FLI1 immunohistochemistry staining. Notably, the EWSR1-FLI1 expression in pancreas cells resulted in a strong depletion of the acinar cell mass and an extensive lipomatosis. Although the E/F mice exhibited spontaneous ADM formation and a shorter overall survival rate compared to KC mice, no development of neoplastic lesion was observed in aging E/F mice.

Conclusions: The expression of the EWSR1-FLI1 oncogene leads to a strong pancreatic atrophy and lipomatosis. ADM formation indicates that pancreatic acinar cells are susceptible for EWSR1-FLI1-mediated oncogenic transformation to a limited extent. However, the EWSR1-FLI1 oncogene is insufficient to induce pancreatic cancer development.
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http://dx.doi.org/10.1016/j.pan.2020.10.033DOI Listing
December 2020

Evaluation of Adjuvant Chemotherapy in Patients With Resected Pancreatic Cancer After Neoadjuvant FOLFIRINOX Treatment.

JAMA Oncol 2020 Nov;6(11):1733-1740

Department of Surgery, Universitaet zu Luebeck, Luebeck, Germany.

Importance: The benefit of adjuvant chemotherapy after resection of pancreatic cancer following neoadjuvant combination treatment with folinic acid, fluorouracil, irinotecan, and oxaliplatin (FOLFIRINOX) is unclear.

Objective: To assess the association of adjuvant chemotherapy with overall survival (OS) in patients after pancreatic cancer resection and neoadjuvant FOLFIRINOX treatment.

Design, Setting, And Participants: This international, multicenter, retrospective cohort study was conducted from January 1, 2012, to December 31, 2018. An existing cohort of patients undergoing resection of pancreatic cancer after FOLFIRINOX was updated and expanded for the purpose of this study. All consecutive patients who underwent pancreatic surgery after at least 2 cycles of neoadjuvant FOLFIRINOX chemotherapy for nonmetastatic pancreatic cancer were retrospectively identified from institutional databases. Patients with resectable pancreatic cancer, borderline resectable pancreatic cancer, and locally advanced pancreatic cancer were eligible for this study. Patients with in-hospital mortality or who died within 3 months after surgery were excluded.

Exposures: The association of adjuvant chemotherapy with OS was evaluated in different subgroups including interaction terms for clinicopathological parameters with adjuvant treatment in a multivariable Cox model. Overall survival was defined as the time starting from surgery plus 3 months (moment eligible for adjuvant therapy), unless mentioned otherwise.

Results: We included 520 patients (median [interquartile range] age, 61 [53-66] years; 279 [53.7%] men) from 31 centers in 19 countries. The median number of neoadjuvant cycles of FOLFIRINOX was 6 (interquartile range, 5-8). Overall, 343 patients (66.0%) received adjuvant chemotherapy, of whom 68 (19.8%) received FOLFIRINOX, 201 (58.6%) received gemcitabine-based chemotherapy, 14 (4.1%) received capecitabine, 45 (13.1%) received a combination or other agents, and 15 (4.4%) received an unknown type of adjuvant chemotherapy. Median OS was 38 months (95% CI, 36-46 months) after diagnosis and 31 months (95% CI, 29-37 months) after surgery. No survival difference was found for patients who received adjuvant chemotherapy vs those who did not (median OS, 29 vs 29 months, univariable hazard ratio [HR], 0.99; 95% CI, 0.77-1.28; P = .93). In multivariable analysis, only the interaction term for lymph node stage with adjuvant therapy was statistically significant: In patients with pathology-proven node-positive disease, adjuvant chemotherapy was associated with improved survival (median OS, 26 vs 13 months; multivariable HR, 0.41 [95% CI, 0.22-0.75]; P = .004). In patients with node-negative disease, adjuvant chemotherapy was not associated with improved survival (median OS, 38 vs 54 months; multivariable HR, 0.85; 95% CI, 0.35-2.10; P = .73).

Conclusions And Relevance: These results suggest that adjuvant chemotherapy after neoadjuvant FOLFIRINOX and resection of pancreatic cancer was associated with improved survival only in patients with pathology-proven node-positive disease. Future randomized studies should be conducted to confirm this finding.
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http://dx.doi.org/10.1001/jamaoncol.2020.3537DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7489392PMC
November 2020

Systematic review and meta-analysis of contemporary pancreas surgery with arterial resection.

Langenbecks Arch Surg 2020 Nov 7;405(7):903-919. Epub 2020 Sep 7.

Department of Visceral, Vascular and Endocrine Surgery, University Hospital Halle (Saale), Martin-Luther-University Halle-Wittenberg, Ernst-Grube-Str. 40, 06120, Halle (Saale), Germany.

Objective: Advances in multimodality treatment paralleled increasing numbers of complex pancreatic procedures with major vascular resections. The aim of this meta-analysis was to evaluate the current outcomes of arterial resection (AR) in pancreatic surgery.

Methods: A systematic literature search was carried out from January 2011 until January 2020. MOOSE guidelines were followed. Predefined outcomes were morbidity, pancreatic fistula, postoperative bleeding and delayed gastric emptying, reoperation rate, mortality, hospital stay, R0 resection rate, and lymph node positivity. Duration of surgery, blood loss, and survival were also analyzed.

Results: Eight hundred and forty-one AR patients were identified in a cohort of 7111 patients. Morbidity and mortality rates in these patients were 66.8% and 5.3%, respectively. Seven studies (579 AR patients) were included in the meta-analysis. Overall morbidity (48% vs 39%, p = 0.1) and mortality (3.2% vs 1.5%, p = 0.27) were not significantly different in the groups with or without AR. R0 was less frequent in the AR group, both in patients without (69% vs 89%, p < 0.001) and with neoadjuvant treatment (50% vs 86%, p < 0.001). Weighted median survival was shorter in the AR group (18.6 vs 32 months, range 14.8-43.1 months, p = 0.037).

Conclusions: Arterial resections increase the complexity of pancreatic surgery, as demonstrated by relevant morbidity and mortality rates. Careful patient selection and multidisciplinary planning remain important.
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http://dx.doi.org/10.1007/s00423-020-01972-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7541389PMC
November 2020

International consensus guidelines on surveillance for pancreatic cancer in chronic pancreatitis. Recommendations from the working group for the international consensus guidelines for chronic pancreatitis in collaboration with the International Association of Pancreatology, the American Pancreatic Association, the Japan Pancreas Society, and European Pancreatic Club.

Pancreatology 2020 Jul 31;20(5):910-918. Epub 2020 May 31.

Department of General Surgery, University of Heidelberg, Im Neuenheimer Feld 110, 69120, Heidelberg, Germany. Electronic address:

Background: Patients with chronic pancreatitis (CP) have an increased risk of pancreatic cancer. We present the international consensus guidelines for surveillance of pancreatic cancer in CP.

Methods: The international group evaluated 10 statements generated from evidence on 5 questions relating to pancreatic cancer in CP. The GRADE approach was used to evaluate the level of evidence available per statement. The working group voted on each statement for strength of agreement, using a nine-point Likert scale in order to calculate Cronbach's alpha reliability coefficient.

Results: In the following domains there was strong consensus: (1) the risk of pancreatic cancer in affected individuals with hereditary pancreatitis due to inherited PRSS1 mutations is high enough to justify surveillance; (2) the risk of pancreatic cancer in patients with CP associated with SPINK1 p. N34S is not high enough to justify surveillance; (3) surveillance should be undertaken in pancreatic specialist centers; (4) surveillance should only be introduced after the age of 40 years and stopped when the patient would no longer be suitable for surgical intervention. All patients with CP should be advised to lead a healthy lifestyle aimed at avoiding risk factors for progression of CP and pancreatic cancer. There was only moderate or weak agreement on the best methods of screening and surveillance in other types of environmental, familial and genetic forms of CP.

Conclusions: Patients with inherited PRSS1 mutations should undergo surveillance for pancreatic cancer, but the best methods for cancer detection need further investigation.
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http://dx.doi.org/10.1016/j.pan.2020.05.011DOI Listing
July 2020

Synchronous arterial resections in pancreatic cancer - still a matter of debate?

Eur J Surg Oncol 2021 02 17;47(2):480-482. Epub 2020 Jun 17.

Department of Visceral, Vascular and Endocrine Surgery, Martin Luther University Halle-Wittenberg, Halle (Saale), Saxony-Anhalt, Germany. Electronic address:

Surgery remains the cornerstone of a multimodality approach aimed at cure in pancreatic cancer (PC). To improve outcomes in PC and widen the indications for surgical resection, surgeons have targeted borderline-resectable (BR) and locally advanced (LA) tumours having demonstrated the feasibility of synchronous arterial (SAR) and venous resections (SVR). However, the true benefit of SARs in PC in terms of improving overall survival has not been fully realised. One of the reasons for this lies in the fact that once the tumour involves the artery, it has already spread along the perineural autonomic plexus that surround it, resulting in early extended local and distant cancer dissemination. Thus, before advocating for the performance of routine SARs in PC, it is important to critically analyse the evidence and develop a structured framework to test if these operations truly hold a beacon of hope for patients with LAPC.
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http://dx.doi.org/10.1016/j.ejso.2020.06.028DOI Listing
February 2021

Deciphering the complex interplay between pancreatic cancer, diabetes mellitus subtypes and obesity/BMI through causal inference and mediation analyses.

Gut 2021 Feb 14;70(2):319-329. Epub 2020 May 14.

National Cancer Registry Ireland, Cork, Ireland.

Objectives: To characterise the association between type 2 diabetes mellitus (T2DM) subtypes (new-onset T2DM (NODM) or long-standing T2DM (LSDM)) and pancreatic cancer (PC) risk, to explore the direction of causation through Mendelian randomisation (MR) analysis and to assess the mediation role of body mass index (BMI).

Design: Information about T2DM and related factors was collected from 2018 PC cases and 1540 controls from the PanGenEU (European Study into Digestive Illnesses and Genetics) study. A subset of PC cases and controls had glycated haemoglobin, C-peptide and genotype data. Multivariate logistic regression models were applied to derive ORs and 95% CIs. T2DM and PC-related single nucleotide polymorphism (SNP) were used as instrumental variables (IVs) in bidirectional MR analysis to test for two-way causal associations between PC, NODM and LSDM. Indirect and direct effects of the BMI-T2DM-PC association were further explored using mediation analysis.

Results: T2DM was associated with an increased PC risk when compared with non-T2DM (OR=2.50; 95% CI: 2.05 to 3.05), the risk being greater for NODM (OR=6.39; 95% CI: 4.18 to 9.78) and insulin users (OR=3.69; 95% CI: 2.80 to 4.86). The causal association between T2DM (57-SNP IV) and PC was not statistically significant (OR=1.08, 95% CI: 0.86 to 1.29, OR=1.06, 95% CI: 0.95 to 1.17). In contrast, there was a causal association between PC (40-SNP IV) and NODM (OR=2.85; 95% CI: 2.04 to 3.98), although genetic pleiotropy was present (MR-Egger: p value=0.03). Potential mediating effects of BMI (125-SNPs as IV), particularly in terms of weight loss, were evidenced on the NODM-PC association (indirect effect for BMI in previous years=0.55).

Conclusion: Findings of this study do not support a causal effect of LSDM on PC, but suggest that PC causes NODM. The interplay between obesity, PC and T2DM is complex.
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http://dx.doi.org/10.1136/gutjnl-2019-319990DOI Listing
February 2021

The role of total pancreatectomy with islet autotransplantation in the treatment of chronic pancreatitis: A report from the International Consensus Guidelines in chronic pancreatitis.

Pancreatology 2020 Jun 14;20(4):762-771. Epub 2020 Apr 14.

Department of Surgery, University of Minnesota Medical Center, Minneapolis, MN, USA; Department of Pediatrics, University of Minnesota Masonic Children's Hospital, Minneapolis, MN, USA. Electronic address:

Background: Advances in our understanding of total pancreatectomy with islet autotransplantation (TPIAT) have been made. We aimed to define indications and outcomes of TPIAT.

Methods: Expert physician-scientists from North America, Asia, and Europe reviewed the literature to address six questions selected by the writing group as high priority topics. A consensus was reached by voting on statements generated from the review.

Results: Consensus statements were voted upon with strong agreement reached that (Q1) TPIAT may improve quality of life, reduce pain and opioid use, and potentially reduce medical utilization; that (Q3) TPIAT offers glycemic benefit over TP alone; that (Q4) the main indication for TPIAT is disabling pain, in the absence of certain medical and psychological contraindications; and that (Q6) islet mass transplanted and other disease features may impact diabetes mellitus outcomes. Conditional agreement was reached that (Q2) the role of TPIAT for all forms of CP is not yet identified and that head-to-head comparative studies are lacking, and that (Q5) early surgery is likely to improve outcomes as compared to late surgery.

Conclusions: Agreement on TPIAT indications and outcomes has been reached through this working group. Further studies are needed to answer the long-term outcomes and maximize efforts to optimize patient selection.
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http://dx.doi.org/10.1016/j.pan.2020.04.005DOI Listing
June 2020

Combined blockade of TGf-β1 and GM-CSF improves chemotherapeutic effects for pancreatic cancer by modulating tumor microenvironment.

Cancer Immunol Immunother 2020 Aug 13;69(8):1477-1492. Epub 2020 Apr 13.

Department of General Surgery, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, 100730, China.

The interactions between tumor immune microenvironment (TIME) and pancreatic cancer cells can affect chemotherapeutic efficacy; however, the mechanisms still remain largely unknown. Thirty items in TIME were comprehensively screened by using tissue microarray from pancreatic cancer patients. Their expressions, interconnections and predictive roles for survival were analyzed. Twenty-one of 30 items could stratify the survival of the patients; however, multivariate analysis found that only 5 independent risk factors could predict worse survival (M2-polarized tumor-associated macrophages (TAMs), IgG4 positive cells, TGF-β1, GM-CSF and lymphangiogenesis). They had a much higher expression levels in tumoral tissue, compared to peritumoral tissue. The Spearman analysis showed that M2-polarized TAM, TGF-β1 and GM-CSF were positively correlated with pancreatic cancer stem cells (PCSC), angiogenesis and lymphangiogenesis. Both human and murine pancreatic cancer cells could induce M2-polarized TAM, which showed substantial roles to decease chemotherapeutic effects. After treated by gemcitabine, both human and murine pancreatic cancer cell lines expressed higher level of immune check points, PCSC markers and varieties of immunosuppressive factors; however, TGF-β1 and GM-CSF had the highest increase. Based on the above results, TGF-β1 and GM-CSF were proposed to be the optimal potential targets to improve chemotherapeutic effects. In immunocompetent murine models, we demonstrated that combined blockade of TGF-β1 and GM-CSF improved the chemotherapeutic effects by inhibition of M2-polarized TAM and induction of CD8 positive T cells. This study presents a novel promising combined strategy to improve the chemotherapeutic effects for pancreatic cancer.
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http://dx.doi.org/10.1007/s00262-020-02542-7DOI Listing
August 2020

Management of the pancreatic transection plane after left (distal) pancreatectomy: Expert consensus guidelines by the International Study Group of Pancreatic Surgery (ISGPS).

Surgery 2020 07 2;168(1):72-84. Epub 2020 Apr 2.

Department of Gastrointestinal and HPB Surgical Oncology, Tata Memorial Hospital, Mumbai, India.

Background: The aim was to evaluate the various operative techniques and outcomes used to manage the pancreatic transection plane (or stump) during a left (distal) pancreatectomy and to develop expert consensus guidelines.

Methods: Evidence-based, clinically relevant questions were discussed and then were circulated among members of the International Study Group of Pancreatic Surgery. After agreement on the questions and statements, voting in a 9-point Likert scale was used to gauge the level of objective support for each.

Results: Studies using the International Study Group of Pancreatic Surgery definition of postoperative pancreatic fistula including 16 randomized trials were reviewed to generate a series of statements set into 14 domains. There was strong consensus in the following statements: there was no difference in the postoperative pancreatic fistula rate after left pancreatectomy between the handsewn and stapler techniques; a stapling technique could not be used in all cases of left pancreatectomy; the use of an energy-based tissue sealant or a chemical sealant device or combinations of these did not impact the postoperative pancreatic fistula rate; there was no difference in the postoperative pancreatic fistula rate between the open, laparoscopic, or robotic approaches; and there are 1 or more clinically important, patient-related risk factors associated with the postoperative pancreatic fistula rate. There was weak or conditional agreement on the use of prophylactic somatostatin analogs, stents, stump closure, stump anastomosis, and the role of abdominal drains.

Conclusion: Areas of strong consensus suggests a change in clinical practice and priority setting. Eight domains with lower agreement will require novel approaches and large multicenter studies to determine future key areas of practice.
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http://dx.doi.org/10.1016/j.surg.2020.02.018DOI Listing
July 2020

Surgery for synchronous and metachronous single-organ metastasis of pancreatic cancer: a SEER database analysis and systematic literature review.

Sci Rep 2020 03 10;10(1):4444. Epub 2020 Mar 10.

Department of Visceral, Vascular and Endocrine Surgery, Martin-Luther-University Halle-Wittenberg, 06120, Halle (Saale), Germany.

Surgery for metastatic pancreatic cancer remains controversial as the survival benefit is questionable. The aim of the present study was to analyze the survival of these patients using data extracted from the surveillance, epidemiology, and end results (SEER) program database. Further, studies on resection for metastatic disease to the lung were systematically reviewed. A total of 11,541 cases with synchronous distant metastasis were analyzed. The median survival of single-organ metastasis was better than of multi-organ metastasis (single-organ 4.0 ± 0.07 months, two-organs 3.0 ± 0.13 months, three/four-organs 2.0 ± 0.19 months; p < 0.0001). Single organ lung metastasis had longer median survival times compared to the other sites (lung 6.0 ± 0.32 months, HR 0.87, 95% CI 0.78-0.97; p = 0.013). Resection of the primary tumor was associated with longer survival in synchronous single-organ metastasis to the lung compared to no resection (14.0 ± 1.93 months vs 6.0 ± 0.31 months, p < 0.0001). A systematic literature review identified 79 cases of metachronous lung metastasis with a survival of 120.0 ± 6.32 months and 83.0 ± 24.84 months following resection of the primary tumor and metastasis, respectively. Lower TNM staging, longer interval to metastasis, and single metastatic lesion correlated with better survival. Resection in highly selected pancreatic cancer patients with synchronous and metachronous lung only metastasis might confer a survival benefit and should be considered on an individual basis.
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http://dx.doi.org/10.1038/s41598-020-61487-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7064579PMC
March 2020

Precision oncology for pancreatic cancer in real-world settings.

Lancet Oncol 2020 04 2;21(4):469-471. Epub 2020 Mar 2.

Department of Visceral, Vascular and Endocrine Surgery, Martin-Luther University Halle-Wittenberg, 06120 Halle (Saale), Germany.

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http://dx.doi.org/10.1016/S1470-2045(20)30148-0DOI Listing
April 2020

Pancreatic Cancer Risk in Relation to Lifetime Smoking Patterns, Tobacco Type, and Dose-Response Relationships.

Cancer Epidemiol Biomarkers Prev 2020 05 12;29(5):1009-1018. Epub 2020 Feb 12.

Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stokholm, Sweden.

Background: Despite smoking being a well-established risk factor for pancreatic cancer, there is a need to further characterize pancreatic cancer risk according to lifespan smoking patterns and other smoking features, such as tobacco type. Our aim was to deeply investigate them within a large European case-control study.

Methods: Tobacco smoking habits and other relevant information were obtained from 2,009 cases and 1,532 controls recruited in the PanGenEU study using standardized tools. Multivariate logistic regression analysis was performed to evaluate pancreatic cancer risk by smoking characteristics and interactions with other pancreatic cancer risk factors. Fractional polynomials and restricted cubic splines were used to test for nonlinearity of the dose-response relationships and to analyze their shape.

Results: Relative to never-smokers, current smokers [OR = 1.72; 95% confidence interval (95% CI), 1.39-2.12], those inhaling into the throat (OR = 1.48; 95% CI, 1.11-1.99) or chest (OR = 1.33; 95% CI, 1.12-1.58), and those using nonfiltered cigarettes (OR = 1.69; 95% CI, 1.10-2.61), were all at an increased pancreatic cancer risk. Pancreatic cancer risk was highest in current black tobacco smokers (OR = 2.09; 95% CI, 1.31-3.41), followed by blond tobacco smokers (OR = 1.43; 95% CI, 1.01-2.04). Childhood exposure to tobacco smoke relative to parental smoking was also associated with increased pancreatic cancer risk (OR = 1.24; 95% CI, 1.03-1.49). Dose-response relationships for smoking duration, intensity, cumulative dose, and smoking cessation were nonlinear and showed different shapes by tobacco type. Effect modification by family history of pancreatic cancer and diabetes was likely.

Conclusions: This study reveals differences in pancreatic cancer risk by tobacco type and other habit characteristics, as well as nonlinear risk associations.

Impact: This characterization of smoking-related pancreatic cancer risk profiles may help in defining pancreatic cancer high-risk populations.
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http://dx.doi.org/10.1158/1055-9965.EPI-19-1027DOI Listing
May 2020

Do we need sequential local therapy following neoadjuvant chemotherapy for locally advanced pancreatic cancer?

EClinicalMedicine 2019 Dec 4;17:100222. Epub 2019 Dec 4.

Department of Visceral, Vascular and Endocrine Surgery, Martin Luther University Halle-Wittenberg, Halle (Saale), Germany.

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http://dx.doi.org/10.1016/j.eclinm.2019.11.015DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6933141PMC
December 2019

Oncogenic Akt-FOXO3 loop favors tumor-promoting modes and enhances oxidative damage-associated hepatocellular carcinogenesis.

BMC Cancer 2019 Sep 5;19(1):887. Epub 2019 Sep 5.

Department of Visceral, Vascular and Endocrine Surgery, University Medical Center Halle, Martin-Luther-University Halle-Wittenberg, Halle, Germany.

Background: Hepatocellular carcinoma (HCC) is the most prevalent primary liver cancer, accounting for 80-90% of cases. Mutations are commonly found in the signaling regulating the PI3K/Akt pathway, leading to oncogenic cell proliferation and survival. Key transcription factors that are negatively regulated downstream of PI3K/Akt are members of the forkhead box O family (FOXO). FOXOs were initially considered as tumor suppressors by inducing cell cycle arrest and apoptosis. However, there is increasing evidence showing that FOXOs, especially FOXO3, can support tumorigenesis.

Methods: To understand the roles of FOXO3 in liver tumorigenesis and hepatocarcinogenesis, we analyzed HCC patient specimens and also established a doxycycline-regulated transgenic mouse model with hepatocyte-specific FOXO3 expression in a constitutively active form.

Results: We found that FOXO3 protein is significantly overexpressed and activated in livers of HCC patients. Hepatic activation of FOXO3 induced extensive hepatic damage and elevated gene expression of several HCC-associated factors. Furthermore, FOXO3 expression enhanced hepatotoxicin-induced tumorigenesis. Mechanistically, FOXO3 activation caused oxidative stress and DNA damage and triggered positive feedback-loop for Akt activation as well as mTORC2 activation. Interestingly, FOXO3 activated not only reactive oxygen species (ROS)-promoting pathways, but also ROS-eliminating systems, which can be associated with the activation of the pentose phosphate pathway.

Conclusions: FOXO3 is a master regulator of ROS in a 'carrot and stick' manner; on one side avoiding cellular crisis while also supporting hepatocellular carcinogenesis. Clinically, we suggest analyzing FOXO3 activation status in patients with liver diseases, in addition to PI3K/Akt signaling. Personalized therapy of FOXO3 inhibition may be a reasonable, depending on the activation status of FOXO3.
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http://dx.doi.org/10.1186/s12885-019-6110-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6728971PMC
September 2019

Immunotherapy of pancreatic cancer.

Prog Mol Biol Transl Sci 2019 22;164:189-216. Epub 2019 Mar 22.

Department of Visceral, Vascular and Endocrine Surgery, Martin-Luther-University Halle-Wittenberg, University Medical Center Halle, Halle, Germany.

Pancreatic ductal adenocarcinoma (PDAC) is predicted to become the second most common cause of cancer-related death in the United States by 2030. So far surgery remains the only curative option for pancreatic cancer, but fewer than 20% of patients have surgically resectable disease. Furthermore, pancreatic cancer exhibits a remarkable resistance to established therapeutic options, including chemotherapy, radiotherapy, and targeted therapy, because pancreatic cancer exhibits numerous mechanisms of resistance like genetic and epigenetic alterations and a complex and dense tumor microenvironment. The tumor microenvironment is populated with different types of immune cells that play a critical role in therapy resistance, tumor progression, and carcinogenesis. Cancer immunotherapy has now been recognized as the fourth pillar of cancer care and a number of preclinical and clinical studies have been conducted for pancreatic cancer. Targeting and modulating the tumor immune microenvironment could not only switch the immune system toward anti-cancer, but also may improve sensitivity toward established chemotherapy. In this review, we discuss both preclinical and clinical studies on pancreatic cancer immunotherapy with natural killer cells, dendritic cells, and chimeric antigen receptor T cells. Furthermore, we summarize strategies for reprogramming the tumor immune microenvironment by targeting macrophages and stromal cell factors in pancreatic cancer. The development of systemic therapies is essential for improving the outcomes of pancreatic cancer patients, and cancer immunotherapy would improve effectiveness of other established therapeutic options, which might together improve the prognosis of pancreatic tumors.
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http://dx.doi.org/10.1016/bs.pmbts.2019.03.006DOI Listing
April 2020

Response to Comment on "The Impact of Positive Resection Margins on Survival and Recurrence Following Resection and Adjuvant Chemotherapy for Pancreatic Ductal Adenocarcinoma" by Niccolo Petrucciani, MD, PhD, FACS, Laura Antolino, MD, Giovanni Moschetta, MD, Giovanni Ramacciato, MD, FACS.

Ann Surg 2019 12;270(6):e130-e131

The Department of Surgery, University of Heidelberg, Heidelberg, Germany The Department of Surgery, Royal Liverpool and Broadgreen University Hospitals NHS Trust, Liverpool, UK The Department of Surgery, University Hospital Halle, Martin-Luther-University Halle-Wittenberg, Germany The Department of Surgery, Royal Liverpool and Broadgreen University Hospitals NHS Trust, Liverpool, UK The Department of Surgery, University of Heidelberg, Heidelberg, Germany.

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http://dx.doi.org/10.1097/SLA.0000000000003371DOI Listing
December 2019

Ring1b-dependent epigenetic remodelling is an essential prerequisite for pancreatic carcinogenesis.

Gut 2019 11 6;68(11):2007-2018. Epub 2019 Apr 6.

Department of Medicine II, University Hospital, LMU Munich, Munich, Germany.

Background And Aims: Besides well-defined genetic alterations, the dedifferentiation of mature acinar cells is an important prerequisite for pancreatic carcinogenesis. Acinar-specific genes controlling cell homeostasis are extensively downregulated during cancer development; however, the underlying mechanisms are poorly understood. Now, we devised a novel in vitro strategy to determine genome-wide dynamics in the epigenetic landscape in pancreatic carcinogenesis.

Design: With our in vitro carcinogenic sequence, we performed global gene expression analysis and ChIP sequencing for the histone modifications H3K4me3, H3K27me3 and H2AK119ub. Followed by a comprehensive bioinformatic approach, we captured gene clusters with extensive epigenetic and transcriptional remodelling. Relevance of Ring1b-catalysed H2AK119ub in acinar cell reprogramming was studied in an inducible Ring1b knockout mouse model. CRISPR/Cas9-mediated Ring1b ablation as well as drug-induced Ring1b inhibition were functionally characterised in pancreatic cancer cells.

Results: The epigenome is vigorously modified during pancreatic carcinogenesis, defining cellular identity. Particularly, regulatory acinar cell transcription factors are epigenetically silenced by the Ring1b-catalysed histone modification H2AK119ub in acinar-to-ductal metaplasia and pancreatic cancer cells. Ring1b knockout mice showed greatly impaired acinar cell dedifferentiation and pancreatic tumour formation due to a retained expression of acinar differentiation genes. Depletion or drug-induced inhibition of Ring1b promoted tumour cell reprogramming towards a less aggressive phenotype.

Conclusions: Our data provide substantial evidence that the epigenetic silencing of acinar cell fate genes is a mandatory event in the development and progression of pancreatic cancer. Targeting the epigenetic repressor Ring1b could offer new therapeutic options.
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http://dx.doi.org/10.1136/gutjnl-2018-317208DOI Listing
November 2019

Outcomes and Risk Score for Distal Pancreatectomy with Celiac Axis Resection (DP-CAR): An International Multicenter Analysis.

Ann Surg Oncol 2019 Mar 4;26(3):772-781. Epub 2019 Jan 4.

Department of Surgery, Cancer Center Amsterdam, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands.

Background: Distal pancreatectomy with celiac axis resection (DP-CAR) is a treatment option for selected patients with pancreatic cancer involving the celiac axis. A recent multicenter European study reported a 90-day mortality rate of 16%, highlighting the importance of patient selection. The authors constructed a risk score to predict 90-day mortality and assessed oncologic outcomes.

Methods: This multicenter retrospective cohort study investigated patients undergoing DP-CAR at 20 European centers from 12 countries (model design 2000-2016) and three very-high-volume international centers in the United States and Japan (model validation 2004-2017). The area under receiver operator curve (AUC) and calibration plots were used for validation of the 90-day mortality risk model. Secondary outcomes included resection margin status, adjuvant therapy, and survival.

Results: For 191 DP-CAR patients, the 90-day mortality rate was 5.5% (95 confidence interval [CI], 2.2-11%) at 5 high-volume (≥ 1 DP-CAR/year) and 18% (95 CI, 9-30%) at 18 low-volume DP-CAR centers (P = 0.015). A risk score with age, sex, body mass index (BMI), American Society of Anesthesiologists (ASA) score, multivisceral resection, open versus minimally invasive surgery, and low- versus high-volume center performed well in both the design and validation cohorts (AUC, 0.79 vs 0.74; P = 0.642). For 174 patients with pancreatic ductal adenocarcinoma, the R0 resection rate was 60%, neoadjuvant and adjuvant therapies were applied for respectively 69% and 67% of the patients, and the median overall survival period was 19 months (95 CI, 15-25 months).

Conclusions: When performed for selected patients at high-volume centers, DP-CAR is associated with acceptable 90-day mortality and overall survival. The authors propose a 90-day mortality risk score to improve patient selection and outcomes, with DP-CAR volume as the dominant predictor.
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http://dx.doi.org/10.1245/s10434-018-07101-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6373251PMC
March 2019
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