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Background: Postoperative pancreatic fistula is the most common severe complication after pancreatic surgery. It associated with increased morbidity and prolonged hospital stay. Identifying patients at low risk for postoperative pancreatic fistula is essential to enable timely removal of drains and facilitate early discharge. Although postoperative hyperamylasemia is linked to postoperative pancreatic fistula, the role of postoperative hyperlipasemia remains unclear. This study aims to investigate the role of postoperative hyperlipasemia in predicting postoperative pancreatic fistula B/C pancreaticoduodenectomy and distal pancreatectomy., Material and Methods: The study included 471 patients who underwent pancreaticoduodenectomy and distal pancreatectomy at our institution between January 1, 2019, and February 28, 2023. Postoperative hyperamylasemia and postoperative hyperlipasemia were defined as values above the upper limit of normal established at our institution., Results: In univariate analysis, postoperative hyperlipasemia and postoperative hyperamylasemia on postoperative day 0 demonstrated the strongest association with postoperative pancreatic fistula B/C. Consequently, a subset of 177 patients with available serum lipase and amylase data underwent further investigation. Besides body mass index and high-risk pathology, both postoperative hyperlipasemia and postoperative hyperamylasemia on postoperative day 0 emerged as independent risk factors for postoperative pancreatic fistula B/C in univariate analysis. In multivariate analysis, postoperative hyperlipasemia on postoperative day 0 emerged as a significant predictor of postoperative pancreatic fistula B/C, with body mass index as independent risk factor of postoperative pancreatic fistula B/C., Conclusion: The absence of postoperative hyperlipasemia on postoperative day 0 could potentially serve as an effective diagnostic tool for identifying patients who are at a low risk of developing postoperative pancreatic fistula B/C after pancreaticoduodenectomy and distal pancreatectomy. Consequently, not only serum amylase, but also serum lipase can be integrated into clinical practice alongside other relevant parameters., Competing Interests: Conflicts of interest/Disclosure The authors have indicated that they have no conflicts of interest regarding the content of this article., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: After pylorus-resecting pancreatoduodenectomy (PrPD), delayed gastric emptying (DGE) might partially be attributed to biliary reflux. We investigated whether the incidence of primary DGE is reduced after Roux-en-Y instead of Billroth-II reconstruction., Methods: Patients undergoing PrPD from 2016 to 2019 at a high-volume center were identified. Excluding causes of secondary DGE, we matched patients with Roux-en-Y and Billroth-II reconstruction in a 1:2 ratio and compared primary DGE., Results: In 24 vs. 48 (Roux-en-Y vs. Billroth-II) patients, DGE (grade B/C) incidence (20.8 % vs. 18.8 %; P  = 1.000), nasogastric tube requirement (median 2 vs. 2 days; P  = 0.844) and time to solid food intake (7 vs. 7 days; P  = 0.933) were comparable. Univariable logistic regression showed no association between DGE and Roux-en-Y reconstruction (OR 1.47; P  = 0.524), in contrast to age (1.08; P  = 0.030) and pancreatic biochemical leak (4.98; P  = 0.007)., Conclusions: Primary DGE did not differ between Roux-en-Y and Billroth-II reconstruction after PrPD. Instead, age and postoperative pancreatic biochemical leak were associated with higher DGE risk., Competing Interests: None of the authors declared a conflict of interest., (© 2024 The Authors.)

Objectives: This study aimed to assess the consistency and replicability of treatment recommendations provided by ChatGPT 3.5 compared to gastrointestinal tumor cases presented at multidisciplinary tumor boards (MTBs). It also aimed to distinguish between general and case-specific responses and investigated the precision of ChatGPT's recommendations in replicating exact treatment plans, particularly regarding chemotherapy regimens and follow-up protocols., Material and Methods: A retrospective study was carried out on 115 cases of gastrointestinal malignancies, selected from 448 patients reviewed in MTB meetings. A senior resident fed patient data into ChatGPT 3.5 to produce treatment recommendations, which were then evaluated against the tumor board's decisions by senior oncology fellows., Results: Among the examined cases, ChatGPT 3.5 provided general information about the malignancy without considering individual patient characteristics in 19% of cases. However, only in 81% of cases, ChatGPT generated responses that were specific to the individual clinical scenarios. In the subset of case-specific responses, 83% of recommendations exhibited overall treatment strategy concordance between ChatGPT and MTB. However, the exact treatment concordance dropped to 65%, notably lower in recommending specific chemotherapy regimens. Cases recommended for surgery showed the highest concordance rates, while those involving chemotherapy recommendations faced challenges in precision., Conclusions: ChatGPT 3.5 demonstrates potential in aligning conceptual approaches to treatment strategies with MTB guidelines. However, it falls short in accurately duplicating specific treatment plans, especially concerning chemotherapy regimens and follow-up procedures. Ethical concerns and challenges in achieving exact replication necessitate prudence when considering ChatGPT 3.5 for direct clinical decision-making in MTBs., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Postoperative pancreatic fistulas are the most frequent major complications after pancreatoduodenectomy. The soft pancreatic texture is a critical, independent risk factor for postoperative pancreatic fistulas after pancreatoduodenectomy. The current gold standard for postoperative pancreatic fistula risk evaluation consists of the surgeon's intraoperative palpation of the pancreatic texture and, thus, lacks objectivity. In this prospective study, we used ultrasound-based shear-wave elastography, image data analysis, and a fistula risk score calculator to correlate the stiffness of pancreatic tissue with the occurrence of clinically relevant postoperative pancreatic fistulas., Methods: We included 100 patients with pancreatic pathologies (71% pancreatic ductal adenocarcinoma) and 100 healthy individuals who were preoperatively assessed via real-time tissue ultrasound-based shear-wave elastography on a Philips EPIQ 7 ultrasound device and had pancreatic parenchyma histologically evaluated with manually stained images., Results: We found a significant difference in the mean elasticity between the soft (1.22 m/s) and the hard pancreas group (2.10 m/s; P < .0001). The mean elasticity significantly correlated with the pancreatic fibrosis rate and the appearance of a postoperative pancreatic fistula after pancreatoduodenectomy. Low elasticity (≤1.2 m/s, mean) correlated with soft and high elasticity (>2.0 m/s, mean) with hard pancreatic parenchyma, as assessed by pathologic evaluation. Multivariate analysis revealed a mean elasticity of <1.3 m/s as a significant cut-off predictor for clinically relevant postoperative pancreatic fistulas (P = .003; Youden-Index = 0.6945)., Conclusion: Preoperative ultrasound-based shear-wave elastography is a feasible and objective clinical diagnostic modality in evaluating pancreatic tissue stiffness. A mean pancreatic elasticity of <1.3 m/s was a significant independent risk predictor of clinically relevant postoperative pancreatic fistulas after pancreatoduodenectomy., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Background: Recent retrospective studies suggest a role for distinct microbiota in the perioperative morbidity and mortality of pancreatic head resections., Objective: We aimed to prospectively investigate the microbial colonization of critical operative sites of pancreatic head resections to identify microbial stratification factors for surgical and long-term oncologic outcomes., Methods: Prospective biomarker study applying 16S rRNA sequencing and microbial culturing to samples collected from various sites of the GI tract and surgical sites of patients during pancreatic head resections at a German single high-volume pancreatic center., Results: A total of 101 patients were included (38 non-cancer, 63 cancer patients [50 PDAC patients]) in the study. In a first data analysis series, 16S rRNA sequencing data were utilized from 96 patients to assess associations of microbiome profiles with clinical parameters and outcomes. In general, microbiome composition varied according to sampling site, cancer, age or preoperative ERCP intervention, notably for the bile microbiome. In the PDAC subcohort, compositional variance of the bile or periampullary microbiome was significantly associated with postoperative complications such as ICU admission; on a taxonomic level we observed Enterococcus spp. to be significantly more abundant in patients developing deep or organ-space surgical site infections (SSI). Elevated Enterococcus relative abundances in the upper GI tract, in turn, were associated with 6-months mortality rates. In a second step, we focused on microbiological cultures collected from bile aspirates during surgery and investigated associations with perioperative complications and long-term survival. Notably, Enterococcus spp. were among the most prevalent pathobiont isolates observed in cancer patient bile specimens that were associated with severe SSIs, and thereby elevated mortality rates up to 24 months. Clinically relevant postoperative pancreatic fistulas or severe SSI were found as other major variables determining short-term mortality in this cancer patient cohort. In the context of adverse microbiological factors, a preoperative ERCP was also observed to segregate long-term survival, and it appeared to interact with the presence of Enterococcus spp. as highest mortality rates were observed in PDAC patients with both preoperative ERCP and presence of E. faecalis in bile aspirates., Conclusions: The presence of Enterococcus spp. in bile ducts of PDAC patients undergoing pancreatic surgery represents a significant risk factor for perioperative infections and, thereby, elevated postoperative and long-term mortality. This finding supports previous data on the use of the antibiotic drug piperacillin-tazobactam as appropriate perioperative antibiotic prophylaxis for preventing adverse outcomes after pancreatoduodenectomy., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Intestinal homeostasis is a crucial factor for complication-free short- and long-term postoperative recovery. The brush border enzyme intestinal alkaline phosphatase (IAP) is an important regulator of gut barrier function and intestinal homeostasis and prevents endotoxemia by detoxifying lipopolysaccharides (LPSs). As IAP is predominantly secreted by enterocytes in the duodenum, we hypothesized that pancreaticoduodenectomy (PD) leads to a significantly stronger decrease in IAP than other major abdominal surgery., Study Design: Pre- and postoperative blood, stool, and intestinal samples were collected from patients undergoing PD, as well as other major surgical procedures without duodenectomy. The samples were analyzed using enzyme histochemistry, the para -nitrophenyl phosphate method for IAP, and the limulus amebocyte lysate assay for LPS., Results: Overall, 88 patients were prospectively enrolled in the study. Fecal IAP activity negatively correlated with serum LPS (r = -0.3603, p = 0.0006). PD led to a significant decline in IAP compared to preoperative baseline levels (p < 0.0001). The decline in IAP correlated with the length of proximal small intestinal resection (r = 0.4271, p = 0.0034). Compared to controls, PD was associated with a much more pronounced reduction in IAP-also after adjusting for surgical trauma (operative time, blood loss; r = 0.4598, p = 0.0086). Simultaneously, PD triggered a clearly more prominent increase in serum LPS compared to controls (p = 0.0001). Increased postoperative LPS was associated with an elongated hospitalization (r = 0.7534, p = 0.0062) and more prominent in pancreatic cancer (p = 0.0009)., Conclusions: Based upon the functional roles for IAP, supplementation with exogenous IAP might be a new treatment option to improve short- and long-term outcome after PD., (Copyright © 2023 by the American College of Surgeons. Published by Wolters Kluwer Health, Inc. All rights reserved.)

Background: Despite recent advances in locoregional, systemic, and novel checkpoint inhibitor treatment, hepatocellular carcinoma (HCC) is still associated with poor prognosis. The feasibility of potentially curative liver resection (LR) and transplantation (LT) is limited by the underlying liver disease and a shortage of organ donors. Especially after LR, high recurrence rates present a problem and circulating tumor cells are a major cause of extrahepatic recurrence. Tigecycline, a commonly used glycylcycline antibiotic, has been shown to have antitumorigenic effects and could be used as a perioperative and adjuvant therapeutic strategy to target circulating tumor cells. We aimed to investigate the effect of tigecycline on HCC cell lines and its mechanisms of action., Methods: Huh7, HepG2, Hep3B, and immortalized hepatocytes underwent incubation with clinically relevant tigecycline concentrations, and the influence on proliferation, migration, and invasion was assessed in two- and three-dimensional in vitro assays, respectively. Bioinformatic analysis was used to identify specific targets of tigecycline. The expression of RAC1 was detected using western blot, RT-PCR and RNA sequencing. ELISA and flow cytometry were utilized to measure reactive oxygen species (ROS) generation upon tigecycline treatment and flow cytometry to detect alterations in cell cycle. Changes in mitochondrial function were detected via seahorse analysis. RNA sequencing was performed to examine involved pathways., Results: Tigecycline treatment resulted in a significant reduction of mitochondrial function with concomitantly preserved mitochondrial size, which preceded the observed decrease in HCC cell viability. The sensitivity of HCC cells to tigecycline treatment was higher than that of immortalized non-cancerous THLE-2 hepatocytes. Tigecycline inhibited both migratory and invasive properties. Tigecycline application led to an increase of detected ROS and an S-phase cell cycle arrest. Bioinformatic analysis identified RAC1 as a likely target for tigecycline and the expression of this molecule was increased in HCC cells as a result of tigecycline treatment., Conclusion: Our study provides evidence for the antiproliferative effect of tigecycline in HCC. We show for the first time that this effect, likely to be mediated by reduced mitochondrial function, is associated with increased expression of RAC1. The reported effects of tigecycline with clinically relevant and achievable doses on HCC cells lay the groundwork for a conceivable use of this agent in cancer treatment., (© 2023. The Author(s).)

Purpose: Immunotherapies have largely failed as treatment options for pancreatic ductal adenocarcinoma (PDAC). In this field, clinical translational studies into personalized treatment are of fundamental importance. In our study, we model tumor-cell immune-cell interactions in a co-culture of primary human PDAC organoids and matched peripheral blood mononuclear cells (PBMCs)., Methods: Using flow cytometry, we evaluated changes in T cell subtypes upon co-culture of patient-derived PDAC organoids and matched PBMCs., Results: After co-culturing PDAC organoids with PBMCs, we observed changes in CD4 + , CD8 + and Treg cell populations. We observed favorable clinical outcome in patients whose PBMCs reacted to the co-culture with organoids., Conclusion: This experimental model allows to investigate interactions between patient derived PDAC organoids and their PBMCs. This co-culture system could serve as a preclinical platform to guide personalized therapeutic strategies in the future., (© 2023. The Author(s).)

The G-protein-coupled receptor LGR6 associates with ligands of the R-Spondin (RSPO) family to potentiate preexisting signals of the canonical WNT pathway. However, its importance in pancreatic ductal adenocarcinoma (PDAC) remains unclear. Here, we show that LGR6 is differentially expressed in various PDAC cell lines of mesenchymal and epithelial phenotype, respectively, siding with the latter subsets. LGR6 expression is altered based upon the cells' WNT activation status. Furthermore, extrinsic enhancement of WNT pathway signaling increased LGR6 expression suggestive of a reinforcing self-regulatory loop in highly WNT susceptible cells. Downregulation of LGR6 on the other hand, seemed to tamper those effects. Last, downregulation of LGR6 reduced cancer stemness as determined by functional in vitro assays. These findings shed new insights into regulatory mechanisms for the canonical WNT pathway in pancreatic cancer cells. It may also have potential value for treatment stratification of PDAC.

While adult pancreatic stem cells are thought not to exist, it is now appreciated that the acinar compartment harbors progenitors, including tissue-repairing facultative progenitors (FPs). Here, we study a pancreatic acinar population marked by trefoil factor 2 (Tff2) expression. Long-term lineage tracing and single-cell RNA sequencing (scRNA-seq) analysis of Tff2-DTR-CreER T2 -targeted cells defines a transit-amplifying progenitor (TAP) population that contributes to normal homeostasis. Following acute and chronic injury, Tff2 + cells, distinct from FPs, undergo depopulation but are eventually replenished. At baseline, oncogenic Kras G12D -targeted Tff2 + cells are resistant to PDAC initiation. However, Kras G12D activation in Tff2 + cells leads to survival and clonal expansion following pancreatitis and a cancer stem/progenitor cell-like state. Selective ablation of Tff2 + cells prior to Kras G12D activation in Mist1 + acinar or Dclk1 + FP cells results in enhanced tumorigenesis, which can be partially rescued by adenoviral Tff2 treatment. Together, Tff2 defines a pancreatic TAP population that protects against Kras-driven carcinogenesis., Competing Interests: Declaration of interests P.L. is Sr. Director of Single-Cell Systems Pharmacology at DarwinHealth, Inc., & Company that has licensed some of the algorithms used in this manuscript from Columbia University. A.C. is a founder, equity holder, and consultant of DarwinHealth Inc., a company that has licensed some of the algorithms used in this work from Columbia University. Columbia University is also an equity holder in DarwinHealth Inc., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Background: Early colorectal cancer (eCRC) is defined as cancer that does not cross the submucosal layer of the colon or rectum, including carcinoma in situ (pTis), pT1a, and pT1b. Early carcinomas differ in their prognosis depending on the risk profile. The differentiation between low and high risk is essential. The low-risk group includes R0-resected, well (G1) or moderately (G2) differentiated tumors without lymphatic vessel invasion (L0), without blood vessel invasion (V0) and a tumor size ≤3 cm. In this constellation, the estimated risk of lymph node metastasis is around 1% or below. The high-risk group includes tumors with incomplete resection (Rx), poor (G3) or undifferentiated (G4) carcinomas, and/or lymphatic and blood vessel invasion (L1) and size ≥3 cm. In a "high-risk" situation, there is a risk for lymph node metastasis of up to 23%., Summary: The incidence of eCRC is rising with a rate of 10% in all endoscopically removed lesions during colonoscopy. For a correct histological evaluation, all suspected lesions should be completely resected. In case of a pT1 lesion in the rectum, pelvic magnetic resonance imaging should be performed to evaluate for suspicious lymph nodes. The therapeutic approach for eCRC is based on histological assessment and ranges from endoscopic resection to radical oncological surgery. The advantages, disadvantages, and associated risks of the individual treatment strategy need to be carefully discussed on a tumor board and with the patient., Key Messages: Treatment options for early colorectal cancer depend on the histological assessment. Poorly differentiated carcinomas, a Kudo ≥ SM2 classified lesion, and a Haggitt level 4 always represent a "high-risk" situation. It should also be mentioned that in rectal cancer, local surgical tumor excision (full-wall excision) is also sufficient for pT1 carcinomas with a "low-risk" constellation (G1/G2; L0, size <3 cm) and an R0 resection., Competing Interests: The authors have no conflicts of interest to declare., (Copyright © 2022 by S. Karger AG, Basel.)

Background: In pancreatic cancer, systemic treatment options in addition to chemotherapy remain scarce, and so far only a small proportion of patients benefit from targeted therapies., Objective: The patients with pancreatic cancer discussed in the CCCMunich LMU Molecular Tumor Board were reviewed to gain a better real-world understanding of the challenges and chances of precision oncology in this hard-to-treat cancer., Methods: Patients with pancreatic cancer who received comprehensive genomic profiling and were discussed in the interdisciplinary Molecular Tumor Board between May 2017 and July 2022 were included. These patients' medical charts, comprehensive genomic profiling results, and Molecular Tumor Board recommendations were analyzed in this retrospective cohort study., Results: Molecular profiles of 165 patients with pancreatic cancer were discussed in the Molecular Tumor Board. In the 149 cases where comprehensive genomic profiling was successful, KRAS mutations were detected in 87.9%, TP53 in 53.0%, and CDKN2A in 14.1%. 33.3% of KRAS wild-type patients harbored targetable mutations, while these were only found in 19.1% of patients with the KRAS mutation; however, this difference was not statistically significant. 63.8% of patients with successful testing received a targeted treatment recommendation by the Molecular Tumor Board; however, only 3.2% of these were put into practice. Compared to a historic cohort of patients with pancreatic cancer with synchronous metastatic disease diagnosed between 2010 and 2017, the patients from the pancreatic cancer cohort with synchronous metastatic disease had a longer survival., Conclusions: This single-center experience emphasizes the challenges of targeted treatment in pancreatic cancer. Very few patients ultimately received the recommended therapies, highlighting the need for more and better targeted treatment options in pancreatic cancer, early comprehensive genomic profiling to allow sufficient time to put Molecular Tumor Board recommendations into practice, and close cooperation with clinical trial units to give patients access to otherwise not available targeted treatments., (© 2023. The Author(s).)

Background: Although primary tumor sidedness (PTS) has a known prognostic role in sporadic colorectal cancer (CRC), its role in Inflammatory Bowel Disease related CRC (IBD-CRC) is largely unknown. Thus, we aimed to evaluate the prognostic role of PTS in patients with IBD-CRC., Methods: All eligible patients with surgically treated, non-metastatic IBD-CRC were retrospectively identified from institutional databases at ten European and Asian academic centers. Long term endpoints included recurrence-free (RFS) and overall survival (OS). Multivariable Cox proportional hazard regression as well as propensity score analyses were performed to evaluate whether PTS was significantly associated with RFS and OS., Results: A total of 213 patients were included in the analysis, of which 32.4% had right-sided (RS) tumors and 67.6% had left-sided (LS) tumors. PTS was not associated with OS and RFS even on univariable analysis (5-year OS for RS vs LS tumors was 68.0% vs 77.3%, respectively, p = 0.31; 5-year RFS for RS vs LS tumors was 62.8% vs 65.4%, respectively, p = 0.51). Similarly, PTS was not associated with OS and RFS on propensity score matched analysis (5-year OS for RS vs LS tumors was 82.9% vs 91.3%, p = 0.79; 5-year RFS for RS vs LS tumors was 85.1% vs 81.5%, p = 0.69). These results were maintained when OS and RFS were calculated in patients with RS vs LS tumors after excluding patients with rectal tumors (5-year OS for RS vs LS tumors was 68.0% vs 77.2%, respectively, p = 0.38; 5-year RFS for RS vs LS tumors was 62.8% vs 59.2%, respectively, p = 0.98)., Conclusions: In contrast to sporadic CRC, PTS does not appear to have a prognostic role in IBD-CRC., Competing Interests: Declaration of competing interest None., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Tumor cell heterogeneity in colorectal cancers within the same genetic background is a well-described phenomenon. In this work, we investigate the role of hematopoietic pre-B-cell leukemia transcription factor (PBX)-interacting protein (HPIP/PBXIP1) in tumor cell subpopulations with differential Wingless-related integration site (WNT) activity as well as its potential associations with epithelial-mesenchymal transition (EMT) and clinical associations in colorectal cancer. We used in situ analyses to identify immunohistochemical expression of PBXIP1 in normal and colorectal cancer tissues and biostatistical approaches to determine its function and regulatory correlations. Clinical associations were analyzed in a case control collection of metastatic and non-metastatic colon cancers and gene expression data sets of colorectal cancers with recorded clinical follow-up data. PBXIP1 was expressed in single epithelial cells from tumor-free colon crypts as well as in tumor cells with high WNT activity. Colorectal cancer cells close to the invasive edge seemed to possess higher PBXIP1 levels indicative of associations with EMT, whereas stromal cells in the tumor microenvironment appeared mostly negative. PBXIP1 expression was associated with local metastasis to lymph nodes as well as distant metastasis to secondary organs in a case-control collection consisting of 91 cases with or without distant metastasis. Furthermore, high expression of PBXIP1 in The Cancer Genome Atlas (TCGA) data set was associated with worse overall survival in colon cancer. PBXIP1 might serve as a novel histological prognostic and regulatory indicator for EMT processes in colorectal cancer that seems to correlate with cancer cell subtypes of high baseline WNT activity., (Copyright © 2022 Elsevier GmbH. All rights reserved.)

Intestinal ganglionic cells in the adult enteric nervous system (ENS) are continually exposed to stimuli from the surrounding microenvironment and need at times to respond to disturbed homeostasis following acute intestinal injury. The kinase DCLK1 and intestinal Dclk1-positive cells have been reported to contribute to intestinal regeneration. Although Dclk1-positive cells are present in adult enteric ganglia, their cellular identity and response to acute injury have not been investigated in detail. Here, we reveal the presence of distinct Dclk1-tdTom+/CD49b+ glial-like and Dclk1-tdTom+/CD49b- neuronal cell types in adult myenteric ganglia. These ganglionic cells demonstrate distinct patterns of tracing over time yet show a similar expansion in response to elevated serotonergic signaling. Interestingly, Dclk1-tdTom+ glial-like and neuronal cell types appear resistant to acute irradiation injury-mediated cell death. Moreover, Dclk1-tdTom+/CD49b+ glial-like cells show prominent changes in gene expression profiles induced by injury, in contrast to Dclk1-tdTom+/CD49b- neuronal cell types. Finally, subsets of Dclk1-tdTom+/CD49b+ glial-like cells demonstrate prominent overlap with Nestin and p75NTR and strong responses to elevated serotonergic signaling or acute injury. These findings, together with their role in early development and their neural crest-like gene expression signature, suggest the presence of reserve progenitor cells in the adult Dclk1 glial cell lineage. NEW & NOTEWORTHY The kinase DCLK1 identifies glial-like and neuronal cell types in adult murine enteric ganglia, which resist acute injury-mediated cell death yet differ in their cellular response to injury. Interestingly, Dclk1-labeled glial-like cells show prominent transcriptional changes in response to injury and harbor features reminiscent of previously described enteric neural precursor cells. Our data thus add to recently emerging evidence of reserve cellular plasticity in the adult enteric nervous system.

Exercise, psychosocial stress, and drugs such as adrenergic agonists and antagonists increase the concentrations of catecholamines and/or alter adrenergic signaling. Intriguingly, exercise studies universally suggest that catecholamines are cancer-inhibiting whereas cancer stress studies typically report the opposite, whereas β-blocker studies show variable effects. Here, we term variable effects of catecholamines in cancer the cancer catecholamine conundrum. Variable effects of catecholamines can potentially be explained by variable expression of nine adrenergic receptor isoforms and by other factors including catecholamine effects on cancer versus immune or endothelial cells. Future studies on catecholamines and cancer should seek to understand the mechanisms that explain variable effects of catecholamines in cancer to utilize beneficial or block detrimental effects of catecholamines in cancer patients., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Myeloid-derived suppressor cells (MDSCs) are one of the main suppressive cell population of the immune system. They play a pivotal role in the establishment of the tumor microenvironment (TME). In the context of cancers or other pathological conditions, MDSCs can differentiate, expand, and migrate in large quantities during circulation, inhibiting the cytotoxic functions of T cells and NK cells. This process is regulated by ROS, iNOS/NO, arginase-1, and multiple soluble cytokines. The definition of MDSCs and their phenotypes in humans are not as well represented as in other organisms such as mice, owing to the absence of the cognate molecule. However, a comprehensive understanding of the differences between different species and subsets will be beneficial for clarifying the immunosuppressive properties and potential clinical values of these cells during tumor progression. Recently, experimental evidence and clinical investigations have demonstrated that MDSCs have a close relationship with poor prognosis and drug resistance, which is considered to be a leading marker for practical applications and therapeutic methods. In this review, we summarize the remarkable position of MDSCs in solid tumors, explain their classifications in different models, and introduce new treatment approaches to target MDSCs to better understand the advancement of new approaches to cancer treatment.

Background: Molecular differences in colorectal cancer (CRC) are associated with the metastatic route. Patient survival is mainly driven by metastatic spread thus it is imperative to understand its key drivers to develop biomarkers for risk stratification, follow-up protocols and personalized therapy. Thus, this study aimed to identify genes associated with the metastatic route in CRC., Material and Methods: CRC patients resected at our clinic from 2005 to 2014 and with a minimum 5-year follow-up were included in this analysis and grouped into CRC with hepatic (HEP), peritoneal (PER) or without distant metastases (M0), and HEP/PER. Firstly, tumor RNA of 6 patients each was isolated by microdissection from formalin-fixed paraffin-embedded specimens and analyzed by a NanoString analysis. Subsequently, these results were validated with immunohistochemistry and correlated to clinicopathological parameters in a larger collective of CRC patients (HEP n = 51, PER n = 44, M0 n = 47, HEP/PER n = 28)., Results: Compared to M0, HEP tumors showed 20 differentially expressed genes associated with epithelial-mesenchymal transition (EMT) and angiogenesis. Compared to M0, PER tumors had 18 differentially expressed genes. The finding of different gene signatures was supported by the multidimensional principal component clustering analysis. Tumor perforation did not influence the metastatic route. CIB1 was homogenously and significantly overexpressed in HEP compared to M0 (p < 0.001), but not in PER. Furthermore, immunohistochemical validation demonstrated that the mean CIB1 expression in HEP was 80% higher than in M0 (p < 0.001)., Conclusion: Gene expression analysis revealed that CIB1 is significantly overexpressed in CRC leading to liver metastases compared to M0 and PER. Thus, the present results suggest that CIB1 may play a crucial role for hematogenous spread to the liver but not for peritoneal carcinomatosis. Consequently, CIB1 seems to be a promising prognostic marker and a potential tool for future targeted therapies as well as early diagnostics and follow-up., (© 2021. The Author(s).)

Background: Colorectal cancer (CRC) is the third most common malignancy worldwide, but the key driver to distant metastases is still unknown. This study aimed to elucidate the link between immunosurveillance and organotropism of metastases in CRC by evaluating different gene signatures and pathways., Material and Methods: CRC patients undergoing surgery at the Department of General, Visceral and Transplantation Surgery at the Ludwig-Maximilian University Hospital Munich (Munich, Germany) were screened and categorized into M0 (no distant metastases), HEP (liver metastases) and PER (peritoneal carcinomatosis) after a 5-year follow-up. Six patients of each group were randomly selected to conduct a NanoString analysis, which includes 770 genes. Subsequently, all genes were further analyzed by gene set enrichment analysis (GSEA) based on seven main cancer-associated databases., Results: Comparing HEP vs. M0, the gene set associated with the Toll-like receptor (TLR) cascade defined by the Reactome database was significantly overrepresented in HEP. HSP90B1, MAPKAPK3, PPP2CB, PPP2R1A were identified as the core enrichment genes. The immunologic signature pathway GSE6875&#95;TCONV&#95;VS&#95;FOXP3&#95;KO&#95;TREG&#95;DN with FOXP3 as downstream target was significantly overexpressed in M0. RB1, TMEM 100, CFP, ZKSCAN5, DDX50 were the core enrichment genes. Comparing PER vs. M0 no significantly differentially expressed gene signatures were identified., Conclusion: Chronic inflammation might enhance local tumor growth. This is the first study identifying immune related gene sets differentially expressed between patients with either liver or peritoneal metastases. The present findings suggest that the formation of liver metastases might be associated with TLR-associated pathways. In M0, a high expression of FOXP3 + tumor infiltrating lymphocytes (TILs) seemed to prevent at least in part metastases. Thus, these correlative findings lay the cornerstone to further studies elucidating the underlying mechanisms of organotropism of metastases., (© 2021. The Author(s).)

The SP/NK1R-complex plays an important role in tumor proliferation. Targeting of the neurokinin-1 receptor in previous studies with its antagonist aprepitant (AP) resulted in anti-tumoral effects in colorectal cancer and hepatoblastoma. However, there is still a lack of knowledge regarding its effects on pancreatic cancer. Therefore, we treated human pancreatic ductal adenocarcinoma (PDAC) cell lines (Capan-1, DanG, HuP-T3, Panc-1, and MIA PaCa-2) and their cancer stem cell-like cells (CSCs) with AP and analyzed functional effects by MTT-, colony, and sphere formation assays, respectively; moreover, we monitored downstream mechanisms by flow cytometry. NK1R inhibition resulted in dose-dependent growth reduction in both CSCs and non-CSCs without induction of apoptosis in most PDAC cell lines. More importantly, we identified striking AP dependent cell cycle arrest in all parental cells. Furthermore, gene expression and the importance of key genes in PDAC tumorigenesis were analyzed combining RT-qPCR in eight PDAC cell lines with publicly available datasets (TCGA, GEO, CCLE). Surprisingly, we found a better overall survival in patients with high NK1R levels, while at the same time, NK1R was significantly decreased in PDAC tissue compared to normal tissue. Interestingly, there is currently no differentiation between the isoforms of NK1R (truncated and full; NK1R-tr and -fl) in any of the indicated public transcriptomic records, although many publications already emphasize on important regulatory differences between the two isoforms of NK1R in many cancer entities. In conclusion, analysis of splice variants might potentially lead to a stratification of PDAC patients for NK1R-directed therapies. Furthermore, we presume PDAC patients with high expressions of NK1R-tr might benefit from treatment with AP to improve chemoresistance. Therefore, analysis of splice variants might potentially lead to a stratification of PDAC patients for NK1R-directed therapies.

Abstract: A 38-year-old woman presented for 18F-FDG PET/CT after multiple intra-abdominal surgical resections of a rare recurrent perivascular epithelioid cell tumor of the gastrointestinal tract. A solitary pelvic metastasis was detected, but surprisingly exhibited neither increased glucose consumption nor contrast enhancement on CT. Follow-up 18F-FDG PET/CT staging in the further disease course revealed multiple abdominal metastases, now, however, with markedly increased 18F-FDG uptake and intraoperatively correlating widespread peritoneal sarcomatosis. This case gives preliminary insight into monitoring of disease progression in metastatic perivascular epithelioid cell tumor, although the underlying pathophysiological bases for varying 18F-FDG uptake in PET/CT are not yet fully understood., Competing Interests: Conflicts of interest and sources of funding: none declared., (Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.)

Objective: Long-standing chronic pancreatitis is an established risk factor for pancreatic ductal adenocarcinoma (PDAC). Interleukin-1β (IL-1β) has been associated in PDAC with shorter survival. We employed murine models to investigate the mechanisms by which IL-1β and chronic pancreatitis might contribute to PDAC progression., Design: We crossed LSL- Kras +/G12D ; Pdx1 -Cre (KC) mice with transgenic mice overexpressing IL-1β to generate KC-IL1β mice, and followed them longitudinally. We used pancreatic 3D in vitro culture to assess acinar-to-ductal metaplasia formation. Immune cells were analysed by flow cytometry and immunohistochemical staining. B lymphocytes were adoptively transferred or depleted in Kras-mutant mice. B-cell infiltration was analysed in human PDAC samples., Results: KC-IL1β mice developed PDAC with liver metastases. IL-1β treatment increased Kras +/G12D pancreatic spheroid formation. CXCL13 expression and B lymphocyte infiltration were increased in KC-IL1β pancreata. Adoptive transfer of B lymphocytes from KC-IL1β mice promoted tumour formation, while depletion of B cells prevented tumour progression in KC-IL1β mice. B cells isolated from KC-IL1β mice had much higher expression of PD-L1, more regulatory B cells, impaired CD8 + T cell activity and promoted tumorigenesis. IL-35 was increased in the KC-IL1β pancreata, and depletion of IL-35 decreased the number of PD-L1 + B cells. Finally, in human PDAC samples, patients with PDAC with higher B-cell infiltration within tumours showed significantly shorter survival., Conclusion: We show here that IL-1β promotes tumorigenesis in part by inducing an expansion of immune-suppressive B cells. These findings point to the growing significance of B suppressor cells in pancreatic tumorigenesis., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2021. No commercial re-use. See rights and permissions. Published by BMJ.)

Increasing evidence indicates that angiogenesis is crucial in the development and progression of gastric cancer (GC). This study aimed to develop a prognostic relevant angiogenesis-related gene (ARG) signature and a nomogram. The expression profile of the 36 ARGs and clinical information of 372 GC patients were extracted from The Cancer Genome Atlas (TCGA). Consensus clustering was applied to divide patients into clusters 1 and 2. Least absolute shrinkage and selection operator (LASSO) Cox regression analyses were used to identify the survival related ARGs and establish prognostic gene signatures, respectively. The Asian Cancer Research Group (ACRG) ( n = 300) was used for external validation. Risk score of ARG signatures was calculated, and a prognostic nomogram was developed. Gene set enrichment analysis of the ARG model risk score was performed. Cluster 2 patients had more advanced clinical stage and shorter survival rates. ARG signatures carried prognostic relevance in both cohorts. Moreover, ARG-risk score was proved as an independent prognostic factor. The predictive value of the nomogram incorporating the risk score and clinicopathological features was superior to tumor, lymph node, metastasis (TNM) staging. The high-risk score group was associated with several cancer and metastasis-related pathways. The present study suggests that ARG-based nomogram could serve as effective prognostic biomarkers and allow a more precise risk stratification.

Cystic tumors of the pancreas (PCN) have increasingly gained importance in the clinical routine as they are frequently diagnosed as an incidental finding due to the continuous improvement in cross-sectional imaging. A differentiation is made between non-neoplastic and neoplastic cysts, whereby the latter has a tendency to malignant transformation to a varying extent. Therefore, they can be considered as precursor lesions of pancreatic cancer (PDAC). In addition to a detailed patient history and examination, imaging modalities, such as computed tomography (CT), magnetic resonance imaging (MRI) and endoscopic ultrasound (EUS) with fine needle aspiration (FNA) are used for the differential diagnosis. The indications for surgical resection of these lesions are based on the current European guidelines from 2018; however, the content is not evidence-based but relies on knowledge and recommendations from experts. According to these consensus recommendations asymptomatic serous cystic neoplasms (SCN) are serous lesions with a low tendency for malignant transformation and can be monitored. In contrast resection is warranted for all mucinous cystic neoplasms (MCN) >4 cm and all solid pseudopapillary neoplasms (SPN). Intraductal papillary mucinous neoplasms (IPMN), which are differentiated into main duct (MD-IPMN) and branch duct type (BD-IPMN) IPMN based on the position in the pancreatic duct system, should be resected as MD-IPMN and mixed type (MT)-IPMN. The risk of malignant transformation in BD-IPMN is variable and depends on risk factors, which are defined clinically and by imaging morphology. The treatment management is therefore carried out on an individual basis following risk estimation. In order to quantify the quality of indications in PCN and thereby also contributing to optimized medical care, prospective long-term studies are urgently needed.

Background: Most patients with pancreatic cancer suffer a relapse, which occurs either locally or systemically in the sense of liver and the lung metastases. Surgery for pancreatic cancer has become more radical due to the increased use of multimodal treatment concepts; however, the role of surgery in cases of recurrence remains controversial., Objective: This review summarizes the surgical treatment options for isolated local recurrence and metachronous oligometastatic pancreatic cancer., Material and Methods: A selective literature search was carried out and the current evidence for surgical treatment is summarized., Results: There are currently no randomized studies on surgery for metastatic pancreatic cancer. Currently available data, however, show that after surgery long-term survival of up to 32-47 months after metastasectomy can be achieved, especially in patients with local recurrence or isolated pulmonary metastases with low morbidity and mortality. Individualized treatment concepts including surgical resection after initial systemic therapy seem promising even for liver metastases. The greatest survival benefits are consistently shown for all localizations in patients with a long as possible disease-free interval after the first operation., Conclusion: The treatment of isolated local recurrence or metachronous oligometastatic pancreatic cancer is an interdisciplinary challenge that should be performed in specialized pancreatic treatment centers only. Surgical resection embedded in a multimodal treatment concept can be meaningful in selected cases.

Exercise is recommended for the healthy population as it increases fitness and prevents diseases. Moreover, exercise is also applied as an adjunct therapy for patients with various chronic diseases including cancer. Childhood cancer is a rare, heterogeneous disease that differs from adult cancer. Improved therapeutic strategies have increased childhood cancer survival rates to above 80% in developed countries. Although this is higher than the average adult cancer survival rate of about 50%, therapy results often in substantial long-term side effects in childhood cancer survivors. Exercise in adult cancer patients has many beneficial effects and may slow down tumor progression and improve survival in some cancer types, suggesting that exercise may influence cancer cell behavior. In contrast to adults, there is not much data on general effects of exercise in children. Whilst it seems possible that exercise might delay cancer progression or improve survival in children as well, there is no reliable data yet to support this hypothesis. Depending on the type of cancer, animal studies of adult cancer types show that the exercise-induced increase of the catecholamines epinephrine and norepinephrine, have suppressive as well as promoting effects on cancer cells. The diverse effects of exercise in adult cancer patients require investigating whether these results can be achieved in children with cancer., (Copyright © 2020 Kesting, Weeber, Schönfelder, Renz, Wackerhage and von Luettichau.)

The enteric neurotransmitter acetylcholine governs important intestinal epithelial secretory and immune functions through its actions on epithelial muscarinic Gq-coupled receptors such as M3R. Its role in the regulation of intestinal stem cell function and differentiation, however, has not been clarified. Here, we find that nonselective muscarinic receptor antagonism in mice as well as epithelial-specific ablation of M3R induces a selective expansion of DCLK1-positive tuft cells, suggesting a model of feedback inhibition. Cholinergic blockade reduces Lgr5-positive intestinal stem cell tracing and cell number. In contrast, Prox1-positive endocrine cells appear as primary sensors of cholinergic blockade inducing the expansion of tuft cells, which adopt an enteroendocrine phenotype and contribute to increased mucosal levels of acetylcholine. This compensatory mechanism is lost with acute irradiation injury, resulting in a paucity of tuft cells and acetylcholine production. Thus, enteroendocrine tuft cells appear essential to maintain epithelial homeostasis following modifications of the cholinergic intestinal niche.

Objective: To assess the perioperative and long-term outcome following pulmonary resection in patients with metachronous metastasis of pancreatic ductal adenocarcinoma (PDAC)., Background: Most patients with PDAC relapse or develop tumor spread to secondary organs. Currently, it remains unclear how to proceed with pulmonary metastasis in the metachronous setting. In particular, the role of surgery remains controversial., Methods: Data of patients with pulmonary metachronous metastasis after PDAC collected from 2003 to 2015 in databases of two high-volume pancreatic cancer centers were retrospectively analyzed. Clinical and pathological aspects of primary PDAC as well as the perioperative and long-term outcome following pulmonary metastasectomy (PM) was evaluated, respectively. Patients with synchronous liver metastasis or metastasis to other secondary organs were excluded. Univariate survival analysis was performed., Results: We identified 15 patients undergoing pulmonary resection for suspected metastasis after primary pancreatic resection. Operative and histopathologic evaluation revealed resectable pancreatic pulmonary metastasis in 11 patients (73.3%). The median disease-free survival (DFS) and overall survival (OS) after PM diagnosis was 18 months and 26 months, respectively. The median time to metachronous metastasis (TMM) was 17 months [3-64 months]. Perioperative morbidity was low with only one readmission (8.3%). There was no perioperative mortality. Patients who developed pulmonary metastasis later than 17 months after primary surgery showed better OS compared to those who did earlier (32.2 vs. 14.75 months, p = 0.025). In addition, patients with high-grade tumors had worse survival (12.4 vs. 31 months, p = 0.02). Elevated serum CEA levels or CA 19-9 levels were also not associated with shortened OS., Conclusions: This study suggests that pulmonary metastasectomy after PDAC is safe and effective. Patients with extended DFS after primary pancreatic surgery as well as favorable tumor grading seem to particularly benefit from pulmonary surgery., (Copyright © 2019. Published by Elsevier Ltd.)

Background: Neuronal signaling has been implicated in the pathophysiology of multiple malignancies. In biliary tract cancers (BTCs), tumor cell expression of nerve growth factor (NGF) and its receptor neurotrophic tropomyosin receptor kinase (NTRK) has been reported in Asian patients and linked to inferior clinical outcome. Furthermore, NTRK fusions have emerged as a promising target in various cancers. Expression patterns of these markers in Caucasian patients remain unknown., Methods: In this study, 106 patients with BTCs were included. Immunohistochemistry for pan-NTRK and NGF-beta was performed on > 90 samples of this cohort. Additionally, samples from two independent cohorts, incorporating 254 cases, were used to confirm the findings of the original cohort., Results: While expression of pan-NTRK and NGF-beta was readily detectable in peri-tumoral nerves, these markers were not detectable in malignant epithelial cells in our cohort., Conclusions: In a large cohort of Caucasian patients with BTC, NTRK and NGF-beta were not detectable, underscoring potential differences between Caucasian and Asian patient populations.

Immunotherapy has become an established pillar of cancer treatment improving the prognosis of many patients with a broad variety of hematological and solid malignancies. The two main drivers behind this success are checkpoint inhibitors (CPIs) and chimeric antigen receptor (CAR) T cells. This review summarizes seminal findings from clinical and translational studies recently presented or published at important meetings or in top-tier journals, respectively. For checkpoint blockade, current studies focus on combinational approaches, perioperative use, new tumor entities, response prediction, toxicity management and use in special patient populations. Regarding cellular immunotherapy, recent studies confirmed safety and efficacy of CAR T cells in larger cohorts of patients with acute lymphoblastic leukemia or diffuse large B cell lymphoma. Different strategies to translate the striking success of CAR T cells in B cell malignancies to other hematological and solid cancer types are currently under clinical investigation. Regarding the regional distribution of registered clinical immunotherapy trials a shift from PD-1 / PD-L1 trials (mainly performed in the US and Europe) to CAR T cell trials (majority of trials performed in the US and China) can be noted.

In many solid tumors, parasympathetic input is provided by the vagus nerve, which has been shown to modulate tumor growth. However, whether cholinergic signaling directly regulates progression of pancreatic ductal adenocarcinoma (PDAC) has not been defined. Here, we found that subdiaphragmatic vagotomy in LSL- Kras +/G12D ; Pdx1 -Cre (KC) mice accelerated PDAC development, whereas treatment with the systemic muscarinic agonist bethanechol restored the normal KC phenotype, thereby suppressing the accelerated tumorigenesis caused by vagotomy. In LSL- Kras +/G12D ;LSL- Trp53 +/R172H ; Pdx1 -Cre mice with established PDAC, bethanechol significantly extended survival. These effects were mediated in part through CHRM1, which inhibited downstream MAPK/EGFR and PI3K/AKT pathways in PDAC cells. Enhanced cholinergic signaling led to a suppression of the cancer stem cell (CSC) compartment, CD11b + myeloid cells, TNFα levels, and metastatic growth in the liver. Therefore, these data suggest that cholinergic signaling directly and indirectly suppresses growth of PDAC cells, and therapies that stimulate muscarinic receptors may be useful in the treatment of PDAC. Significance: Subdiaphragmatic vagotomy or Chrm1 knockout accelerates pancreatic tumorigenesis, in part via expansion of the CSC compartment. Systemic administration of a muscarinic agonist suppresses tumorigenesis through MAPK and PI3K/AKT signaling, in early stages of tumor growth and in more advanced, metastatic disease. Therefore, CHRM1 may represent a potentially attractive therapeutic target. Cancer Discov; 8(11); 1458-73. ©2018 AACR. This article is highlighted in the In This Issue feature, p. 1333 ., (©2018 American Association for Cancer Research.)

Enteroatmospheric fistulas (EAF) are rare but challenging and morbid complications of abdominal surgery and require time- as well as resource-consuming management. Furthermore, they severely affect patients' quality of life. Several treatment modalities for EAF management are described in the literature. We describe 3 consecutive cases of EAF treatment by employing negative pressure wound therapy (NPWT) along with either a special silicone fistula adapter or a Silo-Vac-like system in another case to isolate the fistula from the remaining abdominal wound. Spontaneous fistula closure was achieved in 2 of the 3 cases, and surgical resection of the small bowel segment harbouring EAF opening was possible in a third case after wound conditioning. The rate of fistula closure was 100% (n = 3/3). Compartmentalisation of the contaminated area using NPWT accelerated healing of the open abdominal wound remarkably. In summary, we present a useful tool for the challenging management of EAF and review the literature on different treatment options of EAF available today., (© 2018 Medicalhelplines.com Inc and John Wiley & Sons Ltd.)

Myeloid-biased hematopoietic stem cells (MB-HSCs) play critical roles in recovery from injury, but little is known about how they are regulated within the bone marrow niche. Here we describe an auto-/paracrine physiologic circuit that controls quiescence of MB-HSCs and hematopoietic progenitors marked by histidine decarboxylase (Hdc). Committed Hdc + myeloid cells lie in close anatomical proximity to MB-HSCs and produce histamine, which activates the H 2 receptor on MB-HSCs to promote their quiescence and self-renewal. Depleting histamine-producing cells enforces cell cycle entry, induces loss of serial transplant capacity, and sensitizes animals to chemotherapeutic injury. Increasing demand for myeloid cells via lipopolysaccharide (LPS) treatment specifically recruits MB-HSCs and progenitors into the cell cycle; cycling MB-HSCs fail to revert into quiescence in the absence of histamine feedback, leading to their depletion, while an H 2 agonist protects MB-HSCs from depletion after sepsis. Thus, histamine couples lineage-specific physiological demands to intrinsically primed MB-HSCs to enforce homeostasis., (Published by Elsevier Inc.)

Background: The purpose of this study is to investigate the prognostic value of pre-resection serum carcinoembryonic antigen (CEA) and carbohydrate antigen (CA) 19-9 after resection of ampullary cancer (AC) in consideration of intestinal (IT) and pancreatobiliary (PT) subtypes., Methods: Overall survival (OS) analysis of patients undergoing curative resection of ampullary cancer., Results: Elevated preoperative CEA (P = 0.013) and CA 19-9 levels (P = 0.030) were significant prognostic factors. Subgroup analysis, however, showed both markers having prognostic value only for the IT subgroup. Pre-resection CEA within normal range identified a subgroup of IT patients with an excellent median survival of 145 months. Compared to other AC patients, this low-risk IT CEA - subpopulation was characterized by less frequent advanced pT stages (pT3/pT4, 41 vs. 62%; P = 0.047) and lymph node involvement (pN+, 30 vs. 65%; P = 0.001). OS of this subgroup was significantly better compared to other AC patients (145 vs. 25 months; HR = 3.8; P < 0.001). By multivariate survival analysis, the patient age, the PT subtype, and an elevated pre-resection serum CEA value were identified as independent prognostic variables., Conclusions: In AC, the histomorphologic subclassification is highly relevant regarding the prognostic value of preoperative serum CEA and CA 19-9. IT-patients with normal preoperative CEA represent a favorable subgroup with excellent long-term survival.

The diagnosis of pancreatic ductal adenocarcinoma (PDAC) carries a dismal prognosis, in particular, when patients present with unresectable disease. While significant progress has been made in understanding the biology of PDAC, this knowledge has not translated into a clear clinical benefit and current chemotherapeutic strategies only offer a modest improvement in overall survival. Accordingly, novel approaches are desperately needed. One hypothesis that could-at least in part-explain the desolate response of PDAC to chemotherapy is the so-called cancer stem cell (CSC) concept, which attributes specific traits, such as chemoresistance, metastatic potential and a distinct metabolism to a small cellular subpopulation of the whole tumor. At the same time, however, some of these attributes could make CSCs more permissive for novel therapeutic strategies with compounds that are already in clinical use. Most recently, several publications have tried to enlighten the field with the idea of repurposing established drugs for antineoplastic use. As such, recycling drugs could present an intriguing and fast-track method with new therapeutic paradigms in anti-cancer and anti-CSC treatments. Here, we aim to summarize important aspects and novel findings of this emerging field., Competing Interests: The authors declare no conflicts of interest.