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For decades, treatment of advanced biliary tract cancer (BTC) was confined to the use of chemotherapy. In recent years however, the number of therapeutic options available for patients with unresectable BTC have drastically increased, with immunotherapy and targeted treatment gradually joining the ranks of guideline-recommended treatment regimens. The aim of the present review is to summarise the current knowledge on unresectable BTC focusing on epidemiology, anatomical distribution and current strategies for systemic treatment. We further outline ongoing clinical trials and provide an outlook on future therapeutic interventions. In the realm of gastrointestinal malignancies, the increasing number of systemic treatment options for BTC is finally delivering on the longstanding commitment to personalised oncology. This emphasises the need for considering a comprehensive genomic-based pathology assessment right from the initial diagnosis to fully leverage the expanding array of therapeutic options that have recently become accessible., Competing Interests: Declaration of Competing interest DZ reported receiving honoraria from AstraZeneca, receiving research funding for the institution from Milteny and travel as well as accommodation expenses from AstraZeneca and Amgen. KD has received travel support from Servier, GSK and BMS, as well as honoraria from AstraZeneca. CBW has received honoraria from Amgen, Bayer, BMS, Chugai, Celgene, Falk, GSK, MSD, Merck, Janssen, Ipsen, Roche, Servier, SIRTeX and Taiho; served on advisory boards for Bayer, BMS, Celgene, Janssen, MSD, Servier, Shire/Baxalta, Rafael Pharmaceuticals, RedHill and Roche; has received travel support by Bayer, Celgene, Janssen, RedHill, Roche, Servier and Taiho and research grants (institutional) by Roche. MH reported receiving travel support from Servier and honoraria for scientific presentations from Falk Foundation. SO reported no conflict of interest. JN reported no conflict of interest. MS reported receiving lecture fees from AstraZeneca, Bayer Healthcare, Cook Medical, Sirtex Medical, LIAM GmbH, Balt and research grants from AstraZeneca, Roche, Bayer Healthcare, Sirtex Medical. JR reported reported no conflict of interest. EDT has served as a paid consultant for AstraZeneca, Bayer, BMS, EISAI, Eli Lilly & Co, MSD, Mallinckrodt, Omega, Pfizer, IPSEN, Terumo and Roche. He has received reimbursement of meeting attendance fees and travel expenses from Arqule, Astrazeneca, BMS, Bayer, Celsion and Roche and lecture honoraria from BMS and Falk. He has received third-party funding for scientific research from Arqule, AstraZeneca, BMS, Bayer, Eli Lilly and IPSEN and Roche. FK reported no conflict of interest. HA reported receiving consulting honoraria from Pfizer, Servier. TR reported being employee of Servier Deutschland GmbH. SB had a consulting and advisory role for Celgene, Servier, Incyte, Fresenius, Janssen-Cilag, AstraZeneca, MSD and BMS and received honoraria for scientific presentations from Roche, Celgene, Servier and MSD. VH received honoraria for talks and advisory board role for Merck, Amgen, Roche, Sanofi, Servier, Pfizer, Pierre-Fabre, AstraZeneca, BMS; MSD, Novartis, Terumo, On- cosil, NORDIC, Seagen, GSK. Research funding from Merck, Amgen, Roche, Sanofi, Boehringer-Ingelheim, SIRTEX, Servier., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Peroxisome proliferator-activated receptor gamma (PPARG) is a member of the nuclear receptor family. It is involved in the regulation of adipogenesis, lipid metabolism, insulin sensitivity, vascular homeostasis and inflammation. In addition, PPARG agonists, known as thiazolidinediones, are well established in the treatment of type 2 diabetes mellitus. PPARGs role in cancer is a matter of debate, as pro- and anti-tumour properties have been described in various tumour entities. Currently, the specific role of PPARG in patients with colorectal cancer (CRC) is not fully understood., Material and Methods: The prognostic impact of PPARG expression was investigated by immunohistochemistry in a case-control study using a matched pair selection of CRC tumours (n = 246) with either distant metastases to the liver (n = 82), lung (n = 82) or without distant metastases (n = 82). Its effect on proliferation as well as the sensitivity to the chemotherapeutic drug 5-fluorouracil (5-FU) was examined after activation, inhibition, and transient gene knockdown of PPARG in the CRC cell lines SW403 and HT29., Results: High PPARG expression was significantly associated with pulmonary metastasis (p = 0.019). Patients without distant metastases had a significantly longer overall survival with low PPARG expression in their tumours compared to patients with high PPARG expression (p = 0.045). In the pulmonary metastasis cohort instead, a trend towards longer survival was observed for patients with high PPARG expression in their tumour (p = 0.059). Activation of PPARG by pioglitazone and rosiglitazone resulted in a significant dose-dependent increase in proliferation of CRC cell lines. Inhibition of PPARG by its specific inhibitor GW9662 and siRNA-mediated knockdown of PPARG significantly decreased proliferation. Activating PPARG significantly increased the CRC cell lines sensitivity to 5-FU while its inhibition decreased it., Conclusion: The prognostic effect of PPARG expression depends on the metastasis localization in advanced CRC patients. Activation of PPARG increased malignancy associated traits such as proliferation in CRC cell lines but also increases sensitivity towards the chemotherapeutic agent 5-FU. Based on this finding, a combination therapy of PPARG agonists and 5-FU-based chemotherapy constitutes a promising strategy which should be further investigated., (© 2024. The Author(s).)

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.)

Purpose: For patients with cancer of unknown primary (CUP), treatment options are limited. Precision oncology, the interplay of comprehensive genomic profiling (CGP) and targeted therapies, aims to offer additional treatment options to patients with advanced and hard-to-treat cancers. We aimed to highlight the use of a molecular tumor board (MTB) in the therapeutic management of CUP patients., Methods: In this single-center observational study, CUP patients, presented to the MTB of the Comprehensive Cancer Center Munich LMU, a tertiary care center, were analyzed retrospectively. Descriptive statistics were applied to describe relevant findings., Results: Between June 2016 and February 2022, 61 patients with unfavorable CUP were presented to the MTB, detected clinically relevant variants in 74% (45/61) of patients, of which 64% (29/45) led to therapeutic recommendation. In four out of 29 patients (14%), the treatment recommendations were implemented, unfortunately without resulting in clinical benefit. Reasons for not following the therapeutic recommendation were mainly caused by the physicians' choice of another therapy (9/25, 36%), especially in the context of worsening of general condition, lost to follow-up (7/25, 28%) and death (6/25, 24%)., Conclusion: CGP and subsequent presentation to a molecular tumor board led to a high rate of therapeutic recommendations in patients with CUP. Recommendations were only implemented at a low rate; however, late GCP diagnostic and, respectively, MTB referral were found more frequent for the patients with implemented treatment. This contrast underscores the need for early implementation of CGP into the management of CUP patients., (© 2023. The Author(s).)

Background and Objective: With the rising importance of precision oncology in biliary tract cancer (BTC), the aim of this retrospective single-center analysis was to describe the clinical and molecular characteristics of patients with BTC who underwent comprehensive genomic profiling (CGP) and were discussed in the CCCMunich LMU molecular tumor board (MTB)., Patients and Methods: In this single-center observational study, we included BTC patients with intrahepatic cholangiocarcinoma (iCCA), extrahepatic CCA (eCCA), and gallbladder cancer (GB), who had been discussed in the institutional MTB from May 29, 2017, to July 25, 2022. Patients were followed up until 31 January 2023. Data were retrospectively collected by review of medical charts, and MTB recommendation., Results: In total, 153 cases were registered to the MTB with a median follow-up of 15 months. Testing was successful in 81.7% of the patients. CGP detected targetable alterations in 35.3% of our BTC patients (most commonly ARID1A/ERBB2/IDH1/PIK3CA/BRAF-mutations and FGFR2-fusions). Recommendations for molecularly guided therapy were given in 46.4%. Of those, treatment implementation of targeted therapy followed in 19.4%. In patients receiving the recommended treatment, response rate was 57% and median overall survival was 19 months (vs 8 months in the untreated cohort). The progression-free survival ratio of 1.45 suggest a clinical benefit of molecularly guided treatment., Conclusions: In line with previous work, our series demonstrates feasibility and clinical utility of comprehensive genomic profiling in BTC patients. With the growing number of targeted agents with clinical activity in BTC, CGP should become standard of care in the management of this group of patients., (© 2023. The Author(s).)

Background: Targeting protein for Xenopus kinesin-like protein 2 (TPX2) overexpression in human tumours is associated with increased malignancy. Its effect on gemcitabine resistance in pancreatic ductal adenocarcinoma (PDAC) has not been studied yet., Methods: The prognostic impact of TPX2 expression was examined in the tumour tissue of 139 patients with advanced PDAC (aPDAC) treated within the AIO-PK0104 trial or translational trials and of 400 resected PDAC (rPDAC) patients. The findings were validated using RNAseq data of 149 resected PDAC patients., Results: In the aPDAC cohorts, 13.7% of all samples showed high TPX2 expression, conferring significantly shorter progression-free survival (PFS, HR 5.25, P < 0.001) and overall survival times (OS, HR 4.36, P < 0.001) restricted to gemcitabine-based treated patients (n = 99). In the rPDAC cohort, 14.5% of all samples showed high TPX2 expression, conferring significantly shorter disease-free survival times (DFS, HR 2.56, P < 0.001) and OS times (HR 1.56, P = 0.04) restricted to patients treated with adjuvant gemcitabine. RNAseq data from the validation cohort confirmed the findings., Conclusions: High TPX2 expression may serve as a negative predictor of gemcitabine-based palliative and adjuvant chemotherapy in PDAC and could be used to inform clinical therapy decisions., Clinical Trial Registry: The clinical trial registry identifier is NCT00440167., (© 2023. The Author(s).)

Purpose: Novel biomarkers to better predict outcome and select the best therapeutic strategy for the individual patient are necessary for pancreatic ductal adenocarcinoma (PDAC)., Methods: Using a panel assay, multiple biomarkers (IFN-γ, IL-10, IL-6, IL-8, TNF-α, CEA, CA 19-9, CYFRA 21-1, HE4, PD-1 and PD-L1 levels) were measured in serum samples of 162 patients with resected, locally advanced and metastatic PDAC in this retrospective single-center study. Optimal cut-off values to differentiate prognostic subgroups with significantly different overall survival (OS) were determined by receiver operator characteristics and Youden Index analysis. Marker levels were assessed before the start of chemotherapy and correlated with OS by univariate and multivariate Cox analysis., Results: Median OS for resected patients was 28.2 months, for locally advanced patients 17.9 months and for patients with metastatic disease 8.6 months. CYFRA 21-1 and IL-8 discriminated metastatic from locally advanced patients best (AUC 0.85 and AUC 0.81, respectively). In univariate analyses, multiple markers showed prognostic relevance in the various subgroups. However, multivariate Cox models comprised only CYFRA 21-1 in the resected group (HR 1.37, p = 0.015), IL-10 in locally advanced PDAC (HR 10.01, p = 0.014), as well as CYFRA 21-1 and CA 19-9 in metastatic PDAC (p = 0.008 and p = 0.010) as an independent prognostic marker for overall survival., Conclusion: IL-10 levels may have independent prognostic value in locally advanced PDAC, whereas CYFRA 21-1 levels are prognostic after PDAC surgery. CYFRA 21-1 and IL-8 have been identified to best discriminate metastatic from locally advanced patients., (© 2022. The Author(s).)

In this case report, we discuss a case of pancreatic cancer bearing a BRAF fusion, leading to MAPK activation, MLHph, and finally MSI.

Venous thromboembolism (VTE) comprising deep venous thrombosis and pulmonary embolism is a major cause of morbidity and mortality. Short-term immobility-related conditions are a major risk factor for the development of VTE. Paradoxically, long-term immobilized free-ranging hibernating brown bears and paralyzed spinal cord injury (SCI) patients are protected from VTE. We aimed to identify mechanisms of immobility-associated VTE protection in a cross-species approach. Mass spectrometry-based proteomics revealed an antithrombotic signature in platelets of hibernating brown bears with heat shock protein 47 (HSP47) as the most substantially reduced protein. HSP47 down-regulation or ablation attenuated immune cell activation and neutrophil extracellular trap formation, contributing to thromboprotection in bears, SCI patients, and mice. This cross-species conserved platelet signature may give rise to antithrombotic therapeutics and prognostic markers beyond immobility-associated VTE.

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).)

Introduction: To this date, surgery remains the only potentially curative approach in the treatment of pancreatic cancer. To analyse the clinical impact of a structured post-operative follow-up programme, we retrospectively analysed a cohort of resected pancreatic adenocarcinoma patients treated at LMU Munich., Methods: Pancreatic adenocarcinoma patients who underwent resection and presented for regular follow-up visits at our centre between 2002 and 2017 were identified from two existing study cohorts. Diagnosis of recurrences was categorised by timing (within or outside a scheduled follow-up visit) and detection modality (imaging, CA 19-9 increase, or clinical deterioration) and correlated with disease-free survival and overall survival (OS)., Results: One hundred and twenty-five patients with resected pancreatic adenocarcinoma were included in this analysis. Median OS in the whole cohort was 21.1 months. Of these 125 patients, 103 (82.4%) patients had a documented relapse. Tumour recurrences detected within a scheduled follow-up visit (n = 86, 83.5%) compared to recurrences becoming apparent at an unplanned visit (n = 17, 16.5%) were associated with a significantly improved OS (median 25.5 vs. 20.2 months, p = 0.019). Compared to patients with recurrence detected by clinical deterioration (n = 4, 3.9%), patients with recurrences detected by imaging or laboratory abnormalities (n = 99, 96.0%) had a longer median OS (24.8 vs. 15.1 months, p = 0.007)., Discussion: A structured follow-up after pancreatic ductal adenocarcinoma resection may have an impact on patient outcome. Prospective trials are needed to evaluate the clinical impact of post-operative follow-up programmes., (© 2022 S. Karger AG, Basel.)

Intrahepatic, perihilar, and distal cholangiocarcinoma (iCCA, pCCA, dCCA) are highly malignant tumours with increasing mortality rates due to therapy resistances. Among the mechanisms mediating resistance, overexpression of anti-apoptotic Bcl-2 proteins (Bcl-2, Bcl-x L , Mcl-1) is particularly important. In this study, we investigated whether antiapoptotic protein patterns are prognostically relevant and potential therapeutic targets in CCA. Bcl-2 proteins were analysed in a pan-cancer cohort from the NCT/DKFZ/DKTK MASTER registry trial (n = 1140, CCA n = 72) via RNA-sequencing and transcriptome-based protein activity interference revealing high ranks of CCA for Bcl-x L and Mcl-1. Expression of Bcl-x L , Mcl-1, and Bcl-2 was assessed in human CCA tissue and cell lines compared with cholangiocytes by immunohistochemistry, immunoblotting, and quantitative-RT-PCR. Immunohistochemistry confirmed the upregulation of Bcl-x L and Mcl-1 in iCCA tissues. Cell death of CCA cell lines upon treatment with specific small molecule inhibitors of Bcl-x L (Wehi-539), of Mcl-1 (S63845), and Bcl-2 (ABT-199), either alone, in combination with each other or together with chemotherapeutics was assessed by flow cytometry. Targeting Bcl-x L induced cell death and augmented the effect of chemotherapy in CCA cells. Combined inhibition of Bcl-x L and Mcl-1 led to a synergistic increase in cell death in CCA cell lines. Correlation between Bcl-2 protein expression and survival was analysed within three independent patient cohorts from cancer centers in Germany comprising 656 CCA cases indicating a prognostic value of Bcl-x L in CCA depending on the CCA subtype. Collectively, these observations identify Bcl-x L as a key protein in cell death resistance of CCA and may pave the way for clinical application., (© 2022 The Authors. Liver International published by John Wiley & Sons Ltd.)

Adjuvant chemotherapy has become standard of care for pancreatic ductal adenocarcinoma (PDAC) as it improves patient outcome. However, its clinical meaning in early-stage, UICC I tumors remains uncertain. We examined the effect of adjuvant therapy on disease-free survival (DFS) and overall survival (OS) of UICC stage I PDAC patients treated at an academic tertiary care center between 2000 and 2016. Among 124 patients (69 male, 55 female; median age 68 years, range 41-84 years) with UICC stage I disease, adjuvant therapy improved both DFS (19.8 vs 12.8 months, HR 0.59, 95% CI: 0.37-0.94, P = .03) and OS (40.9 vs 20.3 months, HR 0.54, 95% CI: 0.35-0.84, P = .005). Multivariate analyses and propensity score matching confirmed the prognostic impact of adjuvant therapy independent of localization, differentiation and R-status. Thus, every patient with UICC I PDAC should receive adjuvant chemotherapy as it may improve outcome significantly. Our findings support the concept of PDAC as systemic disease from early stages on., (© 2022 The Authors. International Journal of Cancer published by John Wiley & Sons Ltd on behalf of UICC.)

Adjuvant gemcitabine (aGC) is one standard of care after pancreatic ductal adenocarcinoma (PDAC) resection. No biomarker for its efficacy is established. As bacteria mediate gemcitabine resistance, we analyzed whether lipopolysaccharide (LPS) as surrogate for bacterial colonization is prognostic in PDAC patients treated with aGC or without aGC adjuvant gemcitabine. We detected LPS in 86 tumors from 376 patients, which defined a specific microbiome as revealed by 16 s-rRNA-sequencing. In the 230 aGC patients, LPS conferred worse disease-free survival (8.3 vs 13.7 months; hazard ratio = 1.75, 95% confidence interval = 1.22 to 2.49; log-rank P = .002) and overall survival (21.7 vs 28.5 months; hazard ratio = 1.80, 95% confidence interval = 1.23 to 2.57; log-rank P = .001) but not in the 146 naGC patients, which was confirmed in an independent validation cohort (n = 178). LPS may serve as a negative predictor for aGC efficacy in PDAC, which suggests a role for microbiome modification to overcome bacteria-mediated chemotherapy resistance., (© The Author(s) 2022. Published by Oxford University Press.)