Pancreatic neuroendocrine neoplasms are epigenetically driven tumors, but therapies against underlying epigenetic drivers are currently not available in the clinical practice. We aimed to investigate EZH2 (Enhancer of Zest homolog) expression in PanNEN and the impact of EZH2 inhibition in three different PanNEN preclinical models. EZH2 expression in PanNEN patient samples (n = 172) was assessed by immunohistochemistry and correlated with clinico-pathological data. Viability of PanNEN cell lines treated with EZH2 inhibitor (GSK126) was determined in vitro. Lentiviral transduction of shRNA targeting EZH2 was performed in QGP1 cells, and cell proliferation was measured. Rip1TAG2 mice underwent GSK126 treatment for three weeks starting from week 10 of age. Primary cells isolated from PanNEN patients (n = 6) were cultivated in 3D as islet-like tumoroids and monitored for 10 consecutive days upon GSK126 treatment. Viability was measured continuously for the whole duration of the treatment. We found that high EZH2 expression correlated with higher tumor grade (p < 0.001), presence of distant metastases (p < 0.001), and shorter disease-free survival (p < 0.001) in PanNEN patients. Inhibition of EZH2 in vitro in PanNEN cell lines and in patient-derived islet-like tumoroids reduced cell viability and impaired cell proliferation, while inhibition of EZH2 in vivo in Rip1TAG2 mice reduced tumor burden. Our results show that EZH2 is highly expressed in high-grade PanNENs, and during disease progression it may contribute to aberrations in the epigenetic cellular landscape. Targeting EZH2 may represent a valuable epigenetic treatment option for patients with PanNEN.

The tumor microenvironment is known to play a pivotal role in driving cancer progression and governing response to therapy. This is of significance in pancreatic cancer where the unique pancreatic tumor microenvironment, characterized by its pronounced desmoplasia and fibrosis, drives early stages of tumor progression and dissemination, and contributes to its associated low survival rates. Several molecular factors that regulate interactions between pancreatic tumors and their surrounding stroma are beginning to be identified. Yet broader physiological factors that influence these interactions remain unclear. Here, we discuss a series of preclinical and mechanistic studies that highlight the important role chronic stress plays as a physiological regulator of neural-tumor interactions in driving the progression of pancreatic cancer. These studies propose several approaches to target stress signaling via the β-adrenergic signaling pathway in order to slow pancreatic tumor growth and metastasis. They also provide evidence to support the use of β-blockers as a novel therapeutic intervention to complement current clinical strategies to improve cancer outcome in patients with pancreatic cancer.

Purpose: Dysregulated expression of heat shock proteins (HSP) plays a fundamental role in tumor development and progression. Consequently, HSP90 may be an effective tumor target in oncology, including the treatment of gastrointestinal cancers. Methods: We carried out a systematic review of data extracted from clinicaltrials.gov and pubmed.gov, which included all studies available until January 1st, 2022. The published data was evaluated using primary and secondary endpoints, particularly with focus on overall survival, progression-free survival, and rate of stable disease. Results: Twenty trials used HSP90 inhibitors in GI cancers, ranging from phase I to III clinical trials. Most studies assessed HSP90 inhibitors as a second line treatment. Seventeen of the 20 studies were performed prior to 2015 and only few studies have results pending. Several studies were terminated prematurely, due to insufficient efficacy or toxicity. Thus far, the data suggests that HSP90 inhibitor NVP-AUY922 might improve outcome for colorectal cancer and gastrointestinal stromal tumors. Conclusion: It currently remains unclear which subgroup of patients might benefit from HSP90 inhibitors and at what time point these inhibitors may be beneficial. There are only few new or ongoing studies initiated during the last decade.

Background & Aims: Hepatocellular carcinoma (HCC) is the third leading cause of cancer‐related death worldwide. Liver transplantation (LT) is a curative treatment option. We investigated survival outcomes based on recipient‐donor sex constellation (RDSC) following LT.Methods: We performed a European Liver Transplant Registry analysis, including patients from 1988 to December 2022. The cohort was split into four RDSC groups: female donor female recipient (FDFR), female donor male recipient (FDMR), male donor female recipient (MDFR) and male donor male recipient (MDMR). Survival analysis, including death with recurrence, was performed.Results: In 7601 LT for HCC with an overall median follow‐up of 22.6 months (5.8, 60.7), death was registered in 25.1% and, as primary cause of death, HCC tumour recurrence in 26.0%. There was no statistically significant difference on crude survival estimates among the different RDSC groups (log‐rank p = 0.66) with 10‐year overall survival (OS) of 54.5% in FDFR, 54.6% in FDMR, 59.1% in MDFR and 56.9% in MDMR. On multivariable analysis, RDSC showed a significant effect on OS (FDFR as reference): MDFR (aHR 0.72, p = 0.023). No significant difference was found for FDMR (aHR 0.98, p = 0.821) and MDMR (aHR 0.90, p= 0.288). Regarding overall registered causes of death, differences between RDSC groups were found in rejection (p = 0.017) and cardiovascular (p = 0.046) associated deaths.Conclusions: In female recipients undergoing LT for HCC, male donor grafts were associated with a 28% reduction of mortality compared to female donor grafts.

Introduction: Solid organ transplantation (SOT) is a lifesaving treatment for end‐stage organ failure. Although many factors affect the success of organ transplantation, recipient and donor sex are important biological factors influencing transplant outcome. However, the impact of the four possible recipient and donor sex combinations (RDSC) on transplant outcome remains largely unclear.Methods: A scoping review was carried out focusing on studies examining the association between RDSC and outcomes (mortality, graft rejection, and infection) after heart, lung, liver, and kidney transplantation. All studies up to February 2023 were included.Results: Multiple studies published between 1998 and 2022 show that RDSC is an important factor affecting the outcome after organ transplantation. Male recipients of SOT have a higher risk of mortality and graft failure than female recipients. Differences regarding the causes of death are observed. Female recipients on the other hand are more susceptible to infections after SOT.Conclusion: Differences in underlying illnesses as well as age, immunosuppressive therapy and underlying biological mechanisms among male and female SOT recipients affect the post‐transplant outcome. However, the precise mechanisms influencing the interaction between RDSC and post‐transplant outcome remain largely unclear. A better understanding of how to identify and modulate these factors may improve outcome, which is particularly important in light of the worldwide organ shortage. An analysis for differences of etiology and causes of graft loss or mortality, respectively, is warranted across the RDSC groups.Practitioner points: Recipient and donor sex combinations affect outcome after solid organ transplantation. While female recipients are more susceptible to infections after solid organ transplantation, they have higher overall survival following SOT, with causes of death differing from male recipients. Sex‐differences should be taken into account in the post‐transplant management.

Background: The incidence and mortality of intrahepatic cholangiocarcinoma (ICCA) is increasing worldwide and curative treatment options are limited due to the aggressive tumor biology and often late diagnosis. Resection of the primary tumor remains the only curative therapy available, as the benefit of palliative chemotherapy and radiotherapy is relatively small. In contrast to hepatocellular carcinoma, minimal-invasive thermal tumor ablation, and in particular stereotactic tumor ablation for small primary cancers or metastases, is not established and data are scarce. Methods: We conducted a literature review in the field of ICCA ablation and retrospective analysis of 10 patients treated by stereotactic microwave ablation (SMWA) for either primary ICCA or liver metastases of ICCA. Results: While current guidelines have no consensus for ablation of primary ICCA, some state that it might be an option in inoperable patients or those with recurrent disease. The literature review revealed 11 studies on microwave ablation for ICCA reporting that MWA for ICCA ≤ 5 cm might be safe and could be a treatment option for patients who are not candidates for surgery. No data has been published on stereotactic microwave ablation (SMWA) for ICCA. The analyses of our own data of 10 patients treated by SMWA for primary ICCA (n = 5) or recurrent ICCA (n = 5) show that the treatment is safe and efficient with short hospital stays and low complication rates. Conclusion: Although thermal ablation, and in particular SMWA, might be a minimally invasive and tissue-sparing curative treatment alternative for small ICCA in the diseased liver and ICCA metastases, the oncologic benefit still needs to be shown in larger studies with longer follow-up.