Corina Kim-Fuchs

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: Physical deconditioning affects patients suffering from end-stage liver disease (ESLD). Liver transplantation (LT) is the only curative option for ESLD. Growing evidence suggests that pre-habilitation is beneficial in reducing post-surgical morbidity and mortality. We investigated physical activity (PA) in patients awaiting LT in a country with long waiting times. Methods: Prospective, single center, longitudinal study in Bern, Switzerland between June 2019 and February 2020 (halted due to SARS-CoV-2 pandemic), with follow-up data up to six months post-transplant. Patients were instructed to use a wrist tracker (FitBit) to monitor PA, which was assessed using mixed-effects generalized linear models. The study was approved by the local ethics committee (BASEC ID 2019-00606). Results: Thirty-five patients were included [71% male, median 59 years, body mass index (BMI) 28 kg/m², lab Model End-Stage Liver Disease (MELD) 11], 17 (49%) pre-frail and 5 (14%) frail according to the Liver Frailty Index (LFI). Twenty-eight patients underwent transplantation with 0 ninety-day mortality and 15 (53.6%) composite adverse clinical outcome. Median daily steps were 4,661 [interquartile range (IQR), 1,685–8,609] and weekly moderate PA (MPA) was 41 min (IQR, 0–127 min). Longitudinal analysis showed that female patients and patients on nutritional support had an increase in MPA between weeks 20 and 40. A significant decrease was seen in MPA after week 40, whilst no significant association was seen with age, Child-Pugh Score, LFI or quality of life at time of inclusion. MPA was significantly associated with the occurrence of the composite clinical endpoint after week 30 of waiting time (odds ratio 0.882, P=0.026). World Health Organization (WHO)-recommended MPA was significantly associated with less adverse composite clinical outcomes (PConclusions: In patients listed for LT, MPA decreased over time, showing a significant association with adverse outcome, specifically after week 30 on the waiting list. Our data support the implementation of routine pre-habilitation in patients awaiting LT.

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.

Zusammenfassung. Pankreatische neuroendokrine Tumore (PanNET) sind eine seltene und heterogene Gruppe von Tumoren mit sehr unterschiedlicher klinischer Präsentation. Dementsprechend sind diese im klinischen Alltag initial schwierig zu erkennen und die Diagnosestellung erfolgt häufig verzögert. Die nötigen diagnostischen Schritte beinhalten radiologische und funktionelle / nuklearmedizinische Untersuchungen, um einerseits die Ausdehnung des Primärtumors zu bestimmen und andererseits das Vorliegen von Metastasen zu erkennen. Gegeben falls ist eine Tumorbiopsie indiziert. Die daraus resultierenden Behandlungen beinhalten in Abhängigkeit vom Tumortyp sowie -ausbreitung und der Symptomatik die chirurgische Resektion, die Behandlung mittels Somatostatin-Analoga oder multimodale Therapiekonzepte. Die Therapie der Patienten mit neuroendokrinen Tumoren (NET) muss an einem interdisziplinären Tumorboard an einem spezialisierten Zentrum besprochen werden.

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.

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.

Objective: Disease recurrence following curatively intended hepatectomy for hepatocellular carcinoma (HCC) limits oncologic outcome. Based on the extent, location and time-point of tumor recurrence, different therapeutic modalities are available to treat recurrent HCC. Therefore, our aim was to investigate the role of these treatments and the time-point of recurrence on long-term survival. Methods: Clinicopathological data of patients, who underwent hepatectomy for HCC at a major hepatobiliary center in Switzerland between 2012 and 2019, were assessed. Patients suffering tumor recurrence were stratified according to the treatment modalities for recurrent HCC including surgical treatment (repeat hepatectomy or liver transplantation), interventional treatment, and conservative treatment (chemotherapy or best supportive care). Groups were compared regarding to overall survival (OS). Additionally, long-term outcomes were compared between patients with early (≤ 12 months) and late (> 12 months) tumor recurrence. Results: During the study period, 159 patients underwent hepatectomy for HCC. Median follow-up time was 53 months. After a median time of seven (1-64) months, 74 patients were diagnosed with tumor recurrence (47 %). The majority of patients developed early recurrence (n = 49) and 58 patients had intrahepatic recurrence only. Treatment options were re-resection, liver transplantation, interventional methods, and palliative therapy in 5, 15, 23, and 31 patients, respectively. Surgical treatment was significantly associated with improved OS compared to interventional and conservative treatment (5-year OS: 84% vs. 39% vs. 30%, p < 0.0001). OS was significantly better among patients with late recurrence compared to patients with early recurrence, irrespective of the treatment modality used for the recurrent disease (5-year OS: 70% vs. 38%, p = 0.008). Conclusion: Repeat hepatectomy or liver transplantation for recurrent HCC following hepatectomy is associated with better long-term survival compared to interventional or conservative therapies, especially for patients with late tumor recurrence. Patients with intrahepatic HCC recurrence should be evaluated according to the extent of tumor burden, liver function, and functional status to identify the best candidates for a surgical treatment.

Modern chemotherapy and repeat hepatectomy allow to tailor the surgical strategies for the treatment of colorectal liver metastases (CRLM). This study addresses the hypothesis that parenchymal-sparing hepatectomy reduces postoperative complications while ensuring similar oncologic outcomes compared to the standardized non-parenchymal-sparing procedures. Clinicopathological data of patients who underwent liver resection for CRLM between 2012 and 2019 at a major hepatobiliary center in Switzerland were assessed. Patients were stratified according to the tumor burden score [TBS² = (maximum tumor diameter in cm)² + (number of lesions)²)] and were dichotomized in a lower and a higher tumor burden cohort according to the median TBS. Postoperative outcomes, overall survival (OS) and disease-free survival (DFS) of patients following parenchymal-sparing resection (PSR) for CRLM were compared with those of patients undergoing non-PSR. During the study period, 153 patients underwent liver resection for CRLM with curative intent. PSR was performed in 79 patients with TBS < 4.5, and in 42 patients with TBS ≥ 4.5. In patients with lower tumor burden (TBS < 4.5), PSR was associated with lower complication rate (15.2% vs. 46.2%, p = 0.009), and shorter length of hospital stay (5 vs. 9 days, p = 0.006) in comparison to non-PSR. For TBS < 4.5, PSR resulted in equivalent 5-year OS (48% vs. 39%, p = 0.479) and equivalent 5-year DFS rates (DFS, 44% vs. 29%, p = 0.184) compared to non-PSR. For TBS ≥ 4.5, PSR resulted in lower postoperative complication rate (33.3% vs. 63.2%, p = 0.031), lower length of hospital stay (6 vs. 9 days, p = 0.005), equivalent 5-year OS (29% vs. 22%, p = 0.314), and equivalent 5-year DFS rates (29% vs. 22%, p = 0.896) compared to non-PSR. Among all patients treated with PSR, patients undergoing minimal-invasive hepatectomy had equivalent 5-year OS (42% vs. 37%, p = 0.261) and equivalent 5-year DFS (34% vs. 34%, p = 0.613) rates compared to patients undergoing open hepatectomy. PSR for CRLM is associated with lower postoperative morbidity, shorter length of hospital stay, and equivalent oncologic outcomes compared to non-PSR independently from tumor burden. Our findings suggest that minimal-invasive PSR should be considered as the preferred method for the treatment of curatively resectable CRLM if allowed by tumor size and location.