Physical activity decreases in patients on the liver transplant waiting list and influences postoperative outcome-a prospective cohort study.

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 (P<0.001). Conclusions: 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.

Evolution of humoral immune response to SARS-CoV-2 mRNA vaccine in liver transplant recipients - a longitudinal study.

BACKGROUND AND AIM: Liver transplant recipients show suboptimal vaccine-elicited immune responses to severe acute respiratory coronavirus 2 (SARS-CoV-2) vaccination. This study aimed to assess real-world data on SARS-CoV-2 antibodies after the second and third SARS-CoV-2 vaccination in liver transplant recipients in Switzerland. METHODS: We enrolled liver transplant recipients who attended regular follow-up visits between 01/07/2021 and 30/04/2022 at the outpatient clinic of the Department of Visceral Surgery and Medicine at Bern University Hospital, Switzerland. Following the Swiss Federal Office of Public Health recommendations, we measured SARS-CoV-2 anti-spike IgG antibodies in 117 liver transplant recipients ≥4 weeks after the second SARS-CoV-2 mRNA vaccination from 07/2021-04/2022. In case of antibody levels of <100 AU/ml, patients received a third vaccination and antibodies were re-measured. Patients with antibody levels of >100 AU/ml were defined as "responders", those with 12-100 AU/ml as "partial responders" and those with <12 AU/ml as "non-responders". RESULTS: After two vaccinations, 36/117 (31%) were responders, 42/117 (36%) were partial responders and 39/117 (33%) were non-responders. The humoral immune response improved significantly after the third vaccination, resulting in 31/55 (56%) responders among the previous partial or non-responders. A total of 26 patients developed COVID-19, of whom two had a moderate or severe course (both non-responders after three doses). DISCUSSION: One third of liver transplant recipients showed an optimal response following two vaccinations; a third dose achieved a complete antibody response in more than half of partial and non-responders. We observed only one severe course of COVID-19 and no deaths from COVID-19 in the vaccinated liver transplant recipients.

Heat shock protein 90 (HSP90) inhibitors in gastrointestinal cancer: where do we currently stand?-A systematic review.

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.

Comparison of methods for donor-derived cell-free DNA quantification in plasma and urine from solid organ transplant recipients.

In allograft monitoring of solid organ transplant recipients, liquid biopsy has emerged as a novel approach using quantification of donor-derived cell-free DNA (dd-cfDNA) in plasma. Despite early clinical implementation and analytical validation of techniques, direct comparisons of dd-cfDNA quantification methods are lacking. Furthermore, data on dd-cfDNA in urine is scarce and high-throughput sequencing-based methods so far have not leveraged unique molecular identifiers (UMIs) for absolute dd-cfDNA quantification. Different dd-cfDNA quantification approaches were compared in urine and plasma of kidney and liver recipients: A) Droplet digital PCR (ddPCR) using allele-specific detection of seven common HLA-DRB1 alleles and the Y chromosome; B) high-throughput sequencing (HTS) using a custom QIAseq DNA panel targeting 121 common polymorphisms; and C) a commercial dd-cfDNA quantification method (AlloSeq® cfDNA, CareDx). Dd-cfDNA was quantified as %dd-cfDNA, and for ddPCR and HTS using UMIs additionally as donor copies. In addition, relative and absolute dd-cfDNA levels in urine and plasma were compared in clinically stable recipients. The HTS method presented here showed a strong correlation of the %dd-cfDNA with ddPCR (R 2 = 0.98) and AlloSeq® cfDNA (R 2 = 0.99) displaying only minimal to no proportional bias. Absolute dd-cfDNA copies also correlated strongly (τ = 0.78) between HTS with UMI and ddPCR albeit with substantial proportional bias (slope: 0.25; 95%-CI: 0.19-0.26). Among 30 stable kidney transplant recipients, the median %dd-cfDNA in urine was 39.5% (interquartile range, IQR: 21.8-58.5%) with 36.6 copies/µmol urinary creatinine (IQR: 18.4-109) and 0.19% (IQR: 0.01-0.43%) with 5.0 copies/ml (IQR: 1.8-12.9) in plasma without any correlation between body fluids. The median %dd-cfDNA in plasma from eight stable liver recipients was 2.2% (IQR: 0.72-4.1%) with 120 copies/ml (IQR: 85.0-138) while the median dd-cfDNA copies/ml was below 0.1 in urine. This first head-to-head comparison of methods for absolute and relative quantification of dd-cfDNA in urine and plasma supports a method-independent %dd-cfDNA cutoff and indicates the suitability of the presented HTS method for absolute dd-cfDNA quantification using UMIs. To evaluate the utility of dd-cfDNA in urine for allograft surveillance, absolute levels instead of relative amounts will most likely be required given the extensive variability of %dd-cfDNA in stable kidney recipients.

The impact of perceived donor liver quality on post-transplant outcome.

BACKGROUND: We analysed the impact of perceived liver donor quality on transplant recipient outcomes. METHODS: this prospective cohort study included all deceased liver donors during 2008-2018 in the Swiss Transplant Cohort Study. Perceived low-quality liver donors were defined when refused for ≥5 top listed recipients or for all recipients in at least one centre before being transplanted. The effect of liver donor quality on relisting or recipient death at 1 week and 1 year after transplantation was analysed using Kaplan-Meier and Cox proportional hazard models. A 1:3 matching was also performed using a recipient score. RESULTS: Of 973 liver donors, 187 (19.2%) had perceived poor-quality. Males, obesity, donation after circulatory death and alanine aminotransferase values were significantly associated with perceived poor-quality, with no significant effect of the perceived quality on re-listing or death within the first week and first year post-transplant [(aHR) = 1.45, 95% CI: (0.6, 3.5), P = 0.41 and aHR = 1.52 (95% CI 0.98-2.35), P = 0.06], adjusting by recipient age and gender, obesity, diabetes, prior liver transplantation and model for end-stage liver disease (MELD) score. At 1 year, prior liver transplantation and higher MELD score associated with higher risk of re-listing or death. CONCLUSION: Comparable post-transplant outcomes with different perceived quality liver donors stresses the need to improve donor selection in liver transplantation.

Regression of Graft Steatosis After Liver Transplantation.

Introduction: Liver grafts with limited steatosis are currently used for liver transplantation, but the natural history of graft steatosis is not well known. Project Aims or Questions: This program evaluation aimed at assessing changes of steatosis after liver transplantation. Design: A retrospective chart review was performed assessing presence and severity of steatosis in the liver explant and in time zero donor graft biopsies carried out at the time-point of liver transplantation on histopathology and on imaging one year thereafter in 30 well characterized patients. Results: Ten patients (33%) showed steatosis on explant. Time zero biopsy revealed steatosis in 18 grafts (60%) and no steatosis in 12 (40%). One year after transplantation, 8 patients (27%) had steatosis and 22 patients (63%) had none. Fourteen patients (47%) showed changes in steatosis: 12 showed resolution and 2 showed de novo steatosis. Explant macrovesicular steatosis was associated with presence of steatosis 1 year after transplantation (binary logistic regression model, p = 0.014), but not macrovesicular steatosis in the donor graft at time-point of transplantation. Conclusion: Resolution of graft steatosis was frequent. Presence of steatosis in the recipient's liver, but not graft steatosis, was a risk factor for steatosis 1 year after transplantation. Factors related to the recipient seem to prevail over donor-related factors in determining the persistence or de novo appearance of steatosis after liver transplantation.

Liver Resection for Primary Hepatic Angiosarcoma: Bicentric Analysis of a Challenging Entity.

Primary hepatic angiosarcoma (PHA) is a rare malignant tumor of the liver, and data on patient outcome after surgical treatment are scarce. The aim of this study was to evaluate postoperative morbidity and overall survival (OS) of patients who underwent hepatectomy for PHA. This is a bicentric retrospective analysis of all consecutive patients who underwent liver resection in curative intent for PHA between 2012 and 2019 at the University Hospital of Muenster and the University Hospital of Bern. Nine patients (five female, four male) were included from both centers. Median age was 72 years (44-82). Most lesions (77.8%) were larger than 5 cm, and mean size of the biggest lesion was 9.4 ± 4.5 cm. Major hepatectomy was performed in four (44.4%), and radical resection (R0) was achieved in six (66.7%) patients. Postoperative complication rate was 88.8%, including 44.4% higher than 3a in the Clavien-Dindo classification. OS survival rates at 1, 2, and 3 years were 44.4%, 22.2%, and 12.5%, respectively, and median OS was 5 months. OS was significantly better after radical resection (R0: 15 months vs. R1: 0 months, p = 0.04), whereas presentation with tumor rupture at diagnosis was associated with the worst OS (0 months vs. 15 months, p = 0.005). Disease recurrence occurred in three patients (33.3%) between three and seven months after surgery. Radical resection remains the only potentially curative treatment option for PHA. However, postoperative morbidity is high, and the overall prognosis remains poor. Multimodal therapy options and management strategies are urgently needed and could improve the prognosis of patients suffering from PHA in the future.

Cohort profile: The Swiss Transplant Cohort Study (STCS): A nationwide longitudinal cohort study of all solid organ recipients in Switzerland.

PURPOSE: The Swiss Transplant Cohort Study (STCS) is a prospective multicentre cohort study which started to actively enrol study participants in May 2008. It takes advantage of combining data from all transplant programmes in one unique system to perform comprehensive nationwide reporting and to promote translational and clinical post-transplant outcome research in the framework of Swiss transplantation medicine. PARTICIPANTS: Over 5500 solid organ transplant recipients have been enrolled in all six Swiss transplant centres by end of 2019, around three-quarter of them for kidney and liver transplants. Ninety-three per cent of all transplanted recipients have consented to study participation, almost all of them (99%) contributed to bio-sampling. The STCS genomic data set includes around 3000 patients. FINDINGS TO DATE: Detailed clinical and laboratory data in high granularity as well as patient-reported outcomes from transplant recipients and activities in Switzerland are available in the last decade. Interdisciplinary contributions in diverse fields of transplantation medicine such as infectious diseases, genomics, oncology, immunology and psychosocial science have resulted in approximately 70 scientific papers getting published in peer-review journals so far. FUTURE PLANS: The STCS will deepen its efforts in personalised medicine and digital epidemiology, and will also focus on allocation research and the use of causal inference methods to make complex matters in transplant medicine more understandable and transparent.

Effects of structured intraoperative briefings on patient outcomes: multicentre before-and-after study.

BACKGROUND: Operations require collaboration between surgeons, anaesthetia professionals, and nurses. The aim of this study was to determine whether intraoperative briefings influence patient outcomes. METHODS: In a before-and-after controlled trial (9 months baseline; 9 months intervention), intraoperative briefings were introduced in four general surgery centres between 2015 and 2018. During the operation, the responsible surgeon (most senior surgeon present) briefed the surgical team using the StOP? protocol about: progress of the operation (Status), next steps (Objectives), possible problems (Problems), and encouraged asking questions (?). Differences between baseline and intervention were analysed regarding surgical-site infections (primary outcome), mortality, unplanned reoperations, and duration of hospital stay (secondary outcomes), using inverse probability of treatment (IPT) weighting based on propensity scores. RESULTS: In total, 8256 patients underwent surgery in the study. Endpoint data were available for 7745 patients (93.8 per cent). IPT-weighted and adjusted intention-to-treat analyses showed no differences in surgical-site infections between baseline and intervention (9.8 versus 9.6 per cent respectively; adjusted difference (AD) -0.15 (95 per cent c.i. -1.45 to 1.14) per cent; odds ratio (OR) 0.92, 95 per cent c.i. 0.83 to 1.15; P = 0.797), but there were reductions in mortality (1.6 versus 1.1 per cent; AD -0.54 (-1.04 to -0.03) per cent; OR 0.60, 0.39 to 0.92; P = 0.018), unplanned reoperations (6.4 versus 4.8 per cent; AD -1.66 (-2.69 to -0.62) per cent; OR 0.72, 0.59 to 0.89; P = 0.002), and fewer prolonged hospital stays (21.6 versus 19.8 per cent; AD -1.82 (-3.48 to -0.15) per cent; OR 0.87, 0.77 to 0.98; P = 0.024). CONCLUSION: Short intraoperative briefings improve patient outcomes and should be performed routinely.

Outcomes of surgery depend on patient characteristics and surgeon expertise, but also on teamwork, notably communication. The present study introduces the StOP? protocol, in which the surgeon informs the team about the current status (St), objectives regarding next steps (O), and potential problems (P), and encourages the team to ask questions and raise concerns (?). The results suggest an effect of the StOP? intervention on patient mortality, risk of unplanned reoperation, and duration of hospital stay, but not on surgical-site infections. The study is promising regarding the effect of structured intraoperative communication on important patient outcomes. The study compared patient outcomes at baseline and after implementation of the StOP? protocol, which enhances exchange of structured information within the interdisciplinary surgical team during the course of the operation. The intention-to-treat analyses in this multicentre before-and-after study of 8256 patients undergoing general surgery showed no differences between baseline and intervention for surgical-site infections, but revealed reduced mortality and unplanned reoperations, and fewer prolonged hospital stays during the intervention period.

Parenchymal-sparing hepatectomy for colorectal liver metastases reduces postoperative morbidity while maintaining equivalent oncologic outcomes compared to non-parenchymal-sparing resection.

BACKGROUND: 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. METHODS: Clinicopathological data of patients who underwent liver resection for CRLM between 2012 and 2019 at a 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 recurrence-free survival (RFS) of patients following parenchymal-sparing resection (PSR) for CRLM were compared with those of patients undergoing non-PSR. RESULTS: 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. Perioperative chemotherapy was administered in equal rates in both groups (PSR vs. non-PSR) both in TBS ≥4.5 and TBS <4.5. In patients with lower tumor burden (TBS <4.5), PSR was associated with lower overall complication rate (15.2% vs. 46.2%, p = 0.009), a trend for lower major complication rate (8.9% vs. 23.1%, p = 0.123), 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 RFS rates (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), a trend for lower major complication rate (23.8% vs. 42.2%, p = 0.150), 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 RFS rates (29% vs. 18%, p = 0.156) 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 RFS (34% vs. 34%, p = 0.613) rates compared to patients undergoing open hepatectomy. CONCLUSIONS: PSR for CRLM is associated with lower postoperative morbidity, shorter length of hospital stay, and equivalent oncologic outcomes compared to non-PSR, independently of 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.

Recurrence at surgical margin following hepatectomy for colorectal liver metastases is not associated with R1 resection and does not impact survival.

BACKGROUND: Resection margin status has traditionally been associated with tumor recurrence and oncological outcome following liver resection for colorectal liver metastases. Previous studies, however, did not address the impact of resection margin on the site of tumor recurrence and did not differentiate between true local recurrence at the resection margin and recurrence elsewhere in the liver. This study aimed to determine whether positive resection margins determine local recurrence and whether recurrence at the surgical margin influences long-term survival. METHODS: Clinicopathological data and oncological outcomes of patients who underwent curative resection for colorectal liver metastases between 2012 and 2017 at 2 major hepatobiliary centers (Bern, Switzerland, and Berlin, Germany) were assessed. Cross-sectional imaging following hepatectomy was reviewed by radiologists in both centers to distinguish between recurrence at the resection margin, defined as hepatic local recurrence, and intrahepatic recurrence elsewhere. The association between surgical margin status and location of tumor recurrence was evaluated, and the impact on overall survival was determined. RESULTS: During the study period, 345 consecutive patients underwent hepatectomy for colorectal liver metastases. Histologic surgical margins were positive for tumor cells (R1) in 63 patients (18%). After a median follow-up time of 34 months, tumor recurrence was identified in 154 patients (45%). Hepatic local recurrence was not detected more frequently after R1 than after R0 resection (P = .555). Hepatic local recurrence was not associated with worse overall survival (P = .436), while R1 status significantly impaired overall survival (P = .025). Additionally, overall survival was equivalent between patients with hepatic local recurrence and patients with any intrahepatic and/or extrahepatic recurrence. In patients with intrahepatic recurrence only, oncological outcomes improved if local hepatic therapy was possible (resection or ablation) in comparison to patients treated only with chemotherapy or best supportive care (3-year overall survival: 85% vs 39%; P < .0001). CONCLUSION: The incidence of hepatic local recurrence after hepatectomy for colorectal liver metastases is independent of R1 resection margin status. Additionally, hepatic local recurrence at the resection margin is not associated with worse overall survival compared with any other intra- or extrahepatic recurrence. Therefore, R1 status at hepatectomy seems to be a surrogate factor for advanced disease without influencing location of recurrence and thereby oncological outcome. This finding may support decision-making when extending the indication for surgery in borderline resectable colorectal liver metastases.

Minimal-Invasive Versus Open Hepatectomy for Colorectal Liver Metastases: Bicentric Analysis of Postoperative Outcomes and Long-Term Survival Using Propensity Score Matching Analysis.

Minimal-invasive hepatectomy (MIH) has been increasingly performed for benign and malignant liver lesions with most promising short-term results. However, the oncological role of MIH in the treatment of patients with colorectal liver metastases (CRLM) needs further investigation. Clinicopathological data of patients who underwent liver resection for CRLM between 2012 and 2017 at the Department of Surgery, Charité-Universitätsmedizin Berlin, and the Inselspital Bern were assessed. Postoperative outcomes und long-term survivals of patients following MIH were compared with those after conventional open hepatectomy (OH) after 1:1 propensity score matching. During the study period, 229 and 91 patients underwent liver resection for CRLM at the Charité Berlin and the Inselspital Bern, respectively. Patients who underwent MIH in one of the two centers (n = 69) were compared with a matched cohort of patients who underwent OH. MIH was associated with lower complication rates (23% vs. 44%, p = 0.011), shorter length of intensive care unit stay (ICU, 1 vs. 2 days, p = 0.043), shorter length of hospital stay (7 vs. 11 days, p < 0.0001), and a reduced need for intraoperative transfusions (12% vs. 25%, p = 0.047) compared to OH. R0 status was achieved in 93% and 75% of patients after MIH and OH, respectively (p = 0.005). After a median follow-up of 31 months, MIH resulted in similar five-year overall survival (OS) rate (56% vs. 48%, p = 0.116) in comparison to OH. MIH for CRLM is associated with lower postoperative morbidity, shorter length of ICU and hospital stay, reduced need for transfusions, and comparable oncologic outcomes compared to the established OH. Our findings suggest that MIH should be considered as the preferred method for the treatment of curatively resectable CRLM.

Medical management of metabolic and cardiovascular complications after liver transplantation.

Liver transplantation represents the only curative option for patients with end-stage liver disease, fulminant hepatitis and advanced hepatocellular carcinoma. Even though major advances in transplantation in the last decades have achieved excellent survival rates in the early post-transplantation period, long-term survival is hampered by the lack of improvement in survival in the late post transplantation period (over 5 years after transplantation). The main etiologies for late mortality are malignancies and cardiovascular complications. The latter are increasingly prevalent in liver transplant recipients due to the development or worsening of metabolic syndrome and all its components (arterial hypertension, dyslipidemia, obesity, renal injury, etc.). These comorbidities result from a combination of pre-liver transplant features, immunosuppressive agent side-effects, changes in metabolism and hemodynamics after liver transplantation and the adoption of a sedentary lifestyle. In this review we describe the most prevalent metabolic and cardiovascular complications present after liver transplantation, as well as proposing management strategies.

Stereotactic Image-Guided Microwave Ablation for Malignant Liver Tumors-A Multivariable Accuracy and Efficacy Analysis.

Background: Therapeutic success of thermal ablation for liver tumors depends on precise placement of ablation probes and complete tumor destruction with a safety margin. We investigated factors influencing targeting accuracy and treatment efficacy of percutaneous stereotactic image-guided microwave ablation (SMWA) for malignant liver neoplasms. Materials and methods: All consecutive patients treated with SMWA for malignant liver tumors over a 3-year period were analyzed. A computed tomography-based navigation system was used for ablation probe trajectory planning, stereotactic probe positioning, and validation of probe positions and ablation zones. Factors potentially influencing targeting accuracy [target positioning error (TPE)] and treatment efficacy within 6 months [ablation site recurrence (ASR)] were analyzed in a multivariable regression model, including challenging lesion locations (liver segments I, VII, and VIII; subphrenic location). Results: Three hundred one lesions (174 hepatocellular carcinomas, 87 colorectal liver metastases, 17 neuroendocrine tumors, and 23 others) were targeted in 191 interventions in 153 patients. The median TPE per ablation probe was 2.9 ± 2.3 mm (n = 384). Correction of ablation probe positions by repositioning was necessary in 4 out of 301 lesions (1%). Factors significantly influencing targeting accuracy were cirrhosis (R 0.67, CI 0.22-1.12) and targeting trajectory length (R 0.21, CI 0.12-0.29). Factors significantly influencing early ASR were lesion size >30 mm (OR 5.22, CI 2.44-11.19) and TPE >5 mm (OR 2.48, CI 1.06-5.78). Challenging lesion locations had no significant influence on targeting accuracy or early ASR. Conclusions: SMWA allows precise and effective treatment of malignant liver tumors even for lesions in challenging locations, with treatment efficacy depending on targeting accuracy in our model. Allowing for many tumors to be safely reached, SMWA has the potential to broaden treatment eligibility for patients with otherwise difficult to target tumors.

Verteporfin-induced lysosomal compartment dysregulation potentiates the effect of sorafenib in hepatocellular carcinoma.

Lysosomal sequestration of anti-cancer compounds reduces drug availability at intracellular target sites, thereby limiting drug-sensitivity and inducing chemoresistance. For hepatocellular carcinoma (HCC), sorafenib (SF) is the first line systemic treatment, as well as a simultaneous activator of autophagy-induced drug resistance. The purpose of this study is to elucidate how combination therapy with the FDA-approved photosensitizer verteporfin (VP) can potentiate the antitumor effect of SF, overcoming its acquired resistance mechanisms. HCC cell lines and patient-derived in vitro and in vivo preclinical models were used to identify the molecular mechanism of action of VP alone and in combination with SF. We demonstrate that SF is lysosomotropic and increases the total number of lysosomes in HCC cells and patient-derived xenograft model. Contrary to the effect on lysosomal stability by SF, VP is not only sequestered in lysosomes, but induces lysosomal pH alkalinization, lysosomal membrane permeabilization (LMP) and tumor-selective proteotoxicity. In combination, VP-induced LMP potentiates the antitumor effect of SF, further decreasing tumor proliferation and progression in HCC cell lines and patient-derived samples in vitro and in vivo. Our data suggest that combination of lysosome-targeting compounds, such as VP, in combination with already approved chemotherapeutic agents could open a new avenue to overcome chemo-insensitivity caused by passive lysosomal sequestration of anti-cancer drugs in the context of HCC.

Percutaneous stereotactic image-guided microwave ablation for malignant liver lesions.

Thermal ablation has proven beneficial for hepatocellular carcinoma and possibly for colorectal liver metastases, but data is lacking for other liver metastases. Computer-assisted navigation can increase ablation efficacy and broaden its indications. We present our experience with percutaneous stereotactic image-guided microwave ablation (SMWA) for non-colorectal liver metastases (NCRLM), in form of a retrospective study including all SMWA for NCRLM from 2015 to 2017. Indication for SMWA was determined at a multidisciplinary tumorboard. End-points include recurrence, overall and liver-specific disease progression and complications. Twenty-three patients underwent 25 interventions for 40 lesions, including 17 neuroendocrine tumor, nine breast cancer, four sarcoma, two non-small cell lung cancer, three duodenal adenocarcinoma, one esophageal adenocarcinoma, one pancreatic adenocarcinoma, one ampullary carcinoma, one prostate carcinoma, and one renal cell carcinoma metastases. Median follow-up was 15 months (2-32). Incomplete ablation rate was 2.5% (1/40), local recurrence rate 10% (4/40). Three patients (12%) had minor complications. Overall disease progression was 73.9% (17/23), median disease-free survival 7 months (0-26) and overall survival 18 months (2-39). SIMWA is feasible, safe and minimally invasive for NCRLM in selected patients. While it might offer an alternative to resection or palliative strategies, the oncological benefit needs to be evaluated in a larger patient cohort.