Impact of Back-to-Base Normothermic Machine Perfusion on Complications and Costs: A Multi-Center, Real-World Risk-Matched Analysis.

OBJECTIVE: Assess cost and complication outcomes after liver transplantation (LT) using normothermic machine perfusion (NMP). SUMMARY BACKGROUND DATA: End-ischemic NMP is often used to aid logistics, yet its' impact on outcomes after LT remains unclear, as does its' true impact on costs associated with transplantation. METHODS: Deceased donor liver recipients at two centers (1/1/2019-6/30/2023) were included. Retransplants, splits and combined grafts were excluded. End-ischemic NMP (OrganOx-Metra®) was implemented 10/2022 for extended-criteria DBDs, all DCDs and logistics. NMP-cases were matched 1:2 with cold storage controls (SCS) using the Balance-of-Risk (DBD-grafts) and UK-DCD Score (DCD-grafts). RESULTS: Overall, 803 transplantations were included, 174 (21.7%) receiving NMP. Matching was achieved between 118 NMP-DBDs with 236 SCS; and 37 NMP-DCD with 74 corresponding SCS. For both graft types, median inpatient comprehensive complications index (CCI) values were comparable between groups. DCD-NMP grafts experienced reduced cumulative 90-day CCI (27.6 vs. 41.9, P=0.028). NMP also reduced the need for early relaparotomy and renal-replacement-therapy, with subsequently less-frequent major complications (Clavien-Dindo >IVa). This effect was more pronounced in DCD-transplants. NMP had no protective effect on early biliary complications. Organ acquisition/preservation costs were higher with NMP, yet NMP-treated grafts had lower 90-day pre-transplant costs in context of shorter waiting-list times. Overall costs were comparable for both cohorts. CONCLUSIONS: This is the first risk-adjusted outcome and cost analysis comparing NMP and SCS. In addition to logistical benefits, NMP was associated with a reduction in relaparotomy and bleeding in DBD-grafts, and overall complications and post-LT renal-replacement for DCDs. While organ acquisition/preservation was more costly with NMP, overall 90-day-healthcare costs-per-transplantation were comparable.

Emerging and Clinically Accepted Biomarkers for Hepatocellular Carcinoma.

Hepatocellular carcinoma (HCC) is the third leading cause of cancer-related death and the sixth most diagnosed malignancy worldwide. Serum alpha-fetoprotein (AFP) is the traditional, ubiquitous biomarker for HCC. However, there has been an increasing call for the use of multiple biomarkers to optimize care for these patients. AFP, AFP-L3, and prothrombin induced by vitamin K absence II (DCP) have described clinical utility for HCC, but unfortunately, they also have well established and significant limitations. Circulating tumor DNA (ctDNA), genomic glycosylation, and even totally non-invasive salivary metabolomics and/or micro-RNAS demonstrate great promise for early detection and long-term surveillance, but still require large-scale prospective validation to definitively validate their clinical validity. This review aims to provide an update on clinically available and emerging biomarkers for HCC, focusing on their respective clinical strengths and weaknesses.

Circulating Tumor DNA Profiling in Liver Transplant for Hepatocellular Carcinoma, Cholangiocarcinoma, and Colorectal Liver Metastases: A Programmatic Proof of Concept.

INTRODUCTION: Circulating tumor DNA (ctDNA) is emerging as a promising, non-invasive diagnostic and surveillance biomarker in solid organ malignancy. However, its utility before and after liver transplant (LT) for patients with primary and secondary liver cancers is still underexplored. METHODS: Patients undergoing LT for hepatocellular carcinoma (HCC), cholangiocarcinoma (CCA), and colorectal liver metastases (CRLM) with ctDNA testing were included. CtDNA testing was conducted pre-transplant, post-transplant, or both (sequential) from 11/2019 to 09/2023 using Guardant360, Guardant Reveal, and Guardant360 CDx. RESULTS: 21 patients with HCC (n = 9, 43%), CRLM (n = 8, 38%), CCA (n = 3, 14%), and mixed HCC/CCA (n = 1, 5%) were included in the study. The median follow-up time was 15 months (range: 1-124). The median time from pre-operative testing to surgery was 3 months (IQR: 1-4; range: 0-5), and from surgery to post-operative testing, it was 9 months (IQR: 2-22; range: 0.4-112). A total of 13 (62%) patients had pre-transplant testing, with 8 (62%) having ctDNA detected (ctDNA+) and 5 (32%) not having ctDNA detected (ctDNA-). A total of 18 (86%) patients had post-transplant testing, 11 (61%) of whom were ctDNA+ and 7 (33%) of whom were ctDNA-. The absolute recurrence rates were 50% (n = 5) in those who were ctDNA+ vs. 25% (n = 1) in those who were ctDNA- in the post-transplant setting, though this difference was not statistically significant (p = 0.367). Six (29%) patients (HCC = 3, CCA = 1, CRLM = 2) experienced recurrence with a median recurrence-free survival of 14 (IQR: 6-40) months. Four of these patients had positive post-transplant ctDNA collected following diagnosis of recurrence, while one patient had positive post-transplant ctDNA collected preceding recurrence. A total of 10 (48%) patients had sequential ctDNA testing, of whom n = 5 (50%) achieved ctDNA clearance (+/-). The remainder were ctDNA+/+ (n = 3, 30%), ctDNA-/- (n = 1, 10%), and ctDNA-/+ (n = 1, 11%). Three (30%) patients showed the acquisition of new genomic alterations following transplant, all without recurrence. Overall, the median tumor mutation burden (TMB) decreased from 1.23 mut/Mb pre-transplant to 0.00 mut/Mb post-transplant. CONCLUSIONS: Patients with ctDNA positivity experienced recurrence at a higher rate than the ctDNA- patients, indicating the potential role of ctDNA in predicting recurrence after curative-intent transplant. Based on sequential testing, LT has the potential to clear ctDNA, demonstrating the capability of LT in the treatment of systemic disease. Transplant providers should be aware of the potential of donor-derived cell-free DNA and improved approaches are necessary to address such concerns.

Plasma metabolomic differences in early-onset compared to average-onset colorectal cancer.

Deleterious effects of environmental exposures may contribute to the rising incidence of early-onset colorectal cancer (eoCRC). We assessed the metabolomic differences between patients with eoCRC, average-onset CRC (aoCRC), and non-CRC controls, to understand pathogenic mechanisms. Patients with stage I-IV CRC and non-CRC controls were categorized based on age ≤ 50 years (eoCRC or young non-CRC controls) or  ≥ 60 years (aoCRC or older non-CRC controls). Differential metabolite abundance and metabolic pathway analyses were performed on plasma samples. Multivariate Cox proportional hazards modeling was used for survival analyses. All P values were adjusted for multiple testing (false discovery rate, FDR P < 0.15 considered significant). The study population comprised 170 patients with CRC (66 eoCRC and 104 aoCRC) and 49 non-CRC controls (34 young and 15 older). Citrate was differentially abundant in aoCRC vs. eoCRC in adjusted analysis (Odds Ratio = 21.8, FDR P = 0.04). Metabolic pathways altered in patients with aoCRC versus eoCRC included arginine biosynthesis, FDR P = 0.02; glyoxylate and dicarboxylate metabolism, FDR P = 0.005; citrate cycle, FDR P = 0.04; alanine, aspartate, and glutamate metabolism, FDR P = 0.01; glycine, serine, and threonine metabolism, FDR P = 0.14; and amino-acid t-RNA biosynthesis, FDR P = 0.01. 4-hydroxyhippuric acid was significantly associated with overall survival in all patients with CRC (Hazards ratio, HR = 0.4, 95% CI 0.3-0.7, FDR P = 0.05). We identified several unique metabolic alterations, particularly the significant differential abundance of citrate in aoCRC versus eoCRC. Arginine biosynthesis was the most enriched by the differentially altered metabolites. The findings hold promise in developing strategies for early detection and novel therapies.

Early Onset Intrahepatic Cholangiocarcinoma: Clinical Characteristics, Oncological Outcomes, and Genomic/Transcriptomic Features.

INTRODUCTION: Data on clinical characteristics and disease-specific prognosis among patients with early onset intrahepatic cholangiocarcinoma (ICC) are currently limited. METHODS: Patients undergoing hepatectomy for ICC between 2000 and 2020 were identified by using a multi-institutional database. The association of early (≤50 years) versus typical onset (>50 years) ICC with recurrence-free (RFS) and disease-specific survival (DSS) was assessed in the multi-institutional database and validated in an external cohort. The genomic and transcriptomic profiles of early versus late onset ICC were analyzed by using the Total Cancer Genome Atlas (TCGA) and Memorial Sloan Kettering Cancer Center databases. RESULTS: Among 971 patients undergoing resection for ICC, 22.7% (n = 220) had early-onset ICC. Patients with early-onset ICC had worse 5-year RFS (24.1% vs. 29.7%, p < 0.05) and DSS (36.5% vs. 48.9%, p = 0.03) compared with patients with typical onset ICC despite having earlier T-stage tumors and lower rates of microvascular invasion. In the validation cohort, patients with early-onset ICC had worse 5-year RFS (7.4% vs. 20.5%, p = 0.002) compared with individuals with typical onset ICC. Using the TCGA cohort, 652 and 266 genes were found to be upregulated (including ATP8A2) and downregulated (including UTY and KDM5D) in early versus typical onset ICC, respectively. Genes frequently implicated as oncogenic drivers, including CDKN2A, IDH1, BRAF, and FGFR2 were infrequently mutated in the early-onset ICC patients. CONCLUSIONS: Early-onset ICC has distinct clinical and genomic/transcriptomic features. Morphologic and clinicopathologic characteristics were unable to fully explain differences in outcomes among early versus typical onset ICC patients. The current study offers a preliminary landscape of the molecular features of early-onset ICC.

Risk assessment in liver transplantation for hepatocellular carcinoma: long-term follow-up of a two-centre experience.

BACKGROUND: Liver transplantation (LT) is a well-established treatment for hepatocellular carcinoma (HCC), but there are ongoing debates regarding outcomes and selection. This study examines the experience of LT for HCC at a high-volume centre. METHODS: A prospectively maintained database was used to identify HCC patients undergoing LT from 2000 to 2020 with more than or equal to 3-years follow-up. Data were obtained from the centre database and electronic medical records. The Metroticket 2.0 HCC-specific 5-year survival scale was calculated for each patient. Kaplan-Meier and Cox-regression analyses were employed assessing survival between groups based on Metroticket score and individual donor and recipient risk factors. RESULTS: Five hundred sixty-nine patients met criteria. Median follow-up was 96.2 months (8.12 years; interquartile range 59.9-147.8). Three-year recurrence-free (RFS) and overall survival (OS) were 88.6% ( n =504) and 86.6% ( n =493). Five-year RFS and OS were 78.9% ( n =449) and 79.1% ( n =450). Median Metroticket 2.0 score was 0.9 (interquartile range 0.9-0.95). Tumour size greater than 3 cm ( P =0.012), increasing tumour number on imaging ( P =0.001) and explant pathology ( P <0.001) was associated with recurrence. Transplant within Milan ( P <0.001) or UCSF criteria ( P <0.001) had lower recurrence rates. Increasing alpha-fetoprotein (AFP)-values were associated with more HCC recurrence ( P <0.001) and reduced OS ( P =0.008). Chemoembolization was predictive of recurrence in the overall population ( P =0.043) and in those outside-Milan criteria ( P =0.038). A receiver-operator curve using Metroticket 2.0 identified an optimal cut-off of projected survival greater than or equal to 87.5% for predicting recurrence. This cut-off was able to predict RFS ( P <0.001) in the total cohort and predict both, RFS ( P =0.007) and OS ( P =0.016) outside Milan. Receipt of donation after brain death (DBD) grafts (55/478, 13%) or living-donor grafts (3/22, 13.6%) experienced better survival rates compared to donation after cardiac death (DCD) grafts ( n =15/58, 25.6%, P =0.009). Donor age was associated with a higher HCC recurrence ( P =0.006). Both total ischaemia time (TIT) greater than 6hours ( P =0.016) and increasing TIT correlated with higher HCC recurrence ( P =0.027). The use of DCD grafts for outside-Milan candidates was associated with increased recurrence ( P =0.039) and reduced survival ( P =0.033). CONCLUSION: This large two-centre analysis confirms favourable outcomes after LT for HCC. Tumour size and number, pre-transplant AFP, and Milan criteria remain important recipient HCC-risk factors. A higher donor risk (i.e. donor age, DCD grafts, ischaemia time) was associated with poorer outcomes.

Combining a deep learning model with clinical data better predicts hepatocellular carcinoma behavior following surgery.

Hepatocellular carcinoma (HCC) is among the most common cancers worldwide, and tumor recurrence following liver resection or transplantation is one of the highest contributors to mortality in HCC patients after surgery. Using artificial intelligence (AI), we developed an interdisciplinary model to predict HCC recurrence and patient survival following surgery. We collected whole-slide H&E images, clinical variables, and follow-up data from 300 patients with HCC who underwent transplant and 169 patients who underwent resection at the Cleveland Clinic. A deep learning model was trained to predict recurrence-free survival (RFS) and disease-specific survival (DSS) from the H&E-stained slides. Repeated cross-validation splits were used to compute robust C-index estimates, and the results were compared to those obtained by fitting a Cox proportional hazard model using only clinical variables. While the deep learning model alone was predictive of recurrence and survival among patients in both cohorts, integrating the clinical and histologic models significantly increased the C-index in each cohort. In every subgroup analyzed, we found that a combined clinical and deep learning model better predicted post-surgical outcome in HCC patients compared to either approach independently.

Postoperative morbidity after simultaneous versus staged resection of synchronous colorectal liver metastases: Impact of hepatic tumor burden.

BACKGROUND: We sought to characterize the risk of postoperative complications relative to the surgical approach and overall synchronous colorectal liver metastases tumor burden score. METHODS: Patients with synchronous colorectal liver metastases who underwent curative-intent resection between 2000 and 2020 were identified from an international multi-institutional database. Propensity score matching was employed to control for heterogeneity between the 2 groups. A virtual twins analysis was performed to identify potential subgroups of patients who might benefit more from staged versus simultaneous resection. RESULTS: Among 976 patients who underwent liver resection for synchronous colorectal liver metastases, 589 patients (60.3%) had a staged approach, whereas 387 (39.7%) patients underwent simultaneous resection of the primary tumor and synchronous colorectal liver metastases. After propensity score matching, 295 patients who underwent each surgical approach were analyzed. Overall, the incidence of postoperative complications was 34.1% (n = 201). Among patients with high tumor burden scores, the surgical approach was associated with a higher incidence of postoperative complications; in contrast, among patients with low or medium tumor burden scores, the likelihood of complications did not differ based on the surgical approach. Virtual twins analysis demonstrated that preoperative tumor burden score was important to identify which subgroup of patients benefited most from staged versus simultaneous resection. Simultaneous resection was associated with better outcomes among patients with a tumor burden score <9 and a node-negative right-sided primary tumor; in contrast, staged resection was associated with better outcomes among patients with node-positive left-sided primary tumors and higher tumor burden score. CONCLUSION: Among patients with high tumor burden scores, simultaneous resection of the primary tumor and liver metastases was associated with an increased incidence of postoperative complications.

Comparison of Engineered Liver 3D Models and the Role of Oxygenation for Patient-Derived Tumor Cells and Immortalized Cell Lines Cocultured with Tumor Stroma in the Detection of Hepatotoxins.

In metabolically active tumors, responses of cells to drugs are heavily influenced by oxygen availability via the surrounding vasculature alongside the extracellular matrix signaling. The objective of this study is to investigate hepatotoxicity by replicating critical features of hepatocellular carcinoma (HCC). This includes replicating 3D structures, metabolic activities, and tumor-specific markers. The internal environment of spheroids comprised of cancerous human patient-derived hepatocytes using microparticles is modulated to enhance the oxygenation state and recreate cell-extracellular matrix interactions. Furthermore, the role of hepatic stellate cells in maintaining hepatocyte survival and function is explored and hepatocytes from two cellular sources (immortalized and patient-derived) to create four formulations with and without microparticles are utilized. To investigate drug-induced changes in metabolism and apoptosis in liver cells, coculture spheroids with and without microparticles are exposed to three hepatotoxic drugs. The use of microparticles increases levels of apoptotic markers in both liver models under drug treatments. This coincides with reduced levels of anti-apoptotic proteins and increased levels of pro-apoptotic proteins. Moreover, cells from different origins undergo apoptosis through distinct apoptotic pathways in response to identical drugs. This 3D microphysiological system offers a viable tool for liver cancer research to investigate mechanisms of apoptosis under different microenvironmental conditions.

Optimal policy tree to assist in adjuvant therapy decision-making after resection of colorectal liver metastases.

BACKGROUND: Although systemic postoperative therapy after surgery for colorectal liver metastases is generally recommended, the benefit of adjuvant chemotherapy has been debated. We used machine learning to develop a decision tree and define which patients may benefit from adjuvant chemotherapy after hepatectomy for colorectal liver metastases. METHODS: Patients who underwent curative-intent resection for colorectal liver metastases between 2000 and 2020 were identified from an international multi-institutional database. An optimal policy tree analysis was used to determine the optimal assignment of the adjuvant chemotherapy to subgroups of patients for overall survival and recurrence-free survival. RESULTS: Among 1,358 patients who underwent curative-intent resection of colorectal liver metastases, 1,032 (76.0%) received adjuvant chemotherapy. After a median follow-up of 28.7 months (interquartile range 13.7-52.0), 5-year overall survival was 67.5%, and 3-year recurrence-free survival was 52.6%, respectively. Adjuvant chemotherapy was associated with better recurrence-free survival (3-year recurrence-free survival: adjuvant chemotherapy, 54.4% vs no adjuvant chemotherapy, 46.8%; P < .001) but no overall survival significant improvement (5-year overall survival: adjuvant chemotherapy, 68.1% vs no adjuvant chemotherapy, 65.7%; P = .15). Patients were randomly allocated into 2 cohorts (training data set, n = 679, testing data set, n = 679). The random forest model demonstrated good performance in predicting counterfactual probabilities of death and recurrence relative to receipt of adjuvant chemotherapy. According to the optimal policy tree, patient demographics, secondary tumor characteristics, and primary tumor characteristics defined the subpopulation that would benefit from adjuvant chemotherapy. CONCLUSION: A novel artificial intelligence methodology based on patient, primary tumor, and treatment characteristics may help clinicians tailor adjuvant chemotherapy recommendations after colorectal liver metastases resection.

Update to 'A Contemporary Systematic Review on Liver Transplantation for Unresectable Liver Metastasis of Colorectal Cancer'.

Colorectal cancer is the second most common cause of cancer-related death worldwide, and half of patients present with colorectal liver metastasis (CRLM). Liver transplant (LT) has emerged as a treatment modality for otherwise unresectable CRLM. Since the publication of the Lebeck-Lee systematic review in 2022, additional evidence has come to light supporting LT for CRLM in highly selected patients. This includes reports of >10-year follow-up with over 80% survival rates in low-risk patients. As these updated reports have significantly changed our collective knowledge, this article is intended to serve as an update to the 2022 systematic review to include the most up-to-date evidence on the subject.

Impact of autotransfusion on recurrence of colorectal cancer liver metastasis: Long-term follow-up of patients undergoing curative intent hepatectomy.

INTRODUCTION: Colorectal cancer liver metastasis (CRLM) occurs in upto 50% of cases and drives patient outcomes. Up-front liver resection is the treatment of choice in resectable cases. There is no consensus yet established as to the safety of intraoperative autotransfusion in liver resection for CRLM. METHODS: Patients undergoing curative-intent hepatectomy for CRLM at a single quaternary-care institution from 1999 to 2016 were included. Demographics, surgical variables, Fong Clinical Risk Score (FCRS), use of intraoperative auto and/or allotransfusion, and survival data were analyzed. Propensity score matching (PSM) was performed accounting for allotransfusion, extent of hepatectomy, FCRS, and systemic treatment regimens. RESULTS: Three-hundred sixteen patients were included. The median follow-up was 10.4 years (7.8-14.1 years). The median recurrence-free survival (RFS) and overall survival (OS) in all patients were 1.6 years (interquartile range: 0.63-6.6 years) and 4.4 years (2.1-8.7), respectively.  Before PSM, there was a significantly reduced RFS in the autotransfusion group (0.96 vs. 1.73 years, p = 0.20). There was no difference in OS (4.11 vs. 4.44 years, p = 0.118). Patients in groups of FCRS 0-2 and 3-5 both had reduced RFS when autotransfusion was used (p = 0.005). This reduction in RFS was further found when comparing autotransfusion versus no autotransfusion within the FCRS 0-2 group and within the FCRS 3-5 group (p = 0.027). On Cox-regression analysis, autotransfusion (hazard ratio = 1.423, 1.028-2.182, p = 0.015) remained predictive of RFS. After PSM, there were no differences in FCRS (p = 0.601), preoperative hemoglobin (p = 0.880), allotransfusion (p = 0.130), adjuvant chemotherapy (p = 1.000), immunotherapy (p = 0.172), tumor grade (p = 1.000), use of platinum-based chemotherapy (p = 0.548), or type of hepatic resection (p = 0.967). After matching, there was a higher rate of recurrence with autotransfusion (69.0% vs. 47.6%, p = 0.046). There was also a reduced time to recurrence in the autotransfusion group compared with the group without (p = 0.006). There was no difference in OS after PSM (p = 0.262). CONCLUSION: Autotransfusion may adversely affect recurrence in liver resection for CRLM. Until further studies clarify this risk profile, the use of intraoperative autotransfusion should be critically assessed on a case-by-case basis only when other resuscitation options are not available.

Deep learning-based phenotyping reclassifies combined hepatocellular-cholangiocarcinoma.

Primary liver cancer arises either from hepatocytic or biliary lineage cells, giving rise to hepatocellular carcinoma (HCC) or intrahepatic cholangiocarcinoma (ICCA). Combined hepatocellular- cholangiocarcinomas (cHCC-CCA) exhibit equivocal or mixed features of both, causing diagnostic uncertainty and difficulty in determining proper management. Here, we perform a comprehensive deep learning-based phenotyping of multiple cohorts of patients. We show that deep learning can reproduce the diagnosis of HCC vs. CCA with a high performance. We analyze a series of 405 cHCC-CCA patients and demonstrate that the model can reclassify the tumors as HCC or ICCA, and that the predictions are consistent with clinical outcomes, genetic alterations and in situ spatial gene expression profiling. This type of approach could improve treatment decisions and ultimately clinical outcome for patients with rare and biphenotypic cancers such as cHCC-CCA.

Combined Liver Transplant and Cardiac Surgery: Long-Term Outcomes and Predictors of Success.

OBJECTIVE: We aim to report our institutional outcomes of single-staged combined liver transplantation (LT) and cardiac surgery (CS). SUMMARY BACKGROUND DATA: Concurrent LT and CS is a potential treatment for combined cardiac dysfunction and end-stage liver disease, yet only 54 cases have been previously reported in the literature. Thus, the outcomes of this approach are relatively unknown, and this approach has been previously regarded as extremely risky. METHODS: Thirty-one patients at our institution underwent combined cardiac surgery and liver transplant. Patients with at least one-year follow-up were included. The Leave-One-Out Cross-Validation (LOOCV) machine-learning approach was used to generate a model for mortality. RESULTS: Median follow-up was 8.2 years (IQR 4.6-13.6 y). One- and five-year survival was 74.2% (N=23) and 55% (N=17), respectively. Negative predictive factors of survival included recipient age>60 years (P=0.036), NASH-cirrhosis (P=0.031), Coronary Artery Bypass-Graft (CABG)-based CS (P=0.046) and pre-operative renal dysfunction (P=0.024). The final model demonstrated that renal dysfunction had a relative weighted impact of 3.2 versus CABG (1.7), age ≥60y (1.7) or NASH (1.3). Elevated LT+CS risk score was associated with an increased five-year mortality after surgery (AUC=0.731, P=<0.001). Conversely, the widely accepted STS-PROM calculator was unable to successfully stratify patients according to 1- (P>0.99) or 5-year (P=0.695) survival rates. CONCLUSIONS: This is the largest series describing combined LT+CS, with joint surgical management appearing feasible in highly selected patients. CABG and pre-operative renal dysfunction are important negative predictors of mortality. The four-variable LT+CS score may help predict patients at high risk for post-operative mortality.

Immunotherapy Plus Locoregional Therapy Leading to Curative-Intent Hepatectomy in HCC: Proof of Concept Producing Durable Survival Benefits Detectable with Liquid Biopsy.

BACKGROUND: Immunotherapy has emerged as an improved systemic treatment for select patients with advanced unresectable HCC. Objective response is reported in 30% of patients, yet complete response (pCR) allowing for curative-intent resection is rare. Locoregional therapies (LRTs) seem to show synergistic effects with immunotherapy, though this effect has not been scientifically reported. We report a cohort of patients showing pCR to immunotherapy + LRT as a proof of concept for the proposed treatment approach for locally unresectable HCC. METHODS: Patients with unresectable HCC treated with immunotherapy as an intended destination therapy from 2016 to 2023 were included. The electronic health record was queried for oncologic information, locoregional therapies, surgical interventions, and long-term outcomes. Circulating tumor DNA (ctDNA) testing was obtained using Guardant360, and tumor mutational burden (TMB) was defined as the number of somatic mutations per megabase. RESULTS: Ninety-six patients with advanced HCC received immunotherapy + LRT as a destination therapy. In total, 11 of 96 patients showed a complete response according to mRECIST criteria. Four of these (36.4%) ultimately underwent curative-intent resection. The median follow-up was 24.9 (IQR 15.6-38.3) months. Overall survival rates in those with complete response at 1, 3, and 5 years were 100%, 91%, and 81.8%, respectively, which were significantly improved compared to those of the cohort not achieving pCR (p < 0.001). All four patients undergoing immunotherapy + LRT followed by curative-intent hepatectomy have no evidence of disease (NED). Of those undergoing surgery, ctDNA was cleared in 75% (n = 3), providing an additional objective measurement of complete response. All four patients were TMB+ before beginning this treatment course, with three being TMB-, indicating stable and complete disease response. CONCLUSIONS: Immunotherapy + locoregional therapy can help downstage a significant proportion of patients with initially unresectable HCC, allowing for curative-intent surgery. The survival benefit associated with complete response seems durable up to 3 years after achieving this response. ctDNA measurement was converted from positive to negative in this cohort, providing additional indication of response.

Using the win ratio to compare laparoscopic versus open liver resection for colorectal cancer liver metastases.

Background: We sought to assess the overall benefit of laparoscopic versus open hepatectomy for treatment of colorectal liver metastases (CRLMs) using the win ratio, a novel methodological approach. Methods: CRLM patients undergoing curative-intent resection in 2001-2018 were identified from an international multi-institutional database. Patients were paired and matched based on age, number and size of lesions, lymph node status and receipt of preoperative chemotherapy. The win ratio was calculated based on margin status, severity of postoperative complications, 90-day mortality, time to recurrence, and time to death. Results: Among 962 patients, the majority underwent open hepatectomy (n=832, 86.5%), while a minority underwent laparoscopic hepatectomy (n=130, 13.5%). Among matched patient-to-patient pairs, the odds of the patient undergoing laparoscopic resection "winning" were 1.77 [WR: 1.77, 95% confidence interval (CI): 1.42-2.34]. The win ratio favored laparoscopic hepatectomy independent of low (WR: 2.94, 95% CI: 1.20-6.39), medium (WR: 1.56, 95% CI: 1.16-2.10) or high (WR: 7.25, 95% CI: 1.13-32.0) tumor burden, as well as unilobar (WR: 1.71, 95% CI: 1.25-2.31) or bilobar (WR: 4.57, 95% CI: 2.36-8.64) disease. The odds of "winning" were particularly pronounced relative to short-term outcomes (i.e., 90-day mortality and severity of postoperative complications) (WR: 4.06, 95% CI: 2.33-7.78). Conclusions: Patients undergoing laparoscopic hepatectomy had 77% increased odds of "winning". Laparoscopic liver resection should be strongly considered as a preferred approach to resection in CRLM patients.

Circulating Tumor DNA in Colorectal Cancer Liver Metastasis: Analysis of Patients Receiving Liver Resection and Transplant.

PURPOSE: Liver metastases occur in about 50% of colorectal cancer cases and drive patient outcomes. Circulating tumor DNA (ctDNA) is emerging as a diagnostic, surveillance, and tumor mutational information tool. METHODS: Patients with colorectal cancer liver metastasis (CCLM) seen in a multidisciplinary liver tumor clinic from January to August 2022 received ctDNA testing on each visit. ctDNA was obtained using the Guardant360 platform. Tumor mutational burden (TMB) is defined as the number of identified mutations per megabase of genome analyzed. RESULTS: Fifty-two patients had available ctDNA, with 34 (65%) tested preoperatively and 18 (35%) postoperatively; nine patients had sequential pre- and postoperative testing. The median time to test result was 12 days (IQR, 10-13.5). There were a greater number of somatic mutations identified preoperatively (n = 29 v n = 11) and a greater genomic heterogeneity (P = .0069). The mean TMB score was 12.77 in those without pathologic response to cytotoxic therapy and 6.0 in those with pathologic response (P = .10). All nine patients with sequential testing were positive preoperatively, compared with just three (33.3%) postoperatively (P = .0090). Positive postoperative ctDNA was associated with the increased likelihood of disease recurrence after resection (57%) versus negative ctDNA (0%, P = .0419). CONCLUSION: Routine ctDNA screening in patients with CCLM is logistically feasible. Liver resection and/or transplant may be associated with clearance of detectable ctDNA and a reduction in TMB or genomic heterogeneity. Persistence of ctDNA alterations postresection appears predictive of disease recurrence. Further studies are necessary to confirm these findings, and longitudinal ctDNA testing is needed to monitor changing tumor biology.

Characterization of Salivary and Plasma Metabolites as Biomarkers for HCC: A Pilot Study.

(1) Background: The incidence of hepatocellular carcinoma (HCC) is rising, and current screening methods lack sensitivity. This study aimed to identify distinct and overlapping metabolites in saliva and plasma that are significantly associated with HCC. (2) Methods: Saliva samples were collected from 42 individuals (HCC = 16, cirrhosis = 12, healthy = 14), with plasma samples from 22 (HCC = 14, cirrhosis = 2, healthy = 6). We performed untargeted mass spectrometry on blood and plasma, tested metabolites for associations with HCC or cirrhosis using a logistic regression, and identified enriched pathways with Metaboanalyst. Pearson's correlation was employed to test for correlations between salivary and plasma metabolites. (3) Results: Six salivary metabolites (1-hexadecanol, isooctanol, malonic acid, N-acetyl-valine, octadecanol, and succinic acid) and ten plasma metabolites (glycine, 3-(4-hydroxyphenyl)propionic acid, aconitic acid, isocitric acid, tagatose, cellobiose, fucose, glyceric acid, isocitric acid, isothreonic acid, and phenylacetic acid) were associated with HCC. Malonic acid was correlated between the paired saliva and plasma samples. Pathway analysis highlighted deregulation of the 'The Citric Acid Cycle' in both biospecimens. (4) Conclusions: Our study suggests that salivary and plasma metabolites may serve as independent sources for HCC detection. Despite the lack of correlation between individual metabolites, they converge on 'The Citric Acid Cycle' pathway, implicated in HCC pathogenesis.

An attempt to establish and apply global benchmarks for liver resection of malignant hepatic tumors.

BACKGROUND: Benchmarking is a process of continuous self-evaluation and comparison with best-in-class hospitals to guide quality improvement initiatives. We sought to define global benchmarks relative to liver resection for malignancy and to assess their achievement in hospitals in the United States. METHODS: Patients who underwent curative-intent liver resection for hepatocellular carcinoma, intrahepatic cholangiocarcinoma, or colorectal or neuroendocrine liver metastases between 2000 and 2019 were identified from an international multi-institutional database. Propensity score matching was conducted to balance baseline characteristics between open and minimally invasive approaches. Best-in-class hospitals were defined relative to the achievement rate of textbook oncologic outcomes and case volume. Benchmark values were established relative to best-in-class institutions. The achievement of benchmark values among hospitals in the National Cancer Database was then assessed. RESULTS: Among 2,624 patients treated at 20 centers, a majority underwent liver resection for hepatocellular carcinoma (n = 1,609, 61.3%), followed by colorectal liver metastases (n = 650, 24.8%), intrahepatic cholangiocarcinoma (n = 299, 11.4%), and neuroendocrine liver metastases (n = 66, 2.5%). Notably, 1,947 (74.2%) patients achieved a textbook oncologic outcome. After propensity score matching, 6 best-in-class hospitals with the highest textbook oncologic outcome rates (≥75.0%) were identified. Benchmark values were calculated for margin positivity (≤11.7%), 30-day readmission (≤4.1%), 30-day mortality (≤1.6%), minor postoperative complications (≤24.7%), severe complications (≤12.4%), and failure to achieve the textbook oncologic outcome (≤22.8%). Among the National Cancer Database hospitals, global benchmarks for margin positivity, 30-day readmission, 30-day mortality, severe complications, and textbook oncologic outcome failure were achieved in 62.9%, 27.1%, 12.1%, 7.1%, and 29.3% of centers, respectively. CONCLUSION: These global benchmarks may help identify hospitals that may benefit from quality improvement initiatives, aiming to improve patient safety and surgical oncologic outcomes.