Ashish Saharia

PURPOSE: Cholangiocarcinoma (CCA) has rising incidence and mortality rates. Liver transplantation (LT) offers good outcomes. Tumor molecular profiling may inform peri-LT treatment. MATERIALS AND METHODS: Patients with CCA who underwent LT at a single center between 2014 and 2021 were identified retrospectively. Next-generation sequencing (277 genes) was performed on 28 CCAs from 18 patients, including five perihilar and 24 intrahepatic tumors. RESULTS: Mutations were reported in 45 genes, most frequently IDH1 (5 patients), BAP1 (5), and TP53 (4). BAP1 was associated with neoadjuvant treatment response. Altered genes were organized into five pathways, namely: kinase-RAS (11 patients), TP53 (9), epigenetic (8), SWI-SNF (7) and RB-cell cycle (4). Both TP53 and RB-cell cycle pathway alterations were prognostic. Tumors were clustered into three groups, named here as cell cycle (seven patients), genomic instability (6), and cell survival (5). The latter had no post-transplant deaths. In 18 serially sequenced tumors from eight patients, mutational heterogeneity over time was quantified by Jaccard Index. This reflected both external selection pressures by systemic therapies and intrinsic tumor biology, being the lowest in cell survival tumors. Pathway- and subtype-level changes were rare. CONCLUSION: In this LT cohort, CCA molecular profiling informed prognosis and treatment response. Heterogeneity may depend on early tumorigenesis disruptions, potentially explaining outcome differences.

Background: Liver transplantation (LT) for primary liver cancers achieves excellent patient outcomes, but a minority recur with poor prognosis. Survival may be improved by earlier recurrence detection. This study aims to evaluate the feasibility and performance of a personalized tumor-informed assay utilizing circulating tumor DNA (ctDNA) from peripheral blood for surveillance after LT in patients with hepatocellular carcinoma (HCC) or cholangiocarcinoma (CCA). Methods: Here, we test whether a personalized tumor-informed assay utilizing ctDNA from peripheral blood informs post-LT surveillance. Personalized ctDNA assays were employed for surveillance in 38 LT recipients, alongside standard-of-care imaging and peripheral tumor biomarkers [alpha-fetoprotein (AFP), carbohydrate antigen 19-9 (CA19-9)]. Results: Recurrence was detected radiologically in 6 patients, with positive ctDNA assays in 3 and negative/insufficient to process (ITP) in 3. Nine ITP ctDNA assays were due to insufficient primary tumor tissue. In 31 patients without ITP ctDNA tests, the sensitivity and specificity of ctDNA were 75% [95% confidence interval (CI): 19–99%] and 100% (95% CI: 87–100%). Standard-of-care tumor biomarkers had sensitivity and specificity of 75% (95% CI: 19–99%) and 93% (95% CI: 76–99%), respectively (P>0.99 and P=0.16; McNemar χ²). Only 1 patient had ctDNA positive prior to imaging-based diagnosis. Conclusions: This study corroborates the feasibility of ctDNA assays for recurrence surveillance in LT recipients. The results imply that ctDNA assays show promise in confirming recurrence and minimizing the need for invasive biopsy. However, additional prospective studies are needed to confirm ctDNA test utility in surveillance protocols.

PURPOSE: Hepatocellular carcinoma (HCC) has high relapse rates after standard-of-care (SOC) resection or liver transplantation (LT). We evaluated the utility of circulating tumor DNA (ctDNA) to predict relapse/progression risk in patients with HCC. Materials and Methods: This retrospective analysis examined real-world data from ctDNA testing on 125 patients with HCC (721 plasma samples) undergoing curative-intent treatments and SOC management. Patients were divided into four subcohorts: cohort A (n = 64) and B (n = 52) comprised patients under recurrence monitoring after LT or resection, respectively. Cohort C (n = 4) and D (n = 5) comprised patients under treatment response monitoring with known recurrence or inoperable disease, respectively. A personalized, tumor-informed 16-plex polymerase chain reaction next-generation sequencing assay (Signatera, Natera, Inc, Austin, TX) was used for ctDNA testing. The molecular residual disease (MRD) window was defined as 2-12 weeks post-LT/resection (cohorts A/B), before starting adjuvant therapy (AT). Surveillance window was defined as post-MRD window or 2 weeks post-AT (cohort B) or during ongoing treatment (cohorts C/D). RESULTS: The median follow-up was 40 (1.5-60) months. In cohort A, 97.2% (35/36) of patients with ctDNA negativity in the MRD window remained negative during surveillance. In cohort B, ctDNA was detected in 29.4% (10/34) of patients within the MRD window, all of whom experienced clinical recurrence (hazard ratio [HR], 7.2 [95% CI, 2.6 to 20]; P < .0001). In the surveillance window (cohort B), the ctDNA detection rate was 32.3% (10/31), and all experienced recurrence (HR, 18.0 [95% CI, 3.9 to 85]; P < .0001). In cohorts C/D, on-treatment ctDNA dynamics were concordant with treatment response as measured by imaging. Compared with alpha-fetoprotein, ctDNA had higher sensitivity and a significantly longer lead time (7.9 v 2.2 months) for recurrence detection. CONCLUSION: Serial ctDNA testing effectively identified HCC recurrence early, postresection and post-LT. ctDNA was also useful for treatment response monitoring and could help resolve ambiguous imaging results.

Background.: Perihilar cholangiocarcinoma (phCCA) has excellent outcomes following liver transplantation (LT). Neoadjuvant radiation-based locoregional therapy is standard-of-care. Gemcitabine and cisplatin (gem/cis) combination systemic therapies have improved outcomes in advanced settings, but their efficacy pre-LT has not been studied. Methods.: We review our experience following neoadjuvant gem/cis alone versus radiation-based approaches. Patients with phCCA undergoing LT at a single center between January 2008 and February 2023 were identified retrospectively. Neoadjuvant therapy was categorized as gem/cis systemic therapy (ST) alone, or any ST and radiotherapy (RT). Outcomes were posttransplant overall survival (OS), recurrence-free survival (RFS), waitlist time, and pathologic tumor response. Results.: During study period, 27 phCCA patients underwent LT. One patient decompensated with neoadjuvant therapy and was excluded. Median age was 61 y (interquartile range, 53–68 y) and 14 (54%) were male. Of 26 patients, 12 (46%) received ST and 14 (54%) RT. Six RT patients received gem/cis ST. Median waitlist time was 199 d (interquartile range, 98–405 d) and did not differ by neoadjuvant regimen. Explanted tumors were predominantly T1 stage, without lymphovascular invasion or nodal involvement. Neither pathologic features nor percent tumor necrosis differed by regimen. OS probabilities at 1 and 3 y were 84% and 55% for the cohort. There was no significant difference in OS and RFS when stratified by regimen. Conclusions.: Post-LT OS, RFS, waitlist time, and tumor response were similar in the 2 groups. Patients with phCCA who do not undergo RT may still be considered for LT under appropriate institution-based protocols that adhere to other established criteria.

Background.: Hepatocellular carcinoma (HCC) has a rising incidence and mortality in North America. Liver transplantation (LT) with adjunctive therapies offers excellent outcomes. However, HCC recurrences are associated with high mortality. We investigate whether adjuvant systemic therapy can reduce recurrence, as shown with other malignancies. Methods.: Medical records of patients undergoing LT for HCC at a single center between January 2016 and December 2022 were retrospectively reviewed. Patients were stratified into 3 groups: (1) recipients of adjuvant sorafenib, (2) nonrecipients at high recurrence risk, and (3) nonrecipients at low risk by explant pathology features. The outcomes were overall survival (OS) and recurrence-free survival (RFS). Adjuvant sorafenib recipients were also propensity score matched 1:2 to nonadjuvant recipients based on recurrence risk features. Results.: During the study period, 273 patients with HCC underwent LT and 16 (5.9%) received adjuvant sorafenib therapy. Adjuvant sorafenib recipients were demographically similar to nonrecipients and, on explant pathology, had greater tumor burden, lymphovascular invasion, and poorer differentiation (all P < 0.001). Adverse events were observed in 12 adjuvant sorafenib recipients (75%). OS was similar among the 3 groups (P = 0.2), and adjuvant sorafenib was not associated with OS in multivariable analysis (hazard ratio, 1.31; 95% confidence interval, 0.45-3.78; P = 0.62). RFS was significantly lower in sorafenib patients (hazard ratio, 6.99; 95% confidence interval, 2.12-23.05; P = 0.001). Following propensity matching, adjuvant sorafenib use was not associated with either OS (P = 0.24) or RFS rates (P = 0.65). Conclusions.: In this single-center analysis, adjuvant sorafenib was not associated with OS. Recipients were observed to have shorter RFS, likely due to the increased prevalence of high-risk features, and sorafenib use was associated with high frequencies of adverse events.

Background.: The COVID-19 pandemic has led to an increase in SARS-CoV-2–test positive potential organ donors. The benefits of life-saving liver transplantation (LT) must be balanced against the potential risk of donor-derived viral transmission. Although emerging evidence suggests that the use of COVID-19–positive donor organs may be safe, granular series thoroughly evaluating safety are still needed. Results of 29 consecutive LTs from COVID-19–positive donors at a single center are presented here. Methods.: A retrospective cohort study of LT recipients between April 2020 and December 2022 was conducted. Differences between recipients of COVID-19–positive (n = 29 total; 25 index, 4 redo) and COVID-19–negative (n = 472 total; 454 index, 18 redo) deceased donor liver grafts were compared. Results.: COVID-19–positive donors were significantly younger (P = 0.04) and had lower kidney donor profile indices (P = 0.04) than COVID-19–negative donors. Recipients of COVID-19–positive donor grafts were older (P = 0.04) but otherwise similar to recipients of negative donors. Donor SARS-CoV-2 infection status was not associated with a overall survival of recipients (hazard ratio, 1.11; 95% confidence interval, 0.24-5.04; P = 0.89). There were 3 deaths among recipients of liver grafts from COVID-19–positive donors. No death seemed virally mediated because there was no qualitative association with peri-LT antispike antibody titers, post-LT prophylaxis, or SARS-CoV-2 variants. Conclusions.: The utilization of liver grafts from COVID-19–positive donors was not associated with a decreased overall survival of recipients. There was no suggestion of viral transmission from donor to recipient. The results from this large single-center study suggest that COVID-19–positive donors may be used safely to expand the deceased donor pool.

Transplant oncology is an emerging concept of cancer treatment with a promising prospective outcome. The applications of oncology, transplant medicine, and surgery are the core of transplant oncology to improve patients’ survival and quality of life. The main concept of transplant oncology is to radically cure cancer by removing the diseased organ and replacing it with a healthy one, aiming to improve the survival outcomes and quality of life of cancer patients. Subsequently, it seeks to expand the treatment options and research for hepatobiliary malignancies, which have seen significantly improved survival outcomes after the implementation of liver transplantation (LT). In the case of colorectal cancer (CRC) in the transplant setting, where the liver is the most common site of metastasis of patients who are considered to have unresectable disease, initial studies have shown improved survival for LT treatment compared to palliative therapy interventions. The indications of LT for hepatobiliary malignancies have been slowly expanded over the years beyond Milan criteria in a stepwise manner. However, the outcome improvements and overall patient survival are limited to the specifics of the setting and systematic intervention options. This review aims to illustrate the representative concepts and history of transplant oncology as an emerging discipline for the management of hepatobiliary malignancies, in addition to other emerging concepts, such as the uses of immunotherapy in a peri-transplant setting as well as the use of circulating tumor DNA (ctDNA) for surveillance post-transplantation.

The rationale for administering immune checkpoint inhibitors (ICIs) in the adjuvant setting is to eradicate micro-metastases and, ultimately, prolong survival. Thus far, clinical trials have demonstrated that 1-year adjuvant courses of ICIs reduce the risk of recurrence in melanoma, urothelial cancer, renal cell carcinoma, non-small cell lung cancer, and esophageal and gastroesophageal junction cancers. Overall survival benefit has been shown in melanoma while survival data are still not mature in other malignancies. Emerging data also show the feasibility of utilizing ICIs in the peri-transplant setting for hepatobiliary malignancies. While ICIs are generally well-tolerated, the development of chronic immune-related adverse events, typically endocrinopathies or neurotoxicities, as well as delayed immune-related adverse events, warrants further scrutiny regarding the optimal duration of adjuvant therapy and requires a thorough risk–benefit determination. The advent of blood-based, dynamic biomarkers such as circulating tumor DNA (ctDNA) can help detect minimal residual disease and identify the subset of patients who would likely benefit from adjuvant treatment. In addition, the characterization of tumor-infiltrating lymphocytes, neutrophil-to-lymphocyte ratio, and ctDNA-adjusted blood tumor mutation burden (bTMB) has also shown promise in predicting response to immunotherapy. Until additional, prospective studies delineate the magnitude of overall survival benefit and validate the use of predictive biomarkers, a tailored, patient-centered approach to adjuvant ICIs that includes extensive patient counseling on potentially irreversible adverse effects should be routinely incorporated into clinical practice.