HCMV trimer- and pentamer-specific antibodies synergize for virus neutralization but do not correlate with congenital transmission.

Human cytomegalovirus (HCMV) causes substantial disease in transplant patients and harms the development of the nervous system in babies infected in utero. Thus, there is a major focus on developing safe and effective HCMV vaccines. Evidence has been presented that a major target of neutralizing antibodies (NAbs) is the HCMV pentamer glycoprotein gH/gL/UL128-131. In some studies, most of the NAbs in animal or human sera were found to recognize the pentamer, which mediates HCMV entry into endothelial and epithelial cells. It was also reported that pentamer-specific antibodies correlate with protection against transmission from mothers to babies. One problem with the studies on pentamer-specific NAbs to date has been that the studies did not compare the pentamer to the other major form of gH/gL, the gH/gL/gO trimer, which is essential for entry into all cell types. Here, we demonstrate that both trimer and pentamer NAbs are frequently found in human transplant patients' and pregnant mothers' sera. Depletion of human sera with trimer caused reductions in NAbs similar to that observed following depletion with the pentamer. The trimer- and pentamer-specific antibodies acted in a synergistic fashion to neutralize HCMV and also to prevent virus cell-to-cell spread. Importantly, there was no correlation between the titers of trimer- and pentamer-specific NAbs and transmission of HCMV from mothers to babies. Therefore, both the trimer and pentamer are important targets of NAbs. Nevertheless, these antibodies do not protect against transmission of HCMV from mothers to babies.

Graft-versus-host disease after liver transplantation is associated with bone marrow failure, hemophagocytosis, and DNMT3A mutations.

Graft-versus-host disease after liver transplantation (LT-GVHD) is rare, frequently fatal, and associated with bone marrow failure (BMF), cytopenias, and hyperferritinemia. Given hyperferritinemia and cytopenias are present in hemophagocytic lymphohistiocytosis (HLH), and somatic mutations in hematopoietic cells are associated with hyperinflammatory responses (clonal hematopoiesis of indeterminate potential, CHIP), we identified the frequency of hemophagocytosis and CHIP mutations in LT-GVHD. We reviewed bone marrow aspirates and biopsies, quantified blood/marrow chimerism, and performed next-generation sequencing (NGS) with a targeted panel of genes relevant to myeloid malignancies, CHIP, and BMF. In all, 12 marrows were reviewed from 9 LT-GVHD patients. In all, 10 aspirates were evaluable for hemophagocytosis; 7 had adequate DNA for NGS. NGS was also performed on marrow from an LT cohort (n = 6) without GVHD. Nine of 10 aspirates in LT-GVHD patients showed increased hemophagocytosis. Five (71%) of 7 with LT-GVHD had DNMT3A mutations; only 1 of 6 in the non-GVHD LT cohort demonstrated DNMT3A mutation (p = .04). Only 1 LT-GVHD patient survived. BMF with HLH features was associated with poor hematopoietic recovery, and DNMT3A mutations were over-represented, in LT-GVHD patients. Identification of HLH features may guide prognosis and therapeutics. Further studies are needed to clarify the origin and impact of CHIP mutations on the hyperinflammatory state.

Optimal Timing of Administration of Direct-acting Antivirals for Patients With Hepatitis C-associated Hepatocellular Carcinoma Undergoing Liver Transplantation.

OBJECTIVE: To investigate the optimal timing of direct acting antiviral (DAA) administration in patients with hepatitis C-associated hepatocellular carcinoma (HCC) undergoing liver transplantation (LT). SUMMARY OF BACKGROUND DATA: In patients with hepatitis C (HCV) associated HCC undergoing LT, the optimal timing of direct-acting antivirals (DAA) administration to achieve sustained virologic response (SVR) and improved oncologic outcomes remains a topic of much debate. METHODS: The United States HCC LT Consortium (2015-2019) was reviewed for patients with primary HCV-associated HCC who underwent LT and received DAA therapy at 20 institutions. Primary outcomes were SVR and HCC recurrence-free survival (RFS). RESULTS: Of 857 patients, 725 were within Milan criteria. SVR was associated with improved 5-year RFS (92% vs 77%, P < 0.01). Patients who received DAAs pre-LT, 0-3 months post-LT, and ≥3 months post-LT had SVR rates of 91%, 92%, and 82%, and 5-year RFS of 93%, 94%, and 87%, respectively. Among 427 HCV treatment-naïve patients (no previous interferon therapy), patients who achieved SVR with DAAs had improved 5-year RFS (93% vs 76%, P < 0.01). Patients who received DAAs pre-LT, 0-3 months post-LT, and ≥3 months post-LT had SVR rates of 91%, 93%, and 78% (P < 0.01) and 5-year RFS of 93%, 100%, and 83% (P = 0.01). CONCLUSIONS: The optimal timing of DAA therapy appears to be 0 to 3 months after LT for HCV-associated HCC, given increased rates of SVR and improved RFS. Delayed administration after transplant should be avoided. A prospective randomized controlled trial is warranted to validate these results.

Degree of biliary tract violation during treatment of gallbladder adenocarcinoma is independently associated with development of peritoneal carcinomatosis.

BACKGROUND: Gallbladder cancer (GBC) is often incidentally diagnosed after cholecystectomy. Intra-operative biliary tract violations (BTV) have been recently associated with development of peritoneal disease (PD). The degree of BTV may be associated with PD risk, but has not been previously investigated. METHODS: We reviewed patients with initially non-metastatic GBC treated at our institution from 2003 to 2018. Patients were grouped based on degree of BTV during their treatment: major (e.g., cholecystotomy with bile spillage, n = 27, 29%), minor (e.g., intra-operative cholangiogram, n = 18, 19%), and no violations (n = 48, 55%). Overall survival (OS) and peritoneal disease-free survival (PDFS) were evaluated with Kaplan-Meier and Cox proportional hazards modeling. RESULTS: Ninety-three patients were identified; the median age was 64 years (range 31-87 years). Seventy-six (82%) were incidentally diagnosed. The median follow-up was 23 months; 20 (22%) patients developed PD. The 3-year PDFS for patients with major, minor, and no BTV was 52%, 83%, and 98%, respectively (major vs. none: p < 0.001; minor vs. none: p < 0.01). BTV was not associated with 5-year OS (HR 1.53, p = 0.16). CONCLUSION: Increasing degree of BTV is associated with higher risk of peritoneal carcinomatosis in patients with GBC and should be considered during preoperative risk stratification. Reporting biliary tract violations during cholecystectomy is encouraged.

Macrophage depletion of CMV latently infected donor hearts ameliorates recipient accelerated chronic rejection.

Cytomegalovirus (CMV) infection is linked to acceleration of solid organ transplant vascular sclerosis (TVS) and chronic rejection (CR). Donor latent CMV infection increases cardiac-resident macrophages and T cells leading to increased inflammation, promoting allograft rejection. To investigate the role of cardiac-resident passenger macrophages in CMV-mediated TVS/CR, macrophages were depleted from latently ratCMV (RCMV)-infected donor allografts prior to transplantation. Latently RCMV-infected donor F344 rats were treated with clodronate, PBS, or control liposomes 3 days prior to cardiac transplant into RCMV-naïve Lewis recipients. Clodronate treatment significantly increased graft survival from post-operative day (POD)61 to POD84 and decreased TVS at rejection. To determine the kinetics of the effect of clodronate treatment's effect, a time study revealed that clodronate treatment significantly decreased macrophage infiltration into allograft tissues as early as POD14; altered allograft cytokine/chemokine protein levels, fibrosis development, and inflammatory gene expression profiles. These findings support our hypothesis that increased graft survival as a result of allograft passenger macrophage depletion was in part a result of altered immune response kinetics. Depletion of donor macrophages prior to transplant is a strategy to modulate allograft rejection and reduce TVS in the setting of CMV + donors transplanted into CMV naïve recipients.

Keeping high model for end-stage liver disease score liver transplantation candidates alive.

As the mean Model for End-Stage Liver Disease (MELD) score at time of liver transplantation continues to increase, it is crucial to implement preemptive strategies to reduce wait-list mortality. We review the most common complications that arise in patients with a high MELD score in an effort to highlight strategies that can maximize survival and successful transplantation.

Surgical portosystemic shunts in the era of TIPS and liver transplantation are still relevant.

BACKGROUND: The surgical portosystemic shunts (PSS) are a time-proven modality for treating portal hypertension. Recently, in the era of liver transplantation and the transjugular intrahepatic portosystemic shunts (TIPS), use of the PSS has declined. OBJECTIVES: This study was conducted to evaluate changes in practice, referral patterns, and short- and longterm outcomes of the use of the surgical PSS before and after the introduction of the Model for End-stage Liver Disease (MELD). METHODS: A retrospective analysis of 47 patients undergoing PSS between 1996 and 2011 in a single university hospital was conducted. RESULTS: Subgroups of patients with cirrhosis (53%), Budd-Chiari syndrome (13%), portal vein thrombosis (PVT) (26%), and other pathologies (9%) differed significantly with respect to shunt type, Child-Pugh class, MELD score and perioperative mortality. Perioperative mortality at 60 days was 15%. Five-year survival was 68% (median: 70 months); 5-year shunt patency was 97%. Survival was best in patients with PVT and worst in those with Budd-Chiari syndrome compared to other subgroups. Patency was better in the subgroups of patients with cirrhosis and other pathologies compared with the PVT subgroup. Substantial changes in referral patterns coincided with the adoption of the MELD in 2002, with decreases in the incidence of cirrhosis and variceal bleeding, and increases in non-cirrhotics and hypercoagulopathy. CONCLUSIONS: Although the spectrum of diseases benefiting from surgical PSS has changed, surgical shunts continue to constitute an important addition to the surgical armamentarium. Selected subgroups with variceal bleeding in well-compensated cirrhosis and PVT benefit from the excellent longterm patency offered by the surgical PSS.

Liver Transplant Costs and Activity After United Network for Organ Sharing Allocation Policy Changes.

Importance: A new liver allocation policy was implemented by United Network for Organ Sharing (UNOS) in February 2020 with the stated intent of improving access to liver transplant (LT). There are growing concerns nationally regarding the implications this new system may have on LT costs, as well as access to a chance for LT, which have not been captured at a multicenter level. Objective: To characterize LT volume and cost changes across the US and within specific center groups and demographics after the policy implementation. Design, Setting, and Participants: This cross-sectional study collected and reviewed LT volume from multiple centers across the US and cost data with attention to 8 specific center demographics. Two separate 12-month eras were compared, before and after the new UNOS allocation policy: March 4, 2019, to March 4, 2020, and March 5, 2020, to March 5, 2021. Data analysis was performed from May to December 2022. Main Outcomes and Measures: Center volume, changes in cost. Results: A total of 22 of 68 centers responded comparing 1948 LTs before the policy change and 1837 LTs postpolicy, resulting in a 6% volume decrease. Transplants using local donations after brain death decreased 54% (P < .001) while imported donations after brain death increased 133% (P = .003). Imported fly-outs and dry runs increased 163% (median, 19; range, 1-75, vs 50, range, 2-91; P = .009) and 33% (median, 3; range, 0-16, vs 7, range, 0-24; P = .02). Overall hospital costs increased 10.9% to a total of $46 360 176 (P = .94) for participating centers. There was a 77% fly-out cost increase postpolicy ($10 600 234; P = .03). On subanalysis, centers with decreased LT volume postpolicy observed higher overall hospital costs ($41 720 365; P = .048), and specifically, a 122% cost increase for liver imports ($6 508 480; P = .002). Transplant centers from low-income states showed a significant increase in hospital (12%) and import (94%) costs. Centers serving populations with larger proportions of racial and ethnic minority candidates and specifically Black candidates significantly increased costs by more than 90% for imported livers, fly-outs, and dry runs despite lower LT volume. Similarly, costs increased significantly (>100%) for fly-outs and dry runs in centers from worse-performing health systems. Conclusions and Relevance: Based on this large multicenter effort and contrary to current assumptions, the new liver distribution system appears to place a disproportionate burden on populations of the current LT community who already experience disparities in health care. The continuous allocation policies being promoted by UNOS could make the situation even worse.

Cytomegalovirus CC chemokine promotes immune cell migration.

Cytomegaloviruses manipulate the host chemokine/receptor axis by altering cellular chemokine expression and by encoding multiple chemokines and chemokine receptors. Similar to human cytomegalovirus (HCMV), rat cytomegalovirus (RCMV) encodes multiple CC chemokine-analogous proteins, including r129 (HCMV UL128 homologue) and r131 (HCMV UL130 and MCMV m129/130 homologues). Although these proteins play a role in CMV entry, their function as chemotactic cytokines remains unknown. In the current study, we examined the role of the RCMV chemokine r129 in promoting cellular migration and in accelerating transplant vascular sclerosis (TVS) in our rat heart transplant model. We determined that r129 protein is released into culture supernatants of infected cells and is expressed with late viral gene kinetics during RCMV infection and highly expressed in heart and salivary glands during in vivo rat infections. Using the recombinant r129 protein, we demonstrated that r129 induces migration of lymphocytes isolated from rat peripheral blood, spleen, and bone marrow and from a rat macrophage cell line. Using antibody-mediated cell sorting of rat splenocytes, we demonstrated that r129 induces migration of naïve/central memory CD4(+) T cells. Through ligand-binding assays, we determined that r129 binds rat CC chemokine receptors CCR3, CCR4, CCR5, and CCR7. In addition, mutational analyses identified functional domains of r129 resulting in recombinant proteins that fail to induce migration (r129-ΔNT and -C31A) or alter the chemotactic ability of the chemokine (r129-F43A). Two of the mutant proteins (r129-C31A and -ΔNT) also act as dominant negatives by inhibiting migration induced by wild-type r129. Furthermore, infection of rat heart transplant recipients with RCMV containing the r129-ΔNT mutation prevented CMV-induced acceleration of TVS. Together our findings indicate that RCMV r129 is highly chemotactic, which has important implications during RCMV infection and reactivation and acceleration of TVS.

Impact of locoregional therapy and alpha-fetoprotein on outcomes in transplantation for liver cancer: a UNOS Region 6 pooled analysis.

Liver transplantation (LT) provides optimal long-term disease-free survival for hepatocellular carcinoma (HCC). High pre-LT alpha-fetoprotein (AFP) has been associated with HCC recurrence, but it is unclear whether a drop in AFP or locoregional therapy impacts survival/recurrence after LT. LT-recipients transplanted for HCC in three centers (UNOS Region 6) were reviewed (2006-2009) for demographics, tumor characteristics, locoregional therapy, AFP, recurrence, and survival. Among 211 LT recipients (mean age 56.4 yr, 83% male, mean MELD 12.2), 94% met Milan criteria and 61% received locoregional therapy. Mean disease-free survival (DFS) was 1549.7 d, and 84% are currently alive. Factors affecting DFS included recurrence (RR, 0.074; 95% CI, 0.038-0.14), normal peak AFP (29.6, 95% CI, 2.96-296.3), peak AFP >400 (RR, 0.15; 95% CI, 0.03-0.73) and AFP at LT >400 (RR, 15.5; 95% CI, 2.4-100.5). Twenty-one patients had recurrence and were more likely beyond Milan criteria (5/23(21%) vs. 8/220 (4%), p = 0.0038), with peak AFP >400 and AFP at LT >400 (p = 0.001). Locoregional therapy did not affect mean DFS (1458.0 vs. 1603.8 d, p = 0.05) or recurrence (12.5% vs. 6%). Predictors of recurrence were similar to previous studies, including high AFP and tumor outside Milan criteria. While locoregional therapy itself did not affect DFS/recurrence, a decrease in AFP pre-transplant appears to positively influence outcomes in those who received locoregional therapy.

Coagulopathy after a liver resection: is it over diagnosed and over treated?

BACKGROUND: Prothrombin time-international normalized ratio (PT-INR) is widely utilized to guide plasma therapy and initiation of thromboprophylaxis after a hepatectomy. Thrombelastography (TEG) monitors shear elasticity, which is sensitive to cellular and plasma components in blood, allowing for functional assessment of the life of the clot. The objective of this study was to prospectively compare PT-INR and TEG in liver resection patients. METHODS: Forty patients were enrolled before undergoing an elective hepatectomy. Patients underwent a liver resection utilizing a low central venous pressure (CVP) anaesthetic technique and intermittent Pringle manoeuver. PT-INR and TEG were drawn prior to incision, post-operatively, and post-operative days 1, 3 and 5. RESULTS: All post-operative PT-INR values increased significantly when compared with pre-operative PT-INR (P < 0.01). The time of onset to clot (R-value) decreased significantly at the post-operative time point (P = 0.04), consistent with a relative hypercoagulability. Subsequent R-values were not different compared with the pre-operative R-value. The strength of the clot (maximum amplitude, MA) was unchanged when comparing pre- and post-operative time points. DISCUSSION: In spite of an elevation in PT-INR, patients undergoing a liver resection demonstrated a brief hypercoagulable state, followed by normal coagulation function based on TEG. These data call into question the practice of utilizing PT-INR to guide plasma transfusion and timing of prophylactic anticoagulation after a liver resection.

Parental leave, childcare policies, and workplace bias for hepatology professionals: A national survey.

BACKGROUND: The presence of workplace bias around child-rearing and inadequate parental leave may negatively impact childbearing decisions and sex equity in hepatology. This study aimed to understand the influence of parental leave and child-rearing on career advancement in hepatology. METHODS: A cross-sectional survey of physician members of the American Association for the Study of Liver Diseases (AASLD) was distributed through email listserv in January 2021. The 33-item survey included demographic questions, questions about bias, altering training, career plans, family planning, parental leave, and work accommodations. RESULTS: Among 199 US physician respondents, 65.3% were women, and 83.4% (n = 166) were attendings. Sex and racial differences were reported in several domains, including paid leave, perceptions of bias, and child-rearing. Most women (79.3%) took fewer than the recommended 12 paid weeks of parental leave for their first child (average paid leave 7.5 wk for women and 1.7 for men). A majority (75.2%) of women reported workplace discrimination, including 83.3% of Black and 62.5% of Hispanic women. Twenty percent of women were asked about their/their partners' pregnancy intentions or child-rearing plans during interviews for training. Women were more likely to alter career plans due to child-rearing (30.0% vs. 15.9%, p = 0.030). Women were also more likely to delay having children than men (69.5% vs.35.9%). CONCLUSIONS: Women reported sex and maternity bias in the workplace and during training interviews, which was more frequently experienced by Black and Hispanic women. As two-thirds of women had children during training, it is a particularly influential time to reevaluate programmatic support to address long-term gender disparities in career advancement.

Cytomegalovirus microRNA expression is tissue specific and is associated with persistence.

MicroRNAs (miRNAs) are a class of small noncoding RNAs involved in posttranscriptional regulation. miRNAs are utilized in organisms ranging from plants to higher mammals, and data have shown that DNA viruses also use this method for host and viral gene regulation. Here, we report the sequencing of the small RNAs in rat cytomegalovirus (RCMV)-infected fibroblasts and persistently infected salivary glands. We identified 24 unique miRNAs that mapped to hairpin structures found within the viral genome. While most miRNAs were detected in both samples, four were detected exclusively in the infected fibroblasts and two were specific for the infected salivary glands. The RCMV miRNAs are distributed across the viral genome on both the positive and negative strands, with clusters of miRNAs at a number of locations, including near viral genes r1 and r111. The RCMV miRNAs have a genomic positional orientation similar to that of the miRNAs described for mouse cytomegalovirus, but they do not share any substantial sequence conservation. Similar to other reported miRNAs, the RCMV miRNAs had considerable variation at their 3' and 5' ends. Interestingly, we found a number of specific examples of differential isoform usage between the fibroblast and salivary gland samples. We determined by real-time PCR that expression of the RCMV miRNA miR-r111.1-2 is highly expressed in the salivary glands and that miR-R87-1 is expressed in most tissues during the acute infection phase. Our study identified the miRNAs expressed by RCMV in vitro and in vivo and demonstrated that expression is tissue specific and associated with a stage of viral infection.

Alcoholic versus nonalcoholic cirrhosis in a randomized controlled trial of emergency therapy of bleeding varices.

BACKGROUND: It has been proposed that portal-systemic shunts be avoided in alcoholic cirrhotics because survival rate is allegedly lower in alcoholics than in nonalcoholics. We examined this issue in a randomized controlled trial. METHODS: Two hundred eleven unselected, consecutive patients with cirrhosis and bleeding esophageal varices were randomized to endoscopic sclerotherapy (EST) (n = 106) or emergency portacaval shunt (EPCS) (105). Treatment was initiated within 8 h. EST failure was treated by rescue portacaval shunt (PCS). Ten-year follow-up was 96%. RESULTS: Results strongly favored EPCS over EST (P < 0.001). Among EPCS patients, 83% were alcoholic and 17% nonalcoholic. Outcomes were (1) permanent control of bleeding 100% versus 100%; (2) 5-y survival 71% versus 78%; (3) encephalopathy 14% versus 19%; (4) yearly charges $38,300 versus $43,000. CONCLUSIONS: EPCS results were similar in alcoholic and nonalcoholic cirrhotics. EPCS is an effective first line emergency treatment in all forms of cirrhosis, including alcoholic.

Child-Turcotte score versus MELD for prognosis in a randomized controlled trial of emergency treatment of bleeding esophageal varices in cirrhosis.

BACKGROUND AND AIMS: Bleeding esophageal varices is responsible for much of the high mortality rate in cirrhosis. An important objective of management of bleeding varices is to develop reliable tools for predicting survival, controlling bleeding and encephalopathy, and improve quality of life. This study compared two widely used prognostic tools, the model for end-stage liver disease (MELD) and the Child-Turcotte (C-T) score, in a randomized controlled trial of emergency treatment of bleeding varices. METHODS: We randomized 211 unselected consecutive patients with cirrhosis and bleeding varices to endoscopic sclerotherapy (n = 106) or emergency portacaval shunt (n = 105). Diagnosis and treatment were accomplished within 20 hours. Follow-up was 100% for 10 y. We compared the prognostic powers of MELD and C-T upon entry, and then monthly for the first year and every 3 months thereafter. Statistical analysis included computation of receiver operating curves, the area under the curve, and the proportion of variability. RESULTS: In baseline determinations of MELD versus C-T, there were no significant differences in predicting survival, recurrent encephalopathy, and rebleeding. The Child-Turcotte score was a stronger predictor than MELD of hospital readmissions and readmission days. In serial determinations over years, the prognostic power of both MELD and C-T was substantial, but C-T was significantly more effective in predicting survival and time to recurrent encephalopathy. CONCLUSIONS: In this first long-term comparison of MELD versus C-T in cirrhosis with bleeding varices, C-T was consistently as effective as MELD in predicting survival, encephalopathy, rebleeding, hospital readmissions, and readmission days. In some measures, C-T was a more effective prognostic tool than MELD.

Surgical treatment of intrahepatic cholangiocarcinoma: outcomes and predictive factors.

BACKGROUND: Intrahepatic cholangiocarcinoma (ICC) remains a rare tumour, although its incidence is increasing. Surgical resection is the mainstay of treatment. Published data regarding prognostic factors and optimal patient selection for resection are scant. We sought to determine the clinicopathologic characteristics of resectable ICC and outcomes following surgical treatment. METHODS: We reviewed prospectively collected clinical data including patient, pathologic and operative details. Survival and recurrence outcomes were analysed using Cox hazard models and the Kaplan-Meier method. RESULTS: We identified 31 surgically treated patients. Their 3-year overall survival rate (OS) was 40.1%; median follow-up was 16.2 months (range: 0.2-86.9 months). R0 resection was associated with significantly improved OS compared with R1/R2 resection (3-year OS was 68.6% in R0 vs. 24.0% in R1/R2; P= 0.042). The postoperative complication rate was 58.1%. Two patients died of postoperative liver failure within 30 days. Preoperative hypoalbuminaemia was significantly associated with worse survival. CONCLUSIONS: Surgical therapy for ICC is associated with longterm survival in the subset of nutritionally replete patients in whom an R0 resection can be achieved. Surgical mortality is significant in patients undergoing extended resection. The margin involvement rate is high and surgeons should consider the infiltrative nature of the disease in operative planning.

Neoadjuvant chemotherapy is associated with improved survival in patients undergoing hepatic resection for intrahepatic cholangiocarcinoma.

BACKGROUND: The impact of neoadjuvant chemotherapy (NAC) on overall and recurrence-free survival (OS, RFS) in resectable intrahepatic cholangiocarcinoma (ICC) is poorly characterized. We sought to investigate the association of NAC with oncologic outcomes in ICC. METHODS: We identified n = 52 patients with ICC undergoing hepatectomy from 2004 to 2017. Oncologic outcomes were analyzed using Kaplan-Meier and multivariate Cox proportional hazard modeling. RESULTS: The median patient age was 64-years. NAC was administered in ten (19%) patients, most commonly with gemcitabine-cisplatin (n = 8, 80%). Median RFS and OS were 15 months. and 49 months, respectively. Controlling for stage and margins, NAC was independently associated with improved OS (HR 0.16, P = 0.01) but not RFS (HR 0.54, P = 0.27). NAC was not associated with major post-operative complications (P = 0.25) or R1 margins (P = 0.58). CONCLUSION: NAC in ICC may hold oncologic benefits beyond downstaging borderline resectable disease, such as identifying patients with favorable biology who are more likely to benefit from resection.

Detection of Tumor Multifocality in Resectable Intrahepatic Cholangiocarcinoma: Defining the Optimal Pre-operative Imaging Modality.

BACKGROUND: Multiple tumor foci (MTF) in intrahepatic cholangiocarcinoma (ICC), including satellitosis and true multifocality, is a known negative prognostic factor and can inform pre-operative decision-making. Lack of standardized pre-operative liver staging practices may contribute to undiagnosed MTF and poor outcomes. We sought to investigate the sensitivity of different cross-sectional imaging modalities for MTF at our institution. METHODS: We identified n = 52 patients with ICC who underwent curative-intent resection from 2004 to 2017 in a multidisciplinary hepato-pancreato-biliary cancer program. Timing and modality of pre-operative imaging were recorded. Blinded review of imaging was performed and modalities were evaluated for false-negative rate (FNR) in detecting MTF, satellitosis, and true multifocality. RESULTS: Forty-one (79%) patients underwent CT and 20 (38%) underwent MRI prior to hepatectomy. MTF was pre-operatively identified in six (12%) patients. An additional seven patients had MTF discovered on final surgical pathology, despite a median interval from CT/MRI to surgery of 20 days. On blinded review the FNR of MRI compared to CT for multifocality was 0% vs. 38%, 50% vs 80% for satellitosis, and 22% vs 46% for MTF as a whole. CONCLUSION: CT is inadequate for pre-operative diagnosis of MTF in resectable ICC, even when performed within 30 days of hepatectomy. We recommend liver-protocol MRI as the standard pre-operative imaging modality in non-metastatic ICC.