Robotic living donor nephrectomy is associated with reduced post-operative opioid use compared to hand-assisted laparoscopic approach.

BACKGROUND: Robotic donor nephrectomy (RDN) has emerged as a safe alternative to laparoscopic donor nephrectomy (LDN). Having previously demonstrated comparable efficacy, this study aims to examine postoperative analgesia use (opioid and non-opioid) in the two groups. METHODS: We conducted a retrospective review of 300 living donor nephrectomies performed at our center, comparing 150 RDN's with a contemporary cohort of 150 hand-assisted LDN's. In addition to clinical and demographic information, data on postoperative inpatient opioid and non-opioid analgesia (from patient's arrival to the surgical floor after surgery till the time of discharge) was collected. Opioid dosages were standardized by conversion to morphine milligram equivalents (MME). All patients were managed post-operatively under a standardized ERAS pathway for living donor nephrectomy patients. RESULTS: There were no significant differences in donor age, gender, and BMI between RDN and LDN groups. Total post-operative opioid use (MME's) was significantly lower in RDN patients (RDN 27.1 vs. LDN 46.3; P < 0.0001). Breakdown of opioid use with post-operative (POD) day demonstrated significantly lower use in RDN group on POD1 (RDN 8.6 vs. LDN 17.0; P < 0.05), and POD2 (RDN 3.9 vs LDN 10; P < 0.05). RDN patients had a shorter post-operative length of stay (LOS) (RDN 1.69 days vs. LDN 1.98; P = 0.0003). There were no differences between groups in non-opioid medication use, complications, and readmission rates. CONCLUSION: RDN has comparable safety to hand-assist LDN and offers additional benefits of lower postoperative opioid requirement and a shorter hospital LOS.

Total robotic liver transplant: the final frontier of minimally invasive surgery.

The use of robotic surgery in transplantation is increasing; however, robotic liver transplantation (RLT) remains a challenging undertaking. To our knowledge, this is a report of the first RLT in North America and the first RLT using a whole graft from a deceased donor in the world. This paper describes the preparation leading to the RLT and the surgical technique of the operation. The operation was performed in a 62-year-old man with hepatitis C cirrhosis and hepatocellular carcinoma with a native Model for End-Stage Liver Disease score of 10. The total console time for the operation was 8 hours 30 minutes, and the transplant hepatectomy took 3 hours 30 minutes. Warm ischemia time was 77 minutes. Biliary reconstruction was performed in a primary end-to-end fashion and took 19 minutes to complete. The patient had an uneventful recovery without early allograft dysfunction or surgical complications and continues to do well after 6-months follow-up. This paper demonstrates the feasibility of this operation in highly selected patients with chronic liver disease. Additional experience is required to fully understand the role of RLT in the future of transplant surgery. Narrated video is available at https://youtu.be/TkjDwLryd3I.

Surgery for chronic idiopathic constipation: pediatric and adult patients - a systematic review.

BACKGROUND: Chronic idiopathic constipation (CIC) is a substantial problem in pediatric and adult patients with similar symptoms and workup; however, surgical management of these populations differs. We systematically reviewed the trends and outcomes in the surgical management of CIC in pediatric and adult populations. METHODS: A literature search was performed using Ovid MEDLINE, Embase, Scopus, the Cochrane Central Register of Controlled Trials, and ClinicalTrials.gov between January 1, 1995 and June 26, 2020. Clinical trials and retrospective and prospective studies of patients of any age with a diagnosis of CIC with data of at least 1 outcome of interest were selected. The interventions included surgical resection for constipation or antegrade continence enema (ACE) procedures. The outcome measures included bowel movement frequency, abdominal pain, laxative use, satisfaction, complications, and reinterventions. RESULTS: Adult patients were most likely to undergo resection (94%), whereas pediatric patients were more likely to undergo ACE procedures (96%) as their primary surgery. Both ACE procedures and resections were noted to improve symptoms of CIC; however, ACE procedures were associated with higher complication and reintervention rates. CONCLUSION: Surgical management of CIC in pediatric and adult patients differs with pediatric patients receiving ACE procedures and adults undergoing resections. The evaluation of resections and long-term ACE data in pediatric patients should be performed to inform patients and physicians whether an ACE is an appropriate procedure despite high complication and reintervention rates or whether resections should be considered as an initial approach for CIC.

Short-course radiation with consolidation chemotherapy does not increase operative morbidity compared to long-course chemoradiation: A retrospective study of the US rectal cancer consortium.

BACKGROUND AND OBJECTIVES: Neoadjuvant short-course radiation and consolidation chemotherapy (SC TNT) remains less widely used for rectal cancer in the United States than long-course chemoradiation (LCRT). SC TNT may improve compliance and downstaging; however, a longer radiation-to-surgery interval may worsen pelvic fibrosis and morbidity with total mesorectal excision (TME). A single, US-center retrospective analysis has shown comparable risk of morbidity after neoadjuvant short-course radiation with consolidation chemotherapy (SC TNT) and long-course chemoradiation (LCRT). Validation by a multi-institutional study is needed. METHODS: The US Rectal Cancer Consortium database (2010-2018) was retrospectively reviewed for patients with nonmetastatic, rectal adenocarcinoma treated with neoadjuvant LCRT or SC TNT before TME. The primary endpoint was severe postoperative morbidity. Cohorts were compared by univariate analysis. Multivariable logistic regression modeled the odds of severe complication. RESULTS: Of 788 included patients, 151 (19%) received SC TNT and 637 (81%) LCRT. The SC TNT group had fewer distal tumors (33.8% vs. 50.2%, p < 0.0001) and more clinical node-positive disease (74.2% vs. 47.6%, p < 0.0001). The intraoperative complication rate was similar (SC TNT 5.3% vs. 4.4%, p = 0.65). There was no difference in overall postoperative morbidity (38.4% vs. 46.3%, p = 0.08). Severe morbidity was similar with low anterior resection (9.1% vs. 15.3%, p = 0.10) and abdominoperineal resection (24.4% vs. 29.7%, p = 0.49). SC TNT did not increase the odds of severe morbidity relative to LCRT on multivariable analysis (OR 0.64, 95% CI 0.37-1.10). CONCLUSIONS: SC TNT does not increase morbidity after TME for rectal cancer relative to LCRT. Concern for surgical complications should not discourage the use of SC TNT when aiming to increase the likelihood of complete clinical response.

Global liver transplantation: emerging trends and ethical challenges.

PURPOSE: Liver transplant (LT) is the only definitive treatment for end-stage liver disease (ESLD). This review aims to explore current global LT practices, with an emphasis on challenges and disparities that limit access to LT in different regions of the world. METHODS: A detailed analysis was performed of present-day liver transplant practices throughout the world, including the etiology of liver disease, patient access to transplantation, surgical costs, and ongoing ethical concerns. RESULTS: Annually, only 10% of the patients needing a liver transplant receive an organ. Currently, the USA performs the highest volume of liver transplants worldwide, followed by China and Brazil. In both North America and Europe, nonalcoholic fatty liver disease is becoming the most common indication for LT, compared to hepatitis B and C in most Asian, South American, and African countries. While deceased donor liver transplant remains the most performed type of LT, living donor liver transplant is becoming increasingly popular in some parts of the world where it is often the only option due to a lack of well-developed infrastructure for deceased organ donation. Ethical concerns in liver transplantation fundamentally revolve around the definition of a deceased donor and the exploitation of living donor liver donation systems. CONCLUSION: Globally, liver transplant practices and outcomes are varied, with differences driven by healthcare policies, inequities in healthcare access, and ethical concerns.

The impact of a dedicated operating room team on robotic transplant program growth and fellowship training.

INTRODUCTION: Despite considerable interest in robotic surgery, successful incorporation of robotics into transplant programs has been challenging. Lack of a dedicated OR team with expertise in both robotics and transplant is felt to be a major barrier. This paper assesses the impact of a dedicated robotic transplant team (DART) on program growth and fellowship training at one of the largest robotic transplant programs in North America. METHODS: This is a single center, retrospective review of all robotic operations performed on the transplant surgery service from October 2017 to October 2022. DART was incorporated in February 2020 and included transplant first assists (RFAs), scrub technologists and circulating nurses who received robotic training. Robotic experience before and after DART was compared to assess its impact on program growth and training. RESULTS: Four hundred and two robotic cases were performed by five transplant surgeons: 63 pre-DART and 339 post-DART. 40% of cases were transplant-related and 59.5%, HPB. There was a significant increase in case volume (2.5-10.6 cases/month, p < .0001) and complexity (36.5% vs. 70.3% high complexity cases, p < .0001) post-DART. RFA case coverage increased from 17% to 95%, and participation of transplant fellows as primary surgeons increased from 17% to 95% post-DART period (both p < .05). Conversion rates (9.5% vs. 4.1%) and room turn-around-times (TAT) (58.4 vs. 40.3 min) were lower post-DART (p < .05). There were no emergent conversions, conversions in transplant patients, or robot-related complications in either group. CONCLUSION: OR teams with expertise in robotics and transplant surgery can accelerate growth of robotic transplant programs while maintaining patient safety.

Robotic donor nephrectomy: optimizing outcomes beyond the limitations of laparoscopy.

BACKGROUND: Robotic donor nephrectomy (RDN) has emerged as a safe alternate to laparoscopic donor nephrectomy (LDN), offering improved visualization, instrument dexterity and ergonomics. There is still concern about how to safely transition from LDN to RDN. METHODS: We performed a retrospective review of 150 consecutive living donor operations (75 LDN and 75 RDN) at our center, comparing the first 75 RDN's with the last 75 LDN's performed prior to the initiation of the robotic transplant program. Operative times and complications were used as surrogates of efficiency and safety, respectively, to estimate the learning curve with RDN. RESULTS: RDN was associated with a longer total operative time (RDN 182 vs LDN 144 min; P < 0.0001) but a significantly shorter post-operative length of stay (RDN 1.8 vs LDN 2.1 days; P = 0.0213). Donor complications and recipient outcomes were the same between both groups. Learning curve of RDN was estimated to be about 30 cases. CONCLUSIONS: RDN is a safe alternate to LDN with acceptable donor morbidity and no negative impact on recipient outcomes even during the early part of the RDN learning curve. Surgeon preferences for the robotic approach compared to traditional laparoscopy will require further scrutiny to improve ergonomics and operative efficiency.

Circulating exosomes from brain death and cardiac death donors have distinct molecular and immunologic properties: A pilot study.

BACKGROUND AND AIMS: Comparison of donation after brain death (DBD) and donation after cardiac death (DCD) lung tissue before transplantation have demonstrated activation of pro-inflammatory cytokine pathway in DBD donors. The molecular and immunological properties of circulating exosomes from DBD and DCD donors were not previously described. METHODS: We collected plasma from 18 deceased donors (12 DBD and six DCD). Cytokines were analyzed by 30-Plex luminex Panels. Exosomes were analyzed for liver self-antigen (SAg), Transcription Factors and HLA class II (HLA-DR/DQ) using western blot. C57BL/6 animals were immunized with isolated exosomes to determine strength and magnitude of immune responses. Interferon (IFN)-γ and tumor necrosis factor-α producing cells were quantified by ELISPOT, specific antibodies to HLA class II antigens were measured by ELISA RESULTS: We demonstrate increased plasma levels of IFNγ, EGF, EOTAXIN, IP-10, MCP-1, RANTES, MIP-ß, VEGF, and interleukins - 6/8 in DBD plasma versus DCD. MiRNA isolated from exosome of DBD donors demonstrated significant increase in miR-421, which has been reported to correlate with higher level of Interleukin-6. Higher levels of liver SAg Collagen III (p = .008), pro-inflammatory transcription factors (NF-κB, p < .05; HIF1α, p = .021), CIITA (p = .011), and HLA class II (HLA-DR, p = .0003 and HLA-DQ, p = .013) were detected in exosomes from DBD versus DCD plasma. The circulating exosomes isolated from DBD donors were immunogenic in mice and led to the development of Abs to HLA-DR/DQ. CONCLUSIONS: This study provides potential new mechanisms by which DBD organs release exosomes that can activate immune pathways leading to cytokine release and allo-immune response.

Normothermic Machine Perfusion of Donor Livers for Transplantation in the United States: A Randomized Controlled Trial.

OBJECTIVE: To compare conventional low-temperature storage of transplant donor livers [static cold storage (SCS)] with storage of the organs at physiological body temperature [normothermic machine perfusion (NMP)]. BACKGROUND: The high success rate of liver transplantation is constrained by the shortage of transplantable organs (eg, waiting list mortality >20% in many centers). NMP maintains the liver in a functioning state to improve preservation quality and enable testing of the organ before transplantation. This is of greatest potential value with organs from brain-dead donor organs (DBD) with risk factors (age and comorbidities), and those from donors declared dead by cardiovascular criteria (donation after circulatory death). METHODS: Three hundred eighty-three donor organs were randomized by 15 US liver transplant centers to undergo NMP (n = 192) or SCS (n = 191). Two hundred sixty-six donor livers proceeded to transplantation (NMP: n = 136; SCS: n = 130). The primary endpoint of the study was "early allograft dysfunction" (EAD), a marker of early posttransplant liver injury and function. RESULTS: The difference in the incidence of EAD did not achieve significance, with 20.6% (NMP) versus 23.7% (SCS). Using exploratory, "as-treated" rather than "intent-to-treat," subgroup analyses, there was a greater effect size in donation after circulatory death donor livers (22.8% NMP vs 44.6% SCS) and in organs in the highest risk quartile by donor risk (19.2% NMP vs 33.3% SCS). The incidence of acute cardiovascular decompensation at organ reperfusion, "postreperfusion syndrome," as a secondary outcome was reduced in the NMP arm (5.9% vs 14.6%). CONCLUSIONS: NMP did not lower EAD, perhaps related to the inclusion of lower-risk liver donors, as higher-risk donor livers seemed to benefit more. The technology is safe in standard organ recovery and seems to have the greatest benefit for marginal donors.

Impact of Prehabilitation on Postoperative Mortality and the Need for Non-Home Discharge in High-Risk Surgical Patients.

BACKGROUND: The preoperative period is an important target for interventions (eg Surgical Prehabilitation and Readiness [SPAR]) that can improve postoperative outcomes for older patients with comorbidities. STUDY DESIGN: To determine whether a preoperative multidisciplinary prehabilitation program (SPAR) reduces postoperative 30-day mortality and the need for non-home discharge in high-risk surgical patients, surgical patients enrolled in a prehabilitation program targeting physical activity, pulmonary function, nutrition, and mindfulness were compared with historical control patients from 1 institution's American College of Surgeons (ACS) NSQIP database. SPAR patients were propensity score-matched 1:3 to pre-SPAR NSQIP patients, and their outcomes were compared. The ACS NSQIP Surgical Risk Calculator was used to compare observed-to-expected ratios for postoperative outcomes. RESULTS: A total of 246 patients were enrolled in SPAR. A 6-month compliance audit revealed that overall patient adherence to the SPAR program was 89%. At the time of analysis, 118 SPAR patients underwent surgery with 30 days of follow-up. Compared with pre-SPAR NSQIP patients (n = 4,028), SPAR patients were significantly older with worse functional status and more comorbidities. Compared with propensity score-matched pre-SPAR NSQIP patients, SPAR patients had significantly decreased 30-day mortality (0% vs 4.1%, p = 0.036) and decreased need for discharge to postacute care facilities (6.5% vs 15.9%, p = 0.014). Similarly, SPAR patients exhibited decreased observed 30-day mortality (observed-to-expected ratio 0.41) and need for discharge to a facility (observed-to-expected ratio 0.56) compared with their expected outcomes using the ACS NSQIP Surgical Risk Calculator. CONCLUSIONS: The SPAR program is safe and feasible and may reduce postoperative mortality and the need for discharge to postacute care facilities in high-risk surgical patients.

Liver Transplantation After Hepatic Artery Infusion Pump Therapy: Single-Center Experience and Technical Considerations.

BACKGROUND: Hepatic artery infusion pump (HAIP) therapy has become increasingly commonplace in the treatment of intrahepatic tumors. When combined with standard chemotherapy, HAIP therapy demonstrates a higher response rate than chemotherapy alone. Biliary sclerosis is observed in up to 22 % of patients, for whom no treatment has been standardized. This report describes orthotopic liver transplantation (OLT) both as a treatment for HAIP-induced cholangiopathy and as a possible definitive oncologic treatment after HAIP-bridging therapy. METHODS: A retrospective study reviewed patients who had undergone HAIP placement followed by OLT at the authors' institution. Patient demographics, neoadjuvant treatment, and postoperative outcomes were reviewed. RESULTS: Seven OLTs were performed for patients with prior HAIP placement. The majority were women (n = 6), and the median age was 61 years (range, 44.5-65.5 years). Transplantation was performed for five patients due to biliary complications secondary to HAIP and two patients because of residual tumor after HAIP therapy. All the OLTs had difficult dissections due to adhesions. Because of HAIP-induced damage, atypical arterial anastomoses were required in six patients (2 patients used a recipient common hepatic artery below the gastroduodenal artery takeoff; 2 patients used recipient splenic arterial inflow; 1 patient used the junction of the celiac and splenic arteries; and 1 patient used the celiac cuff). The one patient with standard arterial reconstruction experienced an arterial thrombosis. The graft was salvaged with thrombolysis. Biliary reconstruction was duct-to-duct in five cases and Roux-en-Y in two cases. CONCLUSIONS: The OLT procedure is a feasible treatment option for end-stage liver disease after HAIP therapy. Technical considerations include a more challenging dissection and an atypical arterial anastomosis.

Development and validation of a REcurrent Liver cAncer Prediction ScorE (RELAPSE) following liver transplantation in patients with hepatocellular carcinoma: Analysis of the US Multicenter HCC Transplant Consortium.

HCC recurrence following liver transplantation (LT) is highly morbid and occurs despite strict patient selection criteria. Individualized prediction of post-LT HCC recurrence risk remains an important need. Clinico-radiologic and pathologic data of 4981 patients with HCC undergoing LT from the US Multicenter HCC Transplant Consortium (UMHTC) were analyzed to develop a REcurrent Liver cAncer Prediction ScorE (RELAPSE). Multivariable Fine and Gray competing risk analysis and machine learning algorithms (Random Survival Forest and Classification and Regression Tree models) identified variables to model HCC recurrence. RELAPSE was externally validated in 1160 HCC LT recipients from the European Hepatocellular Cancer Liver Transplant study group. Of 4981 UMHTC patients with HCC undergoing LT, 71.9% were within Milan criteria, 16.1% were initially beyond Milan criteria with 9.4% downstaged before LT, and 12.0% had incidental HCC on explant pathology. Overall and recurrence-free survival at 1, 3, and 5 years was 89.7%, 78.6%, and 69.8% and 86.8%, 74.9%, and 66.7%, respectively, with a 5-year incidence of HCC recurrence of 12.5% (median 16 months) and non-HCC mortality of 20.8%. A multivariable model identified maximum alpha-fetoprotein (HR = 1.35 per-log SD, 95% CI,1.22-1.50, p < 0.001), neutrophil-lymphocyte ratio (HR = 1.16 per-log SD, 95% CI,1.04-1.28, p < 0.006), pathologic maximum tumor diameter (HR = 1.53 per-log SD, 95% CI, 1.35-1.73, p < 0.001), microvascular (HR = 2.37, 95%-CI, 1.87-2.99, p < 0.001) and macrovascular (HR = 3.38, 95% CI, 2.41-4.75, p < 0.001) invasion, and tumor differentiation (moderate HR = 1.75, 95% CI, 1.29-2.37, p < 0.001; poor HR = 2.62, 95% CI, 1.54-3.32, p < 0.001) as independent variables predicting post-LT HCC recurrence (C-statistic = 0.78). Machine learning algorithms incorporating additional covariates improved prediction of recurrence (Random Survival Forest C-statistic = 0.81). Despite significant differences in European Hepatocellular Cancer Liver Transplant recipient radiologic, treatment, and pathologic characteristics, external validation of RELAPSE demonstrated consistent 2- and 5-year recurrence risk discrimination (AUCs 0.77 and 0.75, respectively). We developed and externally validated a RELAPSE score that accurately discriminates post-LT HCC recurrence risk and may allow for individualized post-LT surveillance, immunosuppression modification, and selection of high-risk patients for adjuvant therapies.

Integrated analysis of genomic and transcriptomic data for the discovery of splice-associated variants in cancer.

Somatic mutations within non-coding regions and even exons may have unidentified regulatory consequences that are often overlooked in analysis workflows. Here we present RegTools ( www.regtools.org ), a computationally efficient, free, and open-source software package designed to integrate somatic variants from genomic data with splice junctions from bulk or single cell transcriptomic data to identify variants that may cause aberrant splicing. We apply RegTools to over 9000 tumor samples with both tumor DNA and RNA sequence data. RegTools discovers 235,778 events where a splice-associated variant significantly increases the splicing of a particular junction, across 158,200 unique variants and 131,212 unique junctions. To characterize these somatic variants and their associated splice isoforms, we annotate them with the Variant Effect Predictor, SpliceAI, and Genotype-Tissue Expression junction counts and compare our results to other tools that integrate genomic and transcriptomic data. While many events are corroborated by the aforementioned tools, the flexibility of RegTools also allows us to identify splice-associated variants in known cancer drivers, such as TP53, CDKN2A, and B2M, and other genes.

Outcomes in liver transplant recipients with nonalcoholic fatty liver disease-related HCC: results from the US multicenter HCC transplant consortium.

NAFLD will soon be the most common indication for liver transplantation (LT). In NAFLD, HCC may occur at earlier stages of fibrosis and present with more advanced tumor stage, raising concern for aggressive disease. Thus, adult LT recipients with HCC from 20 US centers transplanted between 2002 and 2013 were analyzed to determine whether NAFLD impacts recurrence-free post-LT survival. Five hundred and thirty-eight (10.8%) of 4981 total patients had NAFLD. Patients with NAFLD were significantly older (63 vs. 58, p<0.001), had higher body mass index (30.5 vs. 27.4, p<0.001), and were more likely to have diabetes (57.3% vs. 28.8%, p<0.001). Patients with NAFLD were less likely to receive pre-LT locoregional therapy (63.6% vs. 72.9%, p<0.001), had higher median lab MELD (15 vs. 13, p<0.001) and neutrophil-lymphocyte ratio (3.8 vs. 2.9, p<0.001), and were more likely to have their maximum pre-LT alpha fetoprotein at time of LT (44.1% vs. 36.1%, p<0.001). NAFLD patients were more likely to have an incidental HCC on explant (19.4% vs. 10.4%, p<0.001); however, explant characteristics including tumor differentiation and vascular invasion were not different between groups. Comparing NAFLD and non-NAFLD patients, the 1, 3, and 5-year cumulative incidence of recurrence (3.1%, 9.1%, 11.5% vs. 4.9%, 10.1%, 12.6%, p=0.36) and recurrence-free survival rates (87%, 76%, and 67% vs. 87%, 75%, and 67%, p=0.97) were not different. In competing risks analysis, NAFLD did not significantly impact recurrence in univariable (HR: 0.88, p=0.36) nor in adjusted analysis (HR: 0.91, p=0.49). With NAFLD among the most common causes of HCC and poised to become the leading indication for LT, a better understanding of disease-specific models to predict recurrence is needed. In this NAFLD cohort, incidental HCCs were common, raising concerns about early detection. However, despite less locoregional therapy and high neutrophil-lymphocyte ratio, explant tumor characteristics and post-transplant recurrence-free survival were not different compared to non-NAFLD patients.

SOX9 Expression Is Superior to Other Stem Cell Markers K19 and EpCAM in Predicting Prognosis in Hepatocellular Carcinoma.

Various stem cell markers (eg, epithelial cell adhesion molecule [EpCAM], cytokeratin 19 [K19]) have been reported as predictors of poor prognosis in hepatocellular carcinoma (HCC). However, the data remain limited, particularly in Western populations, and are often contradictory. In this study, the prognostic value of positive SOX9 immunohistochemistry was compared with that of more established markers EpCAM and K19 in a large cohort (n=216) of North American patients. The independent HCC cohort in The Cancer Gene Atlas (n=360) was utilized to validate our findings. Finally, molecular signatures associated with SOX9 -high HCC were determined. We found that the expression of SOX9, but not EpCAM or K19, was associated with worse overall survival and disease-free survival (DFS) and was an independent prognostic factor for DFS in our North American cohort, in which hepatitis C infection was the most common underlying etiology. High SOX9 mRNA level, but not increased expression of EpCAM mRNA or K19 mRNA, was also associated with worse DFS and was an independent prognostic factor for DFS in The Cancer Gene Atlas cohort. This group had underlying causes, including an increased incidence of hepatitis B, significantly different from our initial cohort. High SOX9 mRNA level is associated with molecular pathways important in HCC pathogenesis. Increased SOX9 expression is clinically and biologically relevant for HCC arising in patients with a variety of underlying etiologies. Immunohistochemistry for SOX9 is a reliable proxy for increased SOX9 mRNA and can be used to predict prognosis in HCC cases.