Resection For Intrahepatic Cholangiocarcinoma Research Articles

The effectiveness of combined extra-hepatic bile duct resection in radically-resected cases with intrahepatic cholangiocarcinoma: a SEER-based retrospective cohort study and an external validation.

To evaluate the effectiveness of the combined extra-hepatic bile duct resection (EHBDR) in cases with intrahepatic cholangiocarcinoma (IHCC) in terms of clinicopathological features and long-term survival. Radically resected cases with IHCC from 2000 to 2020 were identified from Surveillance, Epidemiology, and End Results (SEER) database. Comparative analyses were performed between resected IHCC patients who received EHBDR and those without EHBDR. Moreover, an external validation was further performed based on a single-center cohort. A total of 1521 radically resected cases with IHCC (EHBDR: 189) were identified from SEER database. Comparable age, sex, race, marital status, liver cirrhosis, differentiation status, and adjuvant chemotherapy were acquired between two groups. EHBDR was associated with a higher incidence of adequate lymphadenectomy (P<0.001). The incidence of cases with T3-4 or N+ disease was significantly higher in EHBDR group (P<0.001). Adjuvant radiotherapy was more frequently performed in cases with EHBDR (P<0.001). EHBDR failed to brought any survival benefit and was associated with a worse prognosis even after matching. Similar findings have also been revealed in the external validation cohort (n=522, EHBDR: 117). EHBDR was associated with more extended resections, more aggressive tumor biological features, and worse prognosis. In the matched validation cohort, EHBDR was still associated with a higher incidence of early recurrence. EHBDR was an indicator of advanced stage and failed to brought any survival benefit. It is the tumor stage which really determines the prognosis. More in-depth analyses focusing on different situations of EHBDR with more detailed clinical data are required.

A snapshot on current approaches to lymphadenectomy in liver resection for intrahepatic cholangiocarcinoma: results from an international survey.

The use of lymphadenectomy (LND) during resection of intrahepatic cholangiocarcinoma (ICC) is still debated, leading to differing practices in different centers and countries. The aim of this study was to assess such differences. A survey on LND for ICC was distributed to the members of the International Hepato-PancreatoBiliary Association (IHPBA) and the Italian Chapter of IHPBA (AICEP). Two-hundred thirty-four surgeons completed the survey (88% males; median age 46 years). Preoperative nodal staging was deemed mandatory/very important by 65%. Adequate LND was defined as hepatoduodenal ligament LND by 33%, LND at specific nodal stations by 28% and retrieval of > 5 nodes by 28%. The decision to perform LND was influenced by comorbidities (48%), chronic liver disease (38%) and satellitosis (32%). Most participants modify perioperative management in case of clinically positive nodes, 50% stating they would give neoadjuvant therapy. The role of LND in clinically node negative disease was adequate staging for 88%, survival benefit for 50.5% and clinical trials eligibility for 18.5%. Our survey confirms heterogeneity in the evaluation of role and extent of LND for ICC, how this relates to subjective perception of importance of LND, and need of a systematic approach in this area.

Outcomes of liver resection in hepatitis C virus-related intrahepatic cholangiocarcinoma: A systematic review and meta-analysis.

Cholangiocarcinoma is the second most common primary liver malignancy. Its incidence and mortality rates have been increasing in recent years. Hepatitis C virus (HCV) infection is a risk factor for development of cirrhosis and cholangiocarcinoma. Currently, surgical resection remains the only curative treatment option for cholangiocarcinoma. We aim to study the impact of HCV infection on outcomes of liver resection (LR) in intrahepatic cholangiocarcinoma (ICC). To study the outcomes of curative resection of ICC in patients with HCV (i.e., HCV+) compared to patients without HCV (i.e., HCV-). We conducted a systematic review and meta-analysis of randomized controlled trials (RCTs) and observational studies to assess the outcomes of LR in ICC in HCV+ patients compared to HCV- patients in tertiary care hospitals. PubMed, EMBASE, The Cochrane Library and Scopus were systematically searched from inception till August 2023. Included studies were RCTs and non-RCTs on patients ≥ 18 years old with a diagnosis of ICC who underwent LR, and compared outcomes between patients with HCV+ vs HCV-. The primary outcomes were overall survival (OS) and recurrence-free survival. Secondary outcomes include perioperative mortality, operation duration, blood loss, intrahepatic and extrahepatic recurrence. Seven articles, published between 2004 and 2021, fulfilled the selection criteria. All of the studies were retrospective studies. Age, incidence of male patients, albumin, bilirubin, platelets, tumor size, incidence of multiple tumors, vascular invasion, bile duct invasion, lymph node metastases, and stage 4 disease were comparable between HCV+ and HCV- group. Alanine transaminase [MD 22.20, 95%confidence interval (CI): 13.75, 30.65, P < 0.00001] and aspartate transaminase levels (MD 27.27, 95%CI: 20.20, 34.34, P < 0.00001) were significantly higher in HCV+ group compared to HCV- group. Incidence of cirrhosis was significantly higher in HCV+ group [odds ratio (OR) 5.78, 95%CI: 1.38, 24.14, P = 0.02] compared to HCV- group. Incidence of poorly differentiated disease was significantly higher in HCV+ group (OR 2.55, 95%CI: 1.34, 4.82, P = 0.004) compared to HCV- group. Incidence of simultaneous hepatocellular carcinoma lesions was significantly higher in HCV+ group (OR 8.31, 95%CI: 2.36, 29.26, P = 0.001) compared to HCV- group. OS was significantly worse in the HCV+ group (hazard ratio 2.05, 95%CI: 1.46, 2.88, P < 0.0001) compared to HCV- group. This meta-analysis demonstrated significantly worse OS in HCV+ patients with ICC who underwent curative resection compared to HCV- patients.

Recurrent Intrahepatic Cholangiocarcinoma: A 10-Point Score to Predict Post-Recurrence Survival and Guide Treatment of Recurrence.

Although up to 50-70% of patients with intrahepatic cholangiocarcinoma (ICC) recur following resection, data to predict post-recurrence survival (PRS) and guide treatment of recurrence are limited. Patients who underwent resection of ICC between 2000 and 2020 were identified from an international, multi-institutional database. Data on primary disease as well as laboratory and radiologic data on recurrent disease were collected. Factors associated with PRS were examined and a novel scoring system to predict PRS (PRS score) was developed and internallyvalidated. Among 986 individuals who underwent resection for ICC, 588 (59.6%) patients developed recurrence at a median follow up of 20.3months. Among patients who experienced a recurrence, 97 (16.5%) underwent re-resection/ablation for recurrent ICC; 88 (15.0%) and 403 (68.5%) patients received intra-arterial treatment or systemic chemotherapy/supportive therapy, respectively. Patient American Society of Anesthesiologists (ASA) class > 2 (1 point), primary tumor N1/Nx status (1 point), primary R1 resection margin (1 point), primary tumor G3/G4 grade(1 point), carbohydrate antigen (CA) 19-9 > 37 UI/mL (2 points) at recurrenceand carcinoembryonic antigen (CEA) > 5ng/mL (2 points) at recurrence, as well as recurrent bilateral disease (1 point) and early recurrence (1 point) were included in thePRS score. The PRS score successfully stratified patients relative to PRS and demonstrated strong discriminatory ability (C-index 0.70, 95% confidence interval 0.68-0.72). While a PRS score of 0-3 was associated with a 3-year PRS of 62.5% following resection/ablation for recurrent ICC, a PRS score > 3 was associated with a low 3-year PRS of 35.5% (p = 0.03). The PRS score demonstrated strong discriminatory ability to predict PRS among patients who had developed recurrencefollowing initial resection of ICC. The PRS score may be a useful tool to guide treatment among patients with recurrent ICC.

Tumor burden score and carcinoembryonic antigen predict outcomes in patients with intrahepatic cholangiocarcinoma following liver resection: a multi‑institutional analysis

BackgroundThe prognostic significance of tumor burden score (TBS) in relation to carcinoembryonic antigen (CEA) has not been investigated among patients undergoing hepatectomy for intrahepatic cholangiocarcinoma (ICC). This study aimed to develop and validate a simplified model, a combination of TBS and CEA (CTC grade), for predicting the long-term outcomes of postoperative ICC patients.MethodsPatients who underwent curative − intent resection of ICC between 2011 and 2019 were identified from a large multi − institutional database. The impact of TBS, CEA, and the CTC grade on overall survival (OS) and recurrence − free survival (RFS) was evaluated in both the derivation and validation cohorts. The receiver operating characteristic curve was utilized for assessing the predictive accuracy of the model. Subgroup analyses were performed across 8th TNM stage system stratified by CTC grade to assess the discriminatory capacity within the same TNM stage.ResultsA total of 812 patients were included in the derivation cohort and 266 patients in the validation cohort. Survival varied based on CEA (low: 36.7% vs. high: 9.0%) and TBS (low: 40.3% vs. high: 17.6%) in relation to 5 − year survival (both p < 0.001). As expected, patients with low CTC grade (i.e., low TBS/low CEA) were associated with the best OS as well as RFS, while high CTC grade (i.e., high TBS/high CEA) correlated to the worst outcomes. The model exhibited well performance in both the derivation cohort (area under the curve of 0.694) and the validation cohort (0.664). The predictive efficacy of the CTC grade system remains consistently stable across TNM stages I and III/IV.ConclusionThe CTC grade, a composite parameter derived from the combination of TBS and CEA levels, served as an easy − to − use tool and performed well in stratifying patients with ICC relative to OS and RFS.

Prognostic implications of tumor histology and microenvironment in surgically resected intrahepatic cholangiocarcinoma: a single institutional experience.

Intrahepatic cholangiocarcinoma (ICC) is a highly aggressive malignant neoplasm. Certain histologic features and the tumor microenvironment may impact disease progression. We aim to characterize the clinicopathologic features of ICC to identify prognostic factors. A total of 50 surgically resected ICC (partial or transplant) cases were analyzed. The cohort included 26 men and 24 women with a median age of 62years. Eighteen (36%) cases were multifocal ICC with a mean largest tumor size of 6.5cm. Neoadjuvant and adjuvant chemotherapy was done in eight (16%) and 33 (66%) patients, respectively. Histologically, 42 (84%) were small duct type, seven (14%) large duct type, and one mixed (2%). Thirty (60%) cases showed lymphovascular invasion (LVI) and 11 (22%) with perineural invasion (PNI). Twenty-eight (56%) cases demonstrated dense intratumoral hyaline fibrosis and 18 (36%) with tumor necrosis, each ≥ 10% tumor volume. On follow-up, 35 (70%) patients died of disease after a median disease-specific survival (DSS) of 21months. Univariate analysis revealed that hyaline fibrosis and adjuvant chemotherapy were associated with better DSS, while tumor size, multifocality, necrosis, and peritumoral neutrophil to lymphocyte ratio were associated with worse DSS. In contrast, age, sex, small vs. large duct types, LVI, and individual inflammatory cell counts were not significant prognostic factors. In summary, ICC is a heterogeneous malignancy with variable clinical courses associated with tumor burden, histology, and microenvironment. Targeting specific components within the tumor microenvironments may be a promising approach for treatment in the future.

Contemporary trends and outcomes after liver transplantation and resection for intrahepatic cholangiocarcinoma

BackgroundLiver transplantation has been shown to be superior to resection in highly selected patients with perihilar cholangiocarcinoma, yet has traditionally been contraindicated for intrahepatic cholangiocarcinoma. Herein, we aimed to examine contemporary trends and outcomes for surgical resection and liver transplantation for intrahepatic cholangiocarcinoma. MethodsThe National Cancer Database was queried for patients presenting with stage I-III intrahepatic cholangiocarcinoma between 2010 and 2018 who underwent resection or liver transplantation. Overall survival was compared with Kaplan-Meier and multivariable Cox proportional hazards methods stratified by management. Secondary analysis of patients undergoing transplant for cholangiocarcinoma was performed with the United Network for Organ Sharing database. ResultsOf 2,565 patients, 2,412 (94.0%) underwent resection and 153 (5.96%) liver transplantation of which 84 (54.9%) received neoadjuvant therapy. Utilization of liver transplantation remained between 3.9-7.8% annually. Unadjusted 5-year overall survival was higher for liver transplantation than resection (59.8% vs 39.9%, p=0.0067). Yet, adjusted analysis revealed no significant difference in mortality (hazard ratio 0.91, 95% confidence interval 0.66-1.27, p=0.58). On secondary analysis including 437 patients with all subtypes of cholangiocarcinoma, unadjusted 5-year overall survival was higher for non-cholangiocarcinoma indications (79% vs 52-54%, p<0.001). ConclusionUtilization of liver transplantation for intrahepatic cholangiocarcinoma remains low and many cases are likely incidental. While partial hepatectomy remains the standard of care for patients with resectable disease, our findings suggest that highly selected patients with unresectable intrahepatic cholangiocarcinoma may achieve favorable outcomes after liver transplantation. Granular, prospective data is needed to identify patients most likely to benefit from transplant and allocate scarce liver grafts.

Nodal recurrence mapping and clinical target volumes after resection of intrahepatic cholangiocarcinoma or combined hepatocellular-cholangiocarcinoma

BackgroundScarce evidence exists for clinical target volume (CTV) definitions of regional lymph nodes (LNs) in intrahepatic cholangiocarcinoma (iCCA) or combined hepatocellular-cholangiocarcinoma (cHCC-CCA). We investigated the mapping pattern of nodal recurrence after surgery for iCCA and cHCC-CCA and provided evidence for the nodal CTV definition. MethodsWe retrospectively reviewed the medical records of patients with iCCA or cHCC-CCA who underwent surgery between 2010 and 2020. Eligibility criteria included patients pathologically diagnosed with iCCA or cHCC-CCA after surgery and a first recurrent event in regional LNs during follow-up. All recurrent LNs were registered onto reference computed tomography images based on the vascular structures to reconstruct the node mapping. Fifty-three patients were eligible. LN regions were classified into four risk groups. ResultsHepatic hilar and portal vein-vena cava were the most common recurrent regions, with recurrence rates of 62.3 % and 39.6 % (high-risk regions), respectively. Recurrence rates in the left gastric, diaphragmatic, common hepatic, superior mesenteric vessels, celiac trunk, and paracardial regions ranged from 15.1 % to 30.2 % (intermediate-risk regions). There were fewer recurrences in the para-aortic (16a1, a2, b1) and splenic artery and hilum regions, with rates <10 % (low-risk regions). No LN recurrence was observed in the para-oesophageal or para-aortic region (16b2) (very low-risk regions). Based on node mapping, the CTV should include high- and intermediate-risk regions for pathologically negative LN patients during postoperative radiotherapy. Low-risk regions should be included for pathologically positive LN patients. ConclusionWe provide evidence for CTV delineation in patients with iCCA and cHCC-CCA based on recurrent LN mapping.

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

IntroductionData on clinical characteristics and disease-specific prognosis among patients with early onset intrahepatic cholangiocarcinoma (ICC) are currently limited.MethodsPatients 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.ResultsAmong 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.ConclusionsEarly-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.

Management of Intrahepatic Cholangiocarcinoma: A Narrative Review.

The management of resectable intrahepatic cholangiocarcinoma remains a challenge due to the high risk of recurrence. Numerous clinical trials have identified effective systemic therapies for advanced biliary tract cancer; however, fewer trials have evaluated systemic therapies in the perioperative period. The objective of this review is to summarize the current recommendations regarding the diagnosis, surgical resection, and systemic therapy for anatomically resectable intrahepatic cholangiocarcinoma. Our review demonstrates that surgical resection with microscopic negative margins and lymphadenectomy remains the cornerstone of treatment. High-level evidence regarding specific systemic therapies for use in resectable intrahepatic cholangiocarcinoma remains sparse, as most of the evidence is extrapolated from trials involving heterogeneous tumor populations. Targeted therapies are an evolving practice for intrahepatic cholangiocarcinoma with most evidence coming from phase II trials. Future research is required to evaluate the use of neoadjuvant therapy for patients with resectable and borderline resectable disease.

Impact of Frailty on Short-Term Outcomes of Hepatic Lobectomy in Patients with Intrahepatic Cholangiocarcinoma: Evidence from the US Nationwide Inpatient Sample 2005–2018

Introduction: This study aimed to evaluate associations between frailty and outcomes in patients with intrahepatic cholangiocarcinoma (ICC) undergoing hepatic lobectomy using a large, nationally representative sample. Methods: This population-based, retrospective observational study extracted the data of adults ≥20 years old with ICC undergoing hepatic lobectomy from the US Nationwide Inpatient Sample database between 2005 and 2018. Frailty was assessed by the validated Hospital Frailty Risk Score (HFRS). Associations between frailty and surgical outcomes were analyzed using logistic regression analyses. Results: After exclusions, 777 patients were enrolled, including 427 frail and 350 non-frail. Patients’ mean age was 64.5 (±0.4) years and the majority were males (51.1%) and whites (76.5%). Frailty was significantly associated with increased odds of in-hospital mortality (aOR: 18.51, 95% CI: 6.70, 51.18), non-home discharge (aOR: 3.58, 95% CI: 2.26, 5.66), prolonged LOS (aOR: 5.56, 95% CI: 3.87, 7.99), perioperative cardiac arrest/stroke (aOR: 5.44, 95% CI: 1.62, 18.24), acute respiratory distress syndrome (ARDS)/respiratory failure (aOR: 3.88, 95% CI: 2.40, 6.28), tracheostomy/ventilation (aOR: 3.83, 95% CI: 2.23, 6.58), bleeding/transfusion (aOR: 1.67, 95% CI: 1.24, 2.26), acute kidney injury (AKI) (aOR: 14.37, 95% CI: 7.13, 28.99), postoperative shock (aOR: 4.44, 95% CI: 2.54, 7.74), and sepsis (aOR: 11.94, 95% CI: 6.90, 20.67). Discussion/Conclusion: Among patients with ICC undergoing hepatic lobectomy, HFRS-defined frailty is a strong predictor of worse in-patient outcomes, including in-hospital death, prolonged LOS, unfavorable discharge, and complications (perioperative cardiac arrest/stroke, ARDS/respiratory failure, tracheostomy/ventilation, bleeding/transfusion, AKI, postoperative shock, and sepsis). Study results may help stratify risk in frail patients undergoing hepatic resection for ICC.

Intrahepatic cholangiocarcinoma: Recurrence patterns, genomics and survival.

570 Background: Recurrence is common after resection of intrahepatic cholangiocarcinoma (IHC) but how recurrence patterns impact survival remains unclear. This study investigated the clinicopathologic and genomic factors associated with site of first recurrence and their impact on outcome after curative intent resection. Methods: Patients who underwent curative intent hepatectomy for IHC at two medical centers (MSKCC and EMC) with complete follow up and tumor genomic data were included. Documented sites of first disease recurrence were classified as liver only (LO), extrahepatic (EH) only or simultaneous liver and extrahepatic (SIM). Time to recurrence (TTR) and recurrence-free (RFS) were calculated from time of resection while OS was calculated from time of recurrence. Primary tumors underwent targeted next generation sequencing. Clinical, histopathologic and genomic factors associated with site(s) of recurrence, RFS and OS were assessed. Results: A total of 318 patients (n=296 MSK, n=22 EMC) treated between 1993 and 2021 met inclusion criteria and were analyzed; 232 patients (73%) developed recurrence. TTR was 11 (9.8, 12) months; OS and RFS was 26 (20, 33) and 14 (13, 18) months, respectively, among patients that recurred. Sites of first recurrence were LO 93 (40%), EH 80 (34%) and SIM 59 (26%). Median OS was similar in the LO (33 [26,42] months) and EH groups (33 [23,46] months) but much lower in SIM (12 [9.8,18] months) (p &lt; 0.001). Moderate/poor tumor differentiation (p = 0.004), LVI (p = 0.004), N1 disease (p = 0.003), and PNI (p = 0.012) were associated with SIM; only positive resection margin predicted LO (p = 0.007). No individual genomic or pathway alterations predicted site of initial recurrence; however, for all patients, TP53 mut (HR 2.01, 1.4-2.9; p &lt; 0.001), CDKN2A del (HR 1.96, 1.29-2.98; p = 0.003), CDKN2B del (HR 3.2, 2.03-5.05; p &lt; 0.001) and KRAS mut (HR 2.49, 1.56-3.96; p &lt; 0.001) were associated with worse survival. On multivariable analysis, SIM (HR 2.23, 1.49-3.34; p &lt; 0.001), clinical stage III (HR 1.94, 1.26-2.99; p = 0.011), and alterations in TP53 (HR 2.07, 1.4-3.07; p &lt; 0.001), CDKN2B (HR 4.1, 2.53-6.63; p &lt; 0.001) and KRAS (HR 2.72, 1.68-4.43; p &lt; 0.001) were independent predictors of worse OS. Of note, 13 LO patients were treated with regional chemotherapy after recurrence, with an associated median OS of 49 (33, NR) months compared to 28 (20, 39) months in the 80 patients treated with systemic therapy alone. Conclusions: Recurrence after resection of IHC was common, and the liver was the single most common site (66%). Clinicopathologic and genomic variables had limited ability to predict site of first recurrence. While LO and EH were associated with similar OS, simultaneous recurrences were dramatically worse. The data support adjuvant strategies targeting liver recurrence to improve outcome after resection of IHC.

The role of pre-operative ctDNA in resectable intrahepatic cholangiocarcinoma.

528 Background: Genomic profiling of circulating tumor DNA (ctDNA) is increasingly used in intrahepatic cholangiocarcinoma (iCCA) to inform precision oncology approaches and determine resistance mechanisms to targeted therapies. The application of pre-operative ctDNA testing in the management of iCCA for prognostication remains unclear. Methods: In this retrospective study, we analyzed pre-operative plasma samples from 14 patients who underwent curative resection for iCCA without neoadjuvant therapy. A personalized and tumor-informed assay (Signatera; Natera, Inc.) was used for the detection and quantification of ctDNA. We correlated ctDNA profiles with baseline tumour characteristics and clinical outcomes. Results: The mean interval between pre-operative blood collection and surgery was 43 days (range: 1 to 90 days). ctDNA was detected in all patients except for one with stage Ia (AJCC 8th) disease (Table). The mean pre-operative ctDNA concentration was lowest in the stage Ia group [4.2 mean tumor molecules (MTM)/mL] and highest in the stage II group (134.0 MTM/mL). The mean pre-operative ctDNA concentration did not exhibit a linear correlation with disease recurrence or mortality rates, however, it showed a moderate-to-good linear correlation with the largest pathologic tumor size (R2 = 0.55). Among the three patients who had IDH1/2 mutations tracked in the plasma by Signatera, two patients had positive IDH1/2 detection in ctDNA with mean ctDNA concentrations of 83.7 MTM/mL (range: 33.8 to 133.5 MTM/mL). The patient with the second-highest ctDNA concentration (133.5 MTM/mL and 1818 days follow-up) had stage Ib disease with an IDH1 mutation but has shown no evidence of recurrence. Conclusions: In the pre-operative setting for iCCA resections, ctDNA can be reliably detected across all disease stages using a tumor-informed approach, even when blood is collected up to 90 days before surgery. While single time-point pre-operative ctDNA concentration levels do not appear to correlate with outcomes, similar to previous reports in colon adenocarcinoma, they may correlate with tumor volume. Further studies are needed to evaluate the utility of tumor-informed ctDNA testing in the post-operative setting to detect molecular residual disease for improved prognostication. [Table: see text]

Benchmarks in Liver Resection for Intrahepatic Cholangiocarcinoma

IntroductionBenchmarking in surgery has been proposed as a means to compare results across institutions to establish best practices. We sought to define benchmark values for hepatectomy for intrahepatic cholangiocarcinoma (ICC) across an international population.MethodsPatients who underwent liver resection for ICC between 1990 and 2020 were identified from an international database, including 14 Eastern and Western institutions. Patients operated on at high-volume centers who had no preoperative jaundice, ASA class <3, body mass index <35 km/m2, without need for bile duct or vascular resection were chosen as the benchmark group.ResultsAmong 1193 patients who underwent curative-intent hepatectomy for ICC, 600 (50.3%) were included in the benchmark group. Among benchmark patients, median age was 58.0 years (interquartile range [IQR] 49.0–67.0), only 28 (4.7%) patients received neoadjuvant therapy, and most patients had a minor resection (n = 499, 83.2%). Benchmark values included ≥3 lymph nodes retrieved when lymphadenectomy was performed, blood loss ≤600 mL, perioperative blood transfusion rate ≤42.9%, and operative time ≤339 min. The postoperative benchmark values included TOO achievement ≥59.3%, positive resection margin ≤27.5%, 30-day readmission ≤3.6%, Clavien-Dindo III or more complications ≤14.3%, and 90-day mortality ≤4.8%, as well as hospital stay ≤14 days.ConclusionsBenchmark cutoffs targeting short-term perioperative outcomes can help to facilitate comparisons across hospitals performing liver resection for ICC, assess inter-institutional variation, and identify the highest-performing centers to improve surgical and oncologic outcomes.

Analysis of Preoperative Risk Factors for Early Recurrence in Patients After Hepatic Resection for Intrahepatic Cholangiocarcinoma.

Intrahepatic cholangiocarcinoma (ICC) has a poor prognosis even after curative-intent hepatic resection due to a high recurrence rate. The aim of this study was to investigate preoperative risk factors for early recurrence after surgery for ICC, which may help to identify patients who need preoperative chemotherapy. We retrospectively analyzed 51 patients who had undergone primary surgery for ICC. We investigated the association of preoperative clinical variables with recurrence within 1year after resection for ICC. We then created a high-risk ICC score using the identified preoperative factors and investigated the association of the score with disease-free and overall survival. Recurrence within 1year after surgery for ICC was significantly associated with poor overall survival (P < .01). In the multivariate analysis, preoperative tumor size > 5cm (P = .03) and elevated C-reactive protein-to-albumin ratio (CAR) (P = .04) were significantly associated with recurrence within 1year after surgery. A high-risk ICC score of 2 was associated with poor disease-free survival (P < .01) and overall survival (P = .02) compared with a score of 0 or 1. Our high-risk ICC score, combining preoperative tumor size and CAR, can be an indicator of early recurrence and poor survival in patients after hepatic resection for ICC. Our findings may provide better preoperative risk stratification of patients with ICC, and the high-risk ICC patients may benefit from preoperative therapy.

Ferroptosis-related gene glutathione peroxidase 4 promotes reprogramming of glucose metabolism via Akt-mTOR axis in intrahepatic cholangiocarcinoma.

The role of the ferroptosis-related gene glutathione peroxidase 4 (GPX4) in oncology has been extensively investigated. However, the clinical implications of GPX4 in patients with intrahepatic cholangiocarcinoma (ICC) remain unknown. This study aimed to evaluate the prognostic impact of GPX4 and its underlying molecular mechanisms in patients with ICC. Fifty-seven patients who underwent surgical resection for ICC between 2010 and 2017 were retrospectively analyzed. Based on the immunohistochemistry, patients were divided into GPX4 high (n = 15) and low (n = 42) groups, and clinical outcomes were assessed. Furthermore, the roles of GPX4 in cell proliferation, migration and gene expression were analyzed in ICC cell lines in vitro and in vivo. The results from clinical study showed that GPX4 high group showed significant associations with high SUVmax on 18F-fluorodeoxyglucose-positron emission tomography (≥8.0, P = 0.017), multiple tumors (P = 0.004), and showed glucose transporter 1 (GLUT1) high expression with a trend toward significance (P = 0.053). Overall and recurrence-free survival in the GPX4 high expression group were significantly worse than those in the GPX4 low expression group (P = 0.038 and P < 0.001, respectively). In the experimental study, inhibition of GPX4 attenuated cell proliferation and migration in ICC cell lines. Inhibition of GPX4 also decreased the expression of glucose metabolism-related genes, such as GLUT1 or HIF1α. Mechanistically, these molecular changes are regulated in Akt-mechanistic targets of rapamycin axis. In conclusion, this study suggested the pivotal value of GPX4 serving as a prognostic marker for patients with ICC. Furthermore, GPX4 can mediate glucose metabolism of ICC.

Role of routine lymph node dissection alongside resection of intrahepatic cholangiocarcinoma: Systematic review and meta-analysis

BACKGROUND The global incidence of intrahepatic cholangiocarcinoma (ICCA) is soaring. Due to often delayed presentation, only a narrow spectrum of the disease is usually surgically resectable. To more accurately stage the disease, reduce recurrence, and improve overall survival, surgical teams are increasingly performing intraoperative lymph node dissection (LND) as well. This procedure has its associated morbidity, while there is no consensus or formal guidelines on its role in this setting. Hence, there is a need to better delineate the evidence for performing LND alongside surgical resection of the ICCA. AIM To perform a systematic review and meta-analysis on the role of LND in improving prognostication and survival post-resection of ICCA. METHODS We performed a systematic literature search using Pubmed, Medline, Embase, and the Cochrane Library, for all studies involving LND, ICCA, and surgical resection using several keywords, Medical Subject Headings (MeSH) tags, and appropriate synonyms. All clinical studies comparing curative intent resection of ICCA with LND vs resection without LND were included, while single-arm case series, studies with insufficient data, and duplicates were excluded. We included all English-language studies from the different academic databases up till early December 2022. The primary outcome measures were set for overall survival (OS) and disease-free survival (DFS). RESULTS This systematic review and meta-analysis included 15 studies that fulfilled the selection criteria comprising 11413 patients with surgically-resectable ICCA, of whom 6424 (56.3%) underwent hepatectomy with LND while the remainder underwent hepatectomy only. In patients who underwent LND, on average, 27.7% of the resected lymph nodes were positive for metastatic disease. Overall, the results showed that performing LND did not significantly improve OS or DFS. However, the effect of LND on OS showed a degree of variability by geographical region, in Eastern and Western countries. As LND is increasingly being performed, further time-based analysis was undertaken to identify time-dependent changes in the role of LND. An increasing adoption of LND was not associated with improved OS. Furthermore, no roles were identified for neoadjuvant/adjuvant chemotherapy or increasing lymph node retrieval in improving OS either. CONCLUSION LND might aid in staging, prognosticating, and deciding further management of resected ICCA, but does not improve OS and DFS and is unsuitable for high-risk patients unlikely to benefit from further treatments.

Classification of Intrahepatic Cholangiocarcinoma into Perihilar Versus Peripheral Subtype.

Intrahepatic cholangiocarcinoma (ICC) constitutes a group of heterogeneous malignancies within the liver. We sought to subtype ICC based on anatomical origin of tumors, as well aspropose modifications of the current classification system. Patients undergoing curative-intent resection for ICC, hilar cholangiocarcinoma (CCA), or hepatocellular carcinoma (HCC) were identified from three international multi-institutional consortia of databases. Clinicopathological characteristics and survival outcomes were assessed. Among 1264 patients with ICC, 1066 (84.3%) were classified as ICC-peripheral subtype, whereas 198 (15.7%) were categorized as ICC-perihilar subtype. Compared with ICC-peripheral subtype, ICC-perihilar subtype was more often associated with aggressive tumor characteristics, including a higher incidence of nodal metastasis, macro- and microvascular invasion, perineural invasion, as well as worse overall survival (OS) (median: ICC-perihilar 19.8 vs. ICC-peripheral 37.1 months; p < 0.001) and disease-free survival (DFS) (median: ICC-perihilar 12.8 vs. ICC-peripheral 15.2 months; p = 0.019). ICC-perihilar subtype and hilar CCA had comparable OS (19.8 vs. 21.4 months; p = 0.581) and DFS (12.8 vs. 16.8 months; p = 0.140). ICC-peripheral subtype tumors were associated with more advanced tumor features, as well as worse survival outcomes versus HCC (OS, median: ICC-peripheral 37.1 vs. HCC 74.3 months; p < 0.001; DFS, median: ICC-peripheral 15.2 vs. HCC 45.5 months; p < 0.001). ICC should be classified as ICC-perihilar and ICC-peripheral subtype based on distinct clinicopathological features and survival outcomes. ICC-perihilar subtype behaved more like carcinoma of the bile duct (i.e., hilar CCA), whereas ICC-peripheral subtype had features and a prognosis more akin to a primary liver malignancy.

Using immunovascular characteristics to predict very early recurrence and prognosis of resectable intrahepatic cholangiocarcinoma

ObjectiveTo predict the very early recurrence (VER) of patients with intrahepatic cholangiocarcinoma (ICC) based on TLSs and MVI status, and further perform prognosis stratifications.MethodsA total of 160, 51 ICC patients from two institutions between May 2012 and July 2022 were retrospectively included as training, external validation cohort. Clinical, radiological and pathological variables were evaluated and collected. Univariate and multivariate analysis were applied to select the significant factors related to VER of ICC. The factors selected were combined to perform stratification of overall survival (OS) using the Kaplan-Meier method with the log-rank test.ResultsOverall, 39 patients (24.4%) had VER, whereas 121 (75.6%) did not (non-VER group). In the training cohort, the median OS was 40.5 months (95% CIs: 33.2–47.7 months). The VER group showed significantly worse OS than the non-VER group (median OS: 14.8, 95% CI:11.6–18.0 months vs. 53.4, 34.3–72.6 months; p<0.001), and it was confirmed in the validation cohort (median OS: 22.1, 95% CI: 8.8–35.4 months vs. 40.1, 21.2–59.0 months; p = 0.003). According to the univariate analysis, four variables were significantly different between the VER group and non-VER group (TLSs status, p = 0.028; differentiation, p = 0.023; MVI status, p = 0.012; diameter, p = 0.028). According to the multivariate analysis, MVI-positive status was independently associated with a higher probability of VER (odds ratio [OR], 2.5; 95% CIs,1.16–5.18; p = 0.018), whereas intra-tumoral TLSs-positive status was associated with lower odds of VER (OR, 0.43; 95% CIs, 0.19–0.97; p = 0.041). Based on the TLSs and MVI status, patients of ICC were categorized into four groups: TLSs-positive and MVI-negative (TP/MN); TLSs-negative and MVI-negative (TN/MN); TLSs-positive and MVI-positive (TP/MP), TLSs-negative and MVI-positive groups (TN/MP). In the training cohort, the four groups could be correlated with OS significantly (p<0.001), and it was confirmed in the validation cohort (p<0.001).ConclusionIntra-tumoral TLSs and MVI status are independent predictive factors of VER after surgery, based on which immunovascular stratifications are constructed and associated with OS significantly of resectable intrahepatic cholangiocarcinoma.

Open Prospective Phase II Randomized Trial Studying Preoperative Systemic and Regional Chemotherapy with Gemcitabine and Platinum-Based Agents in Resectable Intrahepatic Cholangiocarcinoma

Введение. У четверти пациентов с резектабельной внутрипеченочной холангиокарциномой (ВПХК) развивается прогрессирование в течение полугода после операции, прогноз жизни таких больных сопоставим с прогнозом жизни при консервативной терапии. Наличие факторов негативного прогноза, в т. ч. нерадикально выполненная резекция, отрицательно влияют на отдаленные результаты. Положительная роль адъювантного подхода у пациентов с резектабельной холангиокарциномой показана лишь в одной проспективной работе III фазы (BILCAP). Предоперационная терапия, согласно ретроспективным данным, может улучшить отдаленные результаты. Цель. Улучшить результаты лечения больных резектабельной ВПХК за счет применения предоперационной химиотерапии. Материалы и методы. Представленный протокол клинического исследования инициирован в ФГБУ «НМИЦ онкологии им Н.Н. Блохина» Минздрава России и одобрен локальным этическим комитетом 22.12.2022 г. Помимо вышеуказанного учреждения, в исследовании приняли участие еще четыре центра. Клиническое исследование зарегистрировано на портале https://db.oncoproct.ru (неоадъювантная химиотерапия при ВПХК). Исследование является многоцентровым, проспективным, рандомизированным. Предполагается оценить безопасность и эффективность неоадъювантной химиотерапии у больных с резектабельной ВПХК в сравнении со стандартным лечением — резекцией печени без предоперационной терапии. Первичная конечная точка: планируется достигнуть 95 % частоты R0 резекций. Вторичные конечные точки: частота объективного ответа, выраженность патоморфологического ответа, отдаленные результаты, переносимость предоперационной химиотерапии, частота и степень пострезекционных осложнений после предоперационной химиотерапии, частота соблюдения условий протокола. Планируется включить 94 пациента с резектабельной ВПХК, которые будут рандомизированы 1:1. Часть пациентов получит три курса системной терапии по схеме гемцитабин/цисплатин. У другой части пациентов введение препаратов в первый день курса будет назначено регионарно, путем внутриартериальной химиоинфузии, на восьмой день курса введение системное. Группа сравнения — исторический контроль — пациенты с резектабельной, по данным обследования, ВПХК, которые были подвергнуты резекции без предоперационной терапии, частота R0 резекции в этой группе составила 81,3 %. Заключение. Основываясь на результатах исследования, протокол которого представлен, будет сделано заключение о безопасности и целесообразности предоперационной химиотерапии при резектабельной ВПХК с использованием гемцитабина и препаратов платины, в т. ч. с применением внутрипеченочной инфузии.