Primary Intrahepatic Cholangiocarcinoma Research Articles

Two case reports of breast cancer combined with synchronous primary intrahepatic cholangiocarcinoma/mixed liver cancer.

This case report discusses multiple primary malignant tumors, which refer to the occurrence of 2 or more different histological types of malignant tumors simultaneously or successively in the same individual. We present 2 female patients who were admitted to the hospital due to a "left breast mass" and were found to have multiple solid masses in the liver upon imaging. Postoperative pathology revealed that one patient had breast invasive ductal carcinoma was complicated with primary intrahepatic cholangiocarcinoma and mixed hepatocellular carcinoma with intrahepatic cholangiocarcinoma. Both patients underwent extensive resection of the lesion. Regular postoperative checkups and follow-ups have been conducted, and both patient's current conditions are stable. The treatment approach adopted in this case report may serve as a favorable reference for the management of similar cases. However, further extensive biological studies are still needed to investigate the biological mechanisms of multiple primary malignant tumors and to discover specific therapeutic approaches to achieve more clinical benefits for patients.

Whole-exome sequencing reveals genomic landscape of intrahepatic cholangiocarcinoma and identifies SAV1 as a potential driver.

Intrahepatic cholangiocarcinoma (ICC) is the second most common primary hepatic malignancy after hepatocellular carcinoma, with poor prognosis and limited treatment options. The genomic features of ICC in Chinese patients remain largely unknown. In this study, we perform deep whole-exome sequencing of 204 Chinese primary ICCs and characterize genomic alterations and clonal evolution, and reveal their associations with patient outcomes. We identify six mutational signatures, including Signatures A and F, which are highly similar to previously described signatures linked to aristolochic acid and aflatoxin exposures, respectively. We also identify 13 significantly mutated genes in the ICC samples, including SAV1. We find that SAV1 was mutated in 2.9% (20/672) of 672 ICC samples. SAV1 mutation is associated with lower SAV1 protein levels, higher rates of tumor recurrence, and shorter overall patient survival. Biofunctional investigations reveal a tumor-suppressor role of SAV1: its inactivation suppresses Hippo signaling, leading to YAP activation, thereby promoting tumor growth and metastasis. Collectively, our results delineate the genomic landscape of Chinese ICCs and identify SAV1 as a potential driver of ICC.

Computed tomography-guided radioactive iodine-125 seed implantation for liver malignancies in challenging locations.

This study aimed to retrospectively assess the safety and efficacy of radioactive iodine-125 (I-125) seed implantation for liver malignancies in challenging locations. Between December 2015 and December 2021, 49 patients with 60 liver malignancies in challenging locations who underwent computed tomography (CT)-guided I-125 seed implantation were retrospectively analyzed. The primary endpoints included technical success rate and overall survival (OS), whereas the secondary endpoints included progression-free survival (PFS), disease control rate (DCR), objective response rate (ORR), and liver recurrence. Potential factors associated with liver recurrence were also evaluated. The technical success rate was 100%. The median follow-up duration was 12 months (range, 2-68 months). The mean OS and PFS were 17.58 months (95% CI: 13.64-21.52 months) and 13.14 months (95% CI: 10.36-15.92 months), respectively. The 2-month, 6-month, and 1-year DCR and ORR were 97.96% and 93.88%, 93.75% and 77.08%, and 93.48% and 60.87%, respectively. The 6- and 12-month tumor recurrence rates were 20.41% and 28.26%, respectively. The Kaplan-Meier method was used to estimate the time of liver recurrence, with our results showing that patients with primary intrahepatic cholangiocarcinoma had an increased likelihood of having earlier liver recurrence. No major complications developed during follow-up. CT-guided radioactive I-125 implantation could be a safe and effective alternative with promising survival benefits and high local control rates for liver malignancies in challenging locations.

Microwave ablation versus liver resection for primary intrahepatic cholangiocarcinoma within Milan criteria: a long-term multicenter cohort study

Ablation has been recommended by worldwide guidelines as first-line treatment for hepatocellular carcinoma (HCC), while evidence regarding its efficacy for primary intrahepatic cholangiocarcinoma (iCCA) is lacking. We aimed to study the efficacy of ablation in treating iCCA by comparing its prognosis with surgery. In this real-world multicenter cohort study from January 2009 to June 2022, 10,441 iCCA patients from ten tertiary hospitals were identified. Patients who underwent curative-intent microwave ablation (MWA) or liver resection (LR) for tumors within Milan criteria were included. One-to-many propensity score matching (PSM) at variable ratios (1:n≤4) was used to balance baseline characteristics. Mediation analysis was applied to identify potential mediators of the survival difference. 944 patients were finally enrolled in this study, with 221 undergoing MWA and 723 undergoing LR. After PSM, 203 patients in the MWA group were matched with 588 patients in the LR group. The median follow-up time was 4.7 years. Compared with LR, MWA demonstrated similar overall survival (5-year 44.8% versus 40.4%; HR 0.96, 95% CI 0.71-1.29, P=.761). There was an improvement in the 5-year disease-free survival rate for MWA from 17.1% during the period of 2009-2016 to 37.3% during 2017-2022, becoming comparable to the 40.8% of LR (P=.129). The proportion of ablative margins ≥5mm increased from 25% to 61% over the two periods, while this proportion of surgical margins was 62% and 77%, respectively. 34.5% of DFS disparity can be explained by the mediation effect of margins (P<.0001). Similar DFS was observed when both ablative and surgical margins exceeded 5mm (HR 0.83, 95% CI 0.52-1.32, P=.41). MWA may be considered as a viable alternative to LR for iCCA within Milan criteria when an adequate margin can be obtained. National Natural Science Foundation of China.

Should lymphadenectomy performed routinely in patients with primary intrahepatic cholangiocarcinoma undergoing curative hepatectomy? A retrospective cohort study with propensity-score matching analysis

BackgroundThe benefit of routine lymphadenectomy (LD) in improving outcomes for patients with primary intrahepatic cholangiocarcinoma (ICC) undergoing curative hepatectomy remains unclear.Materials and methodsThis study enrolled 269 consecutive patients who underwent liver resection for primary ICC from January 2009 to July 2020 in West China Hospital. The association of the nodal status with disease-free survival (DFS) and overall survival (OS) was analyzed using the Cox proportional hazards model and 1:1 propensity score matching (PSM) analysis.ResultsSeventy-five (27.9%) patients underwent curative liver resection combined with LD (LD+ group), while 194 (72.1%) patients received curative liver resection without LD (LD- group and Nx group). Among the LD+ group, metastatic disease was present in 36 patients (48%, N1 group) and absent in 39 patients (N0 group). During the follow-up period, 116 patients (43.1%) experienced tumor recurrence and 101 patients (37.5%) died due to recurrence. Multivariate analysis revealed that lymph node metastasis (N1, HR 3.682, 95% CI 1.949–6.957, p < 0.001) was associated with worse OS, while LD+ status (HR 0.504, 95% CI 0.298–0.853, p = 0.011) was associated with improved OS. Adjuvant therapy was a protective factor for both DFS (HR 0.602, 95% CI, 0.447–0.810, p = 0.001) and OS (HR 0.683, 95% CI 0.484–0.963, p = 0.030). After 1:1 PSM, the LD+ patients (n = 74) displayed similar 1-, 3- and 5-year DFS rates (40.0, 7.9 and 7.9% vs. 29.0, 13.7 and 13.7%, p = 0.741) and OS rates (56.0, 26.6 and 22.2% vs. 58.9, 25.6, and 16.4%, p = 0.644) to the LD- patients (n = 74). Additionally, among the 75 LD+ patients, 48 patients underwent hepatic hilar lymphadenectomy (HHL), and 27 patients underwent extended hepatic hilar lymphadenectomy (EHL). Both DFS (p = 0.504) and OS (p = 0.215) were similar between the HHL and EHL groups.ConclusionRoutine LD and adjuvant therapy may contribute to improved OS according to the crude analysis. LD could provide accurate staging without excessive risk and guide adjuvant therapy based on the tumor stage, potentially resulting in better survival. These results suggest that a routine LD should be considered during curative hepatectomy for ICC.

Perioperative outcome and long-term survival for intrahepatic cholangiocarcinoma after portal vein embolization and subsequent resection: A propensity-matched study

IntroductionIn view of the high therapeutic value of surgical resection for intrahepatic cholangiocarcinomas (ICC), our study addresses the question of clinical management and outcome in case of borderline resectability requiring hypertrophy induction of the future liver remnant prior to resection. MethodsClinical data was collected of all primary ICC cases receiving major liver resection with or without prior portal vein embolization (PVE) from a single high-volume center. PVE was performed via a percutaneous transhepatic access. Propensity score matching was performed. Perioperative morbidity was assessed as well as long-term survival with a minimum follow-up of 36 months. ResultsNo significant difference in perioperative morbidity was seen between the PVE and the control group. For the PVE group, median OS was 28 months vs. 37 months for the control group (p = 0.418), median DFS 18 and 14 months (p = 0.703). Disease progression during hypertrophy was observed in 38% of cases. Here, OS and DFS was reduced to 18 months (p = 0.479) and 6 months (p = 0.013), respectively. In case of positive N-status or multifocal tumor (MF+) OS was also reduced (18 vs. 26 months, p = 0.033; MF+: 9 vs. 36months p = 0.013). ConclusionOur results suggest that the surgical therapy in case of borderline resectability offers acceptable results with non-inferior OS rates compared to cases without preoperative hypertrophy induction and comparable oncological features. In the presence of additional risk factors (multifocal tumor, lymph node metastasis, PD during hypertrophy) the OS is notably reduced.

The MR Imaging of Primary Intrahepatic Lymphoepithelioma-like Cholangiocarcinoma: A Diagnostic Challenge.

To characterize the magnetic resonance imaging features of primary intrahepatic lymphoepithelioma-like cholangiocarcinoma (LELCC). Thirty-four patients with 38 histologically confirmed LELCCs were enrolled retrospectively from January 2014 to August 2022. We evaluated the clinical features, histologic findings, and imaging manifestations on dynamic enhanced MRI. 74% (25/34) of the cases were associated with EBV infection. Moreover, patients infected with EBV exhibited a lower level of Ki-67 proliferation. The serum CA199 level was elevated in 10 patients. The median tumor diameter was 2.8 cm (range, 1.1-8.7 cm). Most tumors were well-defined with a smooth or lobulated margin and showed peripheral hyperintensity and central hypointensity on T2-weighted imaging (T2WI). T2 hyperintense foci were recognized in 8 patients. In the dynamic enhanced MRI, 21 tumors demonstrated Type A enhancement pattern (rim enhancement), 10 demonstrated Type B (rapid wash-in and wash-out), and seven demonstrated Type C (rapid wash-in without wash-out). Capsular enhancement in PVP or DP was found in 22 tumors. A few patients had satellite lesions, portal vein thrombosis, bile duct dilatation, and distal metastasis. Lymph node metastases were discovered pathologically in 11 patients. MRI findings of LELCC vary and are non-specific. While a majority of LELCCs exhibit typical features of intrahepatic cholangiocarcinoma (iCCA), unique findings like T2 hyperintense foci or capsular enhancement could suggest LELCC. EBV infection and elevated tumor markers can aid in differentiation. However, given the mimics of some cases of liver hypervascular lesions, histological examination remains essential for definitive diagnosis.

Anatomic versus non-anatomic resection for early-stage intrahepatic cholangiocarcinoma: a propensity score matching and stabilized inverse probability of treatment weighting analysis

BackgroundRadical resection is still the most cost-effectiveness curative strategy for intrahepatic cholangiocarcinoma (ICC), but it remains controversial on the survival benefit of anatomic resection (AR). In this study, we sought to compare the oncologic outcomes between AR versus non-AR (NAR) as the primary treatment for early-stage ICC patients.MethodsData of ICC patients who underwent hepatectomy and staged at AJCC I were retrospectively collected from 12 hepatobiliary centers in China between Dec 2012 and Dec 2015. Propensity score matching (PSM) and stabilized inverse probability of treatment weighting (IPTW) analysis were performed to minimize the effect of potential confounders, and the perioperative and long-term outcomes between AR and NAR groups were compared.ResultsTwo hundred seventy-eight ICC patients staged at AJCC I were eligible for this study, including 126 patients receiving AR and 152 patients receiving NAR. Compared to the NAR group, the AR group experienced more intraoperative blood loss before and after PSM or stabilized IPTW (all P > 0.05); AR group also experienced more intraoperative transfusion after stabilized IPTW (P > 0.05). In terms of disease-free survival (DFS) and overall survival (OS), no significant differences were observed between the two groups before and after PSM or stabilized IPTW (all P > 0.05). Multivariable Cox regression analyses found that AR was not an independent prognostic factor for either DFS or OS (all P > 0.05). Further analysis also showed that the survival benefit of AR was not found in any subgroup stratified by Child–Pugh grade (A or B), cirrhosis (presence or absence), tumor diameter (≤ 5 cm or > 5 cm) and pathological type (mass-forming or non-mass-forming) with all P > 0.05.ConclusionSurgical approach does not influence the prognosis of patients with stage I primary ICC, and NAR might be acceptable and oncological safety.

Abstract 101: Convergent genomic diversity and novel oncogenic metabolism in intrahepatic cholangiocarcinoma

Abstract Background &amp; Aim: Intrahepatic cholangiocarcinoma(ICC) accounts for about 5% of all primary liver cancer and is reported to be common in Southeast Asia and parts of Chile, but in recent years it has been increasing in other areas including Europe and the United States. ICC leads to a dismal outcome as the commonly used chemotherapy exhibit purely palliative effects on ICC, enabling only a limited improvement in survival until today. As ICC harbors few actionable target genes with inter-tumor genomic heterogeneity, ICC is considered to be one of the most intractable malignancies of all. Therefore, we implemented the multi-omics analysis especially with comprehension of the oncogenic metabolic changes to confer new treatment strategies. This study aims to unravel the evolution of ICC and identify ICC-specific metabolic pathways and essential targets for eradicating ICC. Approach: We collected 12 primary ICC cases and 77 specimens and conducted a multi-omics approach, including genomics, transcriptomics, proteomics, and metabolomics for each material. Results: We demonstrated that intra-tumoral heterogeneity of ICCs with distinct driver genes per case indicates a “neutral evolution manner”, regardless of their tumor stage. Upregulation of BCAT1 and BCAT2 might enrich the ‘branched-chain amino acids (BCAA), such as Val, Leu, and Ile degradation pathway’. ICCs cases with the accumulated ubiquitous metabolites, BCAA exhibited poorer prognosis than those cases without BCAA accumulation significantly. Conclusions: Regardless of the inter-tumor heterogeneity in genomic aberrations among ICC cases, we discovered the ubiquitous enrichment of the BCAA metabolic pathway in each tumor. We propose a novel ICC onco-metabolic pathway that could enable the development of new therapeutic interventions. Citation Format: Yusuke Nakano, Akihiro Kitagawa, Masahiro Hashimoto, Tadashi Abe, Yuichi Hisamatsu, Takeo Toshima, Yusuke Yonemura, Takaaki Masuda, Akira Inoue, Hidetoshi Eguchi, Yuichiro Doki, Koshi Mimori. Convergent genomic diversity and novel oncogenic metabolism in intrahepatic cholangiocarcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 101.

Long-term outcomes of anatomic vs. non-anatomic resection in intrahepatic cholangiocarcinoma with hepatolithiasis: A multicenter retrospective study.

The benefits of anatomic resection (AR) vs. non-anatomic resection (NAR) in patients with primary intrahepatic cholangiocarcinoma (ICC) with hepatolithiasis (HICC) are unclear. This study aimed to compare the long-term outcomes of AR vs. NAR in patients with HICC. A total of 147 consecutive patients with HICC who underwent R0 hepatectomy were included. Overall survival (OS) and recurrence-free survival (RFS) following AR vs. NARs were compared using a 1:1 propensity score matching (PSM) analysis. A subgroup analysis was also conducted according to whether there are lymph node metastases (LNM). In a multivariate analysis, CA 19-9 (>39 U/L), microvascular invasion, LNM, and NAR were independent risk factors for poor RFS and OS rates, whereas multiple tumors were independent risk factors for OS. AR had better 1-, 3-, and 5-year RFS and OS rates than NAR (OS: 78.7, 58.9, and 28.5%, respectively, vs. 61.2, 25.4, and 8.8%, respectively; RFS: 59.5, 36.5, and 20.5%, respectively, vs. 38.2, 12.1, and 6.9%, respectively). After PSM, 100 patients were enrolled. The NAR group also had significantly poorer OS and RFS (OS: 0.016; RFS: p = 0.010) than the AR group. The subgroup analysis demonstrated that in HICC without LNM, OS and RFS were significantly poorer in the NAR group than the AR group, while no significant differences were observed in HICC with LNM before or after PSM. Anatomic resection was associated with better long-term survival outcomes than NAR in patients with HICC, except for patients with LNM.

The influence of the extent of lymph node metastasis on the prognosis for patients with intrahepatic cholangiocarcinoma.

Reports showed that some of intrahepatic cholangiocarcinoma (ICC) patients with lymph node metastasis (LNM) may also gain survival benefit undergone resection. However, the effect of the extent of LNM on prognosis and surgical indication is barely discussed. From September 1994 to November 2018, primary ICC patients undergone initial curable surgery were enrolled. Based on the extent of LNM, we divided these patients into 4 groups, including patients with no LNM (group N0), LNM to hepatoduodenal ligament or common hepatic artery (region A, group A), LNM to gastrohepatic lymph nodes for left liver ICC and periduodenal and peripancreatic lymph node for right liver ICC (region B, group B), or LNM beyond these regions (region C, group C). Multivariable Cox regression analysis was performed to identify the prognostic factors for recurrence-free survival (RFS) and overall survival (OS) in all groups. A total of 133 patients were enrolled. There were 56, 21, 17, and 39 patients in groups N0, A, B, and C, respectively. There was significant difference between groups N0 and C in RFS (P < 0.001) and OS (P = 0.002). When we compared group N0 + A + B with group C, we also found that RFS (P < 0.001) and OS (P = 0.007) were significantly different. In multivariable analysis, the extent of LNM was an independent risk factor for RFS (P < 0.050). ICC patients with the LNM to regions A and B could still achieve good prognosis with resection. Surgery should be carefully considered when LNM to region C.

Molecular and radiopathologic spectrum between HCC and intrahepatic cholangiocarcinoma.

Primary liver cancers (LCs), including HCC and intrahepatic cholangiocarcinoma (iCCA), are derived from a common developmental lineage, conferring a molecular spectrum between them. To elucidate the molecular spectrum, we performed an integrative analysis of transcriptome profiles associated with patients' radiopathologic features. We identified four LC subtypes (LC1-LC4) from RNA-sequencing profiles, revealing intermediate subtypes between HCC and iCCA. LC1 is a typical HCC characterized by active bile acid metabolism, telomerase reverse transcriptase promoter mutations, and high uptake of gadoxetic acid in MRI. LC2 is an iCCA-like HCC characterized by expression of the progenitor cell-like trait, tumor protein p53 mutations, and rim arterial-phase hyperenhancement in MRI. LC3 is an HCC-like iCCA, mainly small duct (SD) type, associated with HCC-related etiologic factors. LC4 is further subclassified into LC4-SD and LC4-large duct iCCAs according to the pathological features, which exhibited distinct genetic variations (e.g., KRAS , isocitrate dehydrogenase 1/2 mutation, and FGF receptor 2 fusion), stromal type, and prognostic outcomes. Our integrated view of the molecular spectrum of LCs can identify subtypes associated with transcriptomic, genomic, and radiopathologic features, providing mechanistic insights into heterogeneous LC progression.

Role of arginase 1 immunohistochemical marker in differentiating hepatocellular carcinoma from other primary and secondary carcinomas of the liver, a tissue microarray study

: Hepatocellular carcinoma (HCC) is the most prevalent type of primary cancer of the liver in adults represent about 80%-90% of all liver cancers. It is essential to differentiate primary HCC and intrahepatic cholangiocarcinoma and metastatic carcinoma. Arginase-1 was considered as the most sensitive and specific marker of benign and malignant hepatocyte. This study aimed to detect the diagnostic role of immunohistochemical expression of arginase-1 in differentiating HCC From cholangiocarcinoma and metastatic carcinomas of the liver in comparison with hepatocyte paraffin antigen -1 (HepPar-1) and Glypican 3. : This is a retrospective study was performed on 117 cases, 77 cases were diagnosed as HCC, 13 cases as cholangiocarcinoma and 27 cases as metastatic carcinomas in the liver. Cases obtained from surgical pathology laboratory at Gastroenterology Center, Mansoura University, Egypt during the period from 2014 to 2017. All the studied cases were immunostained with Arginase 1, Heppar 1and Glypican 3.: Arginase 1 was expressed in all 77 HCC cases with sensitivity (100%), while Arginase 1 was expressed only in 1 cholangiocarcinoma case and negative in other metastatic carcinomas with specificity(97.5%), the overall accuracy was (99.1%). On the other side, Glypican 3 was expressed in 36 out of 77 HCC cases with sensitivity (46.8%), while Glypican 3 was expressed in 3 out of 40 cholangiocarcinoma and other metastatic carcinomas with specificity (92.3%), overall accuracy (62.4%). Heppar 1 was expressed in 69 out of 77 HCC cases with sensitivity (89.6%), while Heppar 1 was negative in all cholangiocarcinoma cases and other metastatic carcinomas with specificity (100%). The overall accuracy was 93.2%.: Arginase 1 is the most sensitive and accurate marker in differentiating HCC from non HCC cases in liver, while heppar is most specific and second accurate marker in differentiating HCC from cholangiocarcinoma and metastatic carcinomas in the liver. Arginase-1 and HepPar-1, are the best markers regarding sensitivity and specificity for small liver biopsies.

Anti-tumor effects and mechanism of a novel camptothecin derivative YCJ100

AimsIn this study, we synthesized a 10-fluorine-substitution derivative of CPT (Camptothecin) YCJ100 and evaluated its antitumor activity and systemic toxicity. Materials and methodsDetermination of in vitro antitumor activity and mechanism of YCJ100 by the MTT assay, Molecular docking, EdU staining, Cell cycle and apoptosis determination, Western blot analysis and Topoisomerase I activity assay. The antitumor effects of YCJ100 were evaluated in primary HCC (hepatocellular carcinoma), ICC (intrahepatic cholangiocarcinoma) mouse models, and pancreatic cancer xenograft models. Key findingsYCJ100 showed superior cytotoxic activity compared to Topotecan in SW480, SW1990, Hep3B, HepG2, A549, A2780, HeLa, and QBC cells. YCJ100 blocked the cell cycle in the G2/M phase, inhibited cell proliferation and induced apoptosis in HepG2 and SW1990 cells. Mechanistically, YCJ100 inhibited topoisomerase I activity in both a cell-free system and a cellular system, similar to the mechanism of Topotecan. YCJ100 showed significant antitumor activity and was more potent than Topotecan in primary HCC and ICC mouse models, as well as a xenograft mouse model. Additionally, YCJ100 showed only minor toxicity to the mouse hematopoietic system, liver, and kidney. These findings indicate that YCJ100 has high antitumor activity and low systemic toxicity. SignificanceOur findings demonstrate that YCJ100, as a Topoisomerase I inhibitor, has in vitro and in vitro antitumor activity. This study provides a new lead compound worthy of further preclinical evaluation and potential clinical development.

A phase Ia/Ib, dose-escalation/expansion study of BI 907828 in combination with BI 754091 (ezabenlimab) and BI 754111 in patients (pts) with advanced solid tumors.

3095 Background: Preclinical data show that combining a murine double minute 2–tumor protein 53 (MDM2–p53) antagonist with immune checkpoint inhibitors produces anti-tumor effects in multiple tumor types. This Phase Ia/Ib study (NCT03964233) is assessing BI 907828, a MDM2–p53 antagonist, combined with immune checkpoint inhibitors in TP53 wild-type cancers. Methods: In Phase Ia (dose escalation), pts with advanced/metastatic solid tumors received escalating doses of BI 907828 guided by a Bayesian Logistic Regression Model (starting dose 10 mg orally) plus ezabenlimab 240 mg (anti-PD-1 antibody) and BI 754111 600 mg (anti-LAG-3 antibody) every 21 days (q3w). Primary endpoint was the maximum tolerated dose (MTD) of BI 907828 based on the number of pts with dose-limiting toxicities (DLTs) during cycle one. During Phase Ia, other studies indicated a lack of added efficacy when BI 754111 was combined with ezabenlimab; therefore, the study design was updated to switch the dose escalation to the doublet combination of BI 907828 plus ezabenlimab. Results: A total of 11 pts received the triplet combination at 10/20/30/45 mg dose levels (DL; n = 3/3/3/2 respectively); all have discontinued treatment. No DLTs were reported in cycle one; MTD was not reached. As of 20th January 2022, 15 pts have received the doublet combination at 30/45 mg DLs (n = 10/5 respectively). One pt (45 mg) had a DLT during cycle one: G2 neutropenia. Four DLTs were reported after cycle one: G3 anemia (30 mg); G2 thrombocytopenia (45 mg); and G3 neutropenia and G4 thrombocytopenia (45 mg). G≥3 adverse events occurred in eight pts; most commonly anemia (n = 6), thrombocytopenia (n = 4) and lymphopenia (n = 3). There were no notable safety findings with BI 907828 45 mg q3w, the recommended dose for expansion (RDE) for BI 907828 monotherapy. Nine of the 15 pts who received doublet therapy were evaluable for response; four had a confirmed partial response (PR; 30 mg, n = 1; 45 mg, n = 3), two biliary tract carcinoma, one urothelial carcinoma, and one myxoid liposarcoma; one had an unconfirmed PR (30 mg) with adenocarcinoma (primary site intrahepatic cholangiocarcinoma). Four pts with liposarcoma and gastric cancer had stable disease. MTD will be reported. In Phase Ib, pts will receive the RDE of BI 907828 plus 240 mg ezabenlimab (q3w). Pts will be recruited to two cohorts: soft tissue sarcomas (liposarcoma, undifferentiated pleomorphic sarcoma, myxofibrosarcoma, synovial sarcoma and leiomyosarcoma) and selected MDM2-amplified tumors (NSCLC, gastric adenocarcinoma, urothelial carcinoma, and biliary tract carcinoma). Primary endpoints are progression-free survival and objective response (RECIST 1.1). Conclusions: The doublet combination of BI 907828 plus ezabenlimab showed a manageable safety profile and early signs of anti-tumor activity. Eleven pts remain on treatment; recruitment is ongoing. Clinical trial information: NCT03964233.

Steroidal saponins from Trillium tschonoskii rhizome repress cancer stemness and proliferation of intrahepatic cholangiocarcinoma

A phytochemical study was carried out on the extract of Trillium tschonoskii rhizomes, resulting in the isolation of thirty-six steroidal glycosides (1–36). Their structures were established mainly by spectroscopic analyses as well as necessary chemical evidence, of which 1–25 were identified as new analogues. Herein, all the isolated analogues were screened for the cytotoxicity against intrahepatic cholangiocarcinoma (ICC) cell lines of HuCCT1 and RBE through tumor colony formation and CCK-8 survival analysis, and the results demonstrated that three compounds 9, 12, and 26 significantly repressed tumor colony and sphere formation in both cell lines, respectively. Furthermore, the three analogues possessed a remarkable inhibitory role of organoid formation established from hydrodynamic induced mouse primary intrahepatic cholangiocarcinoma. Moreover, the functional assays of flow cytometry analysis, cancer stemness related gene expression, and western blotting assays all indicated that compound 26 could significantly repress cancer stem markers. Taken together, these results demonstrate that steroidal glycosides derived from T. tschonoskii rhizomes could be potentially implicated in human ICC therapy.

EANM procedure guideline for the treatment of liver cancer and liver metastases with intra-arterial radioactive compounds

Primary liver tumours (i.e. hepatocellular carcinoma (HCC) or intrahepatic cholangiocarcinoma (ICC)) are among the most frequent cancers worldwide. However, only 10–20% of patients are amenable to curative treatment, such as resection or transplant. Liver metastases are most frequently caused by colorectal cancer, which accounts for the second most cancer-related deaths in Europe. In both primary and secondary tumours, radioembolization has been shown to be a safe and effective treatment option. The vast potential of personalized dosimetry has also been shown, resulting in markedly increased response rates and overall survival. In a rapidly evolving therapeutic landscape, the role of radioembolization will be subject to changes. Therefore, the decision for radioembolization should be taken by a multidisciplinary tumour board in accordance with the current clinical guidelines. The purpose of this procedure guideline is to assist the nuclear medicine physician in treating and managing patients undergoing radioembolization treatment.PreambleThe European Association of Nuclear Medicine (EANM) is a professional non-profit medical association that facilitates communication worldwide among individuals pursuing clinical and research excellence in nuclear medicine. The EANM was founded in 1985. These guidelines are intended to assist practitioners in providing appropriate nuclear medicine care for patients. They are notinflexible rules or requirements of practice and are not intended, nor should they be used, to establish a legal standard of care. The ultimate judgment regarding the propriety of any specific procedure or course of action must be made by medical professionals taking into account the unique circumstances of each case. Thus, there is no implication that an approach differing from the guidelines, standing alone, is below the standard of care. To the contrary, a conscientious practitioner may responsibly adopt a course of action different from that set out in the guidelines when, in the reasonable judgment of the practitioner, such course of action is indicated by the condition of the patient, limitations of available resources or advances in knowledge or technology subsequent to publication of the guidelines. The practice of medicine involves not only the science but also the art of dealing with the prevention, diagnosis, alleviation and treatment of disease. The variety and complexity of human conditions make it impossible to always reach the most appropriate diagnosis or topredict with certainty a particular response to treatment. Therefore, it should be recognised that adherence to these guidelines will not ensure an accurate diagnosis or a successful outcome. All that should be expected is that the practitioner will follow a reasonable course of action based on current knowledge, available resources and the needs of the patient to deliver effective and safe medical care. The sole purpose of these guidelines is to assist practitioners in achieving this objective.

Ultrasensitive and affordable assay for early detection of primary liver cancer using plasma cell-free DNA fragmentomics.

Early detection of primary liver cancer (PLC), including HCC, intrahepatic cholangiocarcinoma (ICC), and combined HCC-ICC (cHCC-ICC), is essential for patients' survival. This study aims to develop an accurate and affordable method for PLC early detection and differentiating ICC from HCC using plasma cell-free DNA (cfDNA) fragmentomic profiles. Whole-genome sequencings (WGS) were performed using plasma cfDNA samples from 192 patients with PLC (159 HCC, 26 ICC, 7 cHCC-ICC) and 170 noncancer controls (including 53 liver cirrhosis [LC] or HBV-positive) enrolled in the training cohort. An ensembled stacked model for PLC detection was constructed using the training cohort. The model performance was assessed in an independent test cohort (189 patients with PLC [157 HCC, 26 ICC, 6 cHCC-ICC], 164 noncancer controls [including 51 LC/HBV]). Our model showed excellent performance for cancer detection in the test cohort (AUC: 0.995, 96.8% sensitivity at 98.8% specificity). It showed excellent sensitivities in detecting early-stage PLC (I: 95.9%, II: 97.9%), small tumors (≤3 cm: 98.2%), and HCC (96.2%) or ICC (100%). The AUC for distinguishing PLC from LC/HBV reached 0.985 (96.8% specificity at 96.1% specificity). Promisingly, our model maintained consistent performances during the downsampling process, even using 1X coverage data (AUC: 0.994, 93.7% sensitivity at 98.8% specificity). A separate model showed potential for distinguishing ICC from HCC (AUC: 0.776). Our model, outperforming previous reports at a lower cost by solely using low-coverage WGS data, exhibits excellent clinical potential for ultrasensitive and affordable detection of PLC and its subtypes.

A blood-based noninvasive miRNA signature for predicting survival outcomes in patients with intrahepatic cholangiocarcinoma.

The prognosis in patients with intrahepatic cholangiocarcinoma (ICC) is generally poor. To improve treatment selection, we sought to identify microRNA (miRNA) signature associated with survival outcomes in ICC. We first analysed the miRNA expression profiles of primary ICC from two public datasets to identify a miRNA panel to detect patients for short-term survival. We then analysed 309 specimens, including 241 FFPE samples from two clinical cohorts (training: n = 177; validation: n = 64) and matched plasma samples (n = 68), and developed a risk-stratification model incorporating the panel and CA 19-9 levels to predict survival outcomes in ICC. We identified a 7-miRNA panel that robustly classified patients with poor outcomes in the discovery cohorts (AUC = 0.80 and 0.88, respectively). We subsequently trained this miRNA panel in a clinical cohort (AUC = 0.83) and evaluated its performance in an independent validation cohort (AUC = 0.82) and plasma samples from the additional validation cohort (AUC = 0.78). Patients in both clinical cohorts who were classified as high-risk had significantly worse prognosis (p < 0.01). The risk-stratification model demonstrated superior performance compared to models (AUC = 0.85). We established a novel miRNA signature that could robustly predict survival outcomes in resected tissues and liquid biopsies to improve the clinical management of patients with ICC.

Loss of FBP1 by aPKC-ι/Snail Pathway-Mediated Repression Promotes Invasion and Aerobic Glycolysis of Intrahepatic Cholangiocarcinoma

Intrahepatic cholangiocarcinoma (ICC) is one of the most commonly diagnosed malignancies worldwide, and the second most common primary liver tumor. The lack of effective diagnostic and treatment methods results in poor patient prognosis and high mortality rate. Atypical protein kinase C-ι (aPKC-ι) is highly expressed in primary and metastatic ICC tissues, and regulates epithelial mesenchymal transition (EMT) through the aPKC-ι/P-Sp1/Snail signaling pathway. Recent studies have correlated aberrant glucose metabolism with EMT. Given the vital role of FBP1 in regulating glucose metabolism in cancer cells, we hypothesized that aPKC-ι downregulates FBP1 in ICC cells through the Snai1 pathway, and enhances glycolysis and metastasis. We confirmed the ability of aPKC-ι promotes glycolysis, invasion and metastasis of cancer cells, and further demonstrated that FBP1 inhibits the malignant properties of ICC cells by antagonizing aPKC-ι. Our findings provide novel insights into the molecular mechanisms of ICC progression and metastasis, as well as a theoretical basis for exploring new treatment strategies.