Extrahepatic Lesions Research Articles

Advanced ultrasound diagnosis of extrahepatic bile duct lesions.

Ultrasound (US) has high specificity and sensitivity, and it should be performed first for patients with suspicion of biliary tract cancer. However, the complicated anatomy in addition to the gas images makes it difficult to delineate the entire extrahepatic bile duct (EHBD). The keys to depiction of EHBD are the "J" shape manipulation in the left lateral decubitus position and the use of magnified images with high-frequency transducers. Furthermore, indirect findings such as gallbladder (GB) distension, BD dilatation, and debris echo in the GB and BD are also important for detecting occult lesions, particularly in the ampullary region of Vater. For the differential diagnosis of BD wall thickening, the spreading pattern in the long and short axial directions should be assessed first. Then, the characteristics of the innermost hyperechoic layer (IHL) and outermost hyperechoic layer (OHL) should be evaluated. Asymmetrical wall thickening, absence of IHL, and presence of irregularity or discontinuity in OHL are characteristic patterns of cholangiocarcinoma (CCA). Because CCA is the most common BD polypoid lesion, it is important to diagnose tumor extension and depth invasion in addition to differential diagnosis. Nodular-type CCA is usually hypoechoic and more likely to invade vertically. In contrast, papillary-type CCA is often hyperechoic and extends laterally. Contrast‑enhanced US may be useful for evaluating these findings. However, if the possibility of CCA cannot be ruled out or a definitive diagnosis is needed, a transpapillary biopsy or endoscopic US-guided tissue acquisition should be considered.

Impact of Metastatic Pattern on Survival in Patients with Posterior Uveal Melanoma: A Retrospective Cohort Study.

Background/Objectives: Metastatic posterior uveal melanoma (PUM) is one of the deadliest types of melanomas. Though the median survival is short, some patients with metastatic disease live for a long time. In this study, we investigated whether the anatomical location of the metastatic lesions is associated with differences in survival. Methods: One hundred and seventy-eight patients with metastatic PUM with baseline whole-body imaging were retrospectively included. The patients were divided into three groups based on the anatomical location of metastases: (1) exclusive liver metastases (hepatic pattern), (2) both hepatic and extrahepatic metastatic lesions (hepatic-extrahepatic pattern), and (3) exclusive extrahepatic lesions (extrahepatic pattern). Survival was investigated using Kaplan-Meier plots, log-rank test, and the Cox proportional hazard model. Results: In total, 95 patients (53%) presented with hepatic pattern, 66 patients (37%) presented with hepatic-extrahepatic pattern, and 17 patients (10%) presented with extrahepatic pattern. Overall survival was significantly longer in patients with extrahepatic pattern (median 17.0 months) compared to those with hepatic pattern (median 11.0 months) and hepatic-extrahepatic pattern (median 7.0 months) (p < 0.001, log-rank test). Multivariate Cox regression analysis showed increased hazard ratios (HR) for hepatic pattern (HR 2.37, 95% CI 1.08-5.17, p = 0.031) and hepatic-extrahepatic pattern (3.25, 95% CI 1.42-7.41, p = 0.005) compared to extrahepatic pattern. Most patients with hepatic (95%) and hepatic-extrahepatic patterns (82%) were diagnosed with metastases by liver ultrasonography screening, whereas 81% of patients with extrahepatic pattern developed symptoms that led to the diagnosis. Conclusions: Extrahepatic pattern was associated with prolonged survival in patients with metastatic PUM, despite there being a larger proportion of symptomatic patients. It is therefore important to consider the anatomical location of the metastatic lesions when stratifying patients into clinical trials.

Spectra of well-differentiated neuroendocrine lesions in the extrahepatic biliary system: a case series.

Neuroendocrine tumours (NETs) occurring in the extrahepatic biliary system are exceedingly rare. While NETs typically manifest as mass lesions, the occurrence of microscopic neuroendocrine cell proliferation without a distinct mass remains undocumented at this location. This study aims to characterise the clinicopathological features of a series of well-differentiated neuroendocrine lesions involving the extrahepatic biliary tree, including mass forming NETs and microscopic non-mass-forming neuroendocrine cell proliferation, designated neuroendocrine cell micronests (NCMs). Surgical resections of NETs/NCMs involving the extrahepatic bile ducts and gallbladder were identified from electronic pathology databases among seven institutions spanning from January 2011 to September 2023. Clinical and histological findings were recorded. Ten patients (four female, six male: age range = 34-75 years) were included in the study. Histopathological examination revealed visible mass-forming lesions in four cases (1.6-14.0 cm in size), identified in the gallbladder (n = two) or extrahepatic bile duct (n = two), all diagnosed as well-differentiated NETs. The remaining six cases revealed incidental non-mass-forming NCMs in either the cystic duct (n = two), common bile duct (n = three) or gallbladder (n = one), ranging from < 0.1 to 0.4 cm; four were associated with biliary lithiasis. No evidence of metastasis or recurrence was seen in the follow-up period (range = 0.1-11.2 years). This study highlights the spectrum of extrahepatic biliary well-differentiated neuroendocrine lesions, ranging from incidental microscopic NCMs to grossly apparent mass-forming NETs, potentially requiring different clinical management. Noteworthy is the frequent association of incidental microscopic neuroendocrine cell proliferations with biliary lithiasis, indicating a potential neuroendocrine metaplastic pathogenesis that merits further exploration.

Diagnosis of isolated hilar-/extrahepatic-type IgG-4-related sclerosing cholangitis can be increased by improved recognition of this condition-A Japanese multicenter analysis.

Patients with isolated IgG4-related sclerosing cholangitis (IgG4-SC) often undergo unnecessary resection. The aim of this study was to validate the revised Japanese diagnostic criteria for isolated IgG-4-SC and to improve awareness about this condition in the population. This was a Japanese retrospective multicenter study. We focused on the data and diagnostic yield obtained using the Japanese diagnostic criteria published initially in 2012 and revised later in 2020 for the diagnosis of isolated IgG4-SC. Patients with isolated IgG4-SC could be classified into two groups based on the primary location of the lesion: the hilar type (n = 40) and the extrahepatic type (n = 13). In total, 10 patients with the hilar type had undergone unnecessary resection. The revised 2020 criteria are useful for the diagnosis of extrahepatic lesions, which are not included in the 2012 criteria. The need for a steroid trial was reduced from 37.7% when the diagnosis was based on the 2012 criteria to 7.6% when the diagnosis was based on the revised 2020 criteria. The diagnostic specificity also improved from 58.5% for the 2012 criteria to 88.7% for the revised 2020 criteria. Our validation of the 2020 criteria for the diagnosis of IgG4-SC could contribute to avoiding unnecessary resection in patients with isolated IgG4-SC, which can be classified into the hilar and extrahepatic types. The 2020 criteria can enhance the diagnosis rate of isolated IgG4-SC and uncover this tough-to-diagnose entity based on inclusion of the imaging findings and decrease the dependence on a steroid trial.

Character and Frequency of the Syntropic Extrahepatic Lesions in Cirrhotic Patients with Hepatopulmonary Syndrome of Various Severity Degree

Introduction. All over the world, and in Ukraine in particular, the incidence of liver diseases is constantly increasing. By practicing the most effective individualized appointment of complex treatment, it should be taken into consideration the involvement of different organ systems to the pathological processes of the cirrhotic patients, which we define as syntropic polymorbid lesions. The aim of the study. To determine the frequency and character of syntropic extrahepatic lesions in cirrhotic patients depending on the hepatopulmonary syndrome severity degree. Materials and methods. In a randomized manner with preliminary stratification by the presence of hepatopulmonary syndrome were studied 93 patients with liver cirrhosis, who underwent the comprehensive clinical-laboratory and instrumental examination. Results. According to the obtained results, most often in patients with liver cirrhosis associated with hepatopulmonary syndrome syntropic extrahepatic lesions affected other organ systems as follows: digestive system - 100.0 % patients under investigation; hematopoietic system - 84.9 %; nervous system - 81.7 %; integumentary system and mucous membranes - 78.5 %; blood circulatory system - 76. 3%;osteoarticular system - 67.7 %; urinary system - 22.6 %. Increased severity of hepatopulmonary syndrome significantly (p &lt; 0.05) correlated with thein creased frequency of lesions. Among syntropic polymorbid lesions of the integumentary system and mucous membranes, 68.8 % patients with hepatopulmonary syndrome had jaundice, 66.7 % - telangiectasia. Among lesions of the osteoarticular system osteopenia was diagnosed in 44.7 % of patients, osteoporosis - in 27.7 %. Among lesions of the circulatory system 52.7% of patients suffered from heart rhythm disorders, 49.5 % - from arterial hypotension, 20.4 % - from cirrhotic cardiomyopathy. Among lesions of the hematopoietic system anemia (76.3 %), coagulopathy (73.1 %) and thrombocytopenia (61.3 %) were diagnosed most often. Digestive system lesionsinclude esophageal veins varicosities (94.6 % of patients), hemorrhoidal veins varicosites (68.8 %), and cirrhotic gastropathy (62.4 %). Among lesions of the urinary systemin 21.5 % of patientswas diagnosed type II hepatorenal syndrome. Among the lesions of central nervous system in 81.7 % of patientswas diagnosed hepatic encephalopathy. The frequency of syndromes and nosological units increased significantly (p &lt; 0.05) with the increase of hepatopulmonary syndrome severity. Conclusions. 100.0 % patients with liver cirrhosis accompanied byhepatopulmonary syndromewere affected by syntropic polymorbid lesionsof the digestive system, 94.6 % of which were represented by esophageal vein varicosites. Out of 84.9 % of patients with hematopoietic lesions anemia was diagnosed in 76.3 %, coagulopathy - in 73.1 % of cases. Of total 81.7 % patients withnervous system injurieshepatic encephalopathy was diagnosed in 81.7 % patients. In 78.5 % cases of damaged skin, its appendages and mucous membranesjaundice covered 68.8 %, and telangiectasia 66.7 % of cases. In 76.3 % of cardiovascular system lesions arrhythmias were diagnosed in 52.7 %.With the increasing severity of hepatopulmonary syndrome, the frequency of the above lesions increased significantly (p &lt; 0.05).

Progression pattern and post-progression survival following atezolizumab and bevacizumab treatment in advanced hepatocellular carcinoma.

Although the combination of atezolizumab and bevacizumab (ATZ + BEV) is a standard treatment for advanced hepatocellular carcinoma (HCC), strategies for addressing treatment failure and prognostic factors of post-progression survival (PPS) remain unestablished. We conducted a multicentre retrospective study to evaluate PPS following ATZ + BEV treatment in patients with advanced HCC. We classified the patients into three groups: BCLC stage B and BCLC stage C without or with new extrahepatic lesions (BCLCp-C1 and BCLCp-C2, respectively) at the time of progression. Of the 204 patients who started ATZ + BEV treatment between October 2020 and September 2022, 110 showed disease progression, with 33, 55 and 22 showing the BCLCp-B, BCLCp-C1 and BCLCp-C2 stages of the disease, respectively. Specifically, patients with the BCLCp-B stage of the disease showed better overall survival than those with the BCLCp-C1 and BCLCp-C2 stages (hazard ratios: 1.93 [95% confidence interval, CI, 1.06-3.51] and 2.64 [95% CI, 1.32-5.30] for HCC stages BCLCp-C1 and BCLCp-C2, respectively). Via multivariable analysis, we identified the BCLCp-C1 and BCLCp-C2 stages, as well as performance status, Child-Pugh class and alpha-fetoprotein as poor prognostic factors for PPS. BCLCp-B1 stage was identified as a better prognostic factor for PPS following ATZ + BEV treatment compared with BCLCp-C1 and BCLCp-C2 stages. This may help in making decisions regarding subsequent treatment after ATZ + BEV.

PERIO-02: Phase 1b pressure enabled regional immuno-oncology trial of nelitolimod (SD-101), a class C TLR9 agonist, delivered via hepatic artery infusion +/- checkpoint inhibition in intrahepatic cholangiocarcinoma and hepatocellular carcinoma.

2622 Background: Immunotherapy (ICI) has shown limited survival benefit in patients (pts) with advanced HCC and intrahepatic cholangiocarcinoma (ICC). Nelitolimod (SD-101), a Class C toll-like receptor-9 (TLR-9 agonist), depletes MDSCs while broadly stimulating the tumor microenvironment. Given safety challenges with IV infusion and distribution limitations of needle injection, we studied hepatic arterial infusion (HAI) of nelitolimod with Pressure-Enabled Drug Delivery (PEDD) to enhance ICI responsiveness. Methods: Pts with advanced HCC or ICC were enrolled. Nelitolimod was dose-escalated without ICI (Cohort A), with pembrolizumab (Cohort B), or with nivolumab + ipilimumab (Cohort C). Nelitolimod administered with HAI for 2 cycles, with 3 weekly doses per cycle using the TriNav device. Primary endpoints included safety and optimal dose determination. Immune cells were examined in blood and tumor tissue using multiplex IF, flow cytometry, and Nanostring. Results: At data cutoff, 29 pts [70% ICC, 30% HCC] were enrolled, 23 received at least one dose of nelitolimod: 3 in Cohort A (4 mg), 8 in Cohort B (2 and 4 mg) and 12 in Cohort C (2 and 4 mg). Median age was 64.5. Only 1 pt was treatment-naïve; 4, 2L (17%); 5, 3L (22%); 14, &gt; 4L (61%). 26% pts had &gt; 10 liver tumors. 3 pts (13%) experienced serious treatment-related adverse events (AE); 1 pt dose-limiting toxicity. Five pts experienced LFT elevations, most G1 with 2 reported as G3. In cohort A, 1 of 3 evaluable pts had SD as best on-treatment response. In cohort B, 1 of 4 evaluable pts had SD as best on-treatment response, others experienced PD by RECIST 1.1. In cohort C 2 mg, 2 of 5 had SD reported at Day 53. At 4 mg dose in cohort C, 3 of 3 pts had disease control, with one CR in the liver (5L ICC) and 2 SD. Decreases were noted in the target liver lesion (31.3 to 17.5 mm), non-target liver lesion, and extra-hepatic lymph nodes on days 53 and 84 with complete response of target liver lesions and stability of extra hepatic nodal lesions reported on Day 154. Median PFS in the Cohort C 4 mg dose level is &gt;120 days. Median OS for this group has not reached (range 120-170 days). Immune effects in cohort C 4 mg pts included increases in liver tumor CD4+ and CD8+ T cells, along with a decrease in the MDSC:CD8+ T cell ratio. Gene expression changes in cohort C 4 mg pts revealed increased Th1 programming in tumor tissue, with increased interferon, cytokine, TLR, Th1, and lymphocyte activation signals in surrounding normal liver. Changes among blood immune cells included increased IFNg and IL2-R expression, with decreased IL17A and VEGFA. Conclusions: HAI of nelitolimod has been well tolerated and associated with encouraging immunologic activity in HCC and ICC. Clinical and biologic activity in cohort C at 4mg is supportive of further enrollment in this cohort. Clinical trial information: NCT05220722 .

Stereotactic body radiation therapy combined with atezolizumab and bevacizumab for hepatocellular carcinoma with extrahepatic metastasis: Preliminary result of a single-arm study.

e16205 Background: IMbrave150 study confirmed the clinical benefit of atezolizumab and bevacizumab in patients with advanced hepatocellular carcinoma (HCC). However, patients with extrahepatic metastasis (EHS) had a poorer prognosis. Studies suggested “abscopal effect” of synchronous radiotherapy and immunotherapy may improve antitumor activity. This study aimed to evaluate efficacy and safety of stereotactic body radiation therapy (SBRT) combined with atezolizumab and bevacizumab in HCC patients with EHS. Methods: This single-arm study included HCC patients with EHS from January 2022 to November 2023 in Fudan University Shanghai Cancer Center. Prior tyrosine kinase inhibitor and/or immune checkpoint inhibitor treatment were eligible. After first dose atezolizumab and bevacizumab, SBRT was performed with a total dose of 25-50 Gy. The primary endpoint was objective response rate (ORR). The secondary endpoints included overall survival (OS), disease control rate (DCR), progression-free survival (PFS), time to progression (TTP), and duration of response (DOR). Results: Thirty-nine patients were included. Fourteen patients were treated as first-line therapy and 25 patients were treated as later-line therapy. The mean age was 56.69±11.21 years and 89.7% were male. Of these patients, 66.7% had hepatitis viral infection and 25.6% had vascular invasion. 53.8% of patients had ≥2 extrahepatic spread lesions. In addition, 33.3% of patients had received prior immunotherapy and 23.1% of patients had received tyrosine kinase inhibitor therapy. The median follow-up was 6.50 (range: 1.43-22.17) months. The ORR and DCR were 43.6% and 92.3%, respectively. The ORR was 57.1% and 36.0% in first-line subgroup and later-line subgroup, respectively. The 12-month OS rates was 54.7%. The median PFS, median TTP and median DOR were 6.73 months, 8.67 months, and 7.17 months, respectively. The incidence of all grade TRAE and grade ≥3 TRAE were 38.5% and 12.8%, respectively. The most common grade ≥3 TRAEs were decreased platelet count (7.7%), decreased white blood cell count (2.6%), pruritus (2.6%) and rectal bleeding (2.6%). No serious adverse events occurred. Conclusions: SBRT combined with systemic atezolizumab and bevacizumab showed encouraging efficacy with manageable safety profile for HCC patients with EHS regardless of prior treatment. Further studies are warranted. Clinical trial information: NCT05396937 . [Table: see text]

PD-1 inhibitor combined with ablation in liver metastasis: A retrospective, multicenter study.

e14644 Background: This study aimed to retrospectively evaluate the efficacy of ablation combined with programmed cell death protein 1 (PD-1) inhibitor versus PD-1 inhibitor monotherapy in patients with liver metastasis. Methods: We retrospectively enrolled patients with liver metastasis who received PD-1 inhibitor therapy with or without ablation at three medical institutions between January 2017 and September 2022. Progression-free survival (PFS) and 1-year survival rates were compared after propensity score matching. Additionally, intrahepatic and extrahepatic lesion progression and treatment-related adverse events were recorded during follow-up. Finally, prognostic factors for the combined therapy group were analyzed. Results: We included 172 patients and classified them into the combined therapy and PD-1 inhibitor monotherapy (n = 86 each) groups. Patients in the combined therapy group had better median PFS and 1-year survival rates than those in the PD-1 inhibitor monotherapy group. Combined therapy was an independent prognostic factor for PFS in the univariate and multivariate analyses. New lesions constituted the main pattern of progression, with combined therapy showing significantly lower intrahepatic progression, but similar extrahepatic progression rates. Adverse events associated with PD-1 inhibitors were comparable between the two groups. Additionally, 8 (9.3%) patients experienced ablation-related complications. However, neither univariate, nor multivariate analyses revealed the predictive factors for PFS in the combined therapy group. Conclusions: Ablation combined with a PD-1 inhibitor was superior to PD-1 inhibitor monotherapy in improving the survival of patients with liver metastasis.

Endoscopic Ultrasound-Guided Tissue Sampling for the Cytohistological Diagnosis of Focal Liver Lesions.

Focal liver lesions (FLL) often require cytohistological evaluation. Endoscopic Ultrasound (EUS)-guided tissue acquisition (EUS-TA) is highly accurate in diagnosing pancreatic and gastrointestinal malignancies. The aim of our study was to evaluate the role of EUS-TA in the characterization of FLL. A retrospective analysis of a prospective database of patients who underwent EUS-TA for the evaluation of FLL. Diagnostic yield, adverse events and factors associated with diagnostic yield were evaluated as endpoints. The effect of variables such as needle size, lesion size, rapid on-site evaluation (ROSE) and the use of cytological or histological needles were analyzed. A total of 114 cases were included (mean age 68.05 ± 11.35 years, 64 male). A correct diagnosis was made using EUS-TA in 100 of the 114 cases (diagnostic yield of 88%). The EUS-TA of additional extrahepatic lesions during the same EUS procedure increased the diagnostic yield to 94%. No adverse events were reported. Multivariate analysis did not identify any factor influencing the diagnostic yield. EUS-TA is a highly accurate and safe technique for the differential diagnosis of FLL and could be considered as the primary approach in this setting.

Tumor burden affects the progression pattern on the prognosis in patients treated with sorafenib.

The study aims to analyze the impact of different progression patterns and tumor burden size on survival of HCC patients, as well as their interactions, through a retrospective cohort study. The study involved 538 patients who had undergone treatment with sorafenib and had shown radiographic progression. The progression pattern was analyzed using Cox regression by including an interaction term between progression pattern and tumor burden, which was then visualized through a graphical analysis. Tumor burden was categorized into low, medium, and high subgroups based on the six-and-twelve criteria, allowing for an exploration of the effect of progression pattern on survival in different tumor burden situations. Compared to patients with only intrahepatic progression (NIH/IHG) with an overall survival (OS) of 14.1/19.9 months and post-progression survival (PPS) of 8.1/13.1 months respectively, patients with extrahepatic lesions (NEH/EHG) had worse overall and postprogressive survival (OS: 9.3/9.2 months, PPS: 4.9/5.1 months). The hazard ratio for extrahepatic progression (NEH/EHG) compared to intrahepatic progression (NIH/IHG) at low, medium, and high tumor burden were [HR 2.729, 95%CI 1.189-6.263], [HR 1.755, 95%CI 1.269-2.427], and [HR 1.117, 95%CI 0.832-1.499], respectively. The study concluded that the interaction between the tumor progression patterns and tumor burden significantly affects the prognosis of HCC patients. As the tumor burden increases, the sensitivity of the patient's risk of death to the progression pattern decreases. These findings are valuable in personalized treatment and trial design.

Organ-specific responses to atezolizumab plus bevacizumab in advanced hepatocellular carcinoma: A multicentre, retrospective study.

Anti-programmed death 1 (PD-1) monotherapy triggers various responses by each organ. In advanced hepatocellular carcinoma (HCC), while extrahepatic lesions demonstrate objective response rates (ORR) of 20%-40%, only 10% of intrahepatic lesions respond. Although first-line atezolizumab/bevacizumab has shown survival benefits in advanced HCC, organ-specific responses remain unexplored. Therefore, we aimed to assess organ-specific responses in patients with advanced HCC receiving atezolizumab/bevacizumab. This retrospective, multicenter, observational study included patients who received first-line atezolizumab/bevacizumab for advanced HCC. Patients with Child-Pugh class A, measurable tumour lesions and serial imaging available for response evaluation were eligible. Between May 2020 and June 2021, 131 patients (median age: 62) from three cancer referral institutions were included. Ninety-one had hepatitis B (69.5%), 108 were at Barcelona clinic liver cancer stage C (82.4%), and 78 had extrahepatic metastasis (59.5%). After a median follow-up of 10.1 months, median progression-free survival was 6.8 months (95% confidence interval [CI], 4.6-9.2), median overall survival remained unreached (95% CI, range unavailable) and the ORR was 29.0%. Among 270 individual tumour lesions, the liver was the most commonly involved organ (n = 158). Atezolizumab/bevacizumab induced ORR of 27.8%, 42.2%, 29.1% and 21.0% for liver, lymph nodes, lungs and other sites, respectively. The organ-specific response rate for intrahepatic tumours decreased with increasing size (35.6%: <5 cm, 15.0%: ≥ 5 cm). Unlike anti-PD-1 monotherapy, atezolizumab/bevacizumab demonstrated favourable responses in intrahepatic lesions, comparable to those in extrahepatic lesions, and may potentially overcome the immune-tolerant hepatic microenvironment in patients with advanced HCC.

PTEN deficiency induces an extrahepatic cholangitis-cholangiocarcinoma continuum via aurora kinase A in mice

The PTEN-AKT pathway is frequently altered in extrahepatic cholangiocarcinoma (eCCA). We aimed to evaluate the role of PTEN in the pathogenesis of eCCA and identify novel therapeutic targets for this disease. The Pten gene was genetically deleted using the Cre-loxp system in biliary epithelial cells. The pathologies were evaluated both macroscopically and histologically. The characteristics were further analyzed by immunohistochemistry, reverse-transcription PCR, cell culture, and RNA sequencing. Some features were compared to those in human eCCA samples. Further mechanistic studies utilized the conditional knockout of Trp53 and Aurora kinase A (Aurka) genes. We also tested the effectiveness of an Aurka inhibitor. We observed that genetic deletion of the Pten gene in the extrahepatic biliary epithelium and peri-ductal glands initiated sclerosing cholangitis-like lesions in mice, resulting in enlarged and distorted extrahepatic bile ducts in mice as early as 1 month after birth. Histologically, these lesions exhibited increased epithelial proliferation, inflammatory cell infiltration, and fibrosis. With aging, the lesions progressed from low-grade dysplasia to invasive carcinoma. Trp53 inactivation further accelerated disease progression, potentially by downregulating senescence. Further mechanistic studies showed that both human and mouse eCCA showed high expression of AURKA. Notably, the genetic deletion of Aurka completely eliminated Pten deficiency-induced extrahepatic bile duct lesions. Furthermore, pharmacological inhibition of Aurka alleviated disease progression. Pten deficiency in extrahepatic cholangiocytes and peribiliary glands led to a cholangitis-to-cholangiocarcinoma continuum that was dependent on Aurka. These findings offer new insights into preventive and therapeutic interventions for extrahepatic CCA. The aberrant PTEN-PI3K-AKT signaling pathway is commonly observed in human extrahepatic cholangiocarcinoma (eCCA), a disease with a poor prognosis. In our study, we developed a mouse model mimicking cholangitis to eCCA progression by conditionally deleting the Pten gene via Pdx1-Cre in epithelial cells and peribiliary glands of the extrahepatic biliary duct. The conditional Pten deletion in these cells led to cholangitis, which gradually advanced to dysplasia, ultimately resulting in eCCA. The loss of Pten heightened Akt signaling, cell proliferation, inflammation, fibrosis, DNA damage, epigenetic signaling, epithelial-mesenchymal transition, cell dysplasia, and cellular senescence. Genetic deletion or pharmacological inhibition of Aurka successfully halted disease progression. This model will be valuable for testing novel therapies and unraveling the mechanisms of eCCA tumorigenesis.

Progression pattern and post-progression survival following atezolizumab and bevacizumab treatment in advanced hepatocellular carcinoma.

539 Background: Although the combination of atezolizumab and bevacizumab (ATZ + BEV) is a standard treatment for advanced hepatocellular carcinoma (HCC), strategies for addressing treatment failure and prognostic factors of post-progression survival remain unestablished. Methods: We conducted a multicenter retrospective study to evaluate post-progression survival following ATZ + BEV treatment in patients with advanced HCC. We classified the patients into four groups: BCLC stage B with or without new intrahepatic lesions (BCLCp-B1 and BCLCp-B2, respectively) and BCLC stage C without or with new extrahepatic lesions (BCLCp-C1 and BCLCp-C2, respectively) at the time of progression. Results: Of the 204 patients who started ATZ + BEV treatment between October 2020 and September 2022, 110 showed disease progression, with 25, 8, 55, and 22 showing the BCLCp-B1, BCLCp-B2, BCLCp-C1, and BCLCp-C2 stages of the disease, respectively. Specifically, patients with the BCLCp-B1 stage of the disease showed better overall survival than those with the BCLCp-B2, BCLCp-C1, and BCLCp-C2 stages (hazard ratios: 2.19 (95% confidence interval [CI], 0.61–7.86), 2.16 (95% CI, 1.13–4.11), and 2.97 (95% CI, 1.42–6.23) for HCC stages BCLCp-B2, BCLCp-C1, and BCLCp-C2, respectively). Via multivariable analysis, we identified the BCLCp-C1 and BCLCp-C2 stages, as well as performance status, Child-Pugh class, and alpha-fetoprotein as poor prognostic factors for post-progression survival. Conclusions: BCLCp-B1 stage was identified as a better prognostic factor for post-progression survival following ATZ + BEV treatment compared with BCLCp-B2 stage as well as BCLCp-C1 and BCLCp-C2 stages. This may help in making decisions regarding subsequent treatment after ATZ + BEV.

Organ-specific response with first-line atezolizumab-bevacizumab versus lenvatinib for patients with advanced hepatocellular carcinoma.

467 Background: Hepatocellular carcinoma (HCC) is the fifth most common cancer and the second leading cause of cancer-related death worldwide. Immune checkpoint inhibitor (ICI)-based treatments have become the mainstay of first-line treatment for unresectable HCC, but there has been a concern that intrahepatic HCC lesions may be less responsive to ICI monotherapy. Methods: This retrospective study included 386 patients with Child-Pugh A unresectable HCC who were treated with first-line atezolizumab-bevacizumab (n = 217) or lenvatinib (n = 169). The organ-specific response was separately evaluated according to the site of the lesions: liver, lung, lymph node (LN), and intra-abdomen based on a radiological evaluation adopted from RECIST v 1.1. Up to 2 lesions were chosen as target lesions in each organ for the organ-specific response evaluation. Results: The median age was 60 years. The majority of study patients were male in both groups (83.4% and 85.8% in the atezolizumab-bevacizumab and lenvatinib groups, respectively). The etiology of HCC was similar between the two groups: hepatitis B virus infection was the most common etiology in both groups (73.3% and 65.7% in the atezolizumab-bevacizumab and lenvatinib groups, respectively), while 21.2% and 29.0% of patients had non-viral HCC, respectively. Extrahepatic spread was identified in 76.0% and 74.6% of patients in the atezolizumab-bevacizumab and lenvatinib groups, respectively: lung, LN, and intra-abdominal metastases were present in 39.6% vs. 39.1%, 30.0% vs. 33.1% and 16.6% vs. 15.4% of patients, respectively. The proportion of patients achieving a ≥ 30% reduction in the tumor burden for each organ category was higher overall in the atezolizumab-bevacizumab group than in the lenvatinib group: 20.2% vs. 11.8%, 23.0% vs. 12.2%, 27.9% vs. 17.9%, and 33.3% vs. 15.0% for intrahepatic, lung, LN and intra-abdominal lesions, respectively. The corresponding values for the subgroup with a viral etiology were 17.3% vs. 8.1%, 18.8% vs. 13.3%, 28.9% vs. 3.6% and 36.0% vs. 12.5%, respectively. Among patients with a non-viral etiology, atezolizumab-bevacizumab was not clearly associated with a better organ-specific response for the LN and intra-abdominal lesions: 20.0% vs. 54.5% and 20.0% vs. 25.0%, respectively, for a ≥ 30% reduction in the tumor burden. Conclusions: Compared to lenvatinib, atezolizumab-bevacizumab was associated with a favorable organ-specific response regardless of the site of the tumor lesions. Unlike anti-PD-1 monotherapy, atezolizumab-bevacizumab had a comparable organ-specific response between intrahepatic and extrahepatic lesions, especially for those with viral etiology HCCs.

Organ-specific response with first-line atezolizumab-bevacizumab versus lenvatinib for patients with advanced hepatocellular carcinoma.

Immune checkpoint inhibitor (ICI)-based treatments have become the mainstay of first-line treatment for unresectable hepatocellular carcinoma (HCC), but there has been a concern that intrahepatic HCC lesions may be less responsive to ICI monotherapy. We aimed to investigate the organ-specific response patterns among unresectable HCC patients treated with first-line atezolizumab-bevacizumab or lenvatinib. This retrospective study included 386 patients with Child-Pugh A unresectable HCC who were treated with first-line atezolizumab-bevacizumab (n = 217) or lenvatinib (n = 169). The organ-specific response was separately evaluated according to the site of the lesions: liver, lung, lymph node (LN), and intraabdomen based on a radiological evaluation adopted from RECIST v 1.1. The median age was 60years. Hepatitis B infection was the most common etiology (n = 270, 69.9%), and 291 (75.4%) patients had a viral etiology. The proportion of patients achieving a ≥ 30% reduction in the tumor burden for each organ category was overall higher in the atezolizumab-bevacizumab group than that in the lenvatinib group: 20.2% vs. 11.8%, 23.0% vs. 12.2%, 27.9% vs. 17.9% and 33.3% vs. 15.0% for intrahepatic, lung, LN, and intraabdominal lesions, respectively. The corresponding values for the subgroup with a viral etiology were 17.3% vs. 8.1%, 18.8% vs. 13.3%, 28.9% vs. 3.6%, and 36.0% vs. 12.5%, respectively. Compared to lenvatinib, atezolizumab-bevacizumab was associated with a favorable organ-specific response regardless of the site of the tumor lesions. Unlike anti-PD-1 monotherapy, atezolizumab-bevacizumab had a comparable organ-specific response between intrahepatic and extrahepatic lesions, especially for those with viral etiology HCCs.

Occult Vertebral Fracture (OVF) in Patients Who Underwent Hepatectomy for Colorectal Liver Metastasis: Strong Association with Oncological Outcomes

Aim: The impact of occult vertebral fracture (OVF) on oncological outcomes after surgery has not been investigated, although its significance in orthopedics has been much debated recently. We evaluated the prognostic significance of OVF on the long-term outcomes of patients with colorectal liver metastases (CRLM) after hepatectomy. Methods: We included 140 patients with CRLM who underwent hepatectomy. OVF was identified using quantitative measurement and preoperative sagittal computed tomography image reconstruction from the 11th thoracic vertebra to the 5th lumber vertebra. Results: OVF was identified in 48 (34%) of the patients. In multivariate analysis, lymph node metastases (p &lt; 0.01), multiple tumors (p = 0.02), extrahepatic lesions (p &lt; 0.01), OVF (p &lt; 0.01), intraoperative bleeding (p = 0.04), and curability 1 or 2 (p &lt; 0.01) were independent and significant predictors of disease-free survival and extrahepatic lesions (p &lt; 0.01), osteosarcopenia (p = 0.02), and OVF (p &lt; 0.01) were independent and significant predictors of overall survival. A higher age, adjuvant chemotherapy for a primary lesion before metachronous liver metastases, osteopenia, and hypoalbuminemia were independent risk factors for OVF. Conclusions: The evaluation of preoperative OVF is a useful prognostic factor for risk stratification and clinical decision-making for patients with CRLM.

The contribution of new methods in cytology for increasing sensitivity in the diagnosis of extrahepatic bile duct lesions.

The aim of this review is to provide a comprehensive analysis of the existing literature pertaining to cytology of extrahepatic bile ducts. A search using the keywords "biliary brush cytology" was conducted in the PubMed database, with a focus on recent articles. The inclusion criteria primarily encompassed publications addressing problematic biliary stenosis. Emphasis was placed on identifying articles that explored innovative or less-utilized examination techniques aimed at enhancing the sensitivity of cytological examination. This review presents a comprehensive overview of the various types of materials used in sampling and the corresponding sampling methods. Additionally, it explores cytological and cytogenetic techniques, such as fluorescence in situ hybridization (FISH) and genetic methods (miRNA, NGS, cfDNA). These techniques possess the potential to improve the accuracy of diagnosing bile duct tumors, although their sensitivity varies. Furthermore, their utilization can facilitate early therapy, which plays a crucial role in patient prognosis. Each examination is always dependent on the quality and quantity of material delivered. A higher sensitivity of these examinations can be achieved by combining biliary cytology and other complementary methods.

Impact of radiological response and pattern of progression in patients with HCC treated by atezolizumab-bevacizumab.

We aim to assess the role of radiological response to atezolizumab-bevacizumab in patients with HCC to predict overall survival. We retrospectively included patients with HCC treated by atezolizumab-bevacizumab in 2 tertiary centers. A retrospective blinded analysis was performed by 2 radiologists to assess Response Evaluation Criteria in Solid Tumor (RECIST 1.1) and modified RECIST (mRECIST) criteria at 12 weeks. Imaging response and treatment decisions in the multidisciplinary tumor board at 12 weeks were registered. Among 125 patients, 9.6% and 20.8% had a response, 39.2% and 35.2% had stable disease, and 51.2% and 44% had progression, according to RECIST 1.1 and mRECIST, respectively, with a substantial interobserver agreement (k coefficient=0.79). Metastasis was independently associated with a higher risk of progression. Patients classified as responders did not reach median survival, which was 16.2 and 15.9 months for patients classified as stable and 9.1 and 9.0 months for patients classified as progressors, in RECIST 1.1 and mRECIST criteria, respectively. We observed a wide variability in the identification of progression in the multidisciplinary tumor board in clinical practice compared with the blind evaluation by radiologists mainly due to discrepancy in the evaluation of the increase in size of intrahepatic lesions. The appearance of new extrahepatic lesions or vascular invasion lesions was associated with a worse overall survival ( p =0.032). RECIST 1.1 and mRECIST criteria predict overall survival with more responders identified by mRECIST and the appearance of new extrahepatic lesion or vascular invasion was associated with a poor prognosis. A noticeable discrepancy was observed between patients classified as progressors at reviewing and the decision reached during the multidisciplinary tumor board.

Liver-Directed Combined Radiotherapy for Downstaging of the Milan Advanced Hepatocellular Carcinoma Converting to Liver Transplantation

Recent success of combined immunotherapy sheds a light to the future of advanced hepatocellular carcinoma patients but still remains as a palliative setting. The best oncologic outcome for HCC can be obtained by curative surgery either by resection or liver transplantation (LT). Efficacy of liver-directed combined radiotherapy (LD-CRT) for downstaging and subsequent surgical resection in locally advanced HCC had been reported earlier by our team. In this study, we investigated the role of LD-CRT as a downstaging strategy for converting advanced hepatocellular carcinoma to LT. We reviewed 55 hepatocellular carcinoma patients who had undergone downstaging LD-CRT and subsequent liver transplantation from January 2009 to February 2022. Patients within Milan criteria at the time of receiving radiotherapy were excluded and clinical characteristics and histopathology of explant liver were evaluated. The overall survival and disease-free survival were assessed using the Kaplan-Meier method RESULTS: The median follow-up period was 48.6 months (range 6.9 - 151.7 months). Of 55 patients, 24 (43.6%) were treatment naïve. At the time of RT, 36 patients presented large tumor (tumor diameter >5 cm) or multiple lesions (>3 lesions), 37 with major vessel involvement or portal vein tumor thrombosis, and 7 with extrahepatic lesion. LD-CRT was given as localized concurrent chemoradiation (CCRT) for 41 patients (74.5%) and transarterial chemoembolization (TACE) plus RT for 10 patents (18.2%). Substantial downstaging has been achieved in 38 (69%) patients with initially over the Milan to within Milan. Specifically, 29 of 37 patients initially with major vessel invasion or with tumor thrombosis were successfully converted to microscopic vessel invasion or tumor thrombus-free status in explant liver. 5-year overall survival was 68.1% and 2-year disease-free survival was 51%, respectively. Recurrence after transplantation was observed in 18 patients (4 intrahepatic recurrence and 14 extrahepatic metastasis) and the majority (14/18) occurred within 2 years. Liver-directed combined radiotherapy as a downstaging strategy for liver transplantation achieved favorable oncologic outcomes in advanced hepatocellular carcinoma patients. This study suggests that active adoption of radiotherapy needs full consideration for locally advanced HCC patients, opening a chance for curative LT.