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Human liver cancer research currently lacks in vitro models that can faithfully recapitulate the pathophysiology of the original tumor. We recently described a novel, near-physiological organoid culture system, wherein primary human healthy liver cells form long-term expanding organoids that retain liver tissue function and genetic stability. Here we extend this culture system to the propagation of primary liver cancer (PLC) organoids from three of the most common PLC subtypes: hepatocellular carcinoma (HCC), cholangiocarcinoma (CC) and combined HCC/CC (CHC) tumors. PLC-derived organoid cultures preserve the histological architecture, gene expression and genomic landscape of the original tumor, allowing for discrimination between different tumor tissues and subtypes, even after long-term expansion in culture in the same medium conditions. Xenograft studies demonstrate that the tumorogenic potential, histological features and metastatic properties of PLC-derived organoids are preserved in vivo. PLC-derived organoids are amenable for biomarker identification and drug-screening testing and led to the identification of the ERK inhibitor SCH772984 as a potential therapeutic agent for primary liver cancer. We thus demonstrate the wide-ranging biomedical utilities of PLC-derived organoid models in furthering the understanding of liver cancer biology and in developing personalized-medicine approaches for the disease., Author(s): Laura Broutier [1]; Gianmarco Mastrogiovanni [1, 2]; Monique MA Verstegen [3]; Hayley E Francies [4]; Lena Morrill Gavarró [2]; Charles R Bradshaw [1]; George E Allen [1]; Robert Arnes-Benito [...]

Background: During the COVID-19 pandemic, a decrease in the number of patients presenting with acute appendicitis was observed. It is unclear whether this caused a shift towards more complicated cases of acute appendicitis. We compared a cohort of patients diagnosed with acute appendicitis during the 2020 COVID-19 pandemic with a 2019 control cohort.Methods: We retrospectively included consecutive adult patients in 21 hospitals presenting with acute appendicitis in a COVID-19 pandemic cohort (March 15 - April 30, 2020) and a control cohort (March 15 - April 30, 2019). Primary outcome was the proportion of complicated appendicitis. Secondary outcomes included prehospital delay, appendicitis severity, and postoperative complication rates.Results: The COVID-19 pandemic cohort comprised 607 patients vs. 642 patients in the control cohort. During the COVID-19 pandemic, a higher proportion of complicated appendicitis was seen (46.9% vs. 38.5%; p = 0.003). More patients had symptoms exceeding 24 h (61.1% vs. 56.2%, respectively, p = 0.048). After correction for prehospital delay, presentation during the first wave of the COVID-19 pandemic was still associated with a higher rate of complicated appendicitis. Patients presenting > 24 h after onset of symptoms during the COVID-19 pandemic were older (median 45 vs. 37 years; p = 0.001) and had more postoperative complications (15.3% vs. 6.7%; p = 0.002).Conclusions: Although the incidence of acute appendicitis was slightly lower during the first wave of the 2020 COVID-19 pandemic, more patients presented with a delay and with complicated appendicitis than in a corresponding period in 2019. Spontaneous resolution of mild appendicitis may have contributed to the increased proportion of patients with complicated appendicitis. Late presenting patients were older and experienced more postoperative complications compared to the control cohort. [ABSTRACT FROM AUTHOR]

Background: The aim was to compare the prognostic accuracy of cross-sectional imaging of the 7th and 8th editions of the American Joint Committee on Cancer(AJCC) staging system for perihilar cholangiocarcinoma(PHC). Methods: All patients with PHC between 2002 and 2014 were included. Imaging at the time of presentation was reassessed and clinical tumor–node–metastasis (cTNM) stage was determined according to the 7th and 8th editions of the AJCC staging system. Comparison of the prognostic accuracy was performed using the concordance index (c-index). Results: A total of 248 PHC patients were included;45 patients(18.1%) underwent a curative-intent resection, whereas 203 patients(81.9%) did not because they were unfit for surgery or were diagnosed with locally advanced or metastatic disease during workup. Prognostic accuracy was comparable between the 7th and 8th editions (c-index 0.57 vs 0.58). For patients who underwent a curative-intent resection, the prognostic accuracy of the 8th edition (0.67) was higher than the 7th (0.65). For patients who did not undergo a curative-intent resection, the prognostic accuracy was poor in both the 7th as the 8th editions (0.54 vs 0.57). Conclusion: The 7th and 8th editions of the AJCC staging system for PHC have comparable prognostic accuracy. Prognostic accuracy was particularly poor in unresectable patients. [ABSTRACT FROM AUTHOR]

Background: Low skeletal muscle mass is associated with increased postoperative morbidity and worse survival following resection for perihilar cholangiocarcinoma (PHC). We investigated the predictive value of skeletal muscle mass and density for overall survival (OS) of all patients with suspected PHC, regardless of treatment. Methods: Baseline characteristics and parameters regarding disease and treatment were collected from all patients with PHC from 2002 to 2014. Skeletal muscle mass and density were measured at the level of the third lumbar vertebra on CT. The association between skeletal muscle mass and density with OS was investigated using the Kaplan-Meier method and Cox survival. Results: Median OS in 233 included patients did not differ between those with and without low skeletal muscle mass (p = 0.203), whereas a significantly different median OS (months) was observed between patients with low (HR 7.0, 95% CI 4.7–9.3) and high (HR 12.1, 95% CI 8.1–16.1) skeletal muscle density (p = 0.004). Low skeletal muscle density was independently associated with decreased OS (HR 1.78, 95% CI 1.03–3.07, p = 0.040) within the first 6 months but not after 6 months (HR 0.68, 95% CI 0.44–1.07, p = 0.093), after adjusting for age, tumour size and suspected peritoneal or other distant metastases on imaging. Conclusion: A time-dependent effect of skeletal muscle density on OS was found in patients with PHC, regardless of subsequent treatment. Low skeletal muscle density may identify patients at risk for early death. [ABSTRACT FROM AUTHOR]

B Background: b Liver transplantation has been performed in a select group of patients presenting with unresectable or primary sclerosing cholangitis (PSC)-associated perihilar cholangiocarcinoma (PHC) in the Mayo Clinic with a reported 5-year survival of 53% on intention-to-treat analysis. After applying the Mayo Clinic inclusion and exclusion criteria, 35 patients were found to be eligible out of a total cohort of 732 patients (4.8%; figure). Median survival from diagnosis for patients eligible for transplantation was 1.1 years (95%CI: 0.4-1.8), and no patient reached 5-year survival. [Extracted from the article]

Background & Aims Ligand binding to inhibitory receptors on immune cells, such as programmed cell death 1 (PD-1) and cytotoxic T-lymphocyte associated protein 4 (CTLA4), down-regulates the T-cell–mediated immune response (called immune checkpoints). Antibodies that block these receptors increase antitumor immunity in patients with melanoma, non–small-cell lung cancer, and renal cell cancer. Tumor-infiltrating CD4 + and CD8 + T cells in patients with hepatocellular carcinoma (HCC) have been found to be functionally compromised. We analyzed HCC samples from patients to determine if these inhibitory pathways prevent T-cell responses in HCCs and to find ways to restore their antitumor functions. Methods We collected HCC samples from 59 patients who underwent surgical resection from November 2013 through May 2017, along with tumor-free liver tissues (control tissues) and peripheral blood samples. We isolated tumor-infiltrating lymphocytes (TIL) and intra-hepatic lymphocytes. We used flow cytometry to quantify expression of the inhibitory receptors PD-1, hepatitis A virus cellular receptor 2 (TIM3), lymphocyte activating 3 (LAG3), and CTLA4 on CD8 + and CD4 + T cells from tumor, control tissue, and blood; we studied the effects of antibodies that block these pathways in T-cell activation assays. Results Expression of PD-1, TIM3, LAG3, and CTLA4 was significantly higher on CD8 + and CD4 + T cells isolated from HCC tissue than control tissue or blood. Dendritic cells, monocytes, and B cells in HCC tumors expressed ligands for these receptors. Expression of PD-1, TIM3, and LAG3 was higher on tumor-associated antigen (TAA)-specific CD8 + TIL, compared with other CD8 + TIL. Compared with TIL that did not express these inhibitory receptors, CD8 + and CD4 + TIL that did express these receptors had higher levels of markers of activation, but similar or decreased levels of granzyme B and effector cytokines. Antibodies against CD274 (PD-ligand1 [PD-L1]), TIM3, or LAG3 increased proliferation of CD8 + and CD4 + TIL and cytokine production in response to stimulation with polyclonal antigens or TAA. Importantly, combining antibody against PD-L1 with antibodies against TIM3, LAG3, or CTLA4 further increased TIL functions. Conclusions The immune checkpoint inhibitory molecules PD-1, TIM3, and LAG3 are up-regulated on TAA-specific T cells isolated from human HCC tissues, compared with T cells from tumor-free liver tissues or blood. Antibodies against PD-L1, TIM3, or LAG3 restore responses of HCC-derived T cells to tumor antigens, and combinations of the antibodies have additive effects. Strategies to block PD-L1, TIM3, and LAG3 might be developed for treatment of primary liver cancer. [ABSTRACT FROM AUTHOR]