205 Background: Serum interleukin-10 (IL-10) is associated with active hepatitis in patients (pts) with hepatitis B viral (HBV) infection. In HBV-related HCC, elevation of serum IL-10 is frequently observed but its significance on the outcome of HCC is unclear. Methods: A prospective cohort of newly diagnosed and inoperable HCC was recruited from a multidisciplinary clinic from Prince of Wales Hospital from 2006 to 2008. The baseline demographics, tumor characteristics/stage, laboratory parameters, virologic factors (HBV DNA, antiviral therapy) and first-line treatment modality were documented at the time of diagnosis. Serum IL-10 was measured by enzyme-linked immunosorbent essay. Univariate and multivariate analyses were conducted. Overall survival (OS) was the primary endpoint. Results: Total 180 new cases of inoperable HCC were evaluated. The median follow-up time was 15.5 months. Median age was 60.5 years. Most (159 pts; 88.3%) were males. 81.1% of them were positive for HBsAg. Total 120 (66.7%) had radiologic evidence of cirrhosis. 20 (11.1%), 85 (47.2%) and 75 (41.7%) received locoablative, trans- arterial/systemic therapy and supportive care respectively. The mean level of serum IL-10 was 18.1pg/ml (range: 2.8-11.7). 114 (63.3%) had log IL-10 higher than 1.0 pg/ml. Pts with log IL-10 >1.0 pg/ml had significantly worse OS than those with log IL-10≤ 1.0 pg/ml (14.8 vs. 4.5 months; HR 2.39; p<.0001). Multivariate analysis found log IL-10 (HR=2.57; p=0.005), CLIP score, TNM stage, treatment modality and the use of anti-viral therapy for HBV infection be the independent prognostic factors. Exploratory analyses showed that pts with Log IL-10>1.0pg/ml had higher ALT and HBV DNA, lower albumin, higher chance of ascites, worse Child-Pugh stage and worse tumor stage (Table). Conclusions: Serum IL-10 is an independent prognostic factor for inoperable HCC. Pts with high IL-10 level have poorer liver reserves and worse tumor staging. [Table: see text] No significant financial relationships to disclose.
Introduction: TSPYL (testis-specified Y encoded protein) family proteins belongs to nucleosome assembly protein (NAP) superfamily. There are 6 TSPYL family members in mice: Tspy/Tspy1, Tspyl1, Tspyl2, Tspyl3, Tspyl4 and Tspyl5. Nucleosome assembly protein superfamily members have been demonstrated that play significant roles in gene expression regulation and neuronal functions as histone chaperons. Data analysis from oncogene database highlighted the widespread expression of TSPYL1 and TSPYL2 in most neuronal cell types and their generic function in suppressing growth of most classes of neuroblastic tumor. TSPYL4, TSPYL5 showed lower expression in different brain tumors compared with the normal brain.In addition, the glioblastoma methylome dataset revealed a general increase in methylation status of TSPYL gene loci in glioblastoma samples Previous investigation in our lab found that TSPYL2 played significant role in cell cycle regulation, but the effect is mild. This makes us wonder whether other members of the TSPYL family also participate in cell cycle regulation control and how they involved in biological process like tumorigenesis and neural development. All these preliminary data intricate us to clarify roles of TSPYL family proteins play in neuron tumor. it is meaningful to figure out the functional roles of TSPYL family members. MATERIAL AND METHOD: we mutate Tspyl1, Tspyl2 and Tspyl4 in mouse ES cells using Crispr/Cas-mediated genome engineering, followed by generating the knockout mice through blastocyst injection. We monitor neural differentiation process of embryonic stem cells with Tspy family protein single, double or triple mutation. We did blastocyst injection with these embryonic stem cell to generate Tspyl1, Tspyl2, Tspyl4, single, double or triple gene mutation mice. Immunoprecipitation –mass spectrometric analysis of Tspyl1 and Tspyl4 were carried to figure out their interaction parters. Results: ES cells with Tspyl1,Tspyl4 single or double mutation could go on normally neuronal development. No significant difference of different stage markers in neuronal development like early stem cell marker nestin or mature neuron marker MAP2 and NeurN.In mice injection, the percentage of chimera mice is low. Chimera mice with relative higher percentage are infertility. IP-MS analysis state that Tspyl1 interact with Testis-specific chromodomain protein Y1,neurogenin 2.Tspyl4 interact with chromodomain-helicase-DNA-binding protein1and WAP four-disulfide core domain protein 1. CONCLUSION: Despite single or double knockout of Tspyl1 or Tspyl4 do not influence normal neuronal development. But their function in epigenetic regulation of tumour formation still need to be further clarified. They may play a role chromosome segregation and spermatogenesis.
509 Background: CARES-310 study (NCT03764293) evaluated the combination of camrelizumab, an anti-PD-1 inhibitor, and rivoceranib, a highly selective VEGFR-2 tyrosine kinase inhibitor, (cam + rivo) vs sorafenib (sora) for the treatment of uHCC. Cam + rivo significantly improved median overall survival ([mOS] 22.1 months [mo] vs 15.1 mo) and median progression-free survival ([mPFS] 5.6 mo vs 3.7 mo) compared to sora. This post-hoc analysis evaluated the impact of baseline albumin-bilirubin (ALBI) grade and Child-Pugh (CP) class on survival outcomes. Methods: In this randomized, open-label, international, multicenter, phase 3 study, patients were randomized 1:1 to receive cam 200 mg IV Q2W + rivo 250 mg PO QD (n=272) or sora 400 mg PO BID (n=271). Median overall survival (mOS), median progression free survival (mPFS), objective response rate (ORR), disease control rate (DCR), and safety were assessed by baseline ALBI grade and CP class. Results: mOS, mPFS, DCR, and ORR improved with cam + rivo vs sora regardless of baseline liver function (Table). Although treatment-related grade 3/4 AEs occurred at a greater rate in the cam + rivo arm vs the sora arm, the rate of these events was similar for patients with baseline ALBI grade 1 and grade 2 (cam + rivo, 82.1% and 81.7% vs sora, 53.9% and 54.0%, respectively). Median time-to-deterioration (mTTD) to CP class B was similar between treatment arms for ALBI grade 1 (not evaluable [NE], NE) and grade 2 (cam + rivo, 10.1 mo; sora, 10.6 mo; HR, 0.99). Conclusions: In this post-hoc analysis of Study CARES-310, the efficacy of cam + rivo was superior to sora regardless of baseline liver function as measured by both ALBI grade and CP class. Despite a higher rate of grade 3/4 AEs, there was no detrimental effect of cam +rivo on liver function in patients with both well- and moderately- preserved liver function compared to sora. These results support cam + rivo as a potential new first-line treatment option for patients with uHCC regardless of baseline liver function. Clinical trial information: NCT03764293 . [Table: see text]
Significance Plasma consists of DNA released from multiple tissues within the body. Using genome-wide bisulfite sequencing of plasma DNA, we obtained a bird’s eye view of the identities and contributions of these tissues to the circulating DNA pool. The tissue contributors and their relative proportions are identified by a bioinformatics deconvolution process that draws reference from DNA methylation signatures representative of each tissue type. We validated this approach in pregnant women, cancer patients, and transplant recipients. This method also allows one to identify the tissue of origin of genomic aberrations observed in plasma DNA. This approach has numerous research and diagnostic applications in prenatal testing, oncology, transplantation monitoring, and other fields.
Genomic screening uncovered interferon-gamma (IFNγ) pathway defects in tumours refractory to immune checkpoint blockade (ICB). However, its non-mutational regulation and reversibility for therapeutic development remain less understood.
BACKGROUNDThe TOPAZ-1 phase III trial demonstrated a survival advantage with durvalumab, an anti-programmed death cell ligand 1 (anti-PD-L1), when used with gemcitabine and cisplatin for patients with advanced biliary tract cancer. In order to gain a broader understanding of the efficacy and tolerability of this new combination in a real-world setting we performed a worldwide multicenter retrospective analysis to investigate the efficacy and safety of this new first-line standard treatment.METHODSThe analyzed population included patients with unresectable, locally advanced or metastatic adenocarcinoma of the biliary tract treated with durvalumab in combination with gemcitabine and cisplatin at 39 sites from 11 countries in Europe, United States, and Asia. The primary endpoint of the study was overall survival (OS).
Abstract Introduction Lenvatinib is approved for the treatment of patients with metastatic or recurrent hepatocellular carcinoma (HCC); however, clinical outcomes of lenvatinib therapy in patients with post‐liver transplantation (LT) HCC recurrence remain unclear. We investigated the efficacy and safety of lenvatinib in patients with post‐LT HCC recurrence. Methods This multinational, multicenter, retrospective study included 45 patients with recurrent HCC after LT who received lenvatinib at six institutions in three countries (Korea, Italy, and Hong Kong) from June 2017 to October 2021. Results At the time of lenvatinib initiation, 95.6% ( n = 43) of patients had Child–Pugh A status, and 35 (77.8%) and 10 (22.2%) participants were classified as having albumin–bilirubin (ALBI) grades 1 and 2, respectively. The objective response rate was 20.0%. With a median follow‐up duration of 12.9 months (95% confidence interval [CI]: 11.2–14.7), the median progression‐free survival and overall survival (OS) were 7.6 (95% CI: 5.3–9.8) months, and 14.5 (95% CI: 0.8–28.2) months, respectively. Patients with ALBI grade 1 showed significantly better OS (52.3 months, [95% CI: not assessable]) than patients with ALBI grade 2 (11.1 months [95% CI: 0.0–30.4 months], p = 0.003). The most common adverse events were hypertension ( n = 25, 55.6%), fatigue ( n = 17, 37.8%), and anorexia ( n = 14, 31.1%). Conclusion Lenvatinib showed consistent efficacy and toxicity profiles in patients with post‐LT HCC recurrence that were comparable to those reported from previous studies among non‐LT HCC patients. The baseline ALBI grade correlated with better OS in post‐LT lenvatinib‐treated patients.
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