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]
The risks of radiological opacities in relation to cumulative silica exposure were estimated in 338 (206 current and 132 previously employed) male granite workers in two quarries. They represented 91 % of all currently employed and 61 % of surviving past workers who had worked for at least 1 year between 1967 and 1985. Cumulative silica exposure was estimated for each man based on quarry- and job-specific measures of past and recent dust concentrations and exposure years. The mean quartz content in respirable dust was 27%. Particle counts were converted to gravimetric equivalents of respirable quartz concentrations. Pneumoconiosis was defined as 1/1 or greater profusion of small rounded or irregular opacities as read by at least two of three experienced readers, using the most recent chest radiographs and ILO standard films. The observed prevalences of small opacities was significantly related to cumulative exposure, and adequately described by a logistic model, incorporating both age and cumulative exposure. A linear model, however, appeared to give a better fit to the data. Nevertheless, both models predicted similar risks of about 6% rounded opacities and 9% irregular opacities in the average 50 year old worker with a cumulative dust exposure of 2.0 mg m−3 year.
Abstract Hepatocellular carcinoma (HCC) is a major global health problem and its treatment outcomes are limited by therapeutic resistance. Cancer stem cells are the roots of tumor growth, recurrence, metastasis and treatment resistance. Signal transducer and activator of transcription 3 (STAT3) is a transcription factor well known to promote carcinogenesis in a number of tumors. The present study aims to investigate the role of STAT3 in HCC. Total STAT3 levels were examined by qRT-PCR in patients with primary HCC who underwent curative partial hepatectomy. Elevated STAT3 levels were significantly associated with poor recurrence-free survival and overall survival of HCC patients (log-rank test, P = 0.019 and 0.008, respectively). Immunohistochemistry (IHC) was performed to determine the activation status of STAT3 in HCC. Phosphorylated (p)-Y705 and p-S727 staining was detected in HCC tissues, albeit with varying patterns of expression. To investigate the efficacy of STAT3-targeted therapeutics in HCC, napabucasin, a cancer stemness inhibitor targeting STAT3-driven gene transcription, and the specific small interfering RNA (siRNA) were examined in HCC cell lines Hep3B, HepG2 and Huh7. Both napabucasin and siRNA prominently downregulated RNA and protein levels of total STAT3 and p-STAT3 of HCC cells. Napabucasin reduced viability, induced death, hindered migration, impaired colony and spheroid formation efficiency of HCC cells, as well as lowered expression levels of the cancer stem cell markers granulin-epithelin precursor (GEP) and CD133 in whole genome RNA sequencing analysis. Notably, napabucasin combined with 5-fluorouracil (5-FU) synergistically inhibited cell proliferation and induced apoptosis, suggesting its potential in sensitizing HCC cells to chemotherapeutic agents. In addition, napabucasin diminished the colony and spheroid formation abilities of chemo-resistant HCC cells (acquired resistance to 5-FU with over 10-fold increase) to a similar extent as their parental counterparts, indicating its potency in targeting chemo-resistant HCC cells via cancer stemness inhibition. Furthermore, napabucasin also suppressed HCC tumor growth in vivo, accompanied with reduced total STAT3 and p-STAT3 levels and proliferation (Ki-67). Overall, the present study highlighted the prognostic significance of STAT3 in HCC, and its functional role in the control of chemo-resistance and cancer stemness in HCC through targeted therapeutics. Citation Format: Carol Lee, Elaine Yee-Ling OR, Charing Ching-Ning Chong, Tan To Cheung, Iris Ming-Jing Xu, Linda Wing-Chi Ng, Marcus Hung-Lam Law, Peter Tin-Chung Li, Stephen Lam Chan, Anthony Wing-Hung Chan, Philip Chun Yeung, Kelvin Kwok-Chai Ng, Paul Bo-San Lai, Siu Tim Cheung. STAT3 regulates chemo-resistance and cancer stemness in hepatocellular carcinoma [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 4151.
4102 Background: RO5137382/GC33 (GC33) is a humanized monoclonal antibody against GPC3 that is frequently expressed in HCC. GC33 interacts with CD16/FcγR3 and triggers antibody-dependent cytotoxicity. GC33 was compared with placebo in a randomized phase II study in advanced HCC patients (pts) who had failed prior systemic therapy. Methods: Pts with advanced HCC who had failed prior systemic therapy, ≥18 years, ECOG 0-1, Child-Pugh A were randomized in a 2:1 ratio to GC33 1600 mg Q2W after two weekly doses versus placebo. Prior to randomization, pts were assigned into 3 cohorts based degree of GPC3 immunohistochemical expression: A (GPC3 2-3+), B (GPC3 1+) and C (GPC3 no expression). Primary endpoint was progression free survival (PFS). Secondary endpoints include overall survival (OS), time to progression (TTP), tolerability, and pharmacokinetics (PK). Tumor assessment was based on RECIST1.0 criteria and safety on CTCAE 4.0. Results: Between February 2012 to March 2013, 185 pts were enrolled: 121 received GC33 and 64 placebo: Median age 64/63, 85/75% male, 46/42% Asian, ECOG 0 65/63%, 74/77% having vascular invasion and/or extra-hepatic metastasis. 49/41% had prior single agent sorafenib. Drug exposure was 98.6% of planned dose, with an identical adverse events profile between the 2 groups. The median PFS, OS, and TTP in the GC33 vs placebo groups in months were: 2.6 vs 1.5 (HR 0.97, p=0.87), 6.8 vs 6.7 (HR 0.99, p=0.97), and 2.9 vs 1.7 (HR 0.96, p=0.85). A subsequent exposure-efficacy analysis showed that increased exposure based on projected Ctroughat cycle 3 day 1 was associated with prolonged PFS and OS. Median PFS for high GC33 exposure group (n=60) was 4 vs 1.5 months for placebo (n=60), and OS 9.7 vs 6.7 months, respectively. Combining higher exposure with FcγR3A-158V polymorphism or CD16 expression intensity may correlate with improved PFS and OS. Conclusions: GC33 did not show a clinical benefit in this advanced, previously treated HCC population, potentially due to suboptimal dosing. Further studies are needed to investigate whether higher GC33 drug exposure and a favored CD16/FcgR3 immune environment may help. Clinical trial information: NCT01507168.
e13091 Background: Lung cancer is the leading cause of cancer death worldwide. We examined the correlation between lung cancer incidence/mortality and country-specific socioeconomic development, and evaluated the most recent global patterns and trends of this cancer in 38 countries. Methods: We retrieved age-standardized incidence rates of lung cancer in 2012 from the GLOBOCAN database. Temporal patterns were assessed for all countries obtained from the Cancer Incidence in Five Continents volumes I-X and the WHO mortality database. Simple linear regression analysis was used to evaluate their correlations with Human Development Index (HDI) and Gross Domestic Product (GDP) per capita. The average annual percent change (AAPC) of the incidence and mortality trends in the most recent 10 years were evaluated from join-point regression analysis according to country and gender. The statistical significance of AAPC was ascertained comparing with zero, and all insignificant AAPCs were regarded as having “stable trends”. Results: The global incidence and mortality of lung cancer varied by 31-fold. Country-specific HDI was strongly correlated with age-standardized incidence (r = 0.70) and mortality (r = 0.67), and so was GDP per capita to a lesser extent (r = 0.24 to 0.55) (all p < 0.001). Among men, 22 and 30 (out of 38 and 36) countries showed declining incidence and mortality trends, respectively; whilst among women, 19 and 16 countries showed increasing incidence and mortality trends, respectively. The AAPCs ranged from -2.8 to -0.6 (incidence) and -3.6 to -1.1 (mortality) among countries with declining trend in men, whereas the AAPC range was 0.4 to 8.9 (incidence) and 1 to 4.4 (mortality) among countries with increasing trends in women. Among women, Brazil, Spain and Cyprus had the greatest incidence increase, and all countries in Western, Southern and Eastern Europe had increasing mortality. Conclusions: Countries with higher socioeconomic development had higher lung cancer incidence and mortality. The incidence and mortality rates of lung cancer were increasing in many countries among women but declining in most countries among men, highlighting the need for regular surveillance and global preventive measures.
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.
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