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Type 2 diabetes mellitus (T2DM) is a classic metaflammatory disease, and the inflammatory states of the pancreatic islet and insulin target organs have been well confirmed. However, abundant evidence demonstrates that there are countless connections between these organs in the presence of a low degree of inflammation. In this review, we focus on cell-cell crosstalk among local cells in the islet and organ-organ crosstalk among insulin-related organs. In contrast to that in acute inflammation, macrophages are the dominant immune cells causing inflammation in the islets and insulin target organs in T2DM. In the inflammatory microenvironment (IME) of the islet, cell-cell crosstalk involving local macrophage polarization and proinflammatory cytokine production impair insulin secretion by β-cells. Furthermore, organ-organ crosstalk, including the gut-brain-pancreas axis and interactions among insulin-related organs during inflammation, reduces insulin sensitivity and induces endocrine dysfunction. Therefore, this crosstalk ultimately results in a cascade leading to β-cell dysfunction. These findings could have broad implications for therapies aimed at treating T2DM.

Hepatic lipid accumulation is an initiation factor in fatty liver disease, and promoting a reduction in hepatic lipid accumulation is an important treatment strategy. DEAD box RNA helicase 17 (DDX17) is a member of the DEAD-box family and a molecular chaperone. Previous studies have demonstrated that DDX17 is a transcriptional coregulator of tumorigenesis, inflammation, and macrophage cholesterol efflux. The liver is the main site for lipid metabolism, and metabolic (dysfunction)-associated fatty liver disease (MAFLD) is one of the most common chronic liver diseases. However, the impact of DDX17 on hepatic lipid accumulation has not been verified. In this study, we found, for the first time, that oleic acid/palmitic acid (OA/PA)-induced lipid accumulation was largely abrogated by DDX17 overexpression in both HepG2 (a human hepatocellular carcinoma line) and Hep1-6 (a murine hepatocellular carcinoma line) cells, and this effect was due to a marked reduction in cellular triglyceride (TG) content. Moreover, the overexpression of DDX17 was accompanied by a significant decrease in the expression of genes involved in de novo fatty acid synthesis (FAS, ACC, and SCD-1) in both HepG2 and Hep1-6 cells. In conclusion, DDX17 protected against OA/PA-induced lipid accumulation in hepatocytes through de novo lipogenesis inhibition.

Lysophosphatidylcholine (LPC), the active metabolite of palmitate, triggers hepatocyte death by activating endoplasmic reticulum stress and JNK signalling-mediated lipoapoptosis. However, LPC-induced cytotoxicity in hepatocytes is not well understood. Here, we found for the first time that LPC-induced cell rounding occurred prior to apoptosis. LPC-induced rounding of cells reduced both cell-extracellular matrix (ECM) adhesion and cell-cell junctions, which promoted detachment-induced apoptosis (defined as anoikis) in hepatocytes. Further study revealed that LPC altered cellular morphology and cell adhesion by inhibiting integrin and cadherin signalling-mediated microfilament polymerization. We also found that ECM supplementation and microfilament cytoskeletal stabilization inhibited LPC-induced hepatocyte death by attenuating anoikis. Our data indicate a novel cytotoxic process and signalling pathway induced by LPC.

With research progress on longevity, we have gradually recognized that cardiac aging causes changes in heart structure and function, including progressive myocardial remodeling, left ventricular hypertrophy, and decreases in systolic and diastolic function. Elucidating the regulatory mechanisms of cardiac aging is a great challenge for biologists and physicians worldwide. In this review, we discuss several key molecular mechanisms of cardiac aging and possible prevention and treatment methods developed in recent years. Insights into the process and mechanism of cardiac aging are necessary to protect against age-related diseases, extend lifespan, and reduce the increasing burden of cardiovascular disease in elderly individuals. We believe that research on cardiac aging is entering a new era of unique significance for the progress of clinical medicine and social welfare.

Cholesterol efflux from macrophages is the initial step of reverse cholesterol transport, an important process for high-density lipoprotein-mediated atheroprotection. G protein-coupled receptor (GPR) 120, which functions as long-chain fatty acid receptor, is well known for its anti-inflammatory and insulin-sensitizing function in macrophages. However, the role of GPR120 on macrophage foam cell formation, the hallmark of atherosclerotic plaques, has not been verified. In this study, we found for the first time that stimulation of GPR120 by its agonist GW9508 elevated the expression of ATP-binding cassette transporters (ABC) A1 and ABCG1 in THP-1 macrophage-derived foam cells and Raw264.7 macrophages, and promoted ABCA1- and ABCG1-mediated cholesterol efflux and reduced cellular cholesteryl ester (CE) content as well. In addition, GPR120 activation was accompanied with the stimulation of AMPK pathway in macrophages; however, the effect of GPR120 on macrophage cholesterol efflux was largely abolished by AMPK inhibition. Moreover, the AMPK activity and the expression of ABCA1 and ABCG1 were markedly abrogated by knockdown of GPR120, or application of phospholipase C (PLC) inhibitor, calcium chelator, or CaMKK inhibitor. Because only free cholesterol can be effluxed from macrophages, we found that activation of AMPK could lead to increase both neutral CEs hydrolysis by upregulation of neutral cholesterol ester hydrolase expression and acid CEs hydrolysis by activation of ULK1. In conclusion, these results demonstrated that GPR120 facilitated ABCA1- and ABCG1-mediated cholesterol efflux through activation of PLC/Ca2+ /CaMKK/AMPK signaling pathway, which induced CE hydrolysis and elevated the expression of ABCA1 and ABCG1 in macrophages.

Doxorubicin, as a first line chemotherapeutic agent, its usage is limited owing to cardiotoxicity. Necroptosis is a new form of programmed cell death, and recent investigations indicated that necroptosis is vitally involved in serious cardiac pathological conditions. Dexrazoxane is the only cardiac protective drug approved by FDA for anthracycline. We aimed to explore whether and how dexrazoxane regulates doxorubicin-induced cardiomyocyte necroptosis. First, doxorubicin could cause heart failure and reduce cardiomyocyte viability by promoting cell apoptosis and necroptosis in vivo and in vitro. Second, necroptosis plays an important role in doxorubicin induced cardiomyocyte injury, which could be inhibited by Nec-1. Third, dexrazoxane increased cell viability and protect heart function by decreasing both cardiomyocyte apoptosis and necroptosis after doxorubicin treatment. Forth, dexrazoxane attenuated doxorubicin-induced inflammation and necroptosis by the inhibition of p38MAPK/NF-κB pathways. These results indicated that dexrazoxane ameliorates cardiotoxicity and protects heart function by attenuating both apoptosis and necroptosis in doxorubicin induced cardiomyocyte injury.

Objective. To investigate the protective effects and regulatory mechanism of miR-488-3p on doxorubicin-induced cardiotoxicity. Methods. The C57BL/6 mice and primary cardiomyocytes were used to construct doxorubicin-induced cardiomyocyte injury models in vivo and in vitro. The levels of miR-488-3p and its downstream target genes were analyzed by quantitative real-time PCR. Mouse cardiac function, cell survival, cellular injury-related proteins, and the apoptosis level of cardiomyocytes were analyzed by echocardiography, MTT analysis, Western blotting, and DNA laddering separately. Results. Cardiomyocyte injury caused by a variety of stimuli can lead to the reduction of miR-488-3p level, especially when stimulated with doxorubicin. Doxorubicin led to significant decrease in cardiac function, cell autophagic flux blockage, and apoptosis in vivo and in vitro. The expression of miR-488-3p’s target gene, CyclinG1, increased remarkably in the doxorubicin-treated neonatal mouse cardiomyocytes. Overexpression of miR-488-3p inhibited CyclinG1 expression, increased cardiomyocyte viability, and attenuated doxorubicin-induced cardiomyocyte autophagic flux blockage and apoptosis. Conclusions. miR-488-3p is one of the important protective miRNAs in doxorubicin-induced cardiotoxicity by inhibiting the expression of CyclinG1, which provides insight into the possible clinical application of miR-488-3p/CyclinG1 as therapeutic targets in doxorubicin-induced cardiovascular diseases.

Estuarine mudflats are profoundly affected by increased coastal erosion and reduced sediment delivery from major rivers. Although managers are having difficulties to control the cause of increased coastal erosion, they can help to manage the resilience of mudflat ecosystems to erosion through river flow regulation. In this study, we associated the resilience of a mudflat ecosystem to erosion with various magnitudes of river flow using a mechanism-based eco-morphodynamic model. Ecosystem resilience was reported in terms of i) what range of erosion rate the system can withstand before function collapse (persistence), ii) at which point function can be recovered (recovery), and iii) the uncertainty of system response to disturbances (response uncertainty). Specifically, the function of intertidal mudflat was characterized by landscape heterogeneity, primary productivity, and sediment stabilization. In a case study of the Yellow River Estuary (YRE) of China, it is found that increased erosion induced a collapse of the functioning state. Once collapsed, the erosion rate at which mudflat could recovered was lower than the erosion rate at which mudflat collapsed. Increased river flow enhanced the resilience of the mudflat ecosystem to erosion by increasing sediment deposition rate, which was an important attribute in the interaction process driving ecosystem resilience. Furthermore, given the same river flow allocation, the system with dynamic grazer population was more resilient than the system with a constant grazer number, highlighting the importance of controlling mudflat aquaculture to optimize the performance of river flow regulation. Our modeling results are dependent on the environment with several assumptions, however, as a preliminary, we believe our work represents a fundamental shift to modeling ecosystem resilience based on the mechanism of bio-physical interactions rather than relying on just quantifying the vital rates of particular species to compare river flow scenarios.

Objectives To investigate the function and regulatory mechanisms of delphinidin in the treatment of hepatocellular carcinoma. Methods HepG2 and HuH-7 cells were treated with different concentrations of delphinidin. Cell viability was analysed by 3-(4,5-dimethyl-thiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. The cell autophagy and autophagic flux were analysed by LC3b-green fluorescent protein (GFP)-Adv and LC3b-GFP-monomeric red fluorescent protein-Adv transfected HepG2 and HuH-7 cells, respectively. Cell apoptosis was analysed by Hoechst33342 staining, terminal deoxynucleotidyl transferase dUTP nick end labeling staining and DNA laddering. Cell autophagy, apoptosis and survival related protein expressions were detected by Western blotting. Key findings After treatment with different concentrations of delphinidin, the cell survival rate was significantly decreased. Delphinidin could block the autophagic flux, resulting in a significant increase in autophagosomes, and led to an increase in cell apoptosis. The combined application of delphinidin and cisplatin could promote the antitumour effect and reduce the dose of cisplatin in tumour cells. Further mechanism studies reveal that delphinidin could inhibit the multidrug resistance gene 1 (MDR1) and the tumour-promoting transcription cofactor DEAD-box helicase 17 (DDX17) expression in tumour cells. Overexpression of DDX17 could reverse delphinidin’s antitumor function in tumour cells. Conclusions Delphinidin has a strong anti-tumour effect by inducing tumour cell autophagic flux blockage and apoptosis by inhibiting of both MDR1 and DDX17 expression.

Objective In this study, we aim to explore the role of bone marrow macrophage‐derived exosomes in hepatic insulin resistance, investigate the substance in exosomes that regulates hepatic insulin signalling pathways, reveal the specific molecular mechanisms involved in hepatic insulin resistance and further explore the role of exosomes in type 2 diabetes. Materials and methods High‐fat diet (HFD)‐fed mice were used as obesity‐induced hepatic insulin resistance model, exosomes were isolated from BMMs which were extracted from HFD‐fed mice by ultracentrifugation. Exosomes were analysed the spectral changes of microRNA expression using a microRNA array. The activation of the insulin signalling pathway and the level of glycogenesis were examined in hepatocytes after transfected with miR‐143‐5p mimics. Luciferase assay and western blot were used to assess the target of miR‐143‐5p. Results BMMs from HFD‐fed mice were polarized towards M1, and miR‐143‐5p was significantly upregulated in exosomes of BMMs from HFD‐fed mice. Overexpression of miR‐143‐5p in Hep1‐6 cells led to decreased phosphorylation of AKT and GSK and glycogen synthesis. Dual‐luciferase reporter assay and western blot demonstrated that mitogen‐activated protein kinase phosphatase‐5 (Mkp5, also known as Dusp10) was the target gene of miR‐143‐5p. Moreover, the overexpression of MKP5 could rescue the insulin resistance induced by transfection miR‐143‐5p mimics in Hep1‐6. Conclusion Bone marrow macrophage‐derived exosomal miR‐143‐5p induces insulin resistance in hepatocytes through repressing MKP5., Up‐regulated miR‐143‐5p in BMM exosomes could be passed to hepatocytes and impaired hepatic glycogenesis by targeting Mkp5.

miR-23a-3p and miR-23b-3p are members of the miR-23~27~24-2 superfamily. The role of miR-23a/b-3p in regulating hepatic lipid accumulation is still unknown. Here, we found that increased miR-23a-3p and miR-23b-3p levels were accompanied by an increase in the protein levels of the sterol regulatory element-binding protein-1 (SREBP-1) and fatty acid synthase (FAS) in the steatotic livers of mice fed a high-fat diet and leptin receptor-deficient type 2 diabetic mice (db/db). Importantly, overexpression of miR-23a/b-3p in Hep1-6 cells elevated the intracellular triglyceride level and upregulated the expression of Srebp-1c and Fas. Taken together, these results suggested that miR-23a/b-3p enhanced mRNA stability by binding the 5'-UTR of Srebp-1c and Fas mRNA, thereby promoting triglyceride accumulation in hepatocytes.

Mitochondria are currently known as novel targets for treating cancer, especially for tumors displaying multidrug resistance (MDR). This present study aimed to develop a mitochondria-targeted delivery system by using triphenylphosphonium cation (TPP+)-conjugated Brij 98 as the functional stabilizer to modify paclitaxel (PTX) nanocrystals (NCs) against drug-resistant cancer cells. Evaluations were performed on 2D monolayer and 3D multicellular spheroids (MCs) of MCF-7 cells and MCF-7/ADR cells. In comparison with free PTX and the non-targeted PTX NCs, the targeted PTX NCs showed the strongest cytotoxicity against both 2D MCF-7 and MCF-7/ADR cells, which was correlated with decreased mitochondrial membrane potential. The targeted PTX NCs exhibited deeper penetration on MCF-7 MCs and more significant growth inhibition on both MCF-7 and MCF-7/ADR MCs. The proposed strategy indicated that the TPP+-modified NCs represent a potentially viable approach for targeted chemotherapeutic molecules to mitochondria. This strategy might provide promising therapeutic outcomes to overcome MDR., Graphical abstract Image, graphical abstractTriphenylphosphonium-modified paclitaxel nanocrystals were prepared for mitochondrial targeting strategy. Cellular uptake of NCs was through endocytosis pathway for avoiding efflux of P-glycoprotein (P-gp). After escaping from endosome, targeting NCs were apt to deliver PTX to mitochondria causing the decrease of mitochondrial membrane potential and then induced cancer cell apoptosis.

Purpose/Objective(s) The survival and larynx preservation were both important in hypopharyngeal cancer. For primary surgery, most patients need total laryngectomy. For primary radical concurrent chemoradiotherapy (CCRT), the non-responders to CCRT had worse outcome compared with surgery. Thus, our cancer center explored a new response-adapted strategy based on early response to radiotherapy. Materials/Methods A total of 423 patients with resectable, III/IVA hypopharyngeal cancer were reviewed between May 2009 and October 2019. There were three main treatment strategies for locally advanced hypopharyngeal carcinoma in our institution, surgery followed by radiotherapy (S+RT group), response-adapted group and radical CCRT/RT (CRT group). The response-adapted strategy was determined by primary tumor regression evaluated at DT 50 Gy, only primary lesions reaching large PR were recommended for radical CCRT, otherwise planned surgery. We defined the survival with functional larynx as total laryngectomy or death from local disease. Results With a medial follow-up of 66.5 months, the 5-year overall survival (OS), locoregional recurrence-free survival (LRRFS), distance metastasis free survival (DMFS) and survival with functional larynx were 49.5%, 45.7%, 47.0% and 52.5% for whole cohort. For different groups, the 5-year OS, LRRFS, DMFS and survival with functional larynx were 54.4%, 52.5%, 52.3% and 47.4% for S+RT group (n = 144); 52.7%, 47.0%, 49.5% and 58.6% for response-adapted group (n = 212); 27.7%, 28.6%, 26.3% and 41.3% for CRT group (n = 67). The response-adapted strategy achieved similar survival and better survival with functional larynx compared with S+RT group, but the baseline between them were unbalanced. We use PSM to balance the two arms, the adjusted 5-year OS, LRRFS and DMFS were 54.8%, 48.7%, 53.5% for response-adapted group vs 52.2% 50.8%, 50.8% for S+RT group, without significant difference. But the adjusted 5-year larynx preservation rate and survival with functional larynx in response-adapted group were 75.1% and 53.8%, better compared with 56.1% and 50.1% in S+RT group (P 0.05) for two groups had no difference. In subgroup analysis, 87.7% (186/212) required total laryngectomy when evaluated before treatment in the response-adapted group, but the 5-year survival with functional larynx were still 57.4%. In multivariable analysis, treatment strategies, ECOG, T and N stage were independently significant for OS, LRRFS, DMFS and survival with functional larynx. Conclusion The response-adapted strategy achieved favorable survival with functional larynx and equally oncologist outcome compared with S+RT strategy. Besides, the response-adapted strategy did not result in additional operative complications and was well tolerated. Therefore, the response-adapted strategy might be an innovative, desirable for locally advanced hypopharyngeal cancer, especially for those with organ preservation intention.

Lipotoxicity-induced apoptosis, also referred to as lipoapoptosis, is one of the important initial factors promoting the progression from hepatosteatosis to nonalcoholic steatohepatitis (NASH). Saturated free fatty acids (SFAs), which are increased significantly in NASH, are directly hepatotoxic which induce hepatocyte lipoapoptosis. Previously, we reported that protein phosphatase 4 (PP4) was a novel regulator of hepatic insulin resistance and lipid metabolism, but its role in hepatic lipoapoptosis remains unexplored. In this study, we found out that PP4 was upregulated in the livers of western diet-fed-induced NASH mice and SFA-treated murine primary hepatocytes and HepG2 cells. In addition, we found for the first time that suppression of PP4 decreased SFA-induced JNK activation and expression of key modulators of hepatocyte lipoapoptosis including p53-upregulated modulator of apoptosis (PUMA) and Bcl-2-interacting mediator (Bim) and reduced hepatocyte lipoapoptosis level as well both in vitro and in vivo. Further study revealed that PP4 induced JNK activation and lipoapoptosis-related protein expression by regulating the RAC1/MLK3 pathway instead of the PERK/CHOP pathway. The effects of palmitate-treated and PP4-induced lipoapoptosis pathway activation were largely abolished by RAC1 inhibition. Moreover, we identified that PP4 interacted with RAC1 and regulated GTPase activity of RAC1. In conclusion, these results demonstrated that PP4 was a novel regulator of hepatocyte lipoapoptosis and mediated hepatocyte lipoapoptosis by regulating the RAC1/MLK3/JNK signaling pathway. Our finding provided new insights into the mechanisms of this process.

Adiponectin is a small peptide secreted and a key component of the endocrine system and immune system. Although globular adiponectin protects myocardial ischemia/reperfusion-induced cardiomyocyte injury, the protective mechanisms remain largely unresolved. Using a neonatal rat ventricular myocyte hypoxia/reoxygenation model, we investigated the role of its potential mechanisms of necroptosis in globular adiponectin-mediated protection in hypoxia/reoxygenation-induced cardiomyocyte injury as compared to apoptosis. We found that globular adiponectin treatment attenuated cardiomyocyte injury as indicated by increased cell viability and reduced lactate dehydrogenase release following hypoxia/reoxygenation. Immunofluorescence staining and Western blotting demonstrated that both necroptosis and apoptosis were triggered by hypoxia/reoxygenation and diminished by globular adiponectin. Necrostatin-1 (RIP1-specific inhibitor) and Z-VAD-FMK (pan-caspase inhibitor) only mimicked the inhibition of necroptosis and apoptosis, respectively, by globular adiponectin in hypoxia/reoxygenation-treated cardiomyocytes. Globular adiponectin attenuated reactive oxygen species production, oxidative damage, and p38MAPK and NF-κB signaling, all important for necroptosis and apoptosis. Collectively, our study suggests that globular adiponectin inhibits hypoxia/reoxygenation-induced necroptosis and apoptosis in cardiomyocytes probably by reducing oxidative stress and interrupting p38MAPK signaling.

The usage of doxorubicin is hampered by its life-threatening cardiotoxicity in clinical practice. Dexrazoxane is the only cardioprotective medicine approved by the FDA for preventing doxorubicin-induced cardiac toxicity. Nevertheless, the mechanism of dexrazoxane is incompletely understood. The aim of our study is to investigate the possible molecular mechanism of dexrazoxane against doxorubicin-induced cardiotoxicity. We established a doxorubicin-induced mouse and cardiomyocyte injury model. Male C57BL/6J mice were randomly distributed into a control group (Con), a doxorubicin treatment group (DOX), a doxorubicin plus dexrazoxane treatment group (DOX+DEX), and a dexrazoxane treatment group (DEX). Echocardiography and histology analyses were performed to evaluate heart function and structure. DNA laddering, qRT-PCR, and Western blot were performed on DOX-treated cardiomyocytes with/without DEX treatment in vitro. Cardiomyocytes were then transfected with miR-17-5p mimics or inhibitors in order to analyze its downstream target. Our results demonstrated that dexrazoxane has a potent effect on preventing cardiac injury induced by doxorubicin in vivo and in vitro by reducing cardiomyocyte apoptosis. MicroRNA plays an important role in cardiovascular diseases. Our data revealed that dexrazoxane could upregulate the expression of miR-17-5p, which plays a cytoprotective role in response to hypoxia by regulating cell apoptosis. Furthermore, the miRNA and protein analysis revealed that miR-17-5p significantly attenuated phosphatase and tensin homolog (PTEN) expression in cardiomyocytes exposed to doxorubicin. Taken together, dexrazoxane might exert a cardioprotective effect against doxorubicin-induced cardiomyocyte apoptosis by regulating the expression of miR-17-5p/PTEN cascade.

Ultraconserved (uc) RNAs, a class of long non-coding RNAs (lncRNAs), are conserved across humans, mice, and rats, but the physiological significance and pathological role of ucRNAs is largely unknown. Here we show that uc.372 is upregulated in the livers of db/db mice, HFD-fed mice, and NAFLD patients. Gain-of-function and loss-of-function studies indicate that uc.372 drives hepatic lipid accumulation in mice by promoting lipogenesis. We further demonstrate that uc.372 binds to pri-miR-195/pri-miR-4668 and suppresses maturation of miR-195/miR-4668 to regulate expression of genes related to lipid synthesis and uptake, including ACC, FAS, SCD1, and CD36. Finally, we identify that uc.372 is located downstream of the insulinoma-associated 2 (INSM2) gene that is transcriptionally activated by upstream transcription factor 1 (USF1). Our findings reveal a novel mechanism by which uc.372 drives hepatic steatosis through inhibition of miR-195/miR-4668 maturation to relieve miR-195/miR-4668-mediated suppression of functional target gene expression., Ultraconserved RNAs are a class of long non-coding RNAs whose functions are yet to be identified. Here Guo and colleagues show that an ultraconserved RNA uc.372 promotes lipogenesis and lipid accumulation within the hepatocytes by suppressing the maturation of miR-195/miR-4668 that inhibits lipogenic gene expression.

PURPOSE/OBJECTIVE(S) Inflammation markers play an important role in tumor proliferation, invasion and metastasis. Oligo-metastases, a state intermediate between widespread metastases and locally confined disease, where curative strategies may be effective for some patients. However, the prognostic value of inflammatory markers and corresponding nomogram in patients with colorectal oligo-metastases has not been adequately documented. MATERIALS/METHODS We retrospectively collected 209 patients with colorectal oligo-metastases. Overall survival (OS), and progression-free survival (PFS) were estimated by Kaplan-Meier survival analysis and Cox regression analysis. The multivariate Cox analysis model was used to build the nomogram, and the calibration curve, concordance index (C-index) and receiver operating characteristics (ROC) were used to evaluate the accuracy of the nomogram. RESULTS The multivariate analysis showed that platelet-to-lymphocyte ratio (PLR) was independently related with OS (HR = 2.396, 95% CI: 1.391-4.126, P = 0.002). Lymph nodes metastases predicted poor OS (HR = 2.472, 95% CI: 1.247-4.903, P = 0.010). While the early N stage had significant survival benefit for OS (HR = 4.602,95% CI: 2.055-10.305, P = 0.001) and PFS (HR = 2.100, 95% CI: 1.364-3.231, P = 0.007). Primary resection (HR = 0.367, 95% CI: 0.148-0.908, P = 0.030) and lower fibrinogen (HR = 2.254, 95% CI: 1.246-4.078, P = 0.007) were independently related with better OS. The Nomograms consisted of above significant risk factors, with C-index of 0.721 and AUC of 0.772 for OS. The calibration and ROC curves showed non-significant deviations between predicted and actual probability of OS. CONCLUSION Pretreatment PLR was independently related with OS in colorectal patients with oligo-metastases. And we built a nomogram including PLR, Lymph nodes metastases, Clinical N stage, Fibrinogen, and Primary resection to predict survivals in colorectal patients with oligo-metastases with a high validity and accuracy.

PURPOSE/OBJECTIVE(S) The high intracranial efficacy of target therapy agents challenges the sequence of local radiation therapy (RT) and systematic tyrosine kinase inhibitors (TKI) in brain metastases (BM) patients. Therefore, we conducted a single institutional retrospective cohort study to demonstrate the appropriate treatment strategy of upfront RT or upfront TKI in these patients, including an assessment of its feasibility and toxicity. MATERIALS/METHODS Patients with brain metastases who received hypofractionated stereotactic radiotherapy (HFSRT) with/without whole brain radiotherapy (WBRT) at our institution from October 2010 to October 2020 were included in this study. The primary endpoint was intracranial progression-free survival (IPFS). The secondary endpoints were overall survival (OS), brain metastases specific survival (BMSS) and toxicity. Intracranial progression was estimated using the Fine-Gray competing risks model. Kaplan-Meier analysis and Log-rank tests were used to evaluate and compare OS and BMSS. Multivariate analysis was performed using Cox logistic regression analysis. RESULTS Among 885 patients, 570 patients enrolled in the study. 130 patients received upfront TKI with RT, 193 patients received upfront RT with TKI, and 247 patients received RT alone. The median follow-up time was 56.4 months. Upfront RT group showed lower intracranial progression risk with adjusted SHR 0.51 (95% CI, 0. 40- 0.667) than upfront TKI group (median IPFS, 17.2 months vs. 8.5 months; P

PURPOSE/OBJECTIVE(S) Hypopharyngeal carcinoma (HPC) is one of the most devastating malignancies among head and neck cancers. Our aim is to analyze the clinical characteristics and prognosis of synchronous and metachronous second primary malignancies (SPMs) in patients with hypopharyngeal carcinoma. MATERIALS/METHODS We retrospectively reviewed 673 patients diagnosed in our institution between May 2009 and October 2019. Endoscopic examination was performed in 97.1% (654/673) of patients before treatment. We defined a synchronous SPM as which developed within 6 months of the index HPC diagnosis, while a metachronous SPM as which developed more than 6 months after initial diagnosis of HPC. The Kaplan-Meier method, propensity score-matched (PSM) and Cox model were used to analyze the data. RESULTS Within the median follow-up of 66.5 months, 71 (10.5%) patients developed gastric/esophageal tumor in situ (Tis) and 143 (21.2%), patients developed SPMs, consisting of 78 with synchronous SPMs and 75 with metachronous SPMs, respectively, with patient overlap. Among the 143 patients, the most common secondary site was esophagus (n = 85), followed by the head and neck squamous cell carcinoma (HNSCC, n = 36), lung (n = 20) and other cancers (n = 19). The 5-year overall survivals (OS) for non-SPMs (n = 459), SPMs (n = 143) and Tis group (n = 71) were 43.8% vs 37.1% vs 42.9%, respectively. Accordingly, the disease-specific survivals (DSS) were 46.3% vs 56.2% vs 47.8%, respectively. We compared synchronous SPMs and no-SPMs groups, the 5-year OS and DSS were 37.1% and 56.2% for synchronous SPMs group (n = 78), compared with 43.8% (P = 0.093) and 46.3% (P = 0.098) for no-SPMs group (n = 459). We use PSM to balance two arms with the ratio of 1:1, resulting in the number of 62 patients in each group. The adjusted 5-year OS and DSS were 23.6% and 32.7% for synchronous SPMs group (n = 62), compared with 49.8% (P < 0.001) and 52.4% (P < 0.001) for no-SPMs group (n = 62). For synchronous and metachronous SPMs, the 5-year OS and DSS were 27.3% and 40.8% for synchronous SPMs group (n = 78) vs 48.8% (P = 0.001) and 70.7% (P = 0.001) for metachronous SPMs group (n = 75). According to the site of the SPMs, the 5-year OS and DSS were 24.5% and 40.4% for esophagus (n = 85), 51.9% and 66.9% for HNSCC (n = 36), 52.0% and 75.1% for lung (n = 20), 60.7% and 83.9% for others (n = 19). The SPMs in esophagus had worse OS than the other three groups (P