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BACKGROUND: Emerging evidence suggested that S-adenosylhomocysteine (SAH) may be a better serum biomarker for cardiovascular disease than homocysteine (Hcy). However, the role of SAH in hepatocellular carcinoma (HCC) prognosis remains unclear. OBJECTIVES: We aimed to prospectively explore the relationships between serum SAH and related metabolites [Hcy, S-adenosylmethionine (SAM)] with HCC survival, and to evaluate the effect modifications by gene polymorphisms in one-carbon metabolism key enzymes. METHODS: We included 1080 newly diagnosed patients with HCC from the Guangdong Liver Cancer Cohort. Serum SAH, Hcy, and SAM were measured utilizing high-performance liquid chromatography-tandem mass spectrometry. Gene polymorphisms in one-carbon metabolism key enzymes were identified using kompetitive allele-specific polymerase chain reaction. Primary outcomes were liver cancer-specific survival (LCSS) and overall survival (OS). Hazard ratios (HRs) and 95% confidence intervals (CIs) were computed using multivariate Cox proportional hazards models. RESULTS: After a median follow-up of 3.6 y, 601 deaths occurred, with 552 (92%) attributed to HCC. Multivariable analysis revealed that patients in the highest quartile of serum SAH concentrations were significantly associated with worse survival compared with those in the lowest quartile, with HRs of 1.58 (95% CI: 1.19, 2.10; P-trend = 0.002) for LCSS and 1.54 (95% CI: 1.18, 2.02; P-trend = 0.001) for OS. There were no significant interactions between serum SAH concentrations and genetic variants of one-carbon metabolism key enzymes. No significant associations were found between serum Hcy, SAM concentrations, and SAM/SAH ratio with LCSS or OS. CONCLUSIONS: Higher serum SAH concentrations, rather than Hcy, were independently associated with worse survival in patients with HCC, regardless of the genetic variants of one-carbon metabolism key enzymes. These findings suggest that SAH may be a novel metabolism-related prognostic biomarker for HCC.
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Background: Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-associated death. Emerging evidence suggests that autophagy plays a critical role in HCC tumorigenesis, metastasis, and prognosis. Choline is an essential nutrient related to prolonged survival and reduced risk of HCC. However, it remains unclear whether this phenomenon is mediated by autophagy. Methods: Two HCC cell lines (HUH-7 and Hep3B) were used in the present study. Cell growth was evaluated by cell counting kit 8 (CCK-8), colony formation, and in vivo mouse xenografts assays. Cell motility was calculated by wound healing and transwell assays. Autophagosomes were measured by transmission electron microscope (TEM), and autophagy flux was detected by mRFP-GFP-labeled LC3 protein. The mRNA level of genes was measured by quantitative real-time polymerase chain reaction (qRT-PCR). The protein levels were detected by Western blotting (WB). Results: We found that choline inhibited the proliferation, migration, and invasion of HCC cells by downregulating autophagy in vitro and in vivo. Upregulated expression of the solute carrier family 5 member 7 (SLC5A7), a specific choline transporter, correlated with better HCC prognosis. We further discovered that choline could promote SLC5A7 expression, upregulate cytoplasm p53 expression to impair the AMPK/mTOR pathway, and attenuate autophagy. Finally, we found that choline acted synergistically with sorafenib to attenuate HCC development in vitro and in vivo. Conclusions: Our findings provide novel insights into choline-mediated autophagy in HCC, providing the foothold for its future application in HCC treatment.
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Background: The role of transarterial chemoembolization (TACE) in the treatment of advanced hepatocellular carcinoma (HCC) is unconfirmed. This study aimed to assess the efficacy and safety of immune checkpoint inhibitors (ICIs) plus anti-vascular endothelial growth factor (anti-VEGF) antibody/tyrosine kinase inhibitors (TKIs) with or without TACE as first-line treatment for advanced HCC. Methods: This nationwide, multicenter, retrospective cohort study included advanced HCC patients receiving either TACE with ICIs plus anti-VEGF antibody/TKIs (TACE-ICI-VEGF) or only ICIs plus anti-VEGF antibody/TKIs (ICI-VEGF) from January 2018 to December 2022. The study design followed the target trial emulation framework with stabilized inverse probability of treatment weighting (sIPTW) to minimize biases. The primary outcome was overall survival (OS). Secondary outcomes included progression-free survival (PFS), objective response rate (ORR), and safety. The study is registered with ClinicalTrials.gov, NCT05332821. Findings: Among 1244 patients included in the analysis, 802 (64.5%) patients received TACE-ICI-VEGF treatment, and 442 (35.5%) patients received ICI-VEGF treatment. The median follow-up time was 21.1 months and 20.6 months, respectively. Post-application of sIPTW, baseline characteristics were well-balanced between the two groups. TACE-ICI-VEGF group exhibited a significantly improved median OS (22.6 months [95% CI: 21.2-23.9] vs 15.9 months [14.9-17.8]; P < 0.0001; adjusted hazard ratio [aHR] 0.63 [95% CI: 0.53-0.75]). Median PFS was also longer in TACE-ICI-VEGF group (9.9 months [9.1-10.6] vs 7.4 months [6.7-8.5]; P < 0.0001; aHR 0.74 [0.65-0.85]) per Response Evaluation Criteria in Solid Tumours (RECIST) version 1.1. A higher ORR was observed in TACE-ICI-VEGF group, by either RECIST v1.1 or modified RECIST (41.2% vs 22.9%, P < 0.0001; 47.3% vs 29.7%, P < 0.0001). Grade ≥3 adverse events occurred in 178 patients (22.2%) in TACE-ICI-VEGF group and 80 patients (18.1%) in ICI-VEGF group. Interpretation: This multicenter study supports the use of TACE combined with ICIs and anti-VEGF antibody/TKIs as first-line treatment for advanced HCC, demonstrating an acceptable safety profile. Funding: National Natural Science Foundation of China, National Key Research and Development Program of China, Jiangsu Provincial Medical Innovation Center, Collaborative Innovation Center of Radiation Medicine of Jiangsu Higher Education Institutions, and Nanjing Life Health Science and Technology Project.
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Tumor-associated macrophages (TAMs) usually adopt a tumor-promoting M2-like phenotype, which largely impedes the immune response and therapeutic efficacy of solid tumors. Repolarizing TAMs from M2 to the antitumor M1 phenotype is crucial for reshaping the tumor immunosuppressive microenvironment (TIME). Herein, we developed self-assembled nanoparticles from the polymeric prodrug of resiquimod (R848) to reprogram the TIME for robust cancer immunotherapy. The polymeric prodrug was constructed by conjugating the R848 derivative to terminal amino groups of the linear dendritic polymer composed of linear poly(ethylene glycol) and lysine dendrimer. The amphiphilic prodrug self-assembled into nanoparticles (PLRS) of around 35 nm with a spherical morphology. PLRS nanoparticles could be internalized by antigen-presenting cells (APCs) in vitro and thus efficiently repolarized macrophages from M2 to M1 and facilitated the maturation of APCs. In addition, PLRS significantly inhibited tumor growth in the 4T1 orthotopic breast cancer model with much lower systemic side effects. Mechanistic studies suggested that PLRS significantly stimulated the TIME by repolarizing TAMs into the M1 phenotype and increased the infiltration of cytotoxic T cells into the tumor. This study provides an effective polymeric prodrug-based strategy to improve the therapeutic efficacy of R848 in cancer immunotherapy.
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Imidazoles , Inmunoterapia , Nanopartículas , Profármacos , Profármacos/química , Profármacos/farmacología , Profármacos/uso terapéutico , Animales , Ratones , Imidazoles/química , Imidazoles/farmacología , Nanopartículas/química , Femenino , Ratones Endogámicos BALB C , Línea Celular Tumoral , Humanos , Macrófagos Asociados a Tumores/efectos de los fármacos , Macrófagos Asociados a Tumores/inmunología , Antineoplásicos/química , Antineoplásicos/farmacología , Células RAW 264.7 , Polietilenglicoles/química , Microambiente Tumoral/efectos de los fármacos , Dendrímeros/química , Dendrímeros/farmacología , Macrófagos/efectos de los fármacos , Macrófagos/inmunología , Macrófagos/metabolismoRESUMEN
BACKGROUND: Indocyanine green (ICG) clearance test is a classical measurement of hepatic reserve, which involves surgical safety and patient recovery of hepatocellular carcinoma (HCC). The authors aim to compare effects of hepatic arterial infusion chemotherapy (HAIC) and transcatheter arterial chemoembolization (TACE) on liver function and outcomes of subsequent hepatectomy. MATERIAL AND METHODS: HCC patients receiving HAIC/TACE in SYSUCC with repeated ICG clearance tests were retrospectively enrolled. ICG eliminating rate (ICG-K), ICG retention rate at 15 min (ICG-R15) and ordinary laboratory tests were collected. Peri-therapeutic changes of values were compared between the groups. Propensity score matching (PSM) and inverse probability of treatment weighing (IPTW) were employed to validate findings. Post-hepatectomy liver failure (PHLF), overall survival (OS) and recurrence-free survival (RFS) were analyzed in patients with subsequent curative hepatectomy. RESULTS: Two hundred and four patients treated with HAIC ( n =130) and TACE ( n =74) were included. ΔICG-R15 was greater in the HAIC arm before matching (mean, 3.8% vs. 0.7%, P <0.001), after PSM (mean, 4.7% vs. 1.1%, P =0.014) and IPTW (mean, 2.0% vs. -3.6%, P <0.001). No difference was found for ΔALB, ΔALBI, ΔTBIL, ΔALT, ΔAST and ΔPT-INR. Multivariable analyses revealed elder age, cirrhosis, HAIC, greater ΔTBIL and ΔALBI were associated with deteriorating ICG-R15. Among those (105 for HAIC and 48 for TACE) receiving hepatectomy, occurrence of grade B/C PHLF (4.8% vs. 8.3%, P =0.616), OS (median, unreached vs. unreached, P =0.94) and RFS (median, 26.7 vs. 17.1 months, P =0.096) were comparable between the two arms. In subgroup analyses, preoperative HAIC yield superior RFS (median, 26.7 vs. 16.2 months, P =0.042) in patients with baseline ICG-R15 less than or equal to 10%. CONCLUSION: Preoperative FOLFOX-HAIC caused apparent impairment of ICG clearance ability than TACE yet comparable impact on liver function and post-hepatectomy outcomes.
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Carcinoma Hepatocelular , Quimioembolización Terapéutica , Hepatectomía , Verde de Indocianina , Pruebas de Función Hepática , Neoplasias Hepáticas , Humanos , Verde de Indocianina/administración & dosificación , Verde de Indocianina/farmacocinética , Neoplasias Hepáticas/terapia , Neoplasias Hepáticas/cirugía , Masculino , Carcinoma Hepatocelular/terapia , Carcinoma Hepatocelular/cirugía , Femenino , Estudios Retrospectivos , Persona de Mediana Edad , Quimioembolización Terapéutica/métodos , Anciano , Resultado del Tratamiento , Hígado , Puntaje de PropensiónRESUMEN
Recent studies have suggested that therapeutic upregulation of CCAAT/enhancer binding protein α (C/EBPα) prevents hepatocellular carcinoma (HCC) progression. However, the mechanisms underlying this outcome are not fully understood. In this study, we investigated the expression and functional roles of C/EBPα in human HCC, with a focus on monocytes/macrophages (Mφs). Paraffin-embedded tissues were used to visualize C/EBPα expression and analyze the prognostic value of C/EBPα+ monocytes/Mφs in HCC patients. The underlying regulatory mechanisms were examined using human monocyte-derived Mφs. The results showed that the expression of C/EBPα on monocytes/Mφs was significantly decreased in intra-tumor tissues compared to the corresponding peri-tumor tissues. C/EBPα+ monocytes/Mφs displayed well-differentiation and antitumor capacities, and the accumulation of these cells in tissue was associated with antitumor immune responses and predicted longer overall survival (OS) of HCC patients. Mechanistic studies demonstrated that C/EBPα was required for Mφ maturation and HLA-DR, CD169 and CD86 expression, which initiates antitumor cytotoxic T-cell responses; however, these effects were inhibited by monocyte autocrine IL-6- and IL-1ß-induced suppression of mTOR1 signaling. Reprogramming Mφs via the upregulation of C/EBPα may provide a novel strategy for cancer immunotherapy in patients with HCC.
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Carcinoma Hepatocelular , Neoplasias Hepáticas , Humanos , Carcinoma Hepatocelular/patología , Neoplasias Hepáticas/patología , Proteína alfa Potenciadora de Unión a CCAAT/metabolismo , Macrófagos/metabolismo , Monocitos/metabolismoRESUMEN
Cholesterol is often enriched in tumor microenvironment (TME); however, its impact on disease progression varies in different tissues and cells. Monocytes/macrophages (Mφ) are major components and regulators of the TME and play pivotal roles in tumor progression and therapeutic responses. We aimed to investigate the profile, effects, and regulatory mechanisms of Mφ cholesterol metabolism in the context of human hepatocellular carcinoma (HCC). Here, we found that patients with high serum levels of cholesterol had shorter survival times and lower response rates to anti-PD-1 treatment. However, the cholesterol content in tumor-infiltrating monocytes/Mφ was significantly lower than that in their counterparts in paired nontumor tissues. The expression of the cholesterol efflux transporter, ABCA1, was upregulated in tumor monocytes/Mφ, and ABCA1 upregulation positively associated with decreased cellular cholesterol content and increased serum cholesterol levels. Mechanistically, autocrine cytokines from tumor-treated monocytes increased LXRα and ABCA1 expression, which led to the generation of immature and immunosuppressive Mφ. Although exogenous cholesterol alone had little direct effect on Mφ, it did act synergistically with tumor-derived factors to promote ABCA1 expression in Mφ with more immunosuppressive features. Moreover, high numbers of ABCA1+ Mφ in HCC tumors associated with reduced CD8+ T-cell infiltration and predicted poor clinical outcome for patients. Our results revealed that dysregulated cholesterol homeostasis, due to the collaborative effects of tumors and exogenous cholesterol, drives the generation of immunosuppressive Mφ. The selective modulation of cholesterol metabolism in Mφ may represent a novel strategy for cancer treatment.
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Carcinoma Hepatocelular , Neoplasias Hepáticas , Humanos , Carcinoma Hepatocelular/patología , Neoplasias Hepáticas/metabolismo , Macrófagos/metabolismo , Monocitos/metabolismo , Colesterol/metabolismo , Colesterol/farmacología , Microambiente TumoralRESUMEN
BACKGROUND: Dental treatment associated with unadaptable occlusal alteration can cause chronic primary myofascial orofacial pain. The serotonin (5-HT) pathway from the rostral ventromedial medulla (RVM) exerts descending modulation on nociceptive transmission in the spinal trigeminal nucleus (Sp5) and facilitates chronic pain. The aim of this study was to investigate whether descending 5-HT modulation from the RVM to the Sp5 is involved in the maintenance of primary myofascial orofacial hyperalgesia after persistent experimental occlusal interference (PEOI) or after delayed removal of experimental occlusal interference (REOI). METHODS: Expressions of 5-HT3A and 5-HT3B receptor subtypes in the Sp5 were assessed by immunofluorescence staining and Western blotting. The release and metabolism of 5-HT in the Sp5 were measured by high-performance liquid chromatography. Changes in the pain behavior of these rats were examined after specific pharmacologic antagonism of the 5-HT3 receptor, chemogenetic manipulation of the RVM 5-HT neurons, or selective down-regulation of 5-HT synthesis in the RVM. RESULTS: Upregulation of the 5-HT3B receptor subtype in the Sp5 was found in REOI and PEOI rats. The concentration of 5-HT in Sp5 increased significantly only in REOI rats. Intrathecal administration of Y-25130 (a selective 5-HT3 receptor antagonist) dose-dependently reversed the hyperalgesia in REOI rats but only transiently reversed the hyperalgesia in PEOI rats. Chemogenetic inhibition of the RVM 5-HT neurons reversed the hyperalgesia in REOI rats; selective down-regulation of 5-HT in advance also prevented the development of hyperalgesia in REOI rats; the above two manipulations did not affect the hyperalgesia in PEOI rats. However, chemogenetic activation of the RVM 5-HT neurons exacerbated the hyperalgesia both in REOI and PEOI rats. CONCLUSIONS: These results provide several lines of evidence that the descending pathway from 5-HT neurons in the RVM to 5-HT3 receptors in the Sp5, plays an important role in facilitating the maintained orofacial hyperalgesia after delayed EOI removal, but has a limited role in that after persistent EOI.
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Dolor Crónico , Hiperalgesia , Ratas , Animales , Hiperalgesia/inducido químicamente , Núcleo Espinal del Trigémino/metabolismo , Receptores de Serotonina 5-HT3/metabolismo , Receptores de Serotonina 5-HT3/uso terapéutico , Serotonina/metabolismo , Ratas Sprague-Dawley , Dolor Facial/etiología , Dolor Crónico/etiologíaRESUMEN
OBJECTIVES: The study aims to investigate the safety and feasibility of retrograde CTO intervention via collateral connection grade 0 (CC-0) septal channel and to identify predictors of collateral tracking failure. BACKGROUND: Guidewire crossing a collateral channel is a critical step for successful retrograde percutaneous coronary intervention (PCI) of chronic total occlusion (CTO). METHODS: Retrograde PCI was attempted in 122 cases of CTO with CC-0 septal collaterals from December 2018 to May 2021. A hydrophilic polymer coating guidewire was used for crossing all intended CC-0 collaterals. A multivariable logistic regression analysis was performed to identify the predictors of guidewire tracking failure via the CC-0 collaterals. RESULTS: Successful guidewire tracking via CC-0 septal channel was achieved in 98 (80.3%) of 122 cases. The independent predictors of CC-0 septal channel guidewire tracking failure included well-developed non-septal collateral (OR: 5.297, 95% CI: 1.107-25.353, p = 0.037) and the ratio length of posterior descending artery (PDA) versus the distance of PDA ostium to cardiac apex ≤2/3 (OR: 3.970, 95% CI: 1.454-10.835, p = 0.007). Collateral perforation, target vessel perforation, and cardiac tamponade occurred in 5 (4.1%), 3 (2.5%), and 6 (4.9%) cases, respectively. There were no complications requiring emergency cardiac surgery or revascularization of nontarget vessel. CONCLUSIONS: Retrograde PCI via CC-0 septal channels with a hydrophilic polymer-coated guidewire is feasible and safe in patients with CTO. Well-developed nonseptal collaterals and short PDA length influence the procedure success and the risk of guidewire tracking failure via CC-0 septal channels.
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Oclusión Coronaria , Intervención Coronaria Percutánea , Humanos , Intervención Coronaria Percutánea/efectos adversos , Intervención Coronaria Percutánea/métodos , Oclusión Coronaria/terapia , Oclusión Coronaria/cirugía , Resultado del Tratamiento , Angiografía Coronaria/métodos , Circulación Colateral , Enfermedad CrónicaRESUMEN
Background: There is limited evidence about vessel wall healing response following implantation of next-generation drug-eluting stents (DES) in patients admitted with a non-ST elevation acute coronary syndrome (NSTE-ACS). Cumulative data indicate that optical coherence tomography (OCT) imaging can optimize percutaneous coronary intervention results and expedite stent endothelialization in the general population but there is lack of data in NSTE-ACS patients. Methods: The EXPECT study is an investigator-initiated, prospective, randomized trial to assess early vascular healing response following next-generation DES implantation in patients admitted with NSTE-ACS based on OCT guidance and evaluation. Sixty patients are randomized at 1:1:1 ratio to OCT-guided percutaneous coronary intervention (PCI) with 3-month follow-up OCT imaging (O3 group, n = 20), to angiography-guided PCI with 3-month follow-up OCT imaging (A3 group, n = 20) and to angiography-guided PCI with 6-month follow-up OCT imaging (A6 group, n = 20). The primary endpoint of the study is stent strut coverage rate at 3- or 6- month follow-up in the studied groups. The secondary endpoints of the study include OCT imaging endpoints, clinical endpoints, and molecular biology endpoints at the different time points. The clinical endpoints comprised of major cardiovascular adverse events and individual components. The molecular biology endpoints comprised of lipid levels and the levels of inflammatory indicators. Discussion: The findings of the EXPECT study are anticipated to provide novel insights into vessel wall healing in NSTE-ACS population following implantation of next-generation DES, underscore the value of OCT imaging in expediting strut coverage in this setting, and explore the potential of an early discontinuation of dual antiplatelet therapy (DAPT) in this population. Clinical Trial Registration: ClinicalTrials.gov, NCT04375319.
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Surgery and drug therapy are the two principal options for cancer treatment. However, their clinical benefits are hindered by the difficulty of accurate location of the tumors and timely monitoring of the treatment efficacy of drugs, respectively. Rapid development of imaging techniques provides promising tools to address these challenges. Compared with conventional imaging techniques such as magnetic resonance imaging and computed tomography etc., fluorescence imaging exhibits high spatial resolution, real-time imaging capability, and relatively low costs devices. The advancements in fluorescent probes further accelerate the implementation of fluorescence imaging in tumor diagnosis and treatment monitoring. In particular, the emergence of site-specifically activatable fluorescent probes fits the demands of tumor delineation and real-time feedback of the treatment efficacy. A variety of small molecule probes or nanoparticle-based probes have been developed and explored for the above-mentioned applications. This review will discuss recent advances in fluorescent probes with a special focus on activatable nanoprobes and highlight the potential implementation of activatable nanoprobes in fluorescence imaging-guided surgery as well as imaging-guided drug therapy.
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Nanopartículas , Neoplasias , Humanos , Colorantes Fluorescentes , Neoplasias/diagnóstico por imagen , Neoplasias/tratamiento farmacológico , Neoplasias/patología , Imagen Óptica/métodos , Tomografía Computarizada por Rayos XRESUMEN
Background: Percutaneous coronary intervention (PCI) has a well-established role in revascularization for coronary artery disease. We performed network meta-analysis to provide evidence on optimal intervention strategies for de novo lesions in small coronary arteries. Materials and methods: Enrolled studies were randomized clinical trials that compared different intervention strategies [balloon angioplasty (BA), biolimus-coated balloon (BCB), bare-metal stent (BMS), new-generation drug-eluting stent (New-DES), older generation sirolimus-eluting stent (Old-SES), paclitaxel-coated balloon (PCB), and paclitaxel-eluting stent (PES)] for de novo lesions in small coronary arteries. The primary outcome was major adverse cardiac events (MACE). Results: A total of 23 randomized clinical trials comparing seven intervention devices were analyzed. In terms of the primary outcome, New-DES was the intervention device with the best efficacy [surface under the cumulative ranking curve (SUCRA), 89.1%; mean rank, 1.7], and the Old-SES [risk ratio (RR), 1.09; 95% confidence interval (CI), 0.45-2.64] and PCB (RR, 1.40; 95% CI, 0.72-2.74) secondary to New-DES, but there was no statistically significant difference between these three intervention devices. All DES and PCB were superior to BMS and BA for MACE in both primary and sensitivity analysis. For secondary outcomes, there was no association between all-cause mortality and myocardial infarction (MI) with any intervention strategy, and additionally, the findings of target lesion revascularization (TLR) were similar to the primary outcomes. Conclusion: Paclitaxel-coated balloon yielded similar outcomes to New-DES for de novo lesions in small coronary arteries. Therefore, this network meta-analysis may provide potential support for PCB as a feasible, effective, and safe alternative intervention strategy for the revascularization of small coronary arteries. Systematic review registration: [https://www.crd.york.ac.uk/PROSPERO/#recordDetails], identifier [CRD42022338433].
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BACKGROUND: Adopting healthy lifestyles and staying mentally health are two cost-effective modifiable strategies that cancer survivors can implement in self-management. We aimed to evaluate the independent, mediation, interaction, and joint associations of combined lifestyle and mental health with mortality in cancer survivors. METHODS: We performed a cohort study including 3145 cancer survivors from National Health and Nutrition Examination Survey (2005-2018). A healthy lifestyle score was constructed based on post-diagnosis body mass index, physical activity, diet, smoking, and drinking. Post-diagnosis mental health was assessed by Patient Health Questionnaire (PHQ-9). Hazard ratios (HRs) and 95% confidence intervals (CIs) for all-cause, cancer, and non-cancer mortality were computed using Cox proportional hazards regression models. RESULTS: After 20,900 person-years of follow-up (median, 6.3 years), cancer survivors with higher lifestyle score had decreased mortality, independent of mental health. Compared to participants with lower lifestyle score (0-1), HRs (95% CIs) for all-cause and non-cancer mortality among those with higher lifestyle score (3-5) were 0.68 (0.52-0.89) and 0.69 (0.56-0.85), respectively. 6.2-10.3% of the associations were mediated by mental health. Similar trends were observed among participants categorized by mental health, those with better mental health had lower mortality, independent of lifestyle. Participants with better mental health benefited more from adopting healthy lifestyles, and vice versa. Combinations of higher healthy lifestyle score and better mental health were associated with significant decreased mortality, the lowest mortality was seen in participants with highest healthy lifestyle score and concurrently with best mental health. CONCLUSIONS: For the first time, in this cohort study with a nationally representative sample of US cancer survivors, we comprehensively explored the complex associations of lifestyle, mental health, and mortality. Evidence derived from this study may give much confidence to cancer survivors and healthcare providers that, changing one's lifestyle and/or staying mentally healthy after cancer diagnosis can improve survival.
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Supervivientes de Cáncer , Neoplasias , Estudios de Cohortes , Humanos , Estilo de Vida , Salud Mental , Neoplasias/complicaciones , Encuestas Nutricionales , Factores de RiesgoRESUMEN
Background and Objectives: Use of drug-coated balloon (DCB)-only strategy for revascularization of native large coronary artery lesions is on the rise. The long-term efficacy of this approach for bifurcation and non-bifurcation lesions remains unknown. We aim to assess the long-term clinical outcomes of DCB-only strategy for the treatment of de novo bifurcation and non-bifurcation lesions in large coronary arteries. Methods: This multicenter, prospective, observational study enrolled 119 patients with de novo coronary lesions in vessels ≥2.75 mm. The primary end point was the rate of clinically driven target lesion failure (TLF), a composite of cardiac death, target vessel myocardial infarction, and clinically driven target lesion revascularization (TLR). Patients were followed up for a median of 2 years. Results: Of 119 patients with 138 lesions, 66 patients (75 lesions) had bifurcation and 53 patients (63 lesions) had non-bifurcation lesions. Average reference vessel diameter was 3.1 ± 0.3 mm, and there was no difference in bifurcation and non-bifurcation group (3.0 ± 0.3 vs. 3.1 ± 0.3mm; p = 0.27). At 2-year follow-up, the TLF occurred in five (4.2%), TLR in four (3.4%), and target vessel revascularization (TVR) in five (4.2%) cases. The frequency of TLR and TVR was higher in the non-bifurcation group (p = 0.04 and 0.02, respectively), but there were no differences in TLF between the two groups (p = 0.17). The cumulative incidence of TLF (Kaplan-Meier estimates) was also not different in the two groups (log-rank p = 0.11). Conclusion: DCB-only strategy for de novo lesions in large coronary arteries appears to be safe and effective for both bifurcation and non-bifurcation lesions. Further randomized clinical trials are warranted to confirm the value of DCB-only strategy in de novo bifurcation lesions of large vessels.
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Cancer immunotherapy restores or enhances the effector function of T cells in the tumor microenvironment, but the efficacy of immunotherapy has been hindered by therapeutic resistance. Here, we identify the proto-oncogene serine/threonine protein kinase PIM2 as a novel negative feedback regulator of IFNγ-elicited tumor inflammation, thus endowing cancer cells with aggressive features. Mechanistically, IL1ß derived from IFNγ-polarized tumor macrophages triggered PIM2 expression in cancer cells via the p38 MAPK/Erk and NF-κB signaling pathways. PIM2+ cancer cells generated by proinflammatory macrophages acquired the capability to survive, metastasize, and resist T-cell cytotoxicity and immunotherapy. A therapeutic strategy combining immune checkpoint blockade (ICB) with IL1ß blockade or PIM2 kinase inhibition in vivo effectively and successfully elicited tumor regression. These results provide insight into the regulatory and functional features of PIM2+ tumors and suggest that strategies to influence the functional activities of inflammatory cells or PIM2 kinase may improve the efficacy of immunotherapy. SIGNIFICANCE: Cross-talk between T cells and macrophages regulates cancer cell PIM2 expression to promote cancer aggressiveness, revealing translational approaches to improve response to ICB in hepatocellular carcinoma.
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Carcinoma Hepatocelular , Neoplasias Hepáticas , Carcinoma Hepatocelular/terapia , Humanos , Inhibidores de Puntos de Control Inmunológico , Inmunoterapia , Neoplasias Hepáticas/terapia , Macrófagos/metabolismo , FN-kappa B/metabolismo , Proteínas Serina-Treonina Quinasas , Proteínas Proto-Oncogénicas/metabolismo , Serina , Treonina , Microambiente Tumoral , Proteínas Quinasas p38 Activadas por Mitógenos/metabolismoRESUMEN
Background: The efficacy of radiofrequency ablation (RFA) for patients with early-stage recurrent hepatocellular carcinoma (HCC) with microvascular invasion (MVI) at the initial hepatectomy is limited. Our study aimed to explore whether adjuvant sorafenib following RFA could improve the situation. Methods: We retrospectively included 211 patients with early-stage (tumor number of ≤3 and tumor size of 2-5 cm) recurrent HCC with MVI at the initial hepatectomy who underwent adjuvant sorafenib following RFA or RFA alone in 13 centers from June 2013 to June 2020. In the combination group, sorafenib of 400 mg twice daily was administered within 7 days after RFA. Overall survival (OS) and recurrence-free survival (RFS) were compared. Subgroup analysis based on MVI grade was performed. MVI grade was based on the practice guidelines for the pathological diagnosis of HCC and included M1 (≤5 MVI sites, all located within adjacent peritumoral liver tissues 0-1 cm away from the tumor margin) and M2 (>5 MVI sites, or any MVI site located within adjacent peritumoral liver tissues > 1 cm away from the tumor margin). Results: A total of 103 patients received the combination therapy and 108 patients received RFA alone. The combination therapy provided better survival than RFA alone (median RFS: 17.7 vs. 13.1 months, P < 0.001; median OS: 32.0 vs. 25.0 months, P = 0.002). Multivariable analysis revealed that treatment allocation was an independent prognostic factor. On subgroup analysis, the combination therapy provided better survival than RFA alone in patients with M1 along with either a tumor size of 3-5 cm, tumor number of two to three, or alpha-fetoprotein (AFP) > 400 µg/L, and in those with M2 along with either a tumor size of 2-3 cm, one recurrent tumor, or AFP ≤ 400 µg/L. Conclusions: Adjuvant sorafenib following RFA was associated with better survival than RFA alone in patients with early-stage recurrent HCC with MVI at the initial hepatectomy. Moreover, MVI grade could guide the application of adjuvant sorafenib.
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OBJECTIVE: To investigate the safety and efficacy of a percutaneous revascularization strategy that is based on the use of drug-coated balloon for the treatment of patients with acute coronary syndrome and de novo Medina type 0,1,0 or 0,0,1 left main stem bifurcation lesions. METHODS: In this multicenter, prospective, proof-of-concept study, patients fulfilling the above criteria were enrolled and received treatment with drug-coated balloon combined with provisional drug-eluting stent implantation in the proximal major branches of the left main stem. Patients who declined this revascularization approach were treated with drug-eluting stent implantation 1-2 mm distally to the left anterior descending or left circumflex artery ostium followed by drug-coated balloon therapy for the ostial disease. The primary endpoint of the study was the calculation of percent diameter stenosis on quantitative coronary angiography post-procedure as well as event rate at 8 months follow-up. RESULTS: A total of 30 patients were enrolled in the study; their mean age was 60.3 ± 7.8 years, while 22 (73.3%) were male. Twenty-two patients were treated only with drugcoated balloon and provisional drug-eluting stent implantation and 8 had drug-eluting stent implantation followed by drug-coated balloon therapy of the ostium of the left main stem major branch. All the procedures were successful with no immediate complications. The percent diameter stenosis of lesion decreased significantly post-procedure from 87.5% (80.0-90.0) to 20% (17.5-30.0), P <.001. During the follow-up period, no major adverse cardiac events were reported. CONCLUSIONS: This proof-of-concept study indicates that ostial drug-coated balloon therapy of the left main stem major branches is safe and effective. Larger clinical data and longer follow-up are needed before advocating its regular use in clinical practice.
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Angioplastia Coronaria con Balón , Stents Liberadores de Fármacos , Anciano , Angiografía Coronaria , Humanos , Masculino , Persona de Mediana Edad , Estudios Prospectivos , Resultado del TratamientoRESUMEN
BACKGROUND: Entecavir (ETV) and tenofovir disoproxil fumarate (TDF) are recommended as first-line choices regarding the treatment of chronic hepatits B. The impact of the two antiviral agents on prognosis of hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC) after curative liver resection remains to be explored. We aimed to assess the effect of antiviral therapy with ETV or TDF after curative resection on the prognosis of patients with HBV-related HCC. METHODS: A total of 1173 consecutive patients who were treated with ETV or TDF after curative liver resection for HCC were enrolled in the study. HCC recurrence, overall survival, postoperative liver function reserve, and early virologic (VR) and biochemical responses (BR) of patients were compared between the ETV and TDF groups by propensity score matching (PSM) from the date of liver resection for HCC. RESULTS: No difference was observed with recurrence-free survival between TDF and ETV in the PSM cohort (hazard ratio [HR], 0.91; 95% confidence interval [CI] 0.70-1.17; P = 0.45). No difference was observed with early VR and BR between TDF and ETV in the PSM cohort. Compared with ETV, TDF therapy was associated with significantly better protection of liver function and higher overall survival rates in the PSM cohort (HR, 0.37; 95% CI 0.20-0.71; P = 0.002). After PSM, 69 (40.8%) patients in the ETV group and 63 (57.3%) patients in the TDF group had single tumor recurrence, while the TDF group had significantly more patients with single tumor recurrence in the PSM cohort (P = 0.007). CONCLUSIONS: For patients who underwent curative resection for HBV-related HCC, TDF treatment had a significantly better overall survival and better protection of liver function, but no difference in the incidences of HCC recurrence than ETV treatment.
Asunto(s)
Carcinoma Hepatocelular , Hepatitis B Crónica , Neoplasias Hepáticas , Antivirales/uso terapéutico , Carcinoma Hepatocelular/patología , Guanina/análogos & derivados , Virus de la Hepatitis B , Hepatitis B Crónica/complicaciones , Hepatitis B Crónica/tratamiento farmacológico , Humanos , Neoplasias Hepáticas/etiología , Pronóstico , Estudios Retrospectivos , Tenofovir/uso terapéutico , Resultado del TratamientoRESUMEN
BACKGROUND & AIMS: Epidemiological evidence linking fibroblast growth factor 21 (FGF21) with hepatocellular carcinoma (HCC) prognosis lacked. We aimed to evaluate the associations between serum FGF21 levels and HCC survival in a large prospective cohort. METHODS: 825 newly diagnosed, previously untreated HCC patients from the Guangdong Liver Cancer Cohort were enrolled between September 2013 and April 2017. Serum FGF21 levels were measured by ELISA. Liver cancer-specific survival (LCSS) and overall survival (OS) were calculated. Multivariable Cox proportional hazards models were performed to calculate the hazard ratios (HRs) and 95% confidence intervals (CIs). RESULTS: Compared with patients in the lowest tertile of serum FGF21 levels, patients in the highest tertile had inferior survival outcomes. HRs in the fully adjusted models were 1.44 (95% CI: 1.07, 1.94; P-trend = .014) and 1.48 (95% CI: 1.12, 1.97; P-trend = .002) for LCSS and OS, respectively. The associations were not significantly modified by selected metabolic disorder diseases or state such as arterial hypertension, diabetes, dyslipidemia, fatty liver, cirrhosis, and body mass index ≥25.0 kg/m2 , except for that stronger associations were observed in patients co-occurred more than three metabolic disorder diseases (P-interaction = .046 for OS and .151 for LCSS), with an HR of 2.01 (95% CI: 1.04, 3.85; P-trend = .009) for OS and 1.51 (95% CI: 0.73, 3.10; P-trend = .195) for LCSS. CONCLUSIONS: Higher serum FGF21 levels were associated with worse survival in HCC patients, suggesting that serum FGF21 may be used as a novel metabolism-related prognostic biomarker for HCC.