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1.
Artigo em Inglês | MEDLINE | ID: mdl-39299550

RESUMO

PURPOSE: To compare the outcomes of transarterial chemoembolization (TACE) alone with those of TACE combined with external beam radiation therapy (EBRT) in patients with hepatocellular carcinoma (HCC) in a multicenter randomized study. METHODS AND MATERIALS: From 2017 to 2022, 74 HCC patients with tumors confined to the liver without vascular invasion were treated with either TACE only (TACE group, 39 patients) or TACE combined with EBRT (TACE + EBRT group, 35 patients). The primary outcome measured was overall survival (OS). Secondary outcomes included progression-free survival (PFS), local tumor control, and the assessment of treatment-related toxicity. RESULTS: Due to slow accrual, the trial was closed prematurely after enrolling 74 patients. All patients received 2 cycles of TACE before randomization. The TACE and TACE + EBRT groups showed comparable patient and tumor characteristics. The TACE group underwent a median of 3 TACE cycles, and the TACE + EBRT group received 2 cycles of TACE, and a median of 5500 cGy in 15 fractions. For the TACE group, the median local control (LC) duration was 13.1 months, whereas for the TACE + EBRT group, the median LC was not achieved (P < .001). The PFS was recorded at 11.6 months in the TACE group compared with 15.4 months in the TACE + EBRT group (P = .072). The median OS reached 36.8 months for the TACE group and extended to 47.1 months for the TACE + EBRT group (P = .654). The incidence of toxicity was comparable between both groups. CONCLUSIONS: Although the number of patients enrolled in this clinical trial did not meet expectations. TACE combined with EBRT was shown to be more effective than TACE alone in improving LC without increasing toxicity, whereas PFS and OS were slightly improved. TACE + EBRT can be used as a standard treatment option for patients with inoperable but confined intrahepatic HCC.

3.
Clin Exp Immunol ; 218(2): 188-198, 2024 Oct 16.
Artigo em Inglês | MEDLINE | ID: mdl-39185713

RESUMO

Preclinical data suggest that type I interferon (IFN) responsiveness is essential for the antitumor effects of radiotherapy (RT). However, its clinical value remains unclear. This study aimed to explore this from a clinical perspective. In cohort 1, data from 152 hepatocellular carcinoma (HCC) patients who received RT were analyzed. Blood samples were taken 1 day before and 2 weeks after RT. RT was found to increase serum levels of IFN-ß (a subtype of IFN-I) in HCC patients (3.42 ±â€…1.57 to 5.51 ±â€…2.11 pg/ml, P < 0.01), particularly in those with favorable responses. Higher post-RT serum IFN-ß levels (≥4.77 pg/ml) were associated with better progression-free survival (HR = 0.58, P < 0.01). Cohort 2 included 46 HCC patients, including 23 who underwent preoperative RT and 23 matched control HCC who received surgical resection without RT. Formalin-fixed paraffin-embedded samples were obtained. Neoadjuvant RT significantly increased IFN-ß expression in tumor tissues compared to direct surgery (8.13% ±â€…5.19% to 15.10% ±â€…5.89%, P < 0.01). Higher post-RT IFN-ß (>median) indicated better disease-free survival (P = 0.049). Additionally, increased CD11c+MHCII+CD141+ antigen-presenting cell subsets and CD103+CD39+CD8+ tumor-infiltrating lymphocytes were found in the higher IFN-ß group (P = 0.02, P = 0.03), which may contribute to the favorable prognosis in higher IFN-ß group. Collectively, these findings suggest that IFN-ß response activated by radiation may serve as a prognostic biomarker for HCC patients undergoing RT.


Assuntos
Carcinoma Hepatocelular , Interferon beta , Neoplasias Hepáticas , Humanos , Carcinoma Hepatocelular/radioterapia , Carcinoma Hepatocelular/mortalidade , Carcinoma Hepatocelular/imunologia , Carcinoma Hepatocelular/patologia , Neoplasias Hepáticas/radioterapia , Neoplasias Hepáticas/mortalidade , Neoplasias Hepáticas/imunologia , Neoplasias Hepáticas/patologia , Masculino , Feminino , Pessoa de Meia-Idade , Interferon beta/uso terapêutico , Idoso , Prognóstico , Adulto
4.
Radiother Oncol ; 199: 110424, 2024 10.
Artigo em Inglês | MEDLINE | ID: mdl-38997092

RESUMO

Various genetic and epigenetic changes associated with genomic instability (GI), including DNA damage repair defects, chromosomal instability, and mitochondrial GI, contribute to development and progression of cancer. These alterations not only result in DNA leakage into the cytoplasm, either directly or through micronuclei, but also trigger downstream inflammatory signals, such as the cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) signaling pathway. Apart from directly inducing DNA damage to eliminate cancer cells, radiotherapy (RT) exerts its antitumor effects through intracellular DNA damage sensing mechanisms, leading to the activation of downstream inflammatory signaling pathways. This not only enables local tumor control but also reshapes the immune microenvironment, triggering systemic immune responses. The combination of RT and immunotherapy has emerged as a promising approach to increase the probability of abscopal effects, where distant tumors respond to treatment due to the systemic immunomodulatory effects. This review emphasizes the importance of GI in cancer biology and elucidates the mechanisms by which RT induces GI remodeling of the immune microenvironment. By elucidating the mechanisms of GI and RT-induced immune responses, we aim to emphasize the crucial importance of this approach in modern oncology. Understanding the impact of GI on tumor biological behavior and therapeutic response, as well as the possibility of activating systemic anti-tumor immunity through RT, will pave the way for the development of new treatment strategies and improve prognosis for patients.


Assuntos
Instabilidade Genômica , Inibidores de Checkpoint Imunológico , Neoplasias , Microambiente Tumoral , Humanos , Neoplasias/radioterapia , Neoplasias/imunologia , Inibidores de Checkpoint Imunológico/uso terapêutico , Inibidores de Checkpoint Imunológico/farmacologia , Microambiente Tumoral/imunologia , Dano ao DNA
5.
Chin Med J (Engl) ; 137(11): 1332-1342, 2024 Jun 05.
Artigo em Inglês | MEDLINE | ID: mdl-38725345

RESUMO

BACKGROUND: To address the need for immunotherapy in patients with advanced primary hepatocellular carcinoma (HCC), combination with radiotherapy (RT) has emerged as a promising strategy. In preclinical studies, irradiated tumors released tumor antigens to synergistically increase the antitumor effect of immunotherapy. Hence, we investigated whether RT enhances the efficacy of anti-programmed death receptor-1 (PD-1) inhibitors in advanced HCC in real-world practice. METHODS: Between August 2018 and June 2021, 172 patients with advanced primary HCC were enrolled in the tertiary center (Zhongshan Hospital of Fudan University); 95 were treated with a combination of RT and the inhibitor of PD-1 (RT-PD1 cohort), and 77 were administered anti-PD-1 therapy (PD1 cohort). The first cycle of PD-1 inhibitors was administered within 60 days or concurrently with RT. Propensity score matching for bias reduction was used to evaluate the clinical outcomes. RESULTS: Among 71 propensity-matched pairs, median progression-free survival was 5.7 months in the RT-PD1 cohort vs. 2.9 months in the PD1 cohort ( P  <0.001). Median overall survival was 20.9 months in the RT-PD1 cohort vs. 11.2 months in the PD1 cohort ( P  = 0.018). Compared with patients in the PD1 cohort, patients in the RT-PD1 cohort had significantly higher objective response rates (40.8%, 29/71 vs. 19.7%, 14/71, P  = 0.006) and disease control rates (62.0%, 44/71 vs. 31.0%, 22/71, P  <0.001). The incidences of toxic effects were not significantly different between the two cohorts. CONCLUSIONS: RT plus anti-PD-1 therapy is well tolerated. RT enhances the efficacy of anti-PD-1 therapy in patients with advanced primary HCC by improving survival outcomes without increased toxic effects.


Assuntos
Carcinoma Hepatocelular , Neoplasias Hepáticas , Receptor de Morte Celular Programada 1 , Pontuação de Propensão , Humanos , Carcinoma Hepatocelular/radioterapia , Carcinoma Hepatocelular/tratamento farmacológico , Carcinoma Hepatocelular/patologia , Neoplasias Hepáticas/radioterapia , Neoplasias Hepáticas/tratamento farmacológico , Masculino , Feminino , Pessoa de Meia-Idade , Idoso , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Inibidores de Checkpoint Imunológico/uso terapêutico , Adulto
6.
Int J Radiat Oncol Biol Phys ; 120(2): 422-431, 2024 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-38631536

RESUMO

PURPOSE: The standard treatment schedule for unresectable stage III non-small cell lung cancer (NSCLC) is chemotherapy with concurrent radiation therapy (60 Gy delivered in 30 fractions), although moderately hypofractionated radiation therapy (Hypo-RT) has also been considered as an alternative strategy. This study aimed to compare the efficacy and toxicity of moderately Hypo-RT with helical TomoTherapy versus conventionally fractionated radiation therapy (Con-RT) in patients with unresectable stage III NSCLC receiving concurrent chemotherapy. METHODS AND MATERIALS: In this randomized, multicenter, nonblinded phase 3 clinical trial, eligible patients were randomised at a 1:1 ratio to either the Hypo-RT group (60 Gy in 20 fractions) or Con-RT group (60 Gy in 30 fractions). All patients received 2 cycles of concurrent platinum-based chemotherapy plus 2 cycles of consolidation therapy. The primary endpoint was 3-year overall survival (OS) in the intention-to-treat population. The secondary endpoints were progression-free survival and treatment-related adverse events. RESULTS: A total of 146 patients were enrolled from July 27, 2018, to November 1, 2021. The median follow-up was 46 months. The 3-year OS rates in the Hypo-RT and Con-RT groups were 58.4% and 38.4%, respectively (P = .02). The median OS from randomisation was 41 months in the Hypo-RT group and 30 months in the Con-RT group (hazard ratio, 0.61; 95% confidence interval, 0.40-0.94; P = .02). There was no significant difference in the rates of grade ≥2 treatment-related adverse events between the 2 groups. CONCLUSIONS: Moderately Hypo-RT using helical TomoTherapy may improve OS in patients with unresectable stage III NSCLC, while maintaining toxicity rates.


Assuntos
Carcinoma Pulmonar de Células não Pequenas , Quimiorradioterapia , Neoplasias Pulmonares , Hipofracionamento da Dose de Radiação , Radioterapia de Intensidade Modulada , Humanos , Carcinoma Pulmonar de Células não Pequenas/radioterapia , Carcinoma Pulmonar de Células não Pequenas/patologia , Carcinoma Pulmonar de Células não Pequenas/mortalidade , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Neoplasias Pulmonares/patologia , Neoplasias Pulmonares/radioterapia , Neoplasias Pulmonares/mortalidade , Neoplasias Pulmonares/tratamento farmacológico , Masculino , Feminino , Pessoa de Meia-Idade , Idoso , Radioterapia de Intensidade Modulada/efeitos adversos , Radioterapia de Intensidade Modulada/métodos , Quimiorradioterapia/efeitos adversos , Quimiorradioterapia/métodos , Intervalo Livre de Progressão , Estadiamento de Neoplasias , Adulto , Resultado do Tratamento , Fracionamento da Dose de Radiação
7.
Clin Transl Radiat Oncol ; 46: 100767, 2024 May.
Artigo em Inglês | MEDLINE | ID: mdl-38576855

RESUMO

Centrally located hepatocellular carcinoma (HCC) is difficult to be radically resected due to its special location close to major hepatic vessels. Thus, we aimed to assess whether stereotactic body radiation therapy (SBRT) can be an effective and safe approach for centrally located HCC. This retrospective study included 172 patients with centrally located HCC who were treated with SBRT. Overall survival (OS) was analyzed as the primary endpoint. Rates of progression-free survival (PFS), local control, intrahepatic relapse, extrahepatic metastasis and toxicities were analyzed as secondary endpoints. The OS rates of 1-, 3-, and 5-year were 97.7%, 86.7%, and 76.3%, respectively. The PFS/local control rates of 1-, 3-, and 5-year were 94.1%/98.2%, 76.8%/94.9%, and 59.3%/92.3%, respectively. The cumulative incidence of intrahepatic relapse/extrahepatic metastases of 1-, 3-, and 5-year were 3.7%/2.9%, 25.0%/7.4%, and 33.3%/9.8%, respectively. Both univariate and multivariate analyses revealed that patients received BED10 at 100 Gy or more had better OS. Radiation-related adverse events were mild to moderate according to Common Terminology Criteria for Adverse Events, and no toxicities over grade 3 were observed. Patients with centrally located HCC in our cohort who received SBRT had similar OS and PFS rates compared to those reported in literatures who received surgery with neoadjuvant or adjuvant intensity-modulated radiation therapy. These results indicate that SBRT is an effective and well-tolerated method for patients with centrally located HCC, suggesting that it may serve as a reasonable alternative treatment for these kind of patients.

8.
Adv Sci (Weinh) ; 11(16): e2308009, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38381090

RESUMO

Many patients with hepatocellular carcinoma (HCC) respond poorly to radiotherapy despite remarkable advances in treatment. A deeper insight into the mechanism of sensitivity of HCC to this therapy is urgently required. It is demonstrated that RECQL4 is upregulated in the malignant cells of patients with HCC. Elevated RECQL4 levels reduce the sensitivity of HCC to radiotherapy by repairing radiation-induced double-stranded DNA (dsDNA) fragments. Mechanistically, the inhibitory effect of RECQL4 on radiotherapy is due to the reduced recruitment of dendritic cells and CD8+ T cells in the tumor microenvironment (TME). RECQL4 disrupts the radiation-induced transformation of the TME into a tumoricidal niche by inhibiting the cGAS-STING pathway in dendritic cells. Knocking out STING in dendritic cells can block the impact of RECQL4 on HCC radiosensitivity. Notably, high RECQL4 expressions in HCC is significantly associated with poor prognosis in multiple independent cohorts. In conclusion, this study highlights how HCC-derived RECQL4 disrupts cGAS-STING pathway activation in dendritic cells through DNA repair, thus reducing the radiosensitivity of HCC. These findings provide new perspectives on the clinical treatment of HCC.


Assuntos
Carcinoma Hepatocelular , Neoplasias Hepáticas , Proteínas de Membrana , Nucleotidiltransferases , RecQ Helicases , Transdução de Sinais , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/imunologia , Carcinoma Hepatocelular/radioterapia , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/radioterapia , Neoplasias Hepáticas/imunologia , Nucleotidiltransferases/metabolismo , Nucleotidiltransferases/genética , Humanos , Proteínas de Membrana/genética , Proteínas de Membrana/metabolismo , Camundongos , Animais , RecQ Helicases/genética , RecQ Helicases/metabolismo , Microambiente Tumoral/imunologia , Células Dendríticas/imunologia , Células Dendríticas/metabolismo , Modelos Animais de Doenças , Tolerância a Radiação/genética , Linhagem Celular Tumoral
10.
Cancer Lett ; 582: 216507, 2024 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-38048841

RESUMO

Although Poly (ADP-ribose) polymerase (PARP) inhibitors have been clinically approved for cancers with BRCA mutations and are known to augment radiotherapy responses, their roles in promoting the abscopal effect and mediating immunotherapy in BRCA-proficient hepatocellular carcinoma (HCC) remain underexplored. Our study elucidates that olaparib enhances the radio-sensitivity of HCC cells. Coadministration of olaparib and irradiation induces significant DNA damage by generating double-strand breaks (DSBs), as revealed both in vitro and in immune-deficient mice. These DSBs activate the cGAS-STING pathway, initiating immunogenic cell death in abscopal tumors. STING activation reprograms the immune microenvironment in the abscopal tumors, triggering the release of type I interferon and chemokines, including CXCL9, CXCL10, CXCL11, and CCL5. This in turn amplifies T cell priming against tumor neoantigens, leading to an influx of activated, neoantigen-specific CD8+ T-cells within the abscopal tumors. Furthermore, olaparib attenuated the immune exhaustion induced by radiation and enhances the responsiveness of HCC to immune checkpoint inhibitors. Collectively, our data advocate that a synergistic regimen of PARP inhibitors and radiotherapy can strategically reinforce both local (primary) and systemic (abscopal) tumor control, bolstering HCC susceptibility to immunotherapy.


Assuntos
Carcinoma Hepatocelular , Neoplasias Hepáticas , Piperazinas , Animais , Camundongos , Carcinoma Hepatocelular/tratamento farmacológico , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/radioterapia , Linfócitos T CD8-Positivos , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/radioterapia , Neoplasias Hepáticas/metabolismo , Ftalazinas/farmacologia , Linhagem Celular Tumoral , Microambiente Tumoral
11.
Int J Radiat Oncol Biol Phys ; 119(1): 219-233, 2024 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-37914138

RESUMO

PURPOSE: Radiation therapy is a vital adjuvant treatment for liver cancer, although the challenge of radiation-induced liver diseases (RILDs) limits its implementation. Kupffer cells (KCs) are a crucial cell population of the hepatic immune system, and their biologic function can be modulated by multiple epigenetic RNA modifications, including N6-methyladenosine (m6A) methylation. However, the mechanism for m6A methylation in KC-induced inflammatory responses in RILD remains unclear. The present study investigated the function of m6A modification in KCs contributing to RILD. METHODS AND MATERIALS: Methylated RNA-immunoprecipitation sequencing and RNA transcriptome sequencing were used to explore the m6A methylation profile of primary KCs isolated from mice after irradiation with 3 × 8 Gy. Western blotting and quantitative real-time PCR were used to evaluate gene expression. DNA pulldown and chromatin immunoprecipitation assays were performed to verify target gene binding and identify binding sites. RESULTS: Methylated RNA-immunoprecipitation sequencing revealed significantly increased m6A modification levels in human KCs after irradiation, suggesting the potential role of upregulated m6A in RILD. In addition, the study results corroborated that methyltransferase-like 3 (METTL3) acts as a main modulator to promote the methylation and gene expression of TEAD1, leading to STING-NLRP3 signaling activation. Importantly, it was shown that IGF2BP2 functions as an m6A "reader" to recognize methylated TEAD1 mRNA and promote its stability. METTL3/TEAD1 knockdown abolished the activation of STING-NLRP3 signaling, protected against RILD, and suppressed inflammatory cytokines and hepatocyte apoptosis. Moreover, clinical human normal liver tissue samples collected after irradiation showed increased expression of STING and interleukin-1ß in KCs compared with nonirradiated samples. Notably, STING pharmacologic inhibition alleviated irradiation-induced liver injury in mice, indicating its potential therapeutic role in RILD. CONCLUSIONS: The results of our study reveal that TEAD1-STING-NLRP3 signaling activation contributes to RILD via METTL3-dependent m6A modification.


Assuntos
Células de Kupffer , Neoplasias Hepáticas , Humanos , Camundongos , Animais , Células de Kupffer/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Regulação para Cima , Piroptose , Neoplasias Hepáticas/metabolismo , RNA Mensageiro/genética , Metiltransferases/genética , Proteínas de Ligação a RNA/fisiologia
12.
Ann Surg Oncol ; 31(2): 883-891, 2024 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-38038788

RESUMO

BACKGROUND: This study aimed to compare the prognostic discrimination power of pretreatment pathologic N stage (prepN), lymph node tumor regression grade (LNTRG), and posttreatment pathologic N (ypN) category for esophageal squamous cell carcinoma (ESCC) patients who received neoadjuvant chemoradiotherapy (nCRT) plus surgery. METHODS: The study reviewed 187 ESCC patients from two medical centers who underwent nCRT plus surgery. Pathologic LNTRG was defined by the proportion of viable tumor area within the tumor bed in lymph nodes (LNs). An average LNTRG then was calculated by averaging the tumor regression grade (TRG) score of all resected LNs. Lymph nodes containing regression changes or vital tumor cells were used for interpretation of the prepN stage, which reflects the estimated number of originally involved LNs. RESULTS: The ypN, prepN, and LNTRG categories had significant prognostic stratification power (p < 0.001, log-rank test). Multivariable cox regression showed that all three categories were independent prognostic factors of disease-free survival (DFS) (p < 0.05). The LNTRG category showed a better prognostic value for DFS prediction than the ypN and prepN categories (Akaike information criterion [AIC]: LNTRG [933.69], ypN [937.56], prepN [937.45]). Additionally, the superior predictive capacity of the LNTRG category was demonstrated by decision curve analysis. Similar results were discovered for patients with remaining diseased LNs. CONCLUSIONS: The three staging categories had prognostic relevance for DFS, with the LNTRG category seeming to have better prognostic indication power. Comprehensive consideration of the ypN status, prepN status, and LN regression may allow for better prognostic stratification of patients.


Assuntos
Carcinoma de Células Escamosas , Neoplasias Esofágicas , Carcinoma de Células Escamosas do Esôfago , Humanos , Carcinoma de Células Escamosas do Esôfago/patologia , Terapia Neoadjuvante , Neoplasias Esofágicas/patologia , Carcinoma de Células Escamosas/patologia , Esofagectomia , Prognóstico , Linfonodos/patologia , Estadiamento de Neoplasias , Estudos Retrospectivos , Quimiorradioterapia
13.
Cancer Lett ; 582: 216594, 2024 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-38135208

RESUMO

AIMS: DNA damage repair (DDR) plays a pivotal role in hepatocellular carcinoma (HCC), driving oncogenesis, progression, and therapeutic response. However, the mechanisms of DDR mediated immune cells and immuno-modulatory pathways in HCC are yet ill-defined. METHODS: Our study introduces an innovative deep machine learning framework for precise DDR assessment, utilizing single-cell RNA sequencing (scRNA-seq) and bulk RNA-seq data. Single-cell RNA sequencing data were obtained and in total 85,628 cells of primary or post-immunotherapy cases were analyzed. Large-scale HCC datasets, including 1027 patients in house together with public datasets, were used for 101 machine-learning models and a novel DDR feature was derived at single-cell resolution (DDRscore). Druggable targets were predicted using the reverse phase protein array (RPPA) proteomic profiling of 169 HCC patients and RNA-seq data from 22 liver cancer cell lines. RESULTS: Our investigation reveals a dynamic interplay of DDR with natural killer cells and B cells in the primary HCC microenvironment, shaping a tumor-promoting immune milieu through metabolic programming. Analysis of HCC post-immunotherapy demonstrates elevated DDR levels that induces epithelial-mesenchymal transition and fibroblast-like transformation, reshaping the fibrotic tumor microenvironment. Conversely, attenuated DDR promotes antigen cross-presentation by dendritic cells and CD8+ T cells, modulating the inflammatory tumor microenvironment. Regulatory network analysis identifies the CXCL10-CXCR3 axis as a key determinant of immunotherapeutic response in low DDR HCC, potentially regulated by transcription factors GATA3, REL, and TBX21. Using machine learning techniques by combining bulk RNA-seq data in house together with public datasets, we introduce DDRscore, a robust consensus DDR scoring system to predict overall survival and resistance to PD-1 therapy in HCC patients. Finally, we identify BRAF as a potential therapeutic target for high DDRscore patients. CONCLUSION: Our comprehensive findings advance our understanding of DDR and the tumor microenvironment in HCC, providing insights into immune regulatory mechanisms mediated via DDR pathways.


Assuntos
Carcinoma Hepatocelular , Neoplasias Hepáticas , Humanos , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/terapia , Linfócitos T CD8-Positivos , Proteômica , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/terapia , Perfilação da Expressão Gênica , Dano ao DNA , Microambiente Tumoral
14.
Radiat Res ; 200(6): 531-537, 2023 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-38014555

RESUMO

Patients with hepatobiliary tumors who accept radiotherapy are at risk for radiation-induced liver fibrosis. MicroRNAs (miRNAs) have been implicated in the pathogenesis of radiation-induced liver damage and possess potential as novel biomarkers and therapeutic targets. However, the role of miR-146a-5p in radiation-induced liver fibrosis is less well understood. The current study was designed to evaluate the role of miR-146a-5p in radiation-induced liver fibrosis in mice and to investigate the possible mechanisms involved in miR-146a-5p-mediated effects. The experiments were performed on Institute of Cancer Research (ICR) mice which received fractionated radiation (30 Gy in 5 fractions) to the liver. The results show radiation could induce histopathological changes, liver dysfunction and fibrosis accompanied with decreased miR-146a-5p expression. miR-146a-5p agomir treatment resulted in recovery of liver function and reduced the amount of alpha-smooth muscle actin (α-SMA), collagen 1, protein tyrosine phosphatase receptor type A (PTPRA) and phosphorylated SRC in the livers of irradiated mice. Therefore, our study reveals that miR-146a-5p inhibits the progression of hepatic fibrosis after radiation treatment. And the beneficial role of miR-146a-5p may be relevant to PTPRA-SRC signaling pathway.


Assuntos
MicroRNAs , Humanos , Camundongos , Animais , MicroRNAs/genética , Cirrose Hepática/genética , Cirrose Hepática/metabolismo , Fibrose , Proteínas Tirosina Fosfatases Classe 4 Semelhantes a Receptores
15.
Liver Cancer ; 12(5): 405-444, 2023 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-37901768

RESUMO

Background: Primary liver cancer, of which around 75-85% is hepatocellular carcinoma in China, is the fourth most common malignancy and the second leading cause of tumor-related death, thereby posing a significant threat to the life and health of the Chinese people. Summary: Since the publication of Guidelines for Diagnosis and Treatment of Primary Liver Cancer in China in June 2017, which were updated by the National Health Commission in December 2019, additional high-quality evidence has emerged from researchers worldwide regarding the diagnosis, staging, and treatment of liver cancer, that requires the guidelines to be updated again. The new edition (2022 Edition) was written by more than 100 experts in the field of liver cancer in China, which not only reflects the real-world situation in China but also may reshape the nationwide diagnosis and treatment of liver cancer. Key Messages: The new guideline aims to encourage the implementation of evidence-based practice and improve the national average 5-year survival rate for patients with liver cancer, as proposed in the "Health China 2030 Blueprint."

16.
Front Oncol ; 13: 1109068, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37534251

RESUMO

Background: While adjuvant chemotherapy has been established as standard practice following radical resection of pancreatic ductal adenocarcinoma (PDAC), the role of adjuvant radiation therapy (RT) and which patients may benefit remains unclear. Methods: This retrospective study included PDAC patients who received pancreatic surgery from April 2012 to December 2019 in Zhongshan Hospital Fudan University. Patients with carcinoma in situ, distant metastasis, and without adjuvant chemotherapy were excluded. Cox proportional hazards modeling of survival were constructed to find potential prognostic factors. Propensity score matching (PSM) and exploratory subgroup analyses were used to create a balanced covariate distribution between groups and to investigate therapeutic effect of radiotherapy in certain subgroups. Results: A total of 399 patients were finally included, 93 of them receiving adjuvant chemoradiotherapy (C+R+) and 306 of them receiving chemotherapy only. Patients in C+R+ group were more likely to be male patients with T3-4 disease. Lymph node metastases was the only negative prognostic factor associated with overall survival (OS). Additional adjuvant RT was not associated with an OS benefit both before and after PSM. Surprisingly, a trend towards improved OS with RT among patients with either T4, N2 disease or R1 resection becomes significant in patients alive more than 1 year after surgery. Conclusion: Adjuvant RT was not associated with an OS benefit across all patients, though did show a possible OS benefit for the subgroup with T4N2 disease or R1 resection at 1 year after surgery.

17.
World J Gastroenterol ; 29(24): 3871-3882, 2023 Jun 28.
Artigo em Inglês | MEDLINE | ID: mdl-37426321

RESUMO

BACKGROUND: Stereotactic body radiotherapy (SBRT) and programmed cell death 1 inhibitors have shown potential in treating hepatocellular carcinoma (HCC) in retrospective studies. AIM: To evaluate the efficacy of combining SBRT with sintilimab for patients with recurrent or oligometastatic HCC. METHODS: This trial involved patients with recurrent or oligometastatic HCC intravenously treated with SBRT plus sintilimab every 3 wk for 12 mo or until disease progression. The primary endpoint was progression-free survival (PFS). RESULTS: Twenty-five patients were enrolled from August 14, 2019, to August 23, 2021. The median treatment duration was 10.2 (range, 0.7-14.6) months. SBRT was delivered at a median dose of 54 (range, 48-60) Gy in 6 (range, 6-10) fractions. The median follow-up time was 21.9 (range, 10.3-39.7) mo, and 32 targeted lesions among 25 patients were evaluated for treatment response according to the Response Evaluation Criteria in Solid Tumors version 1.1. The median PFS was 19.7 mo [95% confidence interval (CI): 16.9-NA], with PFS rates of 68% (95%CI: 52-89) and 45.3% (95%CI: 28-73.4) at 12 and 24 mo, respectively. The median overall survival (OS) was not reached, with OS rates of 91.5% (95%CI: 80.8-100.0) and 83.2% (95%CI: 66.5-100.0) at 12 and 24 mo, respectively. The 1- and 2-year local control rate were 100% and 90.9% (95%CI: 75.4%-100.0%), respectively. The confirmed objective response rate and disease control rate was 96%, and 96%, respectively. Most adverse events were graded as 1 or 2, and grade 3 adverse events were observed in three patients. CONCLUSION: SBRT plus sintilimab is an effective, well-tolerated treatment regimen for patients with recurrent or oligometastatic HCC.


Assuntos
Carcinoma Hepatocelular , Neoplasias Hepáticas , Radiocirurgia , Humanos , Radiocirurgia/efeitos adversos , Estudos Retrospectivos
18.
Cancers (Basel) ; 15(12)2023 Jun 13.
Artigo em Inglês | MEDLINE | ID: mdl-37370774

RESUMO

PURPOSE: Although systemic treatment is the mainstay for advanced hepatocellular carcinoma (HCC), numerous studies have highlighted the added value of local treatment. This study aimed to investigate the clinical efficacy of liver-directed combined radiotherapy (LD combined RT) compared with that of sorafenib, a recommended treatment until recently for locally advanced HCC presenting portal vein tumor thrombosis (PVTT), using a multinational patient cohort. MATERIALS AND METHODS: We identified patients with HCC presenting PVTT treated with either sorafenib or LD combined RT in 10 tertiary hospitals in Asia from 2005 to 2014. Propensity score matching (PSM) was performed to minimize the imbalance between the two groups. The primary endpoint was overall survival (OS), and the secondary endpoints were progression-free survival (PFS) and treatment-related toxicity. RESULTS: A total of 1035 patients (675 in the LD combined RT group and 360 in the sorafenib group) were included in this study. After PSM, 305 patients from each group were included in the analysis. At a median follow-up of 22.5 months, the median OS was 10.6 and 4.2 months for the LD combined RT and sorafenib groups, respectively (p < 0.001). The conversion rate to curative surgery was significantly higher (8.5% vs. 1.0%, p < 0.001), while grade ≥ 3 toxicity was fewer (9.2% vs. 16.1%, p < 0.001) in the LD combined RT group. CONCLUSIONS: LD combined RT improved survival outcomes with a higher conversion rate to curative surgery in patients with locally advanced HCC presenting PVTT. Although further prospective studies are warranted, active multimodal local treatment involving radiotherapy is suggested for locally advanced HCC presenting PVTT.

19.
Int J Radiat Oncol Biol Phys ; 117(4): 928-941, 2023 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-37230431

RESUMO

PURPOSE: Radiation therapy (RT) is indispensable for managing thoracic carcinomas. However, its application is limited by radiation-induced lung injury (RILI), one of the most common and fatal complications of thoracic RT. Nonetheless, the exact molecular mechanisms of RILI remain poorly understood. METHODS AND MATERIALS: To elucidate the underlying mechanisms, various knockout mouse strains were subjected to 16 Gy whole-thoracic RT. RILI was assessed by quantitative real-time polymerase chain reaction, enzyme-linked immunosorbent assay, histology, western blot, immunohistochemistry, and computed tomography examination. To perform further mechanistic studies on the signaling cascade during the RILI process, pulldown, chromatin immunoprecipitation assay, and rescue assays were conducted. RESULTS: We found that the cGAS-STING pathway was significantly upregulated after irradiation exposure in both the mouse models and clinical lung tissues. Knocking down either cGAS or STING led to attenuated inflammation and fibrosis in mouse lung tissues. NLRP3 is hardwired to the upstream DNA-sensing cGAS-STING pathway to trigger of the inflammasome and amplification of the inflammatory response. STING deficiency suppressed the expressions of the NLRP3 inflammasome and pyroptosis-pertinent components containing IL-1ß, IL-18, GSDMD-N, and cleaved caspase-1. Mechanistically, interferon regulatory factor 3, the essential transcription factor downstream of cGAS-STING, promoted the pyroptosis by transcriptionally activating NLRP3. Moreover, we found that RT triggered the release of self-dsDNA in the bronchoalveolar space, which is essential for the activation of cGAS-STING and the downstream NLRP3-mediated pyroptosis. Of note, Pulmozyme, an old drug for the management of cystic fibrosis, was revealed to have the potential to mitigate RILI by degrading extracellular dsDNA and then inhibiting the cGAS-STING-NLRP3 signaling pathway. CONCLUSIONS: These results delineated the crucial function of cGAS-STING as a key mediator of RILI and described a mechanism of pyroptosis linking cGAS-STING activation with the amplification of initial RILI. These findings indicate that the dsDNA-cGAS-STING-NLRP3 axis might be potentially amenable to therapeutic targeting for RILI.

20.
Front Oncol ; 13: 1076428, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37251953

RESUMO

Background: Previous studies have shown that systemic inflammation indicators could predict the survival outcomes of patients with malignant tumors receiving various treatments. Radiotherapy, as a crucial treatment modality, effectively alleviates discomfort in patients with bone metastasis (BM) and greatly improves the quality of life for them. This study aimed to investigate the prognostic value of systemic inflammation index in hepatocellular carcinoma (HCC) patients with BM treated with radiotherapy. Methods: We retrospectively analyzed clinical data collected from HCC patients with BM who received radiotherapy in our institution between January 2017 and December 2021. The pre-treatment neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), and systemic immune-inflammation index (SII) were derived to determine their relationship with overall survival (OS) and progression-free survival (PFS), using the Kaplan-Meier survival curves. The optimal cut-off value of the systemic inflammation indicators for predicting prognosis was assessed by receiver operating characteristic (ROC) curves. Univariate and multivariate analyses were performed to ultimately evaluate the factors associated with survival. Results: The study included 239 patients with a median 14-month follow-up. The median OS was 18 months (95% confidence interval [CI] = 12.0-24.0) and the median PFS was 8.5 months (95% CI = 6.5-9.5). The optimal cut-off values for the patients were determined by ROC curve analysis as follows: SII =395.05, NLR=5.43 and PLR = 108.23. The area under the receiver operating characteristic curve values for SII, NLR and PLR in disease control prediction were 0.750, 0.665 and 0.676, respectively. Elevated systemic immune-inflammation index (SII>395.05) and higher NLR (NLR>5.43) were independently associated with poor OS and PFS. In multivariate analysis, Child-Pugh class (P = 0.038), intrahepatic tumor controlled (P = 0.019), SII (P = 0.001) and NLR (P = 0.007) were independent prognostic factors of OS and Child-Pugh class (P = 0.042), SII (P < 0.001) and NLR (P = 0.002) were independently correlated with PFS. Conclusion: NLR and SII were associated with poor prognosis in HCC patients with BM receiving radiotherapy and might be considered reliable and independent prognostic biomarkers for HCC patients with BM.

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