Chinese Society of Clinical Oncology Breast Cancer(CSCO BC)Guidelines in 2024:International Contributions from China

The Chinese Society of Clinical Oncology Breast Cancer(CSCO BC)guidelines have been widely implemented in China since the first release in 2017.The Guideline Working Committee has also published multiple versions in English,Arabic,and other languages to facilitate communications with international experts.

Chinese Society of Clinical Oncology Breast Cancer(CSCO BC)guidelines in 2022:stratification and classification

In April 2017,the first edition Chinese Society of Clinical Oncology Breast Cancer(CSCO BC)guidelines were released.These guidelines were based on medical evidence,as well as the accessibility and cost effectiveness of various anticancer drugs in China.The CSCO BC guidelines include regimens with a high level of evidence,good product accessibility and high consistent consensus among Chinese experts as level I recommendations.Regimens with a high level of evidence but poor product accessibility or expert consensus are included as level II recommendations.

Pre-hospital application of REBOA for life-threatening hemorrhage

Dear Editor,Most battlefield casualties occur prior to the arrival of medical facilities.Uncontrollable hemorrhage accounts for more than 90%of those potentially survivable battlefield casualties[1].In both military and civilian conditions,non-compressible torso hemorrhage always caused rapid exsanguination and high mortality rates before definitive treatment[2].More than half of the deaths due to non-compressible torso hemorrhage occur before hospital care can be provided[2].Therefore,early and rapid pre-hospital hemorrhage control is essential to reduce mortality.

Dynamics of glutamine synthetase expression in hepatic ischemiareperfusion injury: Implications for therapeutic interventions

BACKGROUND Hepatic ischemia-reperfusion injury(IRI)poses a great challenge in liver surgery and transplantation because of oxidative stress and inflammatory responses.The changes in glutamine synthetase(GS)expression during hepatic IRI remain unclear.AIM To investigate the dynamic expression of GS during hepatic IRI.METHODS Following hepatic ischemia for 1 h and reperfusion,liver tissue samples were collected at 0.5,6,and 24 hours postreperfusion for fixation,embedding,section-ing.Hematoxylin and eosin staining and GS staining were performed.RESULTS GS expression rapidly decreases in hepatocytes around the central vein after IRI,reaching its lowest point at 6 hours postreperfusion,and then gradually recovers.CONCLUSION GS is highly sensitive to IRI,highlighting its potential role as an indicator of liver injury states and a target for therapeutic intervention.

Liver infiltration of multiple immune cells during the process of acute liver injury and repair

BACKGROUND Immune cells,including neutrophils,natural killer(NK)cells,T cells,NKT cells and macrophages,participate in the progression of acute liver injury and hepatic recovery.To date,there has been no systematic study on the quantitative changes in these different immune cells from initial injury to subsequent recovery.AIM To investigate the infiltration changes of various immune cells in acute liver injury models over time,and to study the relationship between the changes in leukocyte cellderived chemotaxin 2(LECT2)and the infiltration of several immune cells.METHODS Carbon tetrachloride-and concanavalin A-induced acute liver injury models were employed to mimic toxin-induced and autoimmune-mediated liver injury respectively.The quantitative changes in various immune cells were monitored at different time points.Serum samples were collected,and liver tissues were harvested.Ly6G,CD161,CD4,CD8 and F4/80 staining were used to indicate neutrophils,NK/NKT cells,CD4^(+)T cells,CD8^(+)T cells and macrophages,respectively.Lect2-KO mice were used to detect the function of LECT2.RESULTS During the injury and repair process,different types of immune cells began to increase,reached their peaks and fell into decline at different time points.Furthermore,when the serum alanine transaminase(ALT)and aspartate transaminase(AST)indices reverted to normal levels 7 d after the injury,the infiltration of immune cells still existed even 14 d after the injury,showing an obvious lag effect.We found that the expression of LECT2 was upregulated in acute liver injury mouse models,and the liver injuries of Lect2-KO mice were less severe than those of wild-type mice.Compared with wild-type mice,Lect2-KO mice had different immune cell infiltration.CONCLUSION The recovery time of immune cells was far behind that of serum ALT and AST during the process of liver repair.LECT2 could regulate monocyte/macrophage chemotaxis and might be used as a therapeutic target for acute liver injury.

Current status and prospect of treatments for recurrent hepatocellular carcinoma

Owing to its heterogeneous and highly aggressive nature,hepatocellular carcinoma(HCC)has a high recurrence rate,which is a non-negligible problem despite the increasing number of available treatment options.Recent clinical trials have attempted to reduce the recurrence and develop innovative treatment options for patients with recurrent HCC.In the event of liver remnant recurrence,the currently available treatment options include repeat hepatectomy,salvage liver transplantation,tumor ablation,transcatheter arterial chemoembolization,stereotactic body radiotherapy,systemic therapies,and combination therapy.In this review,we summarize the strategies to reduce the recurrence of high-risk tumors and aggressive therapies for recurrent HCC.Additionally,we discuss methods to prevent HCC recurrence and prognostic models constructed based on predictors of recurrence to develop an appropriate surveillance program.

Single cell analysis unveils B cell-dominated immune subtypes in HNSCC for enhanced prognostic and therapeutic stratification

Head and neck squamous cell carcinoma(HNSCC)is characterized by high recurrence or distant metastases rate and the prognosis is challenging.There is mounting evidence that tumor-infiltrating B cells(TIL-Bs)have a crucial,synergistic role in tumor control.However,little is known about the role TIL-Bs play in immune microenvironment and the way TIL-Bs affect the outcome of immune checkpoint blockade.Using single-cell RNA sequencing(scRNA-seq)data from the Gene Expression Omnibus(GEO)database,the study identified distinct gene expression patterns in TIL-Bs.HNSCC samples were categorized into TIL-Bs inhibition and TIL-Bs activation groups using unsupervised clustering.This classification was further validated with TCGA HNSCC data,correlating with patient prognosis,immune cell infiltration,and response to immunotherapy.We found that the B cells activation group exhibited a better prognosis,higher immune cell infiltration,and distinct immune checkpoint levels,including elevated PD-L1.A prognostic model was also developed and validated,highlighting four genes as potential biomarkers for predicting survival outcomes in HNSCC patients.Overall,this study provides a foundational approach for B cells-based tumor classification in HNSCC,offering insights into targeted treatment and immunotherapy strategies.

Zinc pretreatment for protection against intestinal ischemiareperfusion injury

BACKGROUND Intestinal ischemia-reperfusion(I/R)injury(II/RI)is a critical condition that results in oxidative stress,inflammation,and damage to multiple organs.Zinc,an essential trace element,offers protective benefits in several tissues during I/R injury,but its effects on intestinal II/RI remain unclear.METHODS C57BL/6 mice were pretreated with zinc sulfate(ZnSO4,10 mg/kg)daily for three days before I/R injury was induced via superior mesenteric artery occlusion(SMAO)and abdominal aortic occlusion(AAO)models.Tissue and serum samples were collected to evaluate intestinal,liver,and kidney damage using Chiu’s score,Suzuki score,and histopathological analysis.Caco-2 cells and intestinal organoids were used for in vitro hypoxia-reoxygenation injury models to measure reactive oxygen species(ROS)and superoxide dismutase(SOD)levels.RESULTS Zinc pretreatment significantly reduced intestinal damage in the SMAO and AAO models(P<0.001).The serum levels of liver enzymes(alanine aminotransferase,aspartate aminotransferase)and kidney markers(creatinine and urea)were lower in the zinc-treated mice than in the control mice,indicating reduced hepatic and renal injury.In vitro,zinc decreased ROS levels and increased SOD activity in Caco-2 cells subject to hypoxia-reoxygenation injury.Intestinal organoids pretreated with zinc exhibited enhanced resilience to hypoxic injury compared to controls.CONCLUSION Zinc pretreatment mitigates II/RI and reduces associated multiorgan damage.These findings suggest that zinc has potential clinical applications in protecting against I/R injuries.

Melatonin inhibits ESCC tumor growth by mitigating the HDAC7/β-catenin/c-Myc positive feedback loop and suppressing the USP10-maintained HDAC7 protein stability

Background:Melatonin,a natural hormone secreted by the pineal gland,has been reported to exhibit antitumor properties through diverse mechanisms of action.However,the oncostatic function of melatonin on esophageal squamous cell carcinoma(ESCC) remains elusive.This study was conducted to investigate the potential effect and underlying molecular mechanism of melatonin as single anticancer agent against ESCC cells.Methods:ESCC cell lines treated with or without melatonin were used in this study.In vitro colony formation and 5-Ethynyl-2’-deoxyuridine(EdU) incorporation assays,and nude mice tumor xenograft model were used to confirm the proliferative capacities of ESCC cells.RNA-seq,qPCR,Western blotting,recombinant lentivirus-mediated target gene overexpression or knockdown,plasmids transfection and co-IP were applied to investigate the underlying molecular mechanism by which melatonin inhibited ESCC cell growth.IHC staining on ESCC tissue microarray and further survival analyses were performed to explore the relationship between target genes’ expression and prognosis of ESCC.Results:Melatonin treatment dose-dependently inhibited the proliferative ability and the expression of histone deacetylase 7(HDAC7),c-Myc and ubiquitin-specific peptidase 10(USP10) in ESCC cells(P<0.05).The expressions of HDAC7,c-Myc and USP10 in tumors were significantly higher than the paired normal tissues from 148 ESCC patients(P<0.001).Then,the Kaplan-Meier survival analysis suggested that ESCC patients with high HDAC7,c-Myc or USP10levels predicted worse overall survival(log-rank P<0.001).Co-IP and Western blotting further revealed that HDAC7physically deacetylated and activated β-catenin thus promoting downstream target c-Myc gene transcription.Notably,our mechanistic study validated that HDAC7/β-catenin/c-Myc could form the positive feedback loop to enhance ESCC cell growth,and USP10 could deubiquitinate and stabilize HDAC7 protein in the ESCC cells.Additionally,we verified that inhibition of the HDAC7/β-catenin/c-Myc axis and USP10/HDAC7 pathway mediated the anti-proliferative action of melatonin on ESCC cells.Conclusions:Our findings elucidate that melatonin mitigates the HDAC7/β-catenin/c-Myc positive feedback loop and inhibits the USP10-maintained HDAC7 protein stability thus suppressing ESCC cell growth,and provides the reference for identifying biomarkers and therapeutic targets for ESCC.

Pancreatic cancer with synchronous liver and colon metastases: A case report

BACKGROUND Metastasis of pancreatic cancer to the colon is rare and the features need to be further elucidated.Herein,we report a rare case of pancreatic cancer with simultaneous liver and colon metastases.CASE SUMMARY A 48-year-old man with intrahepatic space-occupying lesions based on a computed tomography scan was admitted to our hospital for further treatment.Abdominal magnetic resonance imaging revealed a 6.4 cm×4.2 cm mass in the tail of the pancreas and multiple low-density masses in the liver parenchyma.In addition,a mass of 2.2 cm×1.6 cm with surface congestive erosions in the sigmoid colon was detected by colonoscopy.Histopathological examination of biopsies from both the liver and colon lesions revealed a moderately to poorly differentiated adenocarcinoma.Immunohistochemical staining of the colon tumor was positive for cytokeratin(CK)7 and CK,but negative for colorectal adenocarcinoma-related markers CK 20,CDX2,and SATB2,thus indicating that the metastasis originated from the pancreas.Next-generation sequencing for genomic profiling of the liver and colon metastases both found mutations in KRAS(p.G12D)and TP53(c.376-1delG),with microsatellite stable and low tumor mutational burden without actionable or cancer-predisposing gene mutations detected.The patient was subsequently treated with 12 cycles of FOLFIRINOX which led to a sustainable response,followed by ongoing maintenance treatment with irinotecan plus fluorouracil.CONCLUSION For this rare case,careful evaluation of histopathological and immunohistochemical staining results are required.The genomic profiling of colon lesions was revealed for the first time,and FOLFIRINOX showed good treatment efficacy in this patient.

Per-oral endoscopic myotomy is safe and effective for pediatric patients with achalasia:A long-term follow-up study

BACKGROUND Per-oral endoscopic myotomy(POEM)is emerging as a prefer treatment option for pediatric achalasia.However,data are limited on the long-term efficacy of POEM in children and adolescents with achalasia.AIM To evaluate the safety and long-term efficacy of POEM for pediatric patients with achalasia and compare those outcomes with adult patients.METHODS This retrospective cohort study was conducted in patients with achalasia who underwent POEM.Patients aged under 18 years were included in the pediatric group;patients aged between 18 to 65 years who underwent POEM in the same period were assigned to the control group.For investigation of long-term followup,the pediatric group were matched with patients from the control group in a 1:1 ratio.The procedure-related parameters,adverse events,clinical success,gastroesophageal reflux disease(GERD)after POEM,and quality of life(QoL)were evaluated.RESULTS From January 2012 to March 2020,POEM was performed in 1025 patients aged under 65 years old(48 in the pediatric group,1025 in the control group).No significant differences were observed in the occurrence of POEM complications between the two groups(14.6%vs 14.6%;P=0.99).Among the 34 pediatric patients(70.8%)who underwent follow-up for 5.7 years(range 2.6-10.6 years),clinical success was achieved in 35 patients(35/36;97.2%).No differences were observed in post-POEM GERD occurrence(17.6%vs 35.3%;P=0.10).QoL was significantly improved in both groups after POEM.CONCLUSION POEM is safe and effective for pediatric patients with achalasia.It can achieve significant symptoms relief and improve QoL.

Histone deacetylases:Regulation of vascular homeostasis via endothelial cells and vascular smooth muscle cells and the role in vascular pathogenesis

tHistone deacetylases(HDACs)are proteases that play a key role in chromosome structural modification and gene expression regulation,and the involvement of HDACs in can-cer,the nervous system,and the metabolic and immune system has been well reviewed.Our understanding of the function of HDACs in the vascular system has recently progressed,and a significant variety of HDAC inhibitors have been shown to be effective in the treatment of vascular diseases.However,few reviews have focused on the role of HDACs in the vascular sys-tem.In this study,the role of HDACs in the regulation of the vascular system mainly involving endothelial cells and vascular smooth muscle cells was discussed based on recent updates,and the role of HDACs in different vascular pathogenesis was summarized as well.Furthermore,the therapeutic effects and prospects of HDAC inhibitors were also addressed in this review.

MRI/PAI Dual-modal Imaging-guided Precise Tracking of Bone Marrow-derived Mesenchymal Stem Cells Labeled with Nanoparticles for Treating Liver Cirrhosis

Background and Aims:Stem cell transplantation is a potential treatment option for liver cirrhosis(LC).Accurately and noninvasively monitoring the distribution,migration,and prognosis of transplanted stem cells using imaging methods is important for in-depth study of the treatment mechanisms.Our study aimed to develop Au-Fe3O4 silica nanoparticles(NPs)as tracking nanoplatforms for dualmodal stem cell imaging.Methods:Au-Fe3O4 silica NPs were synthesized by seed-mediated growth method and co-precipitation.The efficiency and cytotoxicity of the NPslabeled bone marrow-derived mesenchymal stem cells(BMMSCs)were evaluated by Cell Counting Kit-8 assays,ICPMS,phenotypic characterization,and histological staining.The biodistribution of labeled BM-MSCs injected through different routes(the hepatic artery or tail vein)into rats with LC was detected by magnetic resonance imaging(MRI),photoacoustic imaging(PAI),and Prussian blue staining.Results:Synthesized Au-Fe3O4 silica NPs consisted of a core(star-shaped Au NPs)and an outside silica layer doped with Fe3O4 NPs.After 24 h coincubation with 2.0 OD concentration of NPs,the viability of BM-MSCs was 77.91%±5.86%and the uptake of Au and Fe were(22.65±1.82)µg/mL and(234.03±11.47)µg/mL,respectively.The surface markers of labeled BM-MSCs unchanged significantly.Labeled BMMSCs have osteogenic and adipogenic differentiation potential.Post injection in vivo,rat livers were hypointense on MRI and hyperintense on PAI.Prussian blue staining showed that more labeled BM-MSCs accumulated in the liver of the hepatic artery group.The severity of LC of the rats in the hepatic artery group was significantly alleviated.Conclusions:Au-Fe3O4 silica NPs were suitable MRI/PAI dual-modal imaging nanoplatforms for stem cell tracking in regenerative medicine. Transhepatic arterial infusion of BMMSCs was the optimal route for the treatment of LC.

Emerging role of ubiquitination/deubiquitination modification of PD-1/PD-L1 in cancer immunotherapy

As members of the immune checkpoint family, PD-1 and its ligand PD-L1 play critical roles in maintaining the balance between autoimmunity and tolerance. The interaction of PD-1/PD-L1 is also involved in tumor evasion inside the tumor microenvironment, caused by reduced T cell activation, proliferation, cytotoxic secretion, and survival. Previous research has shown that the expression level of PD-1/PD-L1 may be regulated by ubiquitin-mediated proteasome degradation, which is an important mode of post-translational modification (PTM). PD-1/PD-L1 ubiquitin modification research in tumor immunotherapy is the subject of the present review, which aims to assess the most recent developments in this area. We offer a short explanation of PD-1/PD-L1 as well as some basic background information on the UPS system and discuss many routes that target E3s and DUBs, respectively, in the regulation of PD-1/PD-L1 in tumor immunotherapy. In addition, we offer numerous innovative prospective research areas for the future, as well as novel immunotherapy concepts and ideas. Taken together, the information compiled herein should serve as a comprehensive repository of information about tumor immunotherapy that is currently available, and it should be useful in the design of future studies, as well as the development of potential targets and strategies for future tumor immunotherapy.

Efficacy and safety of subsequent radiotherapy in patients with advanced-stage hepatocellular carcinoma treated with immune checkpoint inhibitors

Background:The development of immunotherapy resistance is associated with a poor prognosis in patients diagnosed with hepatocellular carcinoma(HCC)who are undergoing treatment with immune checkpoint inhibitors(ICI).This study aimed to evaluate the efficacy and safety of subsequent radiotherapy(RT)for patients with advanced-stage HCC who had lesion enlargement or new lesions(NLs)during ICI therapy.Methods:This retrospective observational study enrolled 36 patients with advanced-stage HCC who underwent subsequent RT for lesion enlargement or NLs during ICI therapy from two centers.The primary endpoints were progression-free survival(PFS)and overall survival(OS).The secondary endpoints included objective response rate(ORR),disease control rate(DCR),1-and 2-year local control(LC)rates,in-field PFS(IFPFS),out-field PFS(OFPFS),and safety.Results:The median follow-up time was 15.3 months.The median PFS was 7.4 months[95%confidence interval(CI):3.1-11.7 months],and the median OS was 18.8 months(95%CI:17.1-20.5 months).ORR and DCR were 38.9%and 72.2%,respectively.In addition,the median IFPFS was 17.8 months(95%CI:11.5-24.2 months),median OFPFS was 7.9 months(95%CI:3.4-12.5 months),and estimated 1-and 2-year LC rates were 67.1%and 31.9%,respectively.The most common treatment-related adverse events(all grades)were diarrhea(33.3%),rash(30.6%),and malaise(27.8%);a total of 14(38.9%)patients developed grade 3-4 AEs.Conclusions:Subsequent RT showed reliable antitumor effects and an acceptable safety profile in patients with advanced-stage HCC who had unsatisfactory response to ICI therapy;therefore,it could serve as an optional salvage strategy.

Leukocyte cell-derived chemotaxin 2(LECT2)regulates liver ischemia-reperfusion injury

Background and aim Hepatic ischemia–reperfusion injury(IRI)is a significant challenge in liver transplantation,trauma,hypovolemic shock,and hepatectomy,with limited effective interventions available.This study aimed to investigate the role of leukocyte cell-derived chemotaxin 2(LECT2)in hepatic IRI and assess the therapeutic potential of Lect2-short hairpin RNA(shRNA)delivered through adeno-associated virus(AAV)vectors.Materials and methods This study analyzed human liver and serum samples from five patients undergoing the Pringle maneuver.Lect2-knockout and C57BL/6J mice were used.Hepatic IRI was induced by clamping the hepatic pedicle.Treatments included recombinant human LECT2(rLECT2)and AAV-Lect2-shRNA.LECT2 expression levels and serum biomarkers including alanine aminotransferase(ALT),aspartate aminotransferase(AST),creatinine,and blood urea nitrogen(BUN)were measured.Histological analysis of liver necrosis and quantitative reverse-transcription polymerase chain reaction were performed.Results Serum and liver LECT2 levels were elevated during hepatic IRI.Serum LECT2 protein and mRNA levels increased post reperfusion.Lect2-knockout mice had reduced weight loss;hepatic necrosis;and serum ALT,AST,creatinine,and BUN levels.rLECT2 treatment exacerbated weight loss,hepatic necrosis,and serum biomarkers(ALT,AST,creatinine,and BUN).AAV-Lect2-shRNA treatment significantly reduced weight loss,hepatic necrosis,and serum biomarkers(ALT,AST,creatinine,and BUN),indicating therapeutic potential.Conclusions Elevated LECT2 levels during hepatic IRI increased liver damage.Genetic knockout or shRNA-mediated knockdown of Lect2 reduced liver damage,indicating its therapeutic potential.AAV-mediated Lect2-shRNA delivery mitigated hepatic IRI,offering a potential new treatment strategy to enhance clinical outcomes for patients undergoing liver-related surgeries or trauma.

A Blood Hepatocellular Carcinoma Signature Recognizes Very Small Tumor Nodules with Metastatic Traits

Background and Aims:Hepatocellular carcinoma(HCC)cases with small nodules are commonly treated with radi-ofrequency ablation(RFA),but the recurrence rate remains high.This study aimed to establish a blood signature for identifying HCC with metastatic traits pre-RFA.Methods:Data from HCC patients treated between 2010 and 2017 were retrospectively collected.A blood signature for meta-static HCC was established based on blood levels of alpha-fetoprotein and des-γ-carboxy-prothrombin,cell-free DNA(cfDNA)mutations,and methylation changes in target genes in frozen-stored plasma samples that were collected before RFA performance.The HCC blood signature was validated in patients prospectively enrolled in2021.Results:Of 251 HCC patients in the retrospective study,33.9% experienced recurrence within 1 year post-RFA.The HCC blood signature identified from these patients included des-γ-carboxy-prothrombin≥40mAU/mL with cfDNA mutation score,where cfDNA mutations occurred in the genes of TP53,CTNNB1,and TERT promoter.This signature effectively predicted 1-year post-RFArecurrence of HCC with 92% specificity and 91% sensitivity in the retrospective dataset,and with 87% specificity and 76% sensitivity in the prospective dataset(n=32 patients).Among 14 cases in the prospective study with biopsy tissues available,positivity for the HCC blood signature was associated with a higher HCC tissue score and shorter distance between HCC cells and microvasculature.Conclusions:This study established an HCC blood signature in pre-RFA blood that potentially reflects HCC with metastatic traits and may be valuable for predicting the disease’s early recurrence post-RFA.

Survey on Changes in the Willingness to Receive the COVID-19 Vaccine Among Patients with Breast Cancer in the Postpandemic Era

This study aimed to investigate the status of and changes in the vaccination willingness of patients with breast cancer to increase the coronavirus disease 2019(COVID-19)vaccination rate among these patients.The first survey included patients fromthe FifthMedical Center of the PLA GeneralHospitalwho participated in the Society of ClinicalOncology Breast Cancer CommitteeNCP-02 study conducted from September 16 to December 31,2021.The second survey was conducted from December 9 to December 26,2022,for those who had not received vaccines previously.In total,266 patients completed two questionnaires.A total of 143 patients(53.8%)changed their willingness to receive the vaccination.Among them,45,who were initially unwilling to be vaccinated,changed their stance to become hesitant and 15 changed to become willing.Among those with hesitant attitudes toward vaccines,45 changed their stance to become willing,and 28 changed to become unwilling;10 patients with willing attitudes toward vaccines changed to become hesitant.Those who received surgery(odds ratio(OR),4.24;95%confidence interval(CI),1.45–12.42;P=0.01)andwho lived with older adults or children(OR,2.03;95%CI,1.13–3.62;P=0.02)were more likely to change their attitudes toward COVID-19 vaccines.This finding suggested that patients with breast cancer were cautious about receiving the COVID-19 vaccine.Multiple methods should be used to promote vaccination and reduce vaccine hesitancy.

Expert consensus on the diagnosis and treatment of solid tumors with BRAF mutations

The BRAF gene is an important signaling molecule in human cells that is involved in the regulation of cell growth,differentiation,and survival.When the BRAF gene mutates,it can lead to abnormal activation of the signaling pathway,which promotes cell proliferation,inhibits cell apoptosis,and ultimately contributes to the occurrence and development of cancer.BRAF mutations are widely present in various cancers,including malignant melanoma,thyroid cancer,colorectal cancer,non-small cell lung cancer,and hairy cell leukemia,among others.BRAF is an important target for the treatment of various solid tumors,and targeted combination therapies,represented by BRAF inhibitors,have become one of the main treatment modalities for a variety of BRAF-mutation-positive solid tumors.