Objective Hepatocellular carcinoma(HCC)is the third leading cause of cancer-associated death worldwide.As a first-line drug for advanced HCC treatment,lenvatinib faces a significant hurdle due to the development of bo...Objective Hepatocellular carcinoma(HCC)is the third leading cause of cancer-associated death worldwide.As a first-line drug for advanced HCC treatment,lenvatinib faces a significant hurdle due to the development of both intrinsic and acquired resistance among patients,and the underlying mechanism remains largely unknown.The present study aims to identify the pivotal gene responsible for lenvatinib resistance in HCC,explore the potential molecular mechanism,and propose combinatorial therapeutic targets for HCC management.Methods Cell viability and colony formation assays were conducted to evaluate the sensitivity of cells to lenvatinib and dicoumarol.RNA-Seq was used to determine the differences in transcriptome between parental cells and lenvatinib-resistant(LR)cells.The upregulated genes were analyzed by GO and KEGG analyses.Then,qPCR and Western blotting were employed to determine the relative gene expression levels.Afterwards,the intracellular reactive oxygen species(ROS)and apoptosis were detected by flow cytometry.Results PLC-LR and Hep3B-LR were established.There was a total of 116 significantly upregulated genes common to both LR cell lines.The GO and KEGG analyses indicated that these genes were involved in oxidoreductase and dehydrogenase activities,and reactive oxygen species pathways.Notably,NAD(P)H:quinone oxidoreductase 1(NQO1)was highly expressed in LR cells,and was involved in the lenvatinib resistance.The high expression of NQO1 decreased the production of ROS induced by lenvatinib,and subsequently suppressed the apoptosis.The combination of lenvatinib and NQO1 inhibitor,dicoumarol,reversed the resistance of LR cells.Conclusion The high NQO1 expression in HCC cells impedes the lenvatinib-induced apoptosis by regulating the ROS levels,thereby promoting lenvatinib resistance in HCC cells.展开更多
BACKGROUND Hepatocellular carcinoma(HCC)patients complicated with portal vein tumor thrombus(PVTT)exhibit poor prognoses and treatment responses.AIM To investigate efficacies and safety of the combination of PD-1 inhi...BACKGROUND Hepatocellular carcinoma(HCC)patients complicated with portal vein tumor thrombus(PVTT)exhibit poor prognoses and treatment responses.AIM To investigate efficacies and safety of the combination of PD-1 inhibitor,transcatheter arterial chemoembolization(TACE)and Lenvatinib in HCC subjects comorbid with PVTT.METHODS From January 2019 to December 2020,HCC patients with PVTT types Ⅰ-Ⅳ were retrospectively enrolled at Beijing Ditan Hospital.They were distributed to either the PTL or TACE/Lenvatinib(TL)group.The median progression-free survival(mPFS)was set as the primary endpoint,while parameters like median overall survival,objective response rate,disease control rate(DCR),and toxicity level served as secondary endpoints.RESULTS Forty-one eligible patients were finally recruited for this study and divided into the PTL(n=18)and TL(n=23)groups.For a median follow-up of 21.8 months,the DCRs were 88.9%and 60.9%in the PTL and TL groups(P=0.046),res-pectively.Moreover,mPFS indicated significant improvement(HR=0.25;P<0.001)in PTL-treated patients(5.4 months)compared to TL-treated(2.7 months)patients.There were no treatment-related deaths or differences in adverse events in either group.CONCLUSION A triplet regimen of PTL was safe and well-tolerated as well as exhibited favorable efficacy over the TL regimen for advanced-stage HCC patients with PVTT types Ⅰ-Ⅳ.展开更多
BACKGROUND Recently,combination therapy has shown a better trend towards improved tumour response and survival outcomes than monotherapy in patients with hepatocellular carcinoma(HCC).However,research on triple therap...BACKGROUND Recently,combination therapy has shown a better trend towards improved tumour response and survival outcomes than monotherapy in patients with hepatocellular carcinoma(HCC).However,research on triple therapy[lenvatinib+sintilimab+transarterial chemoembolization(TACE)]as a first-line treatment for advanced HCC is limited.AIM To evaluate the safety and efficacy of triple therapy as a first-line treatment for advanced HCC.METHODS HCC patients with Barcelona Clinic Liver Cancer stage C treated with triple therapy were enrolled.All patients were treated with lenvatinib every day and sintilimab once every 3 wk.Moreover,TACE was performed every 4-6 wk if necessary.The primary outcome of the study was overall survival(OS).The secondary outcomes were the objective response rate(ORR),disease control rate(DCR),and incidence of adverse events.RESULTS Forty HCC patients who underwent triple therapy were retrospectively analysed from January 2019 to January 2022.With a median follow-up of 8.5 months,the 3-,6-,and 12-mo OS rates were 100%,88.5%,and 22.5%,respectively.The ORR and DCR were 45%and 90%,respectively.The median progressive free survival and median OS were not reached.Common complications were observed in 76%of the patients(grade 3,15%;grade 4,2.5%).CONCLUSION Combination therapy comprising lenvatinib,sintilimab and TACE achieved promising outcomes in advanced HCC patients and had manageable effects.展开更多
A 44-year-old patient was admitted with tumor rupture in the left hepatic lateral lobe,and he underwent emergent exploratory laparotomy and proceeded for hepatic left lateral lobectomy on September 19,2021.The final d...A 44-year-old patient was admitted with tumor rupture in the left hepatic lateral lobe,and he underwent emergent exploratory laparotomy and proceeded for hepatic left lateral lobectomy on September 19,2021.The final diagnosis of hepatocellular carcinoma was confirmed by histopathological examination of the surgical specimen.Afterward,the patient received hepatic arterial infusion chemotherapy with FOLFOX(oxaliplatin,fluorouracil,and leucovorin)for 5 cycles.Subsequently,recurrence of the hepatocellular carcinoma was diagnosed in the abdominal cavity.The patient was then treated with lenvatinib.Within less than 1 month of the treatment with lenvatinib,the patient was admitted to the emergency room on June 2,2022,because of acute intra-abdominal bleeding(hematomas).Percutaneous intra-abdominal angiography found that the bleeding vessels were the right gastroepiploic artery and left gastric artery.The patient was stabilized after arterial embolization using gelatin sponges.The diagnosis and management of spontaneous intra-abdominal hematomas are discussed.展开更多
BACKGROUND Programmed death receptor-1(PD-1)inhibitors have been approved as secondline treatment regimen in hepatocellular carcinoma(HCC),but it is still worth studying whether patients can benefit from PD-1 inhibito...BACKGROUND Programmed death receptor-1(PD-1)inhibitors have been approved as secondline treatment regimen in hepatocellular carcinoma(HCC),but it is still worth studying whether patients can benefit from PD-1 inhibitors as first-line drugs combined with targeted drugs and locoregional therapy.AIM To estimate the clinical outcome of transarterial chemoembolization(TACE)and lenvatinib plus PD-1 inhibitors for patients with unresectable HCC(uHCC).METHODS We carried out retrospective research of 65 patients with uHCC who were treated at Peking Union Medical College Hospital from September 2017 to February 2022.45 patients received the PD-1 inhibitors,lenvatinib,TACE(PD-1-Lenv-T)therapy,and 20 received the lenvatinib,TACE(Lenv-T)therapy.In terms of the dose of lenvatinib,8 mg was given orally for patients weighing less than 60 kg and 12 mg for those weighing more than 60 kg.Of the patients in the PD-1 inhibitor combination group,15 received Toripalimab,14 received Toripalimab,14 received Camrelizumab,4 received Pembrolizumab,9 received Sintilimab,and 2 received Nivolumab,1 with Tislelizumab.According to the investigators’assessment,TACE was performed every 4-6 wk when the patient had good hepatic function(Child-Pugh class A or B)until disease progression occurred.We evaluated the efficacy by the modified Response Evaluation Criteria in Solid Tumors(mRECIST criteria).We accessd the safety by the National Cancer Institute Common Terminology Criteria for Adverse Events,v 5.0.The key adverse events(AEs)after the initiation of combination therapy were observed.RESULTS Patients with uHCC who received PD-1-Lenv-T therapy(n=45)had a clearly longer overall survival than those who underwent Lenv-T therapy(n=20,26.8 vs 14.0 mo;P=0.027).The median progression-free survival time between the two treatment regimens was also measured{11.7 mo[95%confidence interval(CI):7.7-15.7]in the PD-1-Lenv-T group vs 8.5 mo(95%CI:3.0-13.9)in the Lenv-T group(P=0.028)}.The objective response rates of the PD-1-Lenv-T group and Lenv-T group were 44.4%and 20%(P=0.059)according to the mRECIST criteria,meanwhile the disease control rates were 93.3%and 64.0%(P=0.003),respectively.The type and frequency of AEs showed little distinction between patients received the two treatment regimens.CONCLUSION Our results suggest that the early combination of PD-1 inhibitors has manageable toxicity and hopeful efficacy in patients with uHCC.展开更多
BACKGROUND Cholangiocarcinoma(CCA)poses a significant clinical challenge due to its low radical resection rate and a propensity for high postoperative recurrence,resulting in a poor dismal.Although the combination of ...BACKGROUND Cholangiocarcinoma(CCA)poses a significant clinical challenge due to its low radical resection rate and a propensity for high postoperative recurrence,resulting in a poor dismal.Although the combination of targeted therapy and immunotherapy has demonstrated notable efficacy in several solid tumors recently,however,its application in CCA remains underexplored and poorly documented.CASE SUMMARY This case report describes a patient diagnosed with stage IV CCA,accompanied by liver and abdominal wall metastases,who underwent palliative surgery.Subsequently,the patient received two cycles of treatment combining lenvatinib with sintilimab,which resulted in a reduction in abdominal wall metastasis,while intrahepatic metastasis displayed progression.This unexpected observation illustrates different responses of intrahepatic and extrahepatic metastases to the same therapy.CONCLUSION Lenvatinib combined with sintilimab shows promise as a potential treatment strategy for advanced CCA.Genetic testing for related driver and/or passenger mutations,as well as an analysis of tumor immune microenvironment analysis,is crucial for optimizing drug combinations and eventually addressing the issue of non-response in specific metastatic sites.展开更多
BACKGROUND Lenvatinib is one of the first-line tyrosine kinase inhibitors used for unresectable hepatocellular carcinoma(HCC). In the present study, we evaluated the potential of early changes in the time-intensity cu...BACKGROUND Lenvatinib is one of the first-line tyrosine kinase inhibitors used for unresectable hepatocellular carcinoma(HCC). In the present study, we evaluated the potential of early changes in the time-intensity curve(TIC) of arterial phase on contrastenhanced ultrasound(CEUS) as early imaging biomarkers of lenvatinib efficacy.AIM To evaluate the potential of the early changes in the TIC of CEUS as early imaging biomarkers of lenvatinib efficacy in patients with unresectable HCC.METHODS We analyzed 20 consecutive patients with unresectable HCC treated with lenvatinib from March to November 2018. Tumor response at 8 wk was assessed by computed tomography using the modified Response Evaluation Criteria in Solid Tumors(m RECIST). CEUS was performed at baseline before treatment(Day 0) and on day 7(Day 7), and the images were analyzed in the arterial phase for 20 seconds after the contrast agent arrived at the target tumor. Three perfusion parameters were extracted from the TICs: the slope of wash-in(Slope),time to peak(TTP) intensity, and the total area under the curve(AUC) during wash-in. The rate of change in the TIC parameters between Day 0 and Day 7 was compared between treatment responders and non-responders based on m RECIST.RESULTS The rate of change for all TIC parameters showed significant differences between the responders(n = 9) and non-responders(n = 11)(Slope, P = 0.025; TTP, P =0.004; and AUC, P = 0.0003). The area under the receiver operating curve values for slope, TTP, and AUC for the prediction of responders were 0.805, 0.869, and0.939, respectively.CONCLUSION CEUS may be useful for the early prediction of tumor response to lenvatinib therapy in patients with unresectable HCC.展开更多
BACKGROUND Lenvatinib has become an indispensable part of treatment regimens for patients with advanced hepatocellular carcinoma(aHCC).Several recent real-world studies appear to have confirmed this;however,there are ...BACKGROUND Lenvatinib has become an indispensable part of treatment regimens for patients with advanced hepatocellular carcinoma(aHCC).Several recent real-world studies appear to have confirmed this;however,there are etiological differences.This necessitates further real-world studies of lenvatinib across diverse populations,such as in China.AIM To investigate the efficacy and safety of lenvatinib in a Chinese HCC patient population under real-world conditions.METHODS This is a retrospective and multiregional study involving patients with aHCC receiving lenvatinib monotherapy.Efficacy was assessed using the Response Evaluation Criteria in Solid Tumors version 1.1.Baseline characteristics and adverse events(AEs)were recorded throughout the entire study.RESULTS In total,54 HCC patients treated with lenvatinib monotherapy were included for final analysis.The objective response rate was 22%(n=12)with a progressionfree survival(PFS)of 168 d;however,AEs occurred in 92.8%of patients.Multivariate analysis showed that the Barcelona Clinic Liver Cancer stage[hazard ratio(HR)0.465;95%CI:0.23-0.93;P=0.031],portal vein tumor thrombus(HR 0.38;95%CI:0.15-0.94;P=0.037)and Child-Pugh classifications(HR 0.468;95%CI:and specificity(83.3%)of decreasing serum biomarkers including alphafetoprotein were calculated in order to predict tumor size reduction.Gene sequencing also provided insights into potential gene mutation signatures related to the effect of lenvatinib.CONCLUSION Our findings confirm previous evidence from the phase III REFLECT study.The majority of patients in this Chinese sample were suffering from concomitant hepatitis B virus-related HCC.However,further analysis suggested that baseline characteristics,changes in serum biomarkers and gene sequencing may hold the key for predicting lenvatinib responses.Further large-scale prospective studies that incorporate more basic medical science measures should be conducted.展开更多
Background:Current chemotherapy for acute myeloid leukemia(AML)mainly involves cytotoxic agents such as doxorubicin(DNR),mitoxantrone(Mito)or 2‐aminopurine‐6‐thiol(6‐TG).However,because these agents are relatively...Background:Current chemotherapy for acute myeloid leukemia(AML)mainly involves cytotoxic agents such as doxorubicin(DNR),mitoxantrone(Mito)or 2‐aminopurine‐6‐thiol(6‐TG).However,because these agents are relatively ineffective,discovering other more effective drugs for AML treatment would be valuable.Methods:The in vitro antitumor effect of lenvatinib on AML cells was examined using the colorimetric MTT assay for assessing cell metabolic activity.AML cells mixed with Poloxamer 407 were injected into nude mice to form subcutaneous tumors.Tumorbearing mice received lenvatinib by oral administration.The antitumor effect of lenvatinib was established by measuring tumor volumes and weights.Results:Lenvatinib inhibited the growth of AML cells in a dose‐dependent manner.We used AML cells to establish subcutaneous tumor tissues by mixing the cell suspension with Poloxamer 407.Poloxamer 407 alone did not influence the subcutaneous growth of AML cells.Treatment of lenvatinib inhibited in vivo tumor growth of AML cells.Conclusion:The multiple‐kinase inhibitor lenvatinib inhibits the in vitro proliferation of AML cells,and restricts the in vivo growth of AML tumors.展开更多
BACKGROUND Both programmed cell death-1(PD-1)inhibitors and lenvatinib,which have a synergistic effect,are promising drugs for tumor treatment.It is generally believed that combination therapy with a PD-1 inhibitor an...BACKGROUND Both programmed cell death-1(PD-1)inhibitors and lenvatinib,which have a synergistic effect,are promising drugs for tumor treatment.It is generally believed that combination therapy with a PD-1 inhibitor and lenvatinib is safe and effective.However,we report a case of toxic epidermal necrolysis(TEN),a grade 4 toxicity,after this combination therapy.CASE SUMMARY A 39-year-old male presented with erythema,blisters and erosions on the face,neck,trunk and limbs 1 wk after receiving combination therapy with lenvatinib and toripalimab,a PD-1 inhibitor.The skin injury covered more than 70%of the body surface area.He was previously diagnosed with liver cancer with cervical vertebra metastasis.Histologically,prominent necrotic keratinocytes,hyperkeratosis,liquefaction of basal cells and acantholytic bullae were observed in the epidermis.Blood vessels in the dermis were infiltrated by lymphocytes and eosinophils.Direct immunofluorescence staining was negative.Thus,the diagnosis was confirmed to be TEN(associated with combination therapy with toripalimab and lenvatinib).Full-dose and long-term corticosteroids,high-dose intravenous immunoglobulin and targeted antibiotic drugs were administered.The rashes gradually faded;however,as expected,the tumor progressed.Therefore, sorafenib and regorafenib were given in succession, and the patient was still alive at the10-mo follow-up.CONCLUSIONCautious attention should be given to rashes that develop after combination therapy with PD-1inhibitors and lenvatinib. Large-dose and long-course glucocorticoids may be crucial for thetreatment of TEN associated with this combination treatment.展开更多
The phase III clinical trial of the novel molecular targeted agent(MTA)lenvatinib for patients with advanced hepatocellular carcinoma(HCC)(REFLECT trial)found that lenvatinib was non-inferior to sorafenib in overall s...The phase III clinical trial of the novel molecular targeted agent(MTA)lenvatinib for patients with advanced hepatocellular carcinoma(HCC)(REFLECT trial)found that lenvatinib was non-inferior to sorafenib in overall survival.Recently,the efficacy of multiple MTAs,including lenvatinib,in practice has been reported,and therapeutic strategies for Barcelona Clinic Liver Cancer(BCLC)intermediate stage HCC are undergoing major changes.Based on these results,lenvatinib could be recommended for patients with transcatheter arterial chemoembolization(TACE)-refractory,ALBI grade 1,within the up-to-seven criteria in the BCLC intermediate stage.Lenvatinib provides a more favorable outcome than TACE,even in cases with large or multinodular HCC beyond the up-to-seven criteria with Child-Pugh grade A.When patients meet the definitions of TACE-refractory or TACE-unsuitable,switching to systemic chemotherapy,including lenvatinib,is for favorable for preserving liver function.If initial treatment,including MTA,has a significant therapeutic effect and downstaging of HCC is obtained,additional TACE or surgical resection should be considered.Lenvatinib also has a therapeutic effect for poorly differentiated type and non-simple nodular type HCC thanks to the survival-prolonging effect of this drug.Furthermore,a significant therapeutic effect is expected in tumors with more than 50%liver involvement or main portal vein invasion,which have traditionally been considered to have a poor prognosis in patients.This suggests that at the start of lenvatinib treatment,HCC patients with ALBI grade 1 may be able to maintain liver functional reserve.展开更多
BACKGROUND Hepatocellular carcinoma(HCC)accompanied by portal vein tumour thrombus(PVTT)presents an aggressive disease course,worsening liver function reserve,and a high recurrence rate.Clinical practice guidelines re...BACKGROUND Hepatocellular carcinoma(HCC)accompanied by portal vein tumour thrombus(PVTT)presents an aggressive disease course,worsening liver function reserve,and a high recurrence rate.Clinical practice guidelines recommend systemic therapy as the first-line option for HCC with portal invasion.However,to achieve longer survival in these patients,the treatment strategy should be concluded with removal of the tumour by locoregional therapy.We experienced a case of initially unresectable HCC with main PVTT converted to radical hepatectomy after lenvatinib treatment.CASE SUMMARY A 59-year-old male with chronic hepatitis C infection visited our clinic as a regular post-surgery follow-up.Contrast-enhanced abdominal computed tomography revealed a liver mass diffusely located at the lateral segment with a massive PVTT extending from the umbilical portion to the main and contralateral third-order portal branches.With the diagnosis of unresectable HCC with Vp4(main trunk/contralateral branch)PVTT,lenvatinib was started at 12 mg/d.The computed tomography taken 3 mo after starting lenvatinib showed regression of the PVTT,which had retreated to the contralateral first-order portal branch.He tolerated the full dose without major adverse effects.With cessation of lenvatinib for 7 d,radical left lobectomy and PVTT thrombectomy were conducted.The patient’s postoperative course was uneventful.Microscopically,the primary lesion showed fibrotic changes,with moderately to poorly differentiated tumour cells surrounded by granulation tissues in some areas.The majority of the PVTT showed necrosis.He was alive without recurrence for 8 mo.CONCLUSION This is the first case of HCC with Vp4 PVTT in which radical conversion hepatectomy was succeeded after lenvatinib treatment.展开更多
BACKGROUND In a phase III trial of lenvatinib as first-line treatment for advanced unresectable hepatocellular carcinoma(uHCC),the drug proved non-inferior to sorafenib in terms of the overall survival,but offered bet...BACKGROUND In a phase III trial of lenvatinib as first-line treatment for advanced unresectable hepatocellular carcinoma(uHCC),the drug proved non-inferior to sorafenib in terms of the overall survival,but offered better progression-free survival.However,the effects of lenvatinib in uHCC patients with a tumor thrombus in the main portal vein and/or a high tumor burden(tumor occupancy more than 50%of the total liver volume),remain unclear,because these were set as exclusion criteria in the aforementioned trial.CASE SUMMARY A 53-year-old man(case 1)and 66-year-old woman(case 2)with uHCC presented to us with a tumor thrombus in both the main portal vein and inferior vena cava,a high tumor burden accompanied by a tumor diameter greater than>100 mm,and distant metastasis,with the residual liver function classified as grade 2A according to the modified Albumin–Bilirubin grading.We started both patients on lenvatinib.The therapeutic effect,as evaluated by the modified Response Evaluation Criteria in Solid Tumors,was rated as partial response in both case 1 and case 2(at 8 wk and 4 wk after the start of lenvatinib administration,respectively).The therapeutic effect was sustained for 6 mo in case 1 and 20 mo in case 2.Fever occurred as an adverse event in both case 1 and 2,and hyperthyroidism and thrombocytopenia in only case 2,neither of which,however,necessitated treatment discontinuation.CONCLUSION Even in hepatocellular carcinoma patients with poor prognostic factors,if the liver function is well-preserved,lenvatinib is effective and safe.展开更多
BACKGROUND Lenvatinib has been shown to be noninferior to sorafenib regarding prognosis and recurrence rate in patients with unresectable hepatocellular carcinoma(HCC)who have not received prior systemic chemotherapy....BACKGROUND Lenvatinib has been shown to be noninferior to sorafenib regarding prognosis and recurrence rate in patients with unresectable hepatocellular carcinoma(HCC)who have not received prior systemic chemotherapy.In patients treated with lenvatinib,40%of cases achieved sufficient tumor reduction to make potential surgery possible.However,the outcomes of such surgery are unknown.We report a successful case of hepatic resection for recurrent HCC after lenvatinib treatment.CASE SUMMARY A 69-year-old man underwent right anterior sectionectomy for HCC in segment 8 of the liver.Ten months later,he was found to have an intrahepatic HCC recurrence that grew rapidly to 10 cm in diameter with sternal bone metastases.After confirming partial response to lenvatinib administration for 2 mo,a second hepatectomy was performed.Pathological examination showed that 80%of the tumor was necrotic.The patient did not develop any adverse effects under lenvatinib treatment.He was discharged at 25 d after surgery.Radiation therapy for bone metastases continued to be given under lenvatinib,and the patient has remained alive for 1 year after the second hepatectomy.CONCLUSION The prognosis of patients with recurrent HCC may be improved by liver resection combined with prior lenvatinib therapy.展开更多
BACKGROUND Recently,hepatic arterial infusion chemotherapy(HAIC)plus lenvatinib has been frequently used to treat unresectable hepatocellular carcinoma(uHCC)in China.In the clinic,the hepatic arteries of some patients...BACKGROUND Recently,hepatic arterial infusion chemotherapy(HAIC)plus lenvatinib has been frequently used to treat unresectable hepatocellular carcinoma(uHCC)in China.In the clinic,the hepatic arteries of some patients shrink significantly during this treatment,leading to improved short-term efficacy.AIM To investigate the relationship between the shrinkage of hepatic arteries and the short-term effect of HAIC plus lenvatinib treatment.METHODS Sixty-seven participants with uHCC were enrolled in this retrospective study.The patients received HAIC every 3 wk,followed by oral lenvatinib after the first HAIC course.Hepatic artery diameters were measured on CT before treatment and after 1 and 2 mo of treatment.Meanwhile,the changes in tumor capillaries were also examined on pathological specimens before and after 1 mo of treatment.The antitumor response after 1,3,and 6 mo of treatment was assessed using the modified Response Evaluation Criteria in Solid Tumors(mRECIST).The relationship between the changes in vessel diameters and the short-term effect of the combination treatment was evaluated by receiver-operating characteristic and logistic regression analyses.RESULTS The hepatic artery diameters were all significantly decreased after 1 and 2 mo of treatment(P<0.001),but there was no difference in the vessel diameters between 1 and 2 mo(P>0.05).The microvessel density in the tumor lesions decreased significantly after 1 mo of combination treatment(P<0.001).According to mRECIST,46,41,and 24 patients had complete or partial responses after 1,3,and 6 mo of treatment,respectively,whereas 21,21,and 32 patients had a stable or progressive disease at these times,respectively.Shrinkage of the tumor-feeding artery was significantly associated with the tumor response after 1,3,and 6 mo of treatment(P<0.001,P=0.004,and P=0.023,respectively);however,changes in other hepatic arteries were not significantly associated with the tumor response.Furthermore,shrinkage of the tumor-feeding artery was an independent factor for treatment efficacy(P=0.001,P=0.001,and P=0.002 and 1,3,and 6 mo,respectively).CONCLUSION The hepatic arteries shrank rapidly after treatment with HAIC plus lenvatinib,and shrinkage of the tumor-feeding artery diameter was closely related to improved short-term efficacy.展开更多
BACKGROUND The management of metastatic progressive radioiodine-resistant differentiated thyroid cancer remains challenging for clinicians.The availability of tyrosine kinase inhibitors(TKIs),sorafenib and lenvatinib,...BACKGROUND The management of metastatic progressive radioiodine-resistant differentiated thyroid cancer remains challenging for clinicians.The availability of tyrosine kinase inhibitors(TKIs),sorafenib and lenvatinib,within the last decade has expanded treatment options;however,these lead to significant adverse effects,which may curtail their use.CASE SUMMARY We report the case of a 47-year-old female with Hurthle cell thyroid cancer who underwent total thyroidectomy followed by radioiodine ablation.During followup,she developed noniodine-avid renal and pulmonary metastases.With respect to her pre-existing diabetes,hypertension,and polycystic kidney disease,the tumor board decided against performing renal metastasectomy because of the risk of future renal decline requiring dialysis.Metastases were treated using sorafenib,which provided stability followed by progression within a year.We switched to lenvatinib,which led to disease regression.However,the patient experienced severe adverse effects,including cardiomyopathy,bicytopenia,renal impairment,and the rarely reported nephrotic syndrome.Renal metastasis is a rare manifestation of Hurthle cell thyroid cancer with only two reported cases in literature.We report the experience of our first case of renal metastasis and its treatment with TKIs.This case serves as a reminder of the adverse drug reactions associated with TKI use.CONCLUSION We advocate close monitoring of patients’hematological and renal profiles as well as their cardiac status using an echocardiogram.展开更多
Lenvatinib,a second-generation multi-receptor tyrosine kinase inhibitor approved by the FDA for first-line treatment of advanced liver cancer,facing limitations due to drug resistance.Here,we applied a multidimensiona...Lenvatinib,a second-generation multi-receptor tyrosine kinase inhibitor approved by the FDA for first-line treatment of advanced liver cancer,facing limitations due to drug resistance.Here,we applied a multidimensional,high-throughput screening platform comprising patient-derived resistant liver tumor cells(PDCs),organoids(PDOs),and xenografts(PDXs)to identify drug susceptibilities for conquering lenvatinib resistance in clinically relevant settings.Expansion and passaging of PDCs and PDOs from resistant patient liver tumors retained functional fidelity to lenvatinib treatment,expediting drug repurposing screens.Pharmacological screening identified romidepsin,YM155,apitolisib,NVP-TAE684 and dasatinib as potential antitumor agents in lenvatinib-resistant PDC and PDO models.Notably,romidepsin treatment enhanced antitumor response in syngeneic mouse models by triggering immunogenic tumor cell death and blocking the EGFR signaling pathway.A combination of romidepsin and immunotherapy achieved robust and synergistic antitumor effects against lenvatinib resistance in humanized immunocompetent PDX models.Collectively,our findings suggest that patient-derived liver cancer models effectively recapitulate lenvatinib resistance observed in clinical settings and expedite drug discovery for advanced liver cancer,providing a feasible multidimensional platform for personalized medicine.展开更多
基金supported by the Global Select Project(No.DJK-LX-2022001)of the Institute of Health and Medicine,Hefei Comprehensive National Science Center.
文摘Objective Hepatocellular carcinoma(HCC)is the third leading cause of cancer-associated death worldwide.As a first-line drug for advanced HCC treatment,lenvatinib faces a significant hurdle due to the development of both intrinsic and acquired resistance among patients,and the underlying mechanism remains largely unknown.The present study aims to identify the pivotal gene responsible for lenvatinib resistance in HCC,explore the potential molecular mechanism,and propose combinatorial therapeutic targets for HCC management.Methods Cell viability and colony formation assays were conducted to evaluate the sensitivity of cells to lenvatinib and dicoumarol.RNA-Seq was used to determine the differences in transcriptome between parental cells and lenvatinib-resistant(LR)cells.The upregulated genes were analyzed by GO and KEGG analyses.Then,qPCR and Western blotting were employed to determine the relative gene expression levels.Afterwards,the intracellular reactive oxygen species(ROS)and apoptosis were detected by flow cytometry.Results PLC-LR and Hep3B-LR were established.There was a total of 116 significantly upregulated genes common to both LR cell lines.The GO and KEGG analyses indicated that these genes were involved in oxidoreductase and dehydrogenase activities,and reactive oxygen species pathways.Notably,NAD(P)H:quinone oxidoreductase 1(NQO1)was highly expressed in LR cells,and was involved in the lenvatinib resistance.The high expression of NQO1 decreased the production of ROS induced by lenvatinib,and subsequently suppressed the apoptosis.The combination of lenvatinib and NQO1 inhibitor,dicoumarol,reversed the resistance of LR cells.Conclusion The high NQO1 expression in HCC cells impedes the lenvatinib-induced apoptosis by regulating the ROS levels,thereby promoting lenvatinib resistance in HCC cells.
基金The study was reviewed and approved by the Beijing Ditan Hospital,Capital Medical University Institutional Review Board(Approval No.JDLC 2021-003-02).
文摘BACKGROUND Hepatocellular carcinoma(HCC)patients complicated with portal vein tumor thrombus(PVTT)exhibit poor prognoses and treatment responses.AIM To investigate efficacies and safety of the combination of PD-1 inhibitor,transcatheter arterial chemoembolization(TACE)and Lenvatinib in HCC subjects comorbid with PVTT.METHODS From January 2019 to December 2020,HCC patients with PVTT types Ⅰ-Ⅳ were retrospectively enrolled at Beijing Ditan Hospital.They were distributed to either the PTL or TACE/Lenvatinib(TL)group.The median progression-free survival(mPFS)was set as the primary endpoint,while parameters like median overall survival,objective response rate,disease control rate(DCR),and toxicity level served as secondary endpoints.RESULTS Forty-one eligible patients were finally recruited for this study and divided into the PTL(n=18)and TL(n=23)groups.For a median follow-up of 21.8 months,the DCRs were 88.9%and 60.9%in the PTL and TL groups(P=0.046),res-pectively.Moreover,mPFS indicated significant improvement(HR=0.25;P<0.001)in PTL-treated patients(5.4 months)compared to TL-treated(2.7 months)patients.There were no treatment-related deaths or differences in adverse events in either group.CONCLUSION A triplet regimen of PTL was safe and well-tolerated as well as exhibited favorable efficacy over the TL regimen for advanced-stage HCC patients with PVTT types Ⅰ-Ⅳ.
基金Capital Health Development and Scientific Research Special Project,No.2022-2-2175.
文摘BACKGROUND Recently,combination therapy has shown a better trend towards improved tumour response and survival outcomes than monotherapy in patients with hepatocellular carcinoma(HCC).However,research on triple therapy[lenvatinib+sintilimab+transarterial chemoembolization(TACE)]as a first-line treatment for advanced HCC is limited.AIM To evaluate the safety and efficacy of triple therapy as a first-line treatment for advanced HCC.METHODS HCC patients with Barcelona Clinic Liver Cancer stage C treated with triple therapy were enrolled.All patients were treated with lenvatinib every day and sintilimab once every 3 wk.Moreover,TACE was performed every 4-6 wk if necessary.The primary outcome of the study was overall survival(OS).The secondary outcomes were the objective response rate(ORR),disease control rate(DCR),and incidence of adverse events.RESULTS Forty HCC patients who underwent triple therapy were retrospectively analysed from January 2019 to January 2022.With a median follow-up of 8.5 months,the 3-,6-,and 12-mo OS rates were 100%,88.5%,and 22.5%,respectively.The ORR and DCR were 45%and 90%,respectively.The median progressive free survival and median OS were not reached.Common complications were observed in 76%of the patients(grade 3,15%;grade 4,2.5%).CONCLUSION Combination therapy comprising lenvatinib,sintilimab and TACE achieved promising outcomes in advanced HCC patients and had manageable effects.
文摘A 44-year-old patient was admitted with tumor rupture in the left hepatic lateral lobe,and he underwent emergent exploratory laparotomy and proceeded for hepatic left lateral lobectomy on September 19,2021.The final diagnosis of hepatocellular carcinoma was confirmed by histopathological examination of the surgical specimen.Afterward,the patient received hepatic arterial infusion chemotherapy with FOLFOX(oxaliplatin,fluorouracil,and leucovorin)for 5 cycles.Subsequently,recurrence of the hepatocellular carcinoma was diagnosed in the abdominal cavity.The patient was then treated with lenvatinib.Within less than 1 month of the treatment with lenvatinib,the patient was admitted to the emergency room on June 2,2022,because of acute intra-abdominal bleeding(hematomas).Percutaneous intra-abdominal angiography found that the bleeding vessels were the right gastroepiploic artery and left gastric artery.The patient was stabilized after arterial embolization using gelatin sponges.The diagnosis and management of spontaneous intra-abdominal hematomas are discussed.
基金Supported by Chinese Academy of Medical Sciences Innovation Fund for Medical Sciences,No.2021-I2M-1-061 and 2021-I2M-1-003Chinese Society of Clinical Oncology-Hengrui Cancer Research Fund,No.Y-HR2019-0239+1 种基金Chinese Society of Clinical Oncology-MSD Cancer Research Fund,No.Y-MSDZD2021-0213National Ten-thousand Talent Program.
文摘BACKGROUND Programmed death receptor-1(PD-1)inhibitors have been approved as secondline treatment regimen in hepatocellular carcinoma(HCC),but it is still worth studying whether patients can benefit from PD-1 inhibitors as first-line drugs combined with targeted drugs and locoregional therapy.AIM To estimate the clinical outcome of transarterial chemoembolization(TACE)and lenvatinib plus PD-1 inhibitors for patients with unresectable HCC(uHCC).METHODS We carried out retrospective research of 65 patients with uHCC who were treated at Peking Union Medical College Hospital from September 2017 to February 2022.45 patients received the PD-1 inhibitors,lenvatinib,TACE(PD-1-Lenv-T)therapy,and 20 received the lenvatinib,TACE(Lenv-T)therapy.In terms of the dose of lenvatinib,8 mg was given orally for patients weighing less than 60 kg and 12 mg for those weighing more than 60 kg.Of the patients in the PD-1 inhibitor combination group,15 received Toripalimab,14 received Toripalimab,14 received Camrelizumab,4 received Pembrolizumab,9 received Sintilimab,and 2 received Nivolumab,1 with Tislelizumab.According to the investigators’assessment,TACE was performed every 4-6 wk when the patient had good hepatic function(Child-Pugh class A or B)until disease progression occurred.We evaluated the efficacy by the modified Response Evaluation Criteria in Solid Tumors(mRECIST criteria).We accessd the safety by the National Cancer Institute Common Terminology Criteria for Adverse Events,v 5.0.The key adverse events(AEs)after the initiation of combination therapy were observed.RESULTS Patients with uHCC who received PD-1-Lenv-T therapy(n=45)had a clearly longer overall survival than those who underwent Lenv-T therapy(n=20,26.8 vs 14.0 mo;P=0.027).The median progression-free survival time between the two treatment regimens was also measured{11.7 mo[95%confidence interval(CI):7.7-15.7]in the PD-1-Lenv-T group vs 8.5 mo(95%CI:3.0-13.9)in the Lenv-T group(P=0.028)}.The objective response rates of the PD-1-Lenv-T group and Lenv-T group were 44.4%and 20%(P=0.059)according to the mRECIST criteria,meanwhile the disease control rates were 93.3%and 64.0%(P=0.003),respectively.The type and frequency of AEs showed little distinction between patients received the two treatment regimens.CONCLUSION Our results suggest that the early combination of PD-1 inhibitors has manageable toxicity and hopeful efficacy in patients with uHCC.
文摘BACKGROUND Cholangiocarcinoma(CCA)poses a significant clinical challenge due to its low radical resection rate and a propensity for high postoperative recurrence,resulting in a poor dismal.Although the combination of targeted therapy and immunotherapy has demonstrated notable efficacy in several solid tumors recently,however,its application in CCA remains underexplored and poorly documented.CASE SUMMARY This case report describes a patient diagnosed with stage IV CCA,accompanied by liver and abdominal wall metastases,who underwent palliative surgery.Subsequently,the patient received two cycles of treatment combining lenvatinib with sintilimab,which resulted in a reduction in abdominal wall metastasis,while intrahepatic metastasis displayed progression.This unexpected observation illustrates different responses of intrahepatic and extrahepatic metastases to the same therapy.CONCLUSION Lenvatinib combined with sintilimab shows promise as a potential treatment strategy for advanced CCA.Genetic testing for related driver and/or passenger mutations,as well as an analysis of tumor immune microenvironment analysis,is crucial for optimizing drug combinations and eventually addressing the issue of non-response in specific metastatic sites.
文摘BACKGROUND Lenvatinib is one of the first-line tyrosine kinase inhibitors used for unresectable hepatocellular carcinoma(HCC). In the present study, we evaluated the potential of early changes in the time-intensity curve(TIC) of arterial phase on contrastenhanced ultrasound(CEUS) as early imaging biomarkers of lenvatinib efficacy.AIM To evaluate the potential of the early changes in the TIC of CEUS as early imaging biomarkers of lenvatinib efficacy in patients with unresectable HCC.METHODS We analyzed 20 consecutive patients with unresectable HCC treated with lenvatinib from March to November 2018. Tumor response at 8 wk was assessed by computed tomography using the modified Response Evaluation Criteria in Solid Tumors(m RECIST). CEUS was performed at baseline before treatment(Day 0) and on day 7(Day 7), and the images were analyzed in the arterial phase for 20 seconds after the contrast agent arrived at the target tumor. Three perfusion parameters were extracted from the TICs: the slope of wash-in(Slope),time to peak(TTP) intensity, and the total area under the curve(AUC) during wash-in. The rate of change in the TIC parameters between Day 0 and Day 7 was compared between treatment responders and non-responders based on m RECIST.RESULTS The rate of change for all TIC parameters showed significant differences between the responders(n = 9) and non-responders(n = 11)(Slope, P = 0.025; TTP, P =0.004; and AUC, P = 0.0003). The area under the receiver operating curve values for slope, TTP, and AUC for the prediction of responders were 0.805, 0.869, and0.939, respectively.CONCLUSION CEUS may be useful for the early prediction of tumor response to lenvatinib therapy in patients with unresectable HCC.
基金Supported by the International Science and Technology Cooperation Projects,No.2016YFE0107100the Capital Special Research Project for Health Development,No.2014-2-4012+2 种基金the Beijing Natural Science Foundation,No.L172055 and No.7192158the National Tenthousand Talent Program,the Fundamental Research Funds for the Central Universities,No.3332018032and the CAMS Innovation Fund for Medical Science(CIFMS),No.2017-I2M-4-003 and No.2018-I2M-3-001.
文摘BACKGROUND Lenvatinib has become an indispensable part of treatment regimens for patients with advanced hepatocellular carcinoma(aHCC).Several recent real-world studies appear to have confirmed this;however,there are etiological differences.This necessitates further real-world studies of lenvatinib across diverse populations,such as in China.AIM To investigate the efficacy and safety of lenvatinib in a Chinese HCC patient population under real-world conditions.METHODS This is a retrospective and multiregional study involving patients with aHCC receiving lenvatinib monotherapy.Efficacy was assessed using the Response Evaluation Criteria in Solid Tumors version 1.1.Baseline characteristics and adverse events(AEs)were recorded throughout the entire study.RESULTS In total,54 HCC patients treated with lenvatinib monotherapy were included for final analysis.The objective response rate was 22%(n=12)with a progressionfree survival(PFS)of 168 d;however,AEs occurred in 92.8%of patients.Multivariate analysis showed that the Barcelona Clinic Liver Cancer stage[hazard ratio(HR)0.465;95%CI:0.23-0.93;P=0.031],portal vein tumor thrombus(HR 0.38;95%CI:0.15-0.94;P=0.037)and Child-Pugh classifications(HR 0.468;95%CI:and specificity(83.3%)of decreasing serum biomarkers including alphafetoprotein were calculated in order to predict tumor size reduction.Gene sequencing also provided insights into potential gene mutation signatures related to the effect of lenvatinib.CONCLUSION Our findings confirm previous evidence from the phase III REFLECT study.The majority of patients in this Chinese sample were suffering from concomitant hepatitis B virus-related HCC.However,further analysis suggested that baseline characteristics,changes in serum biomarkers and gene sequencing may hold the key for predicting lenvatinib responses.Further large-scale prospective studies that incorporate more basic medical science measures should be conducted.
基金supported by the National Natural Science Foundation of China Grant/award number:81702986Beijing Municipal Natural Science Foundation,grant/award number:7142131
文摘Background:Current chemotherapy for acute myeloid leukemia(AML)mainly involves cytotoxic agents such as doxorubicin(DNR),mitoxantrone(Mito)or 2‐aminopurine‐6‐thiol(6‐TG).However,because these agents are relatively ineffective,discovering other more effective drugs for AML treatment would be valuable.Methods:The in vitro antitumor effect of lenvatinib on AML cells was examined using the colorimetric MTT assay for assessing cell metabolic activity.AML cells mixed with Poloxamer 407 were injected into nude mice to form subcutaneous tumors.Tumorbearing mice received lenvatinib by oral administration.The antitumor effect of lenvatinib was established by measuring tumor volumes and weights.Results:Lenvatinib inhibited the growth of AML cells in a dose‐dependent manner.We used AML cells to establish subcutaneous tumor tissues by mixing the cell suspension with Poloxamer 407.Poloxamer 407 alone did not influence the subcutaneous growth of AML cells.Treatment of lenvatinib inhibited in vivo tumor growth of AML cells.Conclusion:The multiple‐kinase inhibitor lenvatinib inhibits the in vitro proliferation of AML cells,and restricts the in vivo growth of AML tumors.
基金Supported by Guangdong Provincial Key Laboratory of Chinese Medicine for Prevention and Treatment of Refractory Chronic Diseases,No. 2018B030322012
文摘BACKGROUND Both programmed cell death-1(PD-1)inhibitors and lenvatinib,which have a synergistic effect,are promising drugs for tumor treatment.It is generally believed that combination therapy with a PD-1 inhibitor and lenvatinib is safe and effective.However,we report a case of toxic epidermal necrolysis(TEN),a grade 4 toxicity,after this combination therapy.CASE SUMMARY A 39-year-old male presented with erythema,blisters and erosions on the face,neck,trunk and limbs 1 wk after receiving combination therapy with lenvatinib and toripalimab,a PD-1 inhibitor.The skin injury covered more than 70%of the body surface area.He was previously diagnosed with liver cancer with cervical vertebra metastasis.Histologically,prominent necrotic keratinocytes,hyperkeratosis,liquefaction of basal cells and acantholytic bullae were observed in the epidermis.Blood vessels in the dermis were infiltrated by lymphocytes and eosinophils.Direct immunofluorescence staining was negative.Thus,the diagnosis was confirmed to be TEN(associated with combination therapy with toripalimab and lenvatinib).Full-dose and long-term corticosteroids,high-dose intravenous immunoglobulin and targeted antibiotic drugs were administered.The rashes gradually faded;however,as expected,the tumor progressed.Therefore, sorafenib and regorafenib were given in succession, and the patient was still alive at the10-mo follow-up.CONCLUSIONCautious attention should be given to rashes that develop after combination therapy with PD-1inhibitors and lenvatinib. Large-dose and long-course glucocorticoids may be crucial for thetreatment of TEN associated with this combination treatment.
文摘The phase III clinical trial of the novel molecular targeted agent(MTA)lenvatinib for patients with advanced hepatocellular carcinoma(HCC)(REFLECT trial)found that lenvatinib was non-inferior to sorafenib in overall survival.Recently,the efficacy of multiple MTAs,including lenvatinib,in practice has been reported,and therapeutic strategies for Barcelona Clinic Liver Cancer(BCLC)intermediate stage HCC are undergoing major changes.Based on these results,lenvatinib could be recommended for patients with transcatheter arterial chemoembolization(TACE)-refractory,ALBI grade 1,within the up-to-seven criteria in the BCLC intermediate stage.Lenvatinib provides a more favorable outcome than TACE,even in cases with large or multinodular HCC beyond the up-to-seven criteria with Child-Pugh grade A.When patients meet the definitions of TACE-refractory or TACE-unsuitable,switching to systemic chemotherapy,including lenvatinib,is for favorable for preserving liver function.If initial treatment,including MTA,has a significant therapeutic effect and downstaging of HCC is obtained,additional TACE or surgical resection should be considered.Lenvatinib also has a therapeutic effect for poorly differentiated type and non-simple nodular type HCC thanks to the survival-prolonging effect of this drug.Furthermore,a significant therapeutic effect is expected in tumors with more than 50%liver involvement or main portal vein invasion,which have traditionally been considered to have a poor prognosis in patients.This suggests that at the start of lenvatinib treatment,HCC patients with ALBI grade 1 may be able to maintain liver functional reserve.
文摘BACKGROUND Hepatocellular carcinoma(HCC)accompanied by portal vein tumour thrombus(PVTT)presents an aggressive disease course,worsening liver function reserve,and a high recurrence rate.Clinical practice guidelines recommend systemic therapy as the first-line option for HCC with portal invasion.However,to achieve longer survival in these patients,the treatment strategy should be concluded with removal of the tumour by locoregional therapy.We experienced a case of initially unresectable HCC with main PVTT converted to radical hepatectomy after lenvatinib treatment.CASE SUMMARY A 59-year-old male with chronic hepatitis C infection visited our clinic as a regular post-surgery follow-up.Contrast-enhanced abdominal computed tomography revealed a liver mass diffusely located at the lateral segment with a massive PVTT extending from the umbilical portion to the main and contralateral third-order portal branches.With the diagnosis of unresectable HCC with Vp4(main trunk/contralateral branch)PVTT,lenvatinib was started at 12 mg/d.The computed tomography taken 3 mo after starting lenvatinib showed regression of the PVTT,which had retreated to the contralateral first-order portal branch.He tolerated the full dose without major adverse effects.With cessation of lenvatinib for 7 d,radical left lobectomy and PVTT thrombectomy were conducted.The patient’s postoperative course was uneventful.Microscopically,the primary lesion showed fibrotic changes,with moderately to poorly differentiated tumour cells surrounded by granulation tissues in some areas.The majority of the PVTT showed necrosis.He was alive without recurrence for 8 mo.CONCLUSION This is the first case of HCC with Vp4 PVTT in which radical conversion hepatectomy was succeeded after lenvatinib treatment.
文摘BACKGROUND In a phase III trial of lenvatinib as first-line treatment for advanced unresectable hepatocellular carcinoma(uHCC),the drug proved non-inferior to sorafenib in terms of the overall survival,but offered better progression-free survival.However,the effects of lenvatinib in uHCC patients with a tumor thrombus in the main portal vein and/or a high tumor burden(tumor occupancy more than 50%of the total liver volume),remain unclear,because these were set as exclusion criteria in the aforementioned trial.CASE SUMMARY A 53-year-old man(case 1)and 66-year-old woman(case 2)with uHCC presented to us with a tumor thrombus in both the main portal vein and inferior vena cava,a high tumor burden accompanied by a tumor diameter greater than>100 mm,and distant metastasis,with the residual liver function classified as grade 2A according to the modified Albumin–Bilirubin grading.We started both patients on lenvatinib.The therapeutic effect,as evaluated by the modified Response Evaluation Criteria in Solid Tumors,was rated as partial response in both case 1 and case 2(at 8 wk and 4 wk after the start of lenvatinib administration,respectively).The therapeutic effect was sustained for 6 mo in case 1 and 20 mo in case 2.Fever occurred as an adverse event in both case 1 and 2,and hyperthyroidism and thrombocytopenia in only case 2,neither of which,however,necessitated treatment discontinuation.CONCLUSION Even in hepatocellular carcinoma patients with poor prognostic factors,if the liver function is well-preserved,lenvatinib is effective and safe.
文摘BACKGROUND Lenvatinib has been shown to be noninferior to sorafenib regarding prognosis and recurrence rate in patients with unresectable hepatocellular carcinoma(HCC)who have not received prior systemic chemotherapy.In patients treated with lenvatinib,40%of cases achieved sufficient tumor reduction to make potential surgery possible.However,the outcomes of such surgery are unknown.We report a successful case of hepatic resection for recurrent HCC after lenvatinib treatment.CASE SUMMARY A 69-year-old man underwent right anterior sectionectomy for HCC in segment 8 of the liver.Ten months later,he was found to have an intrahepatic HCC recurrence that grew rapidly to 10 cm in diameter with sternal bone metastases.After confirming partial response to lenvatinib administration for 2 mo,a second hepatectomy was performed.Pathological examination showed that 80%of the tumor was necrotic.The patient did not develop any adverse effects under lenvatinib treatment.He was discharged at 25 d after surgery.Radiation therapy for bone metastases continued to be given under lenvatinib,and the patient has remained alive for 1 year after the second hepatectomy.CONCLUSION The prognosis of patients with recurrent HCC may be improved by liver resection combined with prior lenvatinib therapy.
文摘BACKGROUND Recently,hepatic arterial infusion chemotherapy(HAIC)plus lenvatinib has been frequently used to treat unresectable hepatocellular carcinoma(uHCC)in China.In the clinic,the hepatic arteries of some patients shrink significantly during this treatment,leading to improved short-term efficacy.AIM To investigate the relationship between the shrinkage of hepatic arteries and the short-term effect of HAIC plus lenvatinib treatment.METHODS Sixty-seven participants with uHCC were enrolled in this retrospective study.The patients received HAIC every 3 wk,followed by oral lenvatinib after the first HAIC course.Hepatic artery diameters were measured on CT before treatment and after 1 and 2 mo of treatment.Meanwhile,the changes in tumor capillaries were also examined on pathological specimens before and after 1 mo of treatment.The antitumor response after 1,3,and 6 mo of treatment was assessed using the modified Response Evaluation Criteria in Solid Tumors(mRECIST).The relationship between the changes in vessel diameters and the short-term effect of the combination treatment was evaluated by receiver-operating characteristic and logistic regression analyses.RESULTS The hepatic artery diameters were all significantly decreased after 1 and 2 mo of treatment(P<0.001),but there was no difference in the vessel diameters between 1 and 2 mo(P>0.05).The microvessel density in the tumor lesions decreased significantly after 1 mo of combination treatment(P<0.001).According to mRECIST,46,41,and 24 patients had complete or partial responses after 1,3,and 6 mo of treatment,respectively,whereas 21,21,and 32 patients had a stable or progressive disease at these times,respectively.Shrinkage of the tumor-feeding artery was significantly associated with the tumor response after 1,3,and 6 mo of treatment(P<0.001,P=0.004,and P=0.023,respectively);however,changes in other hepatic arteries were not significantly associated with the tumor response.Furthermore,shrinkage of the tumor-feeding artery was an independent factor for treatment efficacy(P=0.001,P=0.001,and P=0.002 and 1,3,and 6 mo,respectively).CONCLUSION The hepatic arteries shrank rapidly after treatment with HAIC plus lenvatinib,and shrinkage of the tumor-feeding artery diameter was closely related to improved short-term efficacy.
文摘BACKGROUND The management of metastatic progressive radioiodine-resistant differentiated thyroid cancer remains challenging for clinicians.The availability of tyrosine kinase inhibitors(TKIs),sorafenib and lenvatinib,within the last decade has expanded treatment options;however,these lead to significant adverse effects,which may curtail their use.CASE SUMMARY We report the case of a 47-year-old female with Hurthle cell thyroid cancer who underwent total thyroidectomy followed by radioiodine ablation.During followup,she developed noniodine-avid renal and pulmonary metastases.With respect to her pre-existing diabetes,hypertension,and polycystic kidney disease,the tumor board decided against performing renal metastasectomy because of the risk of future renal decline requiring dialysis.Metastases were treated using sorafenib,which provided stability followed by progression within a year.We switched to lenvatinib,which led to disease regression.However,the patient experienced severe adverse effects,including cardiomyopathy,bicytopenia,renal impairment,and the rarely reported nephrotic syndrome.Renal metastasis is a rare manifestation of Hurthle cell thyroid cancer with only two reported cases in literature.We report the experience of our first case of renal metastasis and its treatment with TKIs.This case serves as a reminder of the adverse drug reactions associated with TKI use.CONCLUSION We advocate close monitoring of patients’hematological and renal profiles as well as their cardiac status using an echocardiogram.
基金This study was partly supported by the National Natural Science Foundation of China(82122069,82073869,30900650,81372501,81572260,81773299,and H2808/82330065)Guangdong Basic and Applied Basic Research Foundation(2021B1515020004,2020B1515120032,2021B1212040017,and 2023B03J0106,China)+1 种基金the Fundamental Research Funds for the Central Universities(23yxqntd001,China)the Opening Project of Guangdong Provincial Key Laboratory of New Drug Design and Evaluation(2020B1212060034,China).
文摘Lenvatinib,a second-generation multi-receptor tyrosine kinase inhibitor approved by the FDA for first-line treatment of advanced liver cancer,facing limitations due to drug resistance.Here,we applied a multidimensional,high-throughput screening platform comprising patient-derived resistant liver tumor cells(PDCs),organoids(PDOs),and xenografts(PDXs)to identify drug susceptibilities for conquering lenvatinib resistance in clinically relevant settings.Expansion and passaging of PDCs and PDOs from resistant patient liver tumors retained functional fidelity to lenvatinib treatment,expediting drug repurposing screens.Pharmacological screening identified romidepsin,YM155,apitolisib,NVP-TAE684 and dasatinib as potential antitumor agents in lenvatinib-resistant PDC and PDO models.Notably,romidepsin treatment enhanced antitumor response in syngeneic mouse models by triggering immunogenic tumor cell death and blocking the EGFR signaling pathway.A combination of romidepsin and immunotherapy achieved robust and synergistic antitumor effects against lenvatinib resistance in humanized immunocompetent PDX models.Collectively,our findings suggest that patient-derived liver cancer models effectively recapitulate lenvatinib resistance observed in clinical settings and expedite drug discovery for advanced liver cancer,providing a feasible multidimensional platform for personalized medicine.
