Clinical outcomes of lenvatinib plus transarterial chemoembolization with or without programmed death receptor-1 inhibitors in unresectable hepatocellular carcinoma

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.

High incidence combination of multiple primary malignant tumors of the digestive system

BACKGROUND Clinical reports of multiple primary malignant tumors(MPMTs)in the digestive system are increasing.In China,although the survival rate of patients with MPMTs is increasing,the quality of life is very low.Many patients have reached the advanced stage when the second primary tumor is found,resulting in no early intervention and treatment.This is due to the misunderstanding of MPMTs by clinicians,who treat such tumors as metastases.Therefore,before a patient has a second primary tumor,doctors should understand some common combinations of digestive system MPMTs to provide clinical guidance to the patient.AIM To explore the high incidence combination of digestive system MPMTs under heterochronism and synchronization.METHODS A total of 1902 patients with MPMTs at Peking Union Medical College Hospital were analyzed retrospectively.They were divided into metachronous MPMT and synchronous MPMT groups,and then the high incidence combinations of the first primary cancer and the second primary cancer in metachronous cancer and synchronous cancer were sorted.Sex and age differences between metachronous and synchronous tumors were tested by the chi square test and t test,respectively.A P value<0.05 was considered as statistically significant,and SPSS version 26.0(SPSS Inc.,Chicago,Illinois,United States)was used for statistical analysis.RESULTS Among the 1902 patients with MPMTs confirmed by pathology,1811(95.2%)cases were secondary primary cancers,89(4.7%)cases were tertiary primary cancers,and 2(0.1%)cases were quaternary primary cancers.Most(88.2%)of the secondary primary cancers were identified as metachronous multiple primary cancers six months after diagnosis of the first primary cancer.The top ten most common MPMTs in the first primary cancer group ranged from high to low as follows:Breast cancer,thyroid cancer,nonuterine cancer,lung cancer,colon cancer,kidney cancer,uterine cancer,bladder cancer,rectal cancer,and gastric cancer.The highest incidence rate of the first primary cancer in male metachronous cancer was lung cancer(11.6%),the highest incidence rate of the second primary cancer was still lung cancer(24.9%),the highest incidence rate of the first primary cancer in female metachronous cancer was breast cancer(32.7%),and the highest incidence rate of the second primary cancer was lung cancer(20.8%).Among them,breast cancer,nonuterine cancer and uterine cancer were female-specific malignant tumor types,and thyroid cancer also accounted for 79.6%of female patients.The top five metachronous cancer combinations,independent of female-specific malignant tumor types and thyroid cancer,were colon cancer and lung cancer(26 cases),kidney cancer and lung cancer(25 cases),rectal cancer and lung cancer(20 cases),gastric cancer and lung cancer(17 cases),and bladder cancer and lung cancer(17 cases).The most common synchronous cancer combination was colon cancer and rectal cancer(15 cases).CONCLUSION Screening for lung cancer should be performed six months after the detection of colon cancer while rectal cancer screening should be performed within six months.

Novel cellular therapies for hepatobiliary malignancies

Background:The mortalities of hepatobiliary malignancies are high.With the failure of conventional chemotherapy and unsatisfactory outcome of molecular targeted drugs,immune-based therapy has become a new focus of research in hepatobiliary cancers treatment.Data sources:We performed a Pub Med search with relevant articles published up to May 2022 and the following keywords:cellular immunotherapy,hepatobiliary cancer,antigen receptor T cell therapy,and receptor-engineered T cell.Information of clinical trials was obtained from https://clinicaltrials.gov/.Results:Cell therapies for hepatobiliary malignancies are at early stage of development.The current review showed that cellular therapies are safe and feasible in patients.These findings provide an important platform for future lager scale clinical trials on immunotherapy in patients with hepatobiliary malignancies.Conclusions:With the continuous advances of cellular immunotherapy,the combination of cellular immunotherapy with surgery,chemotherapy and radiotherapy will be new therapeutic strategies for patients with hepatobiliary cancer.

NOTCH2NLC expanded GGC repeats in patients with cerebral small vessel disease

Objective GGC repeat expansions in the human-specific NOTCH2NLC gene have been reported as the cause of neuronal intranuclear inclusion disease(NIID).Given the clinical overlap of cognitive impairment in NIID and cerebral small vessel disease(CSVD),both diseases have white matter hyperintensity on T2-fluid attenuated inversion recovery sequences of brain MRI,and white matter hyperintensity is a primary neuroimaging marker of CSVD on MRI.Therefore,we hypothesised that the GGC repeat expansions might also contribute to CSVD.To further investigate the relationship between NOTCH2NLC GGC repeat expansions and CSVD,we performed a genetic analysis of 814 patients with the disease.Methods We performed a comprehensive GGC repeat expansion screening in NOTCH2NLC from 814 patients with sporadic CSVD.Their Fazekas score was greater than or equal to 3 points.Repeat-primed PCR and fluorescence amplicon length analyses were performed to identify GGC repeat expansions,and whole-exome sequencing was used to detect any pathogenic mutation in previously reported genes associated with CSVD.Results We identified nine(1.11%)patients with pathogenic GGC repeat expansions ranging from 41 to 98 repeats.The minor allele frequency of expanded GGC repeats in NOTCH2NLC was 0.55%.Conclusion Our findings suggest that intermediate-length and longer-length GGC repeat expansions in NOTCH2NLC are associated with sporadic CSVD.This provides new thinking for studying the pathogenesis of CSVD.