Transcatheter arterial chemoembolization combined with PD-1 inhibitors and Lenvatinib for hepatocellular carcinoma with portal vein tumor thrombus.

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.

Easily applicable predictive score for MPR based on parameters before neoadjuvant chemoimmunotherapy in operable NSCLC: a single-center, ambispective, observational study.

BACKGROUND: Neoadjuvant chemoimmunotherapy (NACI) is promising for resectable nonsmall cell lung cancer (NSCLC), but predictive biomarkers are still lacking. The authors aimed to develop a model based on pretreatment parameters to predict major pathological response (MPR) for such an approach. METHODS: The authors enrolled operable NSCLC treated with NACI between March 2020 and May 2023 and then collected baseline clinical-pathology data and routine laboratory examinations before treatment. The efficacy and safety data of this cohort was reported and variables were screened by Logistic and Lasso regression and nomogram was developed. In addition, receiver operating characteristic curves, calibration curves, and decision curve analysis were used to assess its power. Finally, internal cross-validation and external validation was performed to assess the power of the model. RESULTS: In total, 206 eligible patients were recruited in this study and 53.4% (110/206) patients achieved MPR. Using multivariate analysis, the predictive model was constructed by seven variables, prothrombin time (PT), neutrophil percentage (NEUT%), large platelet ratio (P-LCR), eosinophil percentage (EOS%), smoking, pathological type, and programmed death ligand-1 (PD-L1) expression finally. The model had good discrimination, with area under the receiver operating characteristic curve (AUC) of 0.775, 0.746, and 0.835 for all datasets, cross-validation, and external validation, respectively. The calibration curves showed good consistency, and decision curve analysis indicated its potential value in clinical practice. CONCLUSION: This real world study revealed favorable efficacy in operable NSCLC treated with NACI. The proposed model based on multiple clinically accessible parameters could effectively predict MPR probability and could be a powerful tool in personalized medication.

A multicenter prospective study of TACE combined with lenvatinib and camrelizumab for hepatocellular carcinoma with portal vein tumor thrombus.

BACKGROUND AND AIMS: Hepatocellular carcinoma (HCC) with portal vein tumor thrombus (PVTT) predicts a poor prognosis. The aim of the present study was to evaluate the efficacy and safety of using lenvatinib and camrelizumab combined with transarterial chemoembolization (TACE) to treat HCC with PVTT. METHODS: This was a single-arm, open-label, multicenter, and prospective study. Eligible patients with advanced HCC accompanied by PVTT were enrolled to receive TACE combined with lenvatinib and camrelizumab. The primary endpoint was progression-free survival (PFS), while the secondary endpoints included objective response rate (ORR), disease control rate (DCR), overall survival (OS), and safety. RESULTS: Between April 2020 and April 2022, 69 patients were successfully enrolled. With a median follow-up time of 17.3 months, the median age of the patient cohort was 57 years (range: 49-64 years). According to modified Response Evaluation Criteria in Solid Tumors, the ORR was 26.1% (18 partial responses [PRs]) and the DCR was 78.3% (18 PRs, 36 stable diseases [SDs]). The median PFS (mPFS) and median OS (mOS) were 9.3 and 18.2 months, respectively. And tumor number >3 was identified as an adverse risk factor for both PFS and OS. The most common adverse events across all grades included fatigue (50.7%), hypertension (46.4%), and diarrhea (43.5%). Twenty-four patients (34.8%) experienced Grade 3 toxicity that was relieved by dose adjustment and symptomatic treatment. No treatment-related deaths occurred. CONCLUSIONS: TACE combined with lenvatinib and camrelizumab is a well-tolerated modality treatment with promising efficacy for advanced HCC with PVTT.

Development of a Multivariate Prognostic Model for Lenvatinib Treatment in Hepatocellular Carcinoma.

BACKGROUND: Lenvatinib is a first-line agent for advanced hepatocellular carcinoma (HCC), but individual responses to treatment are highly heterogeneous. The aim of this study was to investigate the clinical parameters that influence the efficacy of Lenvatinib and to develop a prognostic model. METHODS: We retrospectively enrolled 333 Lenvatinib-treated patients with HCC with a median age of 57 years. Two hundred nd sixty-three of these patients had BCLC (2022) stage C. The median overall survival (mOS) time within the cohort was 12.1 months, and the median progression-free survival (mPFS) time was 4.7 months. Univariate Cox regression, best subset regression, and Lasso regression were used to screen primary variables for possible contribution to OS, multivariate Cox analysis was used to fit selected models, and the final model was selected using the maximum area under the curve (AUC) and minimum AIC. Receiver operating curves (ROC), calibration curves, and decision curve analysis were plotted to assess model performance, and 5-fold cross-validation was performed for internal validation. X-tile software was used to select the best cutoff points and to divide the study cohort into 3 different risk groups. RESULTS: Seven variables were included in the final model: BCLC stage, prior transarterial chemoembolization and immunotherapy history, tumor number, prognostic nutritional index, log (alpha-fetoprotein), and log (platelet-to-lymphocyte ratio). We named this final model the "multivariate prognostic model for Lenvatinib" (MPML), and a nomogram was constructed to predict the probability of survival at 6, 9, and 12 months. The MPML had good discrimination, calibration, and applicability. Cross-validation showed mean AUC values of 0.7779, 0.7738, and 0.7871 at 6, 9, and 12 months, respectively. According to nomogram points, mOS time was 21.57, 8.70, and 5.37 months in the low, medium, and high-risk groups, respectively (P < .001), and these differences were also observed in the PFS survival curve (P < .001). CONCLUSIONS: The MPML stratified patients according to baseline clinical characteristics had a strong performance in predicting Lenvatinib efficacy and has the potential for use as an auxiliary clinical tool for individualized decision-making.

Treatment options for unresectable hepatocellular carcinoma with hepatitis virus infection following sorafenib failure.

BACKGROUND: Currently, there are a few treatment options for unresectable hepatocellular carcinoma (HCC) after progression following sorafenib (SOR) therapy, but with limited benefit. The purpose of this study was to investigate the efficacy and safety of tyrosine kinase inhibitors (TKIs) combined with immune checkpoint inhibitors (ICIs) as second-line treatment. METHODS: From May 2018 to May 2021, a total of 93 HCCs who failed SOR treatment were included in this study and divided into TKI group (n = 37) and TKI-ICI group (n = 56). Overall survival (OS), progression-free survival (PFS), objective response rate (ORR), disease control rate (DCR) and safety were estimated among the two groups. In addition, univariate and multivariate Cox regression analyses were performed for OS and PFS to identify possible prognostic factors. RESULTS: With a median follow-up time of 13.7 months, the median age of patients was 56 (range, 50-64) years and most were male. All of the patients were hepatitis virus-related HCC. Both median OS (7.63 months vs 19.23 months, P < 0.001) and median PFS (2.97 months vs 8.63 months, P < 0.001) were significantly improved in the TKI-ICI group compared to the TKI group. A significant increase in DCR was demonstrated in the TKI-ICI group compared to the TKI group (83.9% vs 45.9%, P = 0.0003), although no significant difference in ORR was reported (21.4% vs 8.1%, P = 0.1552). Multivariate Cox regression analysis of OS and PFS revealed that second-line regimen was an independent protective factor affecting death and progression in HCCs after SOR failure. In addition, Child-Pugh B7 was an independent risk factor of OS. Finally, there was no significant difference in the incidence of any grade or grade 3/4 adverse events (AEs) between the two groups, and no treatment-related deaths were observed. CONCLUSION: This real-world study suggests that the combination of TKIs and ICIs benefits more than mono-TKIs and is well tolerated in HCCs with hepatitis virus infection after SOR failure.

Prognostic model of immune checkpoint inhibitors combined with anti-angiogenic agents in unresectable hepatocellular carcinoma.

Background: The combination of immune checkpoint inhibitors (ICIs) and anti-angiogenic agents has shown promising efficacy in unresectable hepatocellular carcinoma (HCC), but until now no clinical prognostic models or predictive biomarkers have been established. Methods: From 2016 to 2021, a total of 258 HCCs treated with ICIs and tyrosine kinase inhibitors (TKIs) were retrospectively enrolled, as the study cohort. Patients' baseline data was extracted by least absolute and shrinkage selection operator (LASSO) and Cox regression. Finally, a prognostic model in the form of nomogram was developed. Model performance was assessed in terms of discrimination, calibration, and clinical utility. A 5-fold cross-validation was used to evaluate the internal repeatability of the model. In addition, the patient cohort was divided into three subgroups according to nomogram scores. Their survivals were estimated by Kaplan-Meier methods and the differences were analyzed using log-rank tests. Results: Seven clinical parameters were selected: Eastern Cooperative Oncology Group performance status (ECOG PS), combination of transarterial chemoembolization (TACE), extrahepatic metastasis (EHM), platelet to lymphocyte ratio (PLR), alanine aminotransferase (ALT), alpha-fetoprotein (AFP), and Child-Pugh score. The model had an area under the curve (AUC) of 0.777 at 1 year and 0.772 at 2 years. Receiver operating characteristic (ROC) curve, calibration curve and decision curve analysis (DCA) showed that the discrimination, consistency and applicability of the model were good. In addition, cross-validation validated the discrimination of the model, and the C index value of the model is 0.7405. The median overall survival (OS) of the high-, medium- and low-risk subgroups was 7.58, 17.50 and 53.17 months, respectively, with a significant difference between the groups (P < 0.0001). Conclusion: We developed a comprehensive and simple prognostic model for the combination of ICIs plus TKIs. And it may predict the efficacy of the combination regimen for unresectable HCC.

Prognostic models for outcome prediction in patients with advanced hepatocellular carcinoma treated by systemic therapy: a systematic review and critical appraisal.

OBJECTIVE: To describe and analyze the predictive models of the prognosis of patients with hepatocellular carcinoma (HCC) undergoing systemic treatment. DESIGN: Systematic review. DATA SOURCES: PubMed and Embase until December 2020 and manually searched references from eligible articles. ELIGIBILITY CRITERIA FOR STUDY SELECTION: The development, validation, or updating of prognostic models of patients with HCC after systemic treatment. RESULTS: The systematic search yielded 42 eligible articles: 28 articles described the development of 28 prognostic models of patients with HCC treated with systemic therapy, and 14 articles described the external validation of 32 existing prognostic models of patients with HCC undergoing systemic treatment. Among the 28 prognostic models, six were developed based on genes, of which five were expressed in full equations; the other 22 prognostic models were developed based on common clinical factors. Of the 28 prognostic models, 11 were validated both internally and externally, nine were validated only internally, two were validated only externally, and the remaining six models did not undergo any type of validation. Among the 28 prognostic models, the most common systemic treatment was sorafenib (n = 19); the most prevalent endpoint was overall survival (n = 28); and the most commonly used predictors were alpha-fetoprotein (n = 15), bilirubin (n = 8), albumin (n = 8), Child-Pugh score (n = 8), extrahepatic metastasis (n = 7), and tumor size (n = 7). Further, among 32 externally validated prognostic models, 12 were externally validated > 3 times. CONCLUSIONS: This study describes and analyzes the prognostic models developed and validated for patients with HCC who have undergone systemic treatment. The results show that there are some methodological flaws in the model development process, and that external validation is rarely performed. Future research should focus on validating and updating existing models, and evaluating the effects of these models in clinical practice. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42020200187 .

Clinical study of lenvatinib in the treatment of hepatitis virus-related hepatocellular carcinoma and antiviral therapy.

Background: Lenvatinib is recommended as a first-line tyrosine kinase inhibitor for advanced hepatocellular carcinoma (HCC) since 2017. The aim of this study was to compare the clinical action of lenvatinib in hepatitis B virus (HBV)-related HCC and hepatitis C virus (HCV)-related HCC. Methods: A continuous cohort of advanced HCC was retrospectively enrolled. And the patients were divided into HBV-related HCC and HCV-related HCC based on previous history of hepatitis virus infection. Then propensity score matching (PSM) was conducted to compare objective response rate (ORR),disease control rate (DCR),progression-free survival (PFS),overall survival (OS) and safety between the two groups. Results: A total of 203 eligible patients were included, with 72 HBV-related HCC and 36 HCV-related HCC after PSM. Both ORR (20.8% vs. 5.6%, P = .0759) and DCR (76.4% vs. 52.8%, P = .0232) were significantly higher in the HBV-related HCC than in the HCV-related HCC. Although no statistical differences in PFS (6.1 months vs. 3.3 months, P = .17) and OS (14.9 months vs. 17.7 months, P = .96) were observed between the two groups, there was a trend of difference in the PFS survival curve. On multivariate regression analysis of PFS, both HBV infection (HR, .54; 95% CI, .31-.95; P = .0332) and antiviral time >5 years (HR, .49; 95% CI, .26-.9; P = .0219) were identified as independent favorable factors, and AFP >200 ng/mL (HR, 1.88; 95% CI, 1.1-3.22; P = .0216) were found to be an independent adverse factor. In addition, compared with HCC who received the first dose of antiviral drugs less than 5 years, the patients who were administered those drugs over 5 years had a significantly favorable PFS (11.27 months vs. 3.87 months, P = .0011). Lenvatinib was well tolerated in all patients and the adverse events (AEs) were similar between the two groups. Conclusion: It seemed that lenvatinib benefited more in HBV-related advanced HCC in delaying disease progression, compared to those with HCV-related advanced HCC.

Transit time flow measurement predicts graft patency in off-pump coronary artery bypass grafting upon 5-year angiographic follow-up.

OBJECTIVE: This retrospective study sought to evaluate the efficacy of transit time flow measurement (TTFM) as a means of predicting bypass graft patency as assessed by coronary artery angiography upon 5-year follow-up. METHODS: Of 311 patients undergone isolated off-pump coronary artery bypass graft surgery from January 2014 through December 2014, 202 (65%) underwent both intraoperative TTFM and angiography at follow-up. 610 grafts, 202 left internal mammary artery grafts and 408 saphenous vein grafts were checked. Any grafts that exhibited Fitzgibbon type B or O lesions upon angiographic evaluation were considered to be failing. Receiver operating characteristic curves were used to identify the optimal TTFM values for predicting graft patency. RESULTS: A total of 610 grafts were included in this analysis, including 202 LIMA grafts and 408 SV grafts, of which 107, 129, 129, and 43 anastomosed to DIAG, OM, PDA, and PLA, respectively. LIMA, DIAG, OM, PDA, and PLA bypass grafts had overall patency rates of 95.0%, 74.8%, 73.6%, 71.5%, and 74.4%, respectively, upon 5-year follow up. No significant differences in TTFM values (MGF, PI, and DF) were observed when comparing outcomes associated with individual or sequential SV grafting. MGF was found to be predictive of graft failure regardless of the target vessel (P < 0.05). While PI was found to predict LIMA, OM, and PDA graft failure (P < 0.05), it was not associated with the failure of grafts associated with DIAG and PLA vessels. Similarly, DF was found to predict OM and PDA graft failure (P < 0.05), but was not significantly associated with the failure of grafts associated with LIMA, DIAG, or PLA vessels. CONCLUSION: LIMA bypass grafts were associated with better 5-year graft patency relative to SV bypass grafts. Similar graft patency rates were observed for both individual and sequential bypass grafts. MGF was able to predict bypass graft failure in patients that underwent off-pump CABG surgery.

Erratum: B7-H3 promotes the cell cycle-mediated chemoresistance of colorectal cancer cells by regulating CDC25A: Erratum.

[This corrects the article DOI: 10.7150/jca.37255.].

B7-H3 inhibits the IFN-γ-dependent cytotoxicity of Vγ9Vδ2 T cells against colon cancer cells.

The immunoregulatory protein B7-H3, a member of the B7 family, has been confirmed to be highly expressed in colon cancer. However, the exact influence of B7-H3 on the features and antitumor ability of γδT cells in colon cancer remains unknown. In the present study, we investigated that the proportions of B7-H3+ γδT cells were distinctly increased in the peripheral blood and tumor tissues of colon cancer patients. B7-H3 blockade or knockdown promoted proliferation, inhibited cell apoptosis and induced the expression of activation markers (CD25 and CD69) on Vδ2 T cells. In contrast, treatment with the B7-H3 agonist 4H7 had the opposite effect. Furthermore, B7-H3 suppressed IFN-γ expression by inhibiting T-bet in Vδ2 T cells. Moreover, B7-H3 mediated the inhibition of Vδ2 T cell cytotoxicity via the downregulation of IFN-γ and perforin/granzyme B expression. More importantly, blocking the B7-H3 function significantly enhanced the cytotoxicity of Vδ2 T cells against colon cancer cells in vivo. Therefore, the inhibition or blockade of B7-H3 is a potential immunotherapeutic approach for colon cancer.

B7-H3 promotes the cell cycle-mediated chemoresistance of colorectal cancer cells by regulating CDC25A.

Colorectal cancer (CRC) is one of the most common malignancies, and chemoresistance is one of the key obstacles in the clinical outcome. Here, we studied the function of B7-H3 in regulating cell cycle-mediated chemoresistance in CRC. The ability of B7-H3 in regulating chemoresistance was investigated via cell viability, clonogenicity, apoptosis and cycle analysis in vitro. Moreover, the role of B7-H3/CDC25A axis in regulating chemoresistance in vivo in the xenograft tumor models by intraperitoneal injection of oxaliplatin (L-OHP) and CDC25A inhibitors. The correlation between B7-H3 and CDC25A was examined in the CRC patients by immunohistochemistry (IHC) and pathological analyses. We found that B7-H3 could effectively enhance the resistance to a chemotherapeutic drug (oxaliplatin or 5-fluorouracil) via CDC25A. B7-H3 regulated the expression of CDC25A by the STAT3 signaling pathway in CRC cells. Furthermore, overexpression of B7-H3 enhanced chemoresistance by reducing the G2/M phase arrest in a CDC25A-dependent manner. Silencing CDC25A or treatment with CDC25A inhibitor could reverse the B7-H3-induced chemoresistance of cancer cells. Moreover, both B7-H3 and CDC25A were significantly upregulated in CRC samples compared with normal adjacent tissues and that the levels correlated with tumor stage. CDC25A was positively correlated with B7-H3 expression in this cohort. Taken together, our findings provide an alternative mechanism by which CRC cells can acquire chemoresistance via the B7-H3/CDC25A axis.

Tim-3 suppresses the killing effect of Vγ9Vδ2 T cells on colon cancer cells by reducing perforin and granzyme B expression.

Gamma delta (γδ) T cell-based tumor immunotherapy has been one of the most promising cancer immunotherapeutic strategies. However, the key regulators of the Vγ9Vδ2 T cell-mediated antitumor response remain unclear. Recently, mounting reports have indicated that Tim-3 performs critical roles in the regulation of the activities of immune cells, including Vγ9Vδ2 T cells. However, the roles of Tim-3 in Vγ9Vδ2 T cell-mediated killing of colon cancer cells and the underlying mechanism remain largely unknown. Here, the proportion of Tim-3+ γδ T cells was significantly increased in both the peripheral blood and colon cancer tissue of patients and was significantly associated with TNM staging and tumor volume. Additionally, the activation of Tim-3 signaling significantly inhibited the killing efficiency of Vγ9Vδ2 T cells against colon cancer cells. In addition, Tim-3 signaling reduced the expression of perforin and granzyme B in Vγ9Vδ2 T cells. Blocking the perforin/granzyme B pathway also decreased the cytotoxicity of Vγ9Vδ2 T cells to colon cancer cells. Moreover, Tim-3 signaling reduced the perforin and granzyme B expression of Vγ9Vδ2 T cells in an ERK1/2 signaling pathway-dependent manner. This knowledge reveals that Tim-3 may be a promising therapeutic target to improve Vγ9Vδ2 T cell-based adoptive immunotherapy for colon cancer.

Noninvasive Positive-Pressure Ventilation in Treatment of Hypoxemia After Extubation Following Type-A Aortic Dissection.

OBJECTIVES: To assess the efficacy of noninvasive positive-pressure ventilation (NPPV) in improving hypoxemia after extubation for Stanford type-A aortic dissection and to compare NPPV using a mask or a helmet. DESIGN: Prospective, interventional study. SETTING: Department of Cardiac Surgery of the Beijing Anzhen Hospital, a tertiary university hospital. PARTICIPANTS: Patients experiencing hypoxemia within 24 hours after extubation for Stanford type-A aortic dissection. INTERVENTIONS: The patients were divided into the following 3 groups: high-flux inhalation of oxygen with a Venturi mask (control patients), NPPV with a mask (mask group), and NPPV with a helmet (helmet group) (n = 25/group). MEASUREMENTS AND MAIN RESULTS: Data for blood gas analysis, vital signs, heart function, and complications were collected before the treatment, after 1 and 6 hours of treatment, and at the end of treatment. The oxygen partial pressure/fraction of inspired oxygenation index or PaO2/FIO2 ratio and the oxygen partial pressure were higher and carbon dioxide partial pressure was lower in the mask and helmet groups compared with that of control patients. Compared with control patients and the mask group, the helmet group showed a slower heart rate, lower average arterial pressure, and improved left ventricular ejection fraction, leading to a lower incidence of reintubation and a shorter hospital stay. CONCLUSIONS: NPPV with a helmet may quickly improve oxygen partial pressure, decrease carbon dioxide partial pressure, decrease the reintubation rate, and effectively shorten the hospital stay after extubation for Stanford type-A aortic dissection.

[Postoperative acute renal failure in adult patients with cardiac surgery: evaluation of the RIFLE classification].

OBJECTIVE: To evaluate the ability of the RIFLE classification to predict hospital mortality in adult patients who underwent cardiac surgery. METHODS: From October 1st 2006 to December 31st 2006, five hundred and nine adult patients who underwent coronary artery bypass grafting and/or valve operation were enrolled in this study. Renal function was assessed daily according to the RIFLE classification, meanwhile, APACHE II score and SOFA score were also evaluated, as well as the maximum scores were recorded. RESULTS: Mean duration of ventilation support was 18 (14-19) hours, the time of ICU stay was 1.4 +/- 1.0 days, and the time of postoperative hospital stay was 12.0 (10.0-15.0) days. 167 patients (32.8%) incurred postoperative ARF according to the RIFLE classification. The overall mortality was 4.3% (22/502). A significant increase (P < 0.01) was observed for mortality based on RIFLE classification. By applying the area under the receiver operating characteristic curve, the RIFLE classification had more powerful discrimination power [0.933, (95% CI 0.872-0.995), P < 0.001]. CONCLUSIONS: ARF is one of the major complications in postcardiotomy patients. Analytical data suggested the good discriminative power of the RIFLE classification for predicting inpatient mortality of adult postoperative patient with ARF, and the RIFLE classification is simple and practically performed. According to the RIFLE classification, patients with RIFLE class I or class F incur a significantly increased risk of in-hospital mortality compared with those who never develop ARF.