A Prospective, Single-Arm, Phase 2 Study of Modified Transarterial Chemoembolization Using Low-Dose Chemotherapy with Blank Microspheres Plus Low-Dose Lenvatinib and Microwave Ablation in Patients with Large (≥7 cm) Unresectable Hepatocellular Carcinoma: The TALEM Trial.

Introduction: For patients with large unresectable hepatocellular carcinoma (HCC), the effectiveness of conventional transarterial chemoembolization (cTACE) remains suboptimal. This study investigated the efficacy and safety of modified TACE using low-dose chemotherapy with blank microspheres (BMS-TACE) plus low-dose lenvatinib (LD-LEN) and microwave ablation (MWA) in patients with large unresectable HCC. Methods: In this prospective, single-arm, phase 2 study, patients with unresectable HCC exceeding the up-to-seven criteria, with maximum tumor diameter ≥7 cm, and without macrovascular invasion or extrahepatic metastases, received initial BMS-TACE (lipiodol, low-dose doxorubicin, and lobaplatin up to 30 mg each, and blank microspheres; subsequently modified and repeated in most patients) plus LD-LEN (4-8 mg/day) and MWA. The primary endpoint was downstaging rate (DSR); secondary endpoints were objective response rate (ORR), progression-free survival (PFS), overall survival (OS), and adverse events. Results: From November 2019 to March 2022, 43 patients were enrolled. Median follow-up was 21.2 months. Median largest tumor diameter was 11.2 cm (interquartile range [IQR], 7-25). Following BMS-TACE and LD-LEN, downstaging occurred in 37 (86.0%) patients, 32 of whom received MWA, and 8 of whom had a complete response (CR) without MWA. ORR was 93.0% (CR in 32 [74.4%] and partial response in 8 [18.6%] patients). The 1-, 2-, and 3-year PFS rates were 57.5%, 25.9%, and 18.1%, respectively (median PFS, 14.7 months [95% CI: 8.1-19.5]). The 1-, 2-, and 3-year OS rates were 85.8%, 67.7%, and 61.6%, respectively (median OS, 36.4 months [95% CI: 26.8-not reached]). After BMS-TACE, a significant decline in CD11b+/CD33+/HLA-DR- myeloid-derived suppressor cells and early elevation in CXCR5+/CD8+ and CXCR5+/CD4+ T cells were observed (both p < 0.05). Conclusion: BMS-TACE plus LD-LEN and MWA resulted in promising efficacy and tolerable toxicity in patients with large unresectable HCC exceeding the up-to-seven criteria with a maximum tumor diameter ≥7 cm and without macrovascular invasion or extrahepatic metastases.

Overall Survival Rates Become Similar Between Percutaneous Ablation and Hepatic Resection With Increasing Age Among Elderly Patients With Early Hepatocellular Carcinoma.

Background: This study aimed to investigate the efficacy and safety of percutaneous ablation versus hepatectomy in an elderly population with hepatocellular carcinoma (HCC). Methods: Retrospective data on patients aged ≥ 65 years with very-early/early stages of HCC (≤ 50 mm) were obtained from three centers in China. Inverse probability of treatment weighting analysis was performed after stratifying the patients by age (65 - 69, 70 - 74 and ≥ 75 years). Results: Of the 1,145 patients, 561 and 584 underwent resection and ablation, respectively. For patients aged 65 - 69 and 70 - 74 years, resection resulted in significantly better overall survival (OS) than ablation (age 65 - 69, P < 0.001, hazard ratio (HR) = 0.27; age 70 - 74, P = 0.012, HR = 0.64). However, in patients aged ≥ 75 years, resection and ablation resulted in a similar OS (P = 0.44, HR = 0.84). An interactive effect existed between treatment and age (effect of treatment on OS, age 65 - 69 as the reference, for age 70 - 74, P = 0.039; for age ≥ 75, P = 0.002). The HCC-related death rate was higher in patients aged 65 - 69, and the liver/other cause-related death rate was higher in patients aged > 69. Multivariate analyses showed that the type of treatment, number of tumors, α-fetoprotein level, serum albumin level and associated diabetes mellitus were independent factors associated with OS, but not hypertension or heart diseases. Conclusion: With increasing patient age, the treatment outcomes of ablation become similar to those of resection. A higher liver/other cause-related death rate in very elderly patients may shorten the life expectancy, which may lead to the same OS regardless of whether resection or ablation is chosen.

Investigating Mechanisms of Response or Resistance to Immune Checkpoint Inhibitors by Analyzing Cell-Cell Communications in Tumors Before and After Programmed Cell Death-1 (PD-1) Targeted Therapy: An Integrative Analysis Using Single-cell RNA and Bulk-RNA Sequencing Data.

Currently, a significant proportion of cancer patients do not benefit from programmed cell death-1 (PD-1)-targeted therapy. Overcoming drug resistance remains a challenge. In this study, single-cell RNA sequencing and bulk RNA sequencing data from samples collected before and after anti-PD-1 therapy were analyzed. Cell-cell interaction analyses were performed to determine the differences between pretreatment responders and nonresponders and the relative differences in changes from pretreatment to posttreatment status between responders and nonresponders to ultimately investigate the specific mechanisms underlying response and resistance to anti-PD-1 therapy. Bulk-RNA sequencing data were used to validate our results. Furthermore, we analyzed the evolutionary trajectory of ligands/receptors in specific cell types in responders and nonresponders. Based on pretreatment data from responders and nonresponders, we identified several different cell-cell interactions, like WNT5A-PTPRK, EGFR-AREG, AXL-GAS6 and ACKR3-CXCL12. Furthermore, relative differences in the changes from pretreatment to posttreatment status between responders and nonresponders existed in SELE-PSGL-1, CXCR3-CCL19, CCL4-SLC7A1, CXCL12-CXCR3, EGFR-AREG, THBS1-a3b1 complex, TNF-TNFRSF1A, TNF-FAS and TNFSF10-TNFRSF10D interactions. In trajectory analyses of tumor-specific exhausted CD8 T cells using ligand/receptor genes, we identified a cluster of T cells that presented a distinct pattern of ligand/receptor expression. They highly expressed suppressive genes like HAVCR2 and KLRC1, cytotoxic genes like GZMB and FASLG and the tissue-residence-related gene CCL5. These cells had increased expression of survival-related and tissue-residence-related genes, like heat shock protein genes and the interleukin-7 receptor (IL-7R), CACYBP and IFITM3 genes, after anti-PD-1 therapy. These results reveal the mechanisms underlying anti-PD-1 therapy response and offer abundant clues for potential strategies to improve immunotherapy.

Preoperative identification of microvascular invasion in hepatocellular carcinoma by XGBoost and deep learning.

PURPOSE: Microvascular invasion (MVI) is a valuable predictor of survival in hepatocellular carcinoma (HCC) patients. This study developed predictive models using eXtreme Gradient Boosting (XGBoost) and deep learning based on CT images to predict MVI preoperatively. METHODS: In total, 405 patients were included. A total of 7302 radiomic features and 17 radiological features were extracted by a radiomics feature extraction package and radiologists, respectively. We developed a XGBoost model based on radiomics features, radiological features and clinical variables and a three-dimensional convolutional neural network (3D-CNN) to predict MVI status. Next, we compared the efficacy of the two models. RESULTS: Of the 405 patients, 220 (54.3%) were MVI positive, and 185 (45.7%) were MVI negative. The areas under the receiver operating characteristic curves (AUROCs) of the Radiomics-Radiological-Clinical (RRC) Model and 3D-CNN Model in the training set were 0.952 (95% confidence interval (CI) 0.923-0.973) and 0.980 (95% CI 0.959-0.993), respectively (p = 0.14). The AUROCs of the RRC Model and 3D-CNN Model in the validation set were 0.887 (95% CI 0.797-0.947) and 0.906 (95% CI 0.821-0.960), respectively (p = 0.83). Based on the MVI status predicted by the RRC and 3D-CNN Models, the mean recurrence-free survival (RFS) was significantly better in the predicted MVI-negative group than that in the predicted MVI-positive group (RRC Model: 69.95 vs. 24.80 months, p < 0.001; 3D-CNN Model: 64.06 vs. 31.05 months, p = 0.027). CONCLUSION: The RRC Model and 3D-CNN models showed considerable efficacy in identifying MVI preoperatively. These machine learning models may facilitate decision-making in HCC treatment but requires further validation.

Efficacy of Hepatic Resection vs. Radiofrequency Ablation for Patients With Very-Early-Stage or Early-Stage Hepatocellular Carcinoma: A Population-Based Study With Stratification by Age and Tumor Size.

Background: Because of the poor health conditions of elderly patients (age >65) with very-early-stage and early-stage hepatocellular carcinoma (HCC), primary treatment via hepatic resection (HR), or radiofrequency ablation (RFA) must be considered. However, few studies have examined this issue. Methods: A retrospective cohort was obtained from the Surveillance, Epidemiology, and End Results (SEER) database from 2004 to 2015. Patients were grouped by tumor size (0-20, 21-30, 31-35, and 31-50 mm) and age (>65 and ≤65). Overall survival (OS) and disease-specific survival (DSS) were assessed. Results: In total, 1912 patients aged >65 and 2,784 patients aged ≤65 were analyzed after propensity score matching (PSM). For patients >65 with tumors ≤20 mm, OS and DSS did not differ significantly between the RFA and HR groups (p = 0.47 and p = 0.76, respectively). For patients with tumors measuring 21-30 mm, the HR group had better OS and a trend toward better DSS compared with the RFA group (p = 0.03 and p = 0.09, respectively). For patients with tumors measuring 31-50 mm, the HR group had better OS and DSS compared with the RFA group (p < 0.001 for both). For patients <65, the HR group had better OS and DSS compared with the RFA group for all tumor sizes. Conclusions: For elderly patients (age >65), RFA is recommended for tumors ≤20 mm. For patients older than 65 with tumors measuring 21-50 mm and for those younger than 65 with tumors of any size, HR is the better choice.

Alcohol drinking as an unfavorable prognostic factor for male patients with nasopharyngeal carcinoma.

The relationship between alcohol drinking and the prognosis of nasopharyngeal carcinoma (NPC) is unknown. To investigate the prognostic value of alcohol drinking on NPC, this retrospective study was conducted on 1923 male NPC patients. Patients were classified as current, former and non-drinkers according to their drinking status. Furthermore, they were categorized as heavy drinkers and mild/none drinkers based on the intensity and duration of alcohol drinking. Survival outcomes were compared using Kaplan-Meier analysis and Cox proportional hazards model. We found that current drinkers had significantly lower overall survival (OS) rate (5-year OS: 70.2% vs. 76.4%, P < 0.001) and locoregional recurrence-free survival (LRFS) rate (5-year LRFS: 69.3% vs. 77.5%, P < 0.001) compared with non-drinkers. Drinking ≥14 drinks/week, and drinking ≥20 years were both independent unfavorable prognostic factors for OS (hazard ratio [HR] = 1.38, 95% confidence interval [CI] 1.05-1.81, P = 0.022; HR = 1.38, 95% CI 1.09-1.75, P = 0.007). Stratified analyses further revealed that the negative impacts of alcohol were manifested mainly among older patients and among smokers. In conclusion, alcohol drinking is a useful predictor of prognosis in male NPC patients; drinkers, especially heavy drinkers have poorer prognosis.