Novel nomograms based on microvascular invasion grade for early-stage hepatocellular carcinoma after curative hepatectomy.

Microvascular invasion (MVI) is a critical risk factor for postoperative recurrence of hepatocellular carcinoma (HCC). This study aimed to firstly develop and validate nomograms based on MVI grade for predicting recurrence, especially early recurrence, and overall survival in patients with early-stage HCC after curative resection. We retrospectively reviewed the data of patients with early-stage HCC who underwent curative hepatectomy in the First Affiliated Hospital of Fujian Medical University (FHFU) and Mengchao Hepatobiliary Hospital of Fujian Medical University (MHH). Kaplan-Meier curves and Cox proportional hazards regression models were used to analyse disease-free survival (DFS) and overall survival (OS). Nomogram models were constructed on the datasets from the 70% samples of and FHFU, which were validated using bootstrap resampling with 30% samples as internal validation and data of patients from MHH as external validation. A total of 703 patients with early-stage HCC were included to create a nomogram for predicting recurrence or metastasis (DFS nomogram) and a nomogram for predicting survival (OS nomogram). The concordance indexes and calibration curves in the training and validation cohorts showed optimal agreement between the predicted and observed DFS and OS rates. The predictive accuracy was significantly better than that of the classic HCC staging systems.

Navoximod modulates local HSV-1 replication to reshape tumor immune microenvironment for enhanced immunotherapy via an injectable hydrogel.

Oncolytic virotherapy can lead to tumor lysis and systemic anti-tumor immunity, but the therapeutic potential in humans is limited due to the impaired virus replication and the insufficient ability to overcome the immunosuppressive tumor microenvironment (TME). To solve the above problems, we identified that Indoleamine 2, 3-dioxygenase 1 (IDO1) inhibitor Navoximod promoted herpes simplex virus type 1 (HSV-1) replication and HSV-1-mediated oncolysis in tumor cells, making it a promising combination modality with HSV-1-based virotherapy. Thus, we loaded HSV-1 and Navoximod together in an injectable and biocompatible hydrogel (V-Navo@gel) for hepatocellular carcinoma (HCC) virotherapy. The hydrogel formed a local delivery reservoir to maximize the viral replication and distribution at the tumor site with a single-dose injection. Notably, V-Navo@gel improved the disease-free survival time of HCC- bearing mice and protects the mice against tumor recurrence. What's more, V-Navo@gel also showed an effective therapeutic efficacy in the rabbit orthotopic liver cancer model. Mechanistically, we further discovered that our combination strategy entirely reprogramed the TME through single-cell RNA sequencing. All these results collectively indicated that the combination of Navoximod with HSV-1 could boost the viral replication and reshape TME for tumor eradication through the hydrogel reservoir.

Indocyanine green angiography for lower incidence of anastomotic leakage after transanal total mesorectal excision: a propensity score-matched cohort study.

Background: Anastomotic leakage (AL) is the most serious complication that can arise during colorectal surgery. Indocyanine green (ICG) angiography offers an intraoperative assessment of colonic vascular perfusion in real time. We aimed to assess ICG's effects on the AL rate in patients who have undergone transanal total mesorectal excision (TaTME) for rectal cancer. Methods: This retrospective cohort study was conducted at our center from October 2018 to March 2022 to analyze the clinical data of patients with rectal cancer who have undergone TaTME after propensity score matching (PSM). The primary outcome was the proximal colonic transection line modification and clinical AL rate. Results: A total of 143 patients in the non-ICG group and 143 patients in the ICG group were included after PSM. The proximal colonic transection line of seven patients in the non-ICG group was modified, while 18 were in the ICG group (4.9% vs. 12.5%, p = 0.023). Twenty-three patients (16.1%) in the non-ICG group and five patients (3.5%) in the ICG group were diagnosed with AL (p < 0.001). The ICG group had a less hospital readmission rate than the non-ICG group (0.7% vs. 7.7%, p = 0.003). The between-group differences in basic line and other outcomes were not significant. Conclusions: ICG angiography is a safe and feasible method to help surgeons identify potentially poor colonic vascular perfusion and modify the proximal colonic transection line, resulting in a significant reduction in AL and hospital readmission rates.

Dysregulation of global circular RNA abundance regulated by spliceosomes predicts prognosis in hepatocellular carcinoma.

CircRNAs have been reported to play crucial roles in tumor progression and recurrence, showing potential as biomarkers in cancer. However, the global abundance of circRNA and their involvement in hepatocellular carcinoma (HCC) development have not been fully explored. Whole transcriptome sequencing was performed on tumor and peritumor from 60 patients with HCC to quantify the expression of circRNAs, and the global circRNA abundance was calculated by circRNA index (CRI). Gene-set enrichment analysis and weighted gene co-expression network analysis were used to reveal the biological signaling pathways associated with the global circRNA abundance. The correlation between the global circRNA abundance and the infiltration level of CD8+ T cells was explored by immunohistochemical assays. Small interfering RNA was used to knock down the pre-messenger RNA spliceosome in HCC cell lines to verify the regulation of spliceosome in global circRNA abundance. We found that dysregulation of global circRNA abundance in both tumor and peritumor could lead to worse prognosis. The immunohistochemical assay further revealed that the dysregulation of global circRNA abundance in both tumor and peritumor would obstruct the CD8+ T cells from invading into the tumor, which might explain its correlation with HCC prognosis. We also demonstrated that the spliceosome genes were the main factors to regulate the global circRNA abundance in HCC, and these results were also confirmed by knockdown experiments. Conclusion: This study revealed the association between the global circRNA abundance and patients' prognosis and its underlying mechanism.

Personalized neoantigen vaccine combined with PD-1 blockade increases CD8+ tissue-resident memory T-cell infiltration in preclinical hepatocellular carcinoma models.

BACKGROUND: Personalized neoantigen vaccine could induce a robust antitumor immune response in multiple cancers, whose efficacy could be further enhanced by combining with programmed cell death 1 blockade (α-PD-1). However, the corresponding immune response and synergistic mechanisms remain largely unclear. Here, we aimed to develop clinically available combinational therapeutic strategy and further explore its potential antitumor mechanisms in hepatocellular carcinoma (HCC). METHODS: Neoantigen peptide vaccine (NeoVAC) for murine HCC cell line Hepa1-6 was developed and optimized by neoantigen screening and adjuvant optimization. Then the synergistic efficacy and related molecular mechanisms of NeoVAC combined with α-PD-1 in HCC were evaluated by orthotopic HCC mouse model, single-cell RNA sequencing, tetramer flow cytometry, immunofluorescence, etc. The tumor-killing capacity of CD8+ tissue-resident memory T cells (CD8+ TRMs) was assessed by orthotopic HCC mouse model, and autologous patient-derived cells. RESULTS: NeoVAC, which consisted of seven high immunogenic neoantigen peptides and clinical-grade Poly(I:C), could generate a strong antitumor immune response in HCC mouse models. Significantly, its efficacy could be further improved by combining with α-PD-1, with 80% of durable tumor regression and long-term immune memory in orthotopic HCC models. Moreover, in-depth analysis of the tumor immune microenvironment showed that the percentage of CD8+ TRMs was remarkedly increased in NeoVAC plus α-PD-1 treatment group, and positively associated with the antitumor efficacy. In vitro and in vivo T-cell cytotoxicity assay further confirmed the strong tumor-killing capacity of CD8+ TRMs sorting from orthotopic mouse HCC or patient's HCC tissue. CONCLUSIONS: This study showed that NeoVAC plus α-PD-1 could induce a strong antitumor response and long-term tumor-specific immune memory in HCC by increasing CD8+ TRMs infiltration, which might serve as a potential immune-therapeutic target for HCC.

Neoantigen Immunotherapeutic-Gel Combined with TIM-3 Blockade Effectively Restrains Orthotopic Hepatocellular Carcinoma Progression.

Herein, we integrate the Hepa1-6 liver cancer-specific neoantigen, toll-like receptor 9 agonist and stimulator of interferon genes agonist by silk-hydrogel package, and combine with TIM-3 blockade to elicit robust antitumor immunity for effectively suppressing orthotopic hepatocellular carcinoma (HCC) progression. Unlike intradermal injection of simple mixed components with short-term immune protection, the neoantigen immunotherapeutic-gels evoke long-term immune protection to achieve significant prophylactic and therapeutic activity against HCC through only one-shot administration without any side effects. Notably, the synergized immunotherapy by further combining NGC-gels with TIM-3 antibody significantly reduces regulatory T-cells and increases the IFN-γ and IL-12p70 levels in tumor tissues for promoting the infiltration of IFN-γ+CD8+T-cells and 41BB+CD8+T-cells to achieve complete remission (4/7) and prevent pulmonary metastasis in orthotopic HCC, and establish long-term memory against tumor rechallenge with remarkably longer survival time (180 days). Overall, this study provides an attractive and promising synergistic strategy for HCC immunotherapy with possible clinical translation prospects.

Copy number profiling of circulating free DNA predicts transarterial chemoembolization response in advanced hepatocellular carcinoma.

Transarterial chemoembolization (TACE) is the most commonly used treatment for advanced hepatocellular carcinoma (HCC), but still lacks accurate real-time biomarkers for monitoring its therapeutic efficacy. Here, we explored whether copy number profiling of circulating free DNA (cfDNA) could be utilized to predict responses and prognosis in HCC patients with TACE treatment. In total, 266 plasma cfDNA samples were collected from 64 HCC patients, 57 liver cirrhosis (LC) patients and 32 healthy volunteers. We performed low-depth whole-genome sequencing (LD-WGS) on cfDNA samples to conduct copy number variant (CNV) analysis and tumour fraction (TFx) quantification. Then, the correlation between TFx/CNVs and therapeutic efficacy, treatment outcomes and lipiodol deposition were explored. The change in TFx during TACE treatment was associated with patients' tumour burden, and could accurately and earlier predict treatment response and prognosis, providing an alternative strategy other than mRECIST. Meanwhile, the chromosomal 16q/NQO1 amplification indicated worse therapeutic response; in patients who underwent multiple TACE sessions, TFx change during their first TACE treatment reflected the long-term survival; additionally, the copy number amplification of chromosome 1q, 3p, 6p, 8q, 10p, 12q, 18p or 18q affected lipiodol deposition. Overall, we have provided a new liquid biopsy approach for future TACE management of HCC patients.

Personalized neoantigen vaccine prevents postoperative recurrence in hepatocellular carcinoma patients with vascular invasion.

BACKGROUND: Clinically, prophylactic anti-recurrence treatments for hepatocellular carcinoma (HCC) patients after radical surgery are extremely limited. Neoantigen based vaccine can generate robust anti-tumor immune response in several solid tumors but whether it could induce anti-tumor immune response in HCC and serve as a safe and effective prophylactic strategy for preventing postoperative HCC recurrence still remain largely unclear. METHODS: Personalized neoantigen vaccine was designed and immunized for 10 HCC patients with high risk of postoperative recurrence in a prime-boost schedule. The safety and immune response were assessed through adverse events, tissue sequencing, ELISpot, TCR sequencing. The clinical response was evaluated by recurrence-free survival (RFS) and personalized circulating tumor DNA (ctDNA) sequencing. RESULTS: In the 10 enrolled patients, no obvious adverse events were observed during neoantigen vaccinations. Until the deadline of clinical trial, 8 of 10 patients were confirmed with clinical relapse by imaging, the other 2 patients remained relapse-free. From receiving first neoantigen vaccination, the median RFS of 10 patients were 7.4 months. Among 7 patients received all planned neoantigen vaccinations, 5 of them demonstrated neoantigen-induced T cell responses and have significantly longer RFS after radical surgery than other 5 patients without responsive neoantigens or only with prime vaccination and propensity scores matching control patients (p = 0.035). Moreover, tracking personalized neoantigen mutations in ctDNA could provide real-time evaluation of clinical response in HCC patients during neoantigen vaccination and follow up. CONCLUSION: Personalized neoantigen vaccine is proved as a safe, feasible and effective strategy for HCC anti-recurrence, and its progression could be sensitively monitored by corresponding neoantigen mutations in ctDNA, and thus provided solid information for individualized medicine in HCC. TRIAL REGISTRATION: This study was registered at Chinese Clinical Trial Registry; Registration number: ChiCTR1900020990 .

Abdominal Oblique Internal and External Muscles Gap Colostomy for Lower Incidence of Parastomal Hernia and Higher Quality of Life: A Retrospective Cohort Study.

BACKGROUND: Parastomal hernia and fecal incontinence cause severe distress to the rectal cancer patients with stoma after abdominoperineal resection. We attempted a new colostomy technique through the gap between the abdominal oblique internal and external muscles to prevent parastomal hernia and improve quality of life. METHODS: This cohort study retrospectively examined clinical data from a total of 114 consecutive rectal cancer patients who underwent laparoscopic abdominoperineal resection in our center from March 2016 to March 2018 after propensity score matching. Group A included 57 patients who underwent colostomy through the gap between the abdominal oblique internal and oblique external muscles, while group B included 57 patients who underwent extraperitoneal colostomy. Patients' quality of life was evaluated using Fecal Incontinence Quality of Life (FIQL) Scale. RESULTS: Group A had a lower incidence of parastomal hernia (0% vs. 15.7%, p = 0.004) and higher quality of life, especially in lifestyle, coping/behavior and embarrassment domains (all p values < 0.05) than group B both during the follow-up period. The incidence of other outcomes did not differ between the groups. CONCLUSIONS: Colostomy through the gap between the abdominal oblique internal and oblique external muscle is a new technique showing both safety and effectiveness for preventing parastomal hernia and improving quality of life after laparoscopic abdominoperineal resection.

Development and Validation of a Machine Learning Prognostic Model for Hepatocellular Carcinoma Recurrence After Surgical Resection.

Surgical resection remains primary curative treatment for patients with hepatocellular carcinoma (HCC) while over 50% of patients experience recurrence, which calls for individualized recurrence prediction and early surveillance. This study aimed to develop a machine learning prognostic model to identify high-risk patients after surgical resection and to review importance of variables in different time intervals. The patients in this study were from two centers including Eastern Hepatobiliary Surgery Hospital (EHSH) and Mengchao Hepatobiliary Hospital (MHH). The best-performed model was determined, validated, and applied to each time interval (0-1 year, 1-2 years, 2-3 years, and 3-5 years). Importance scores were used to illustrate feature importance in different time intervals. In addition, a risk heat map was constructed which visually depicted the risk of recurrence in different years. A total of 7,919 patients from two centers were included, of which 3,359 and 230 patients experienced recurrence, metastasis or died during the follow-up time in the EHSH and MHH datasets, respectively. The XGBoost model achieved the best discrimination with a c-index of 0.713 in internal validation cohort. Kaplan-Meier curves succeed to stratify external validation cohort into different risk groups (p < 0.05 in all comparisons). Tumor characteristics contribute more to HCC relapse in 0 to 1 year while HBV infection and smoking affect patients' outcome largely in 3 to 5 years. Based on machine learning prediction model, the peak of recurrence can be predicted for individual HCC patients. Therefore, clinicians can apply it to personalize the management of postoperative survival.

Impact of body mass index on short-term outcomes of laparoscopic gastrectomy in Asian patients: A meta-analysis.

AIM: To perform a meta-analysis to investigate the correlation between body mass index (BMI) and the short-term outcomes of laparoscopic gastrectomy (LG) for gastric cancer (GC) in Asian patients. METHODS: The PubMed, Cochrane, EMBASE, and Web of Science databases were searched for studies that focused on the impact of obesity on the short-term outcomes of LG for GC in Asian patients who were classified into a high BMI (BMI ≥ 25 kg/m2) or low BMI group (BMI < 25 kg/m2). The results are expressed using the pooled odds ratio (OR) for binary variables and standard mean difference (SMD) for continuous variables with 95% confidence interval (CI), and were calculated according to the fixed-effects model while heterogeneity was not apparent or a random-effects model while heterogeneity was apparent. RESULTS: Nine studies, with a total sample size of 6077, were included in this meta-analysis. Compared with the low BMI group, the high BMI group had longer operative time (SMD = 0.26, 95%CI: 0.21 to 0.32, P < 0.001), greater blood loss (SMD = 0.19, 95%CI: 0.12 to 0.25, P < 0.001), and fewer retrieved lymph nodes (SMD = -0.13, 95%CI: 0.18 to 0.07, P < 0.001). There was no significant difference between the high and low BMI groups in postoperative complications (OR = 1.12, 95%CI: 0.95 to 1.33, P = 0.169), the duration of postoperative hospital stay (SMD = 0.681, 95%CI: -0.05 to 0.07, P = 0.681), postoperative mortality (OR = 1.95, 95%CI: 0.78 to 4.89, P = 0.153), or time to resuming food intake (SMD = 0.00, 95%CI: -0.06 to 0.06, P = 0.973). CONCLUSION: Our meta-analysis provides strong evidence that despite being associated with longer operative time, greater blood loss, and fewer retrieved lymph nodes, BMI has no significant impact on the short-term outcomes of LG for GC in Asian patients, including postoperative complications, the duration of postoperative hospital stay, postoperative mortality, and time to resuming food intake. BMI may be a poor risk factor for short-term outcomes of LG. Other indices should be taken into account.