Neoadjuvant targeted immunotherapy followed by surgical resection versus upfront surgery for hepatocellular carcinoma with macrovascular invasion: A multicenter study.

Background: This study aimed to investigate the safety and efficacy of preoperative targeted immunotherapy followed by surgical resection for hepatocellular carcinoma (HCC) patients with macrovascular invasion. Method: Clinical information of HCC patients with macrovascular invasion was collected from four medical centers. These patients were divided into two cohorts: the upfront surgery group (n=40) and the neoadjuvant group (n=22). Comparisons between the two groups were made with appropriate statistical methods. Results: HCC Patients with macrovascular invasion in the neoadjuvant group were associated with increased incidence of postoperative ascites (72.73% vs. 37.5%, P=0.008), but shorter postoperative hospital stay (10 days vs. 14 days, P=0.032). Furthermore, targeted immunotherapy followed by surgical resection significantly reduced the postoperative recurrence rate at both 3 months and 1 year (9% versus 28.9%, 32.1% versus 67.9%, respectively; P=0.018), but increased the postoperative nononcologic mortality rate within 1 year (20.1% vs. 2.8%; P= 0.036). Conclusion: For HCC patients with macrovascular invasion, preoperative targeted immunotherapy significantly decreased the postoperative tumor recurrence rate while maintaining relative safety, but such a treatment may also result in chronic liver damage and increased risk of nononcologic mortality.

Exploration of prognostic and treatment markers in hepatocellular carcinoma via GPCR-related genes analysis.

Background: G protein-coupled receptors (GPCRs), the biggest family of signaling receptors, account for 34 % of all the drug targets approved by the Food and Drug Administration (FDA). It has been gradually recognized that GPCRs are of significance for tumorigenesis, but in-depth studies are still required to explore specific mechanisms. In this study, the role of GPCRs in hepatocellular carcinoma (HCC) was elucidated, and GPCR-related genes were employed for building a risk-score model for the prognosis and treatment efficacy prediction of HCC patients. Methods: Patients' data on HCC were sourced from the Liver Hepatocellular Carcinoma-Japan (LIRI-JP) and The Cancer Genome Atlas (TCGA) databases, while GPCR-related genes were obtained from the Molecular Signatures Database (MSigDB). Univariant and multivariant Cox regression analyses, as well as least absolute shrinkage and selection operator (LASSO) were performed with the aim of identifying differentially expressed GPCR-related genes and grouping patients. Differential expression and functional enrichment analyses were performed; protein-protein interaction (PPI) mechanisms were explored; hub genes and micro ribonucleic acid (miRNA)-target gene regulatory networks were constructed. The tumor immune dysfunction and exclusion (TIDE) algorithm was utilized to evaluate immune infiltration levels and genetic variations. Sensitivity to immunotherapy and common antitumor drugs was predicted via the database Genomics of Drug Sensitivity in Cancer (GDSC). Results: A GPCR-related risk score containing eight GPCR-related genes (atypical chemokine receptor 3 (ACKR3), C-C chemokine receptor type 3 (CCR3), CCR7, frizzled homolog 5 (FZD5), metabotropic glutamate receptor 8 (GRM8), hydroxycarboxylic acid receptor 1 (HCAR1), 5-hydroxytryptamine receptor 5A (HTR5A) and nucleotide-binding oligomerization domain-like receptor family pyrin domain containing 6 (NLRP6)) was set up. In addition, patients were classified into groups with high and low risks. Patients in the high-risk group exhibited a worse prognosis but demonstrated a more favorable immunotherapy response rate compared with those in the low-risk group. Distinct sensitivity to chemotherapeutic drugs was observed. A clinical prediction model on the basis of GPCR-related risk scores was constructed. Areas under the curves (AUC) corresponding to one-, three- and five-year survival were 0.731, 0.765 and 0.731, respectively. Conclusions: In this study, an efficient HCC prognostic prediction model was constructed by only GPCR-related genes, which are all potential targets for HCC treatment.

Urinary biomarkers for hepatocellular carcinoma: current knowledge for clinicians.

Hepatocellular carcinoma (HCC) is the most predominant primary liver cancer, causing many illnesses and deaths worldwide. The insidious clinical presentation, difficulty in early diagnosis, and the highly malignant nature make the prognosis of HCC extremely poor. The complex and heterogeneous pathogenesis of HCC poses significant challenges to developing therapies. Urine-based biomarkers for HCC, including diagnostic, prognostic, and monitoring markers, may be valuable supplements to current tools such as serum α-fetoprotein (AFP) and seem promising for progress in precision medicine. Herein, we reviewed the major urinary biomarkers for HCC and assessed their potential for clinical application. Molecular types, testing platforms, and methods for building multimolecule models in the included studies have shown great diversity, thus providing abundant novel tools for future clinical transformation and applications.

Integrated analysis revealing a novel stemness-metabolism-related gene signature for predicting prognosis and immunotherapy response in hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is a malignant lethal tumor and both cancer stem cells (CSCs) and metabolism reprogramming have been proven to play indispensable roles in HCC. This study aimed to reveal the connection between metabolism reprogramming and the stemness characteristics of HCC, established a new gene signature related to stemness and metabolism and utilized it to assess HCC prognosis and immunotherapy response. The clinical information and gene expression profiles (GEPs) of 478 HCC patients came from the Gene Expression Omnibus (GEO) and the Cancer Genome Atlas (TCGA). The one-class logistic regression (OCLR) algorithm was employed to calculate the messenger ribonucleic acid expression-based stemness index (mRNAsi), a new stemness index quantifying stemness features. Differentially expressed analyses were done between high- and low-mRNAsi groups and 74 differentially expressed metabolism-related genes (DEMRGs) were identified with the help of metabolism-related gene sets from Molecular Signatures Database (MSigDB). After integrated analysis, a risk score model based on the three most efficient prognostic DEMRGs, including Recombinant Phosphofructokinase Platelet (PFKP), phosphodiesterase 2A (PDE2A) and UDP-glucuronosyltransferase 1A5 (UGT1A5) was constructed and HCC patients were divided into high-risk and low-risk groups. Significant differences were found in pathway enrichment, immune cell infiltration patterns, and gene alterations between the two groups. High-risk group patients tended to have worse clinical outcomes and were more likely to respond to immunotherapy. A stemness-metabolism-related model composed of gender, age, the risk score model and tumor-node-metastasis (TNM) staging was generated and showed great discrimination and strong ability in predicting HCC prognosis and immunotherapy response.

An immune-related biomarker index for predicting the effectiveness of immunotherapy and prognosis in hepatocellular carcinoma.

OBJECTIVE: Currently, there are no recognized biomarkers for predicting the immunotherapy response and prognosis of hepatocellular carcinoma (HCC). This study aimed to establish an immune-related gene prognostic index (IRGPI) for HCC, and to investigate the clinical, immune, molecular, and microenvironmental characteristics of the IRGPI subgroups, as well as their impact on the effectiveness of immune checkpoint inhibitors (ICIs) therapy and patients' prognosis. METHODS: We analyzed the LIHC dataset (n = 424) from the The Cancer Genome Atlas (TCGA) database and the GSE10140 dataset (n = 84) from the Gene Expression Omnibus (GEO) database using weighted gene co-expression network analysis (WGCNA) and univariate/multivariate Cox regression analysis to identify immune-related hub genes with prognostic significance. Subsequently, The IRGPI was then established with these special genes obtained, and the molecular, immune, and clinicopathological characteristics of the IRGPI subgroups, along with their predictive role in ICIs treatment and HCC prognosis, were investigated. RESULTS: The IRGPI was composed of nine genes, namely CHGA, GAL, CCR3, MMP7, STC1, UCN, OXT, SOCS2, and GCG. The IRGPI-high group exhibited a worse prognosis in both the TCGA and GEO databases compared to the IRGPI-low group. The IRGPI-high group was primarily associated with adaptive immune response and cell-cell interaction pathways and exhibited a higher frequency of gene mutations (such as TP53 and CTNNB1), higher expression of PD-L1 and CTLA4, a higher proportion of macrophages M0 and follicular helper T cells, and a higher APC_co_inhibition and T_cell_co-inhibition immune score. Furthermore, the IRGPI-high group was associated with worse immune subtypes, clinicopathological characteristics, immunotherapy response, and clinical prognosis. CONCLUSION: IRGPI is a biomarker with significant potential for predicting the immunotherapy response and prognosis of HCC patients, and is closely related to the immunosuppressive microenvironment and poorer clinicopathological characteristics.

Application and Progress of Cultured Models of Gallbladder Carcinoma.

Gallbladder carcinoma (GBC) is a malignant tumor of the biliary system that is aggressive, difficult to detect early, and has a low surgical resection rate and poor prognosis. Appropriate in vitro growth models are expected to focus on the study of the biological behavior and assess treatment effects. Nonetheless, cancer initiation, progression, and invasion include spatiotemporal changes and changes in the cell microenvironment intracellular communication, and intracellular molecules, making the development of in vitro growth models very challenging. Recent advances in biomaterial methods and tissue engineering, particularly advances in bioprinting procedures, have paved the way for advances in the creative phase of in vitro cancer research. To date, an increasing number of cultured models of gallbladder disease have emerged, such as two-dimensional (2D) GBC growth cell cultures, three-dimensional (3D) GBC growth cell cultures, xenograft models, and 3D bioprinting methods. These models can serve as stronger platforms, focusing on tumor growth initiation, the association with the microenvironment, angiogenesis, motility, aggression, and infiltration. Bioprinted growth models can also be used for high-throughput drug screening and validation, as well as translational opportunities for individual cancer therapy. This study focused on the exploration, progress, and significance of the development of GBC cultural models. We present our views on the shortcomings of existing models, investigate new innovations, and plan future improvements and application possibilities for cancer models.

Safety and Perioperative Outcomes of Laparoscopic vs. Open Hepatectomy of Central-Located Liver Lesions: A Multicenter, Propensity Score-Matched, Retrospective Cohort Study.

BACKGROUND: Short-term outcomes of laparoscopic hepatectomy of central-located liver lesions (LHCL) compared with traditional open hepatectomy of central-located liver lesions (OHCL) remain unclear. The aim of this study was to explore the safety and efficacy of LHCL. METHODS: A retrospective analysis was performed on 262 patients who underwent hepatectomies involving resections of liver segment II, IV or VIII from January 2015 to June 2021 in two institutions. Patients in the LHCL group were matched in a 1:2 ratio to patients in the OHCL group. RESULTS: After propensity score-matched (PSM) analysis, 61 patients remained in the LHCL group and 122 patients were in the OHCL group. What needs to be mentioned is that although not significant, patients in the OHCL group had increased lesion size (4.3 vs. 3.6 cm, p = 0.052), number (single/multiple, 84.8%/15.2% vs. 93.4%/6.6%, p = 0.097), and number of liver segments involved (one/two/three, 47.3%/42.0%/10.7% vs. 57.4%36.1%/10.7%, p = 0.393). To ensure surgical safety, fewer patients in the LHCL group underwent vascular exclusion than those in the OHCL group (p = 0.004). In addition, LHCL was associated with lower blood loss (p = 0.001) and transfusion requirement (p = 0.004). In terms of short-term outcomes, the LHCL group had significantly lower levels of peak ALT (p < 0.001), peak DBIL (p = 0.042), peak PT (p = 0.012), and higher levels of bottom ALB (p = 0.049). Moreover, the LHCL group demonstrated quicker postoperative recovery, which was represented by shorter time to first flatus, time to oral intake, time to drain off, and hospital stay (all p < 0.001). Importantly, the LHCL group had a significantly reduced occurrence of postoperative complications (p < 0.001) and similar R0 resection rates (p = 0.678) when compared to the OHCL group. CONCLUSION: LHCL is associated with increased safety and better perioperative outcomes and thus could be recommended for patients with central space-occupying liver lesions when appropriately selecting the surgical procedure according to the total tumor burden and carefully handled by experienced surgeons. From the experience of our center, LHCL could be performed to solitary lesion involving liver segment IV/V/VIII, <5 cm, with good safety and feasibility.

A Nomogram to Predict Individual Survival of Patients with Liver-Limited Metastases from Gastroenteropancreatic Neuroendocrine Neoplasms: A US Population-Based Cohort Analysis and Chinese Multicenter Cohort Validation Study.

INTRODUCTION: Although gastroenteropancreatic neuroendocrine neoplasms (GEP-NENs) with liver metastasis encompass a wide variety of clinical conditions with various prognosis, no statistical model for predicting the prognosis of these patients has been established. We sought to establish a more elaborative and individualized nomogram to predict survival of patients with liver-limited metastatic GEP-NENs. In addition, this nomogram was validated by both the Surveillance, Epidemiology, and End Results (SEER) database and a Chinese multicenter cohort. METHODS: Patients diagnosed with GEP-NENs with liver-limited metastasis between 2010 and 2016 were identified from the SEER database. Kaplan-Meier survival analysis was performed to analyze survival outcomes. A nomogram was established based on the independent prognostic variables identified from univariate and multivariate Cox regression analyses. The nomogram was evaluated in both an internal validation SEER dataset and an external validation dataset composed of patients from the Chinese multicenter cohort. RESULTS: A total of 1,474 patients from the SEER database and 192 patients from the multicenter cohort were included. Age, tumor size, differentiation, primary tumor resection, and liver metastasis resection were identified as independent prognostic factors by univariate and multivariate Cox analyses and were verified by Kaplan-Meier survival analysis (all p < 0.0001). A nomogram was developed and validated by calibration curves and areas under the curve of the external validation cohort, which showed good consistency and veracity in predicting overall survival. CONCLUSION: A nomogram was developed for the first time to predict the survival of patients with liver-limited metastases from GEP-NENs. Both internal and external validation demonstrated excellent discrimination and calibration of our nomogram. Based on this prognostic model, clinicians could develop more personalized treatment strategies and surveillance protocols.

An ectopic adrenocortical oncocytic adenoma in the liver highly mimicking hepatocellular carcinoma: case report and literature review.

BACKGROUND: Ectopic adrenocortical tissue is a lesion usually found incidentally during autopsy or inguinal surgery. Here, we demonstrate an extremely unusual case of intrahepatic adrenocortical adenoma which highly mimicks hepatocellular carcinoma (HCC) and brings challenges for clinicians and pathologists. The diagnostic pitfalls have been discussed in detail to provide clues for guiding differential diagnosis and future treatment. CASE PRESENTATION: A 44-year-old man was admitted into our hospital for evaluation of a hepatic mass identified during routine examination. Enhanced CT revealed its margin displayed apparent enhancement in arterial phase, but hypointensity in portal and delayed phase. HCC was suspected and partial hepatectomy was performed. Microscopically, cells were arranged in solid sheets. Most of the tumor cells were large, polygonal, had prominent nucleoli and were rich in eosinophilic cytoplasm. Pleomorphic nucleus was frequently found. Focally, smaller cells were found with small nuclei and granular cytoplasm. Immunohistochemically, tumor cells were negative for Arg-1, glypican-3 (GPC3), hepatocyte specific antigen (HSA), and positive for synaptophysin (Syn), α-inhibin, and Melan A. The Ki-67 index was 1 %. The final diagnosis was ectopic adrenocortical oncocytic adenoma and the patient was uneventful after the surgery. CONCLUSION: Intrahepatic adrenocortical adenoma in the liver can hardly be diagnosed through radiology and little experience in pathology has been reported. In the present case, massive oncocytic changes and huge pleomorphism add greatly to the difficulties of making correct diagnosis. This lesion should be carefully kept in mind and a combination of markers is suggested for differentiating from HCC.

Mutational spectrum and precision oncology for biliary tract carcinoma.

Background: The genomic spectrum of biliary tract carcinoma (BTC) has been characterized and is associated with distinct anatomic and etiologic subtypes, yet limited studies have linked genomic alterations with personalized therapies in BTC patients. Methods: This study analyzed 803 patients with BTC:164 with gallbladder cancer, 475 with intrahepatic cholangiocarcinoma (ICC) and 164 with extrahepatic cholangiocarcinoma. We determined genomic alterations, mutational signatures related to etiology and histopathology and prognostic biomarkers. Personalized targeted therapies for patients harboring potentially actionable targets (PATs) were investigated. Results: The median tumor mutation burden (TMB) was 1.23 Mut/Mb, with 4.1% of patients having hypermutated BTCs. Unlike the results obtained from the Western population, the most frequently altered cancer-related genes in our cohort included TP53 (53%), KRAS (26%), ARID1A (18%), LRP1B (14%) and CDKN2A (14%). Germline mutations occurred mostly in DNA damage repair genes. Notably, 35.8% of the ICCs harbored aristolochic acid related signatures and an elevated TMB. TP53 and KRAS mutations and amplified 7q31.2 were demonstrated to negatively affect patient prognosis. Moreover, 19 genes were proposed to be PATs in BTCs, with 25.4% of patients harboring these PATs. Forty-six patients received PAT-matched targeted therapies, achieving a 26.1% objective response rate; the median progression-free survival (PFS) was 5.0 months, with 56.8% of patients obtaining PFS benefits. Conclusions: Extensive genomic diversity and heterogeneity were observed among BTC patients, with contributions according to potential etiology exposures, anatomical subtypes and clinicopathological characteristics. We also demonstrated that patients with refractory BTCs who have PATs can derive considerable benefit from receiving a matched therapy, initiating further prospective clinical trials guided by molecular profiling among this aggressive cancer.

CK20 and lymph node involvement predict adverse outcome of malignant intraductal papillary neoplasm of the bile duct.

OBJECTIVES: To identify prognostic factors of malignant intraductal papillary neoplasm of the bile duct (m-IPNB). MATERIALS AND METHODS: We included 38 consecutive cases which underwent surgical resection and diagnosed as IPNB with malignant component from January 2003 to January 2017. Clinicopathological variables were collected to conduct survival analysis and identify prognostic factors. RESULTS: The median overall survival (OS) of m-IPNB was 76.0 months, with 1-, 3-, and 5-year survival rates of 97.2%, 73.5%, and 59.8%, respectively. The median RFS was 48.0 months with 1-, 3-, and 5-year recurrence-free survival (RFS) rate was 83.2%, 59.8%, and 44.6%, respectively. Univariate analysis showed that elevation of carcinoembryonic antigen CEA, lymph node involvement, resection margin status, degree of periductal invasion, and positive expression of CK20 were associated with both OS and RFS of m-IPNB. After multivariate Cox models analysis, lymph node involvement and positive expression of CK20 were identified as independent prognostic factors for OS, while lymph node involvement and resection margin status were independent prognostic factors for RFS. The median OS of patients with m-IPNB involving lymphatic metastases and positive expression of CK20 was 27.0±8.8 months and 51.0±12.4 months, respectively. The median RFS of cases with lymph node involvement and R1 resection was 10.0±3.3 months and 25.0±6.9 months, respectively. However, there was no significant difference in OS or RFS between cases of pancreaticobiliary and intestinal subtype. CONCLUSIONS: Lymph node involvement and positive expression of CK20 are independent prognostic factors for shorter OS of m-IPNB, while patients with lymph node involvement and positive resection margin are at higher risk of tumor recurrence.

Preoperative neutrophil-lymphocyte and platelet-lymphocyte ratios as independent predictors of T stages in hilar cholangiocarcinoma.

Background: The purpose of this study was to evaluate the relationship between preoperative inflammatory markers (neutrophil-lymphocyte ratio (NLR) and platelet-lymphocyte ratio (PLR)) and different American Joint Committee on Cancer (AJCC) T stages in patients with hilar cholangiocarcinoma. Methods: A total of 101 patients who underwent surgical treatment for hilar cholangiocarcinoma between 2003 and 2014 in Peking Union Medical College Hospital were retrospectively analyzed. Receiver-operating curves were used to calculate optimal cutoff values for the NLR and the PLR. Univariate and multivariate analyses were used to identify whether the NLR and PLR can independently predict different AJCC T stages. Results: Multivariate analysis showed that higher NLR and PLR independently predicted advanced AJCC T stages (OR 3.74, 95% CI 1.09-12.83, P=0.036; and OR 7.86, 95% CI 2.25-27.43, P=0.001, respectively). At a threshold of 2.75, the NLR was 75.9% sensitive and 66.7% specific for different AJCC T stages; at a threshold of 172.25, the PLR was 65.5% sensitive and 80.6% specific. Conclusion: Preoperative NLR and PLR can be used as independent predictors of different AJCC T stages in patients with hilar cholangiocarcinoma.

Alterations in DNA Damage Repair Genes in Primary Liver Cancer.

PURPOSE: Alterations in DNA damage repair (DDR) genes produce therapeutic biomarkers. However, the characteristics and significance of DDR alterations remain undefined in primary liver cancer (PLC). EXPERIMENTAL DESIGN: Patients diagnosed with PLC were enrolled in the trial (PTHBC, NCT02715089). Tumors and matched blood samples from participants were collected for a targeted next-generation sequencing assay containing exons of 450 cancer-related genes, including 31 DDR genes. The OncoKB knowledge database was used to identify and classify actionable alterations, and therapeutic regimens were determined after discussion by a multidisciplinary tumor board. RESULTS: A total of 357 patients with PLC were enrolled, including 214 with hepatocellular carcinoma, 122 with ICC, and 21 with mixed hepatocellular-cholangiocarcinoma. A total of 92 (25.8%) patients had at least one DDR gene mutation, 15 of whom carried germline mutations. The most commonly altered DDR genes were ATM (5%) and BRCA1/2 (4.8%). The occurrence of DDR mutations was significantly correlated with a higher tumor mutation burden regardless of the PLC pathologic subtype. For DDR-mutated PLC, 26.1% (24/92) of patients possessed at least one actionable alteration, and the actionable frequency in DDR wild-type PLC was 18.9% (50/265). Eight patients with the BRCA mutation were treated by olaparib, and patients with BRCA2 germline truncation mutations showed an objective response. CONCLUSIONS: The landscape of DDR mutations and their association with genetic and clinicopathologic features demonstrated that patients with PLC with altered DDR genes may be rational candidates for precision oncology treatment.

Nomogram to predict overall survival after gallbladder cancer resection in China.

AIM: To integrate clinically significant variables related to prognosis after curative resection for gallbladder carcinoma (GBC) into a predictive nomogram. METHODS: One hundred and forty-two GBC patients who underwent curative intent surgical resection at Peking Union Medical College Hospital (PUMCH) were included. This retrospective case study was conducted at PUMCH of the Chinese Academy of Medical Sciences and Peking Union Medical College (CAMS & PUMC) in China from January 1, 2003 to January 1, 2018. The continuous variable carbohydrate antigen 19-9 (CA19-9) was converted into a categorical variable (cCA19-9) based on the normal reference range. Stages 0 to IIIA were merged into one category, while the remaining stages were grouped into another category. Pathological grade X (GX) was treated as a missing value. A multivariate Cox proportional hazards model was used to select variables to construct a nomogram. Discrimination and calibration of the nomogram were performed via the concordance index (C-index) and calibration plots. The performance of the nomogram was estimated using the calibration curve. Receiver operating characteristic (ROC) curve analysis and decision curve analysis (DCA) were performed to evaluate the predictive accuracy and net benefit of the nomogram, respectively. RESULTS: Of these 142 GBC patients, 55 (38.7%) were male, and the median and mean age were 64 and 63.9 years, respectively. Forty-eight (33.8%) patients in this cohort were censored in the survival analysis. The median survival time was 20 months. A series of methods, including the likelihood ratio test and Akaike information criterion (AIC) as well as stepwise, forward, and backward analyses, were used to select the model, and all yielded identical results. Jaundice [hazard ratio (HR) = 2.9; 95% confidence interval (CI): 1.60-5.27], cCA19-9 (HR = 3.2; 95%CI: 1.91-5.39), stage (HR = 1.89; 95%CI: 1.16-3.09), and resection (R) (HR = 2.82; 95%CI: 1.54-5.16) were selected as significant predictors and combined into a survival time predictive nomogram (C-index = 0.803; 95%CI: 0.766-0.839). High prediction accuracy (adjusted C-index = 0.797) was further verified via bootstrap validation. The calibration plot demonstrated good performance of the nomogram. ROC curve analysis revealed a high sensitivity and specificity. A high net benefit was proven by DCA. CONCLUSION: A nomogram has been constructed to predict the overall survival of GBC patients who underwent radical surgery from a clinical database of GBC at PUMCH.

A four-gene-based prognostic model predicts overall survival in patients with hepatocellular carcinoma.

With the development of new advances in hepatocellular carcinoma (HCC) management and noninvasive radiological techniques, high-risk patient groups such as those with hepatitis virus are closely monitored. HCC is increasingly diagnosed early, and treatment may be successful. In spite of this progress, most patients who undergo a hepatectomy will eventually relapse, and the outcomes of HCC patients remain unsatisfactory. In our study, we aimed to identify potential gene biomarkers based on RNA sequencing data to predict and improve HCC patient survival. The gene expression data and clinical information were acquired from The Cancer Genome Atlas (TCGA) database. A total of 339 differentially expressed genes (DEGs) were obtained between the HCC (n = 374) and normal tissues (n = 50). Four genes (CENPA, SPP1, MAGEB6 and HOXD9) were screened by univariate, Lasso and multivariate Cox regression analyses to develop the prognostic model. Further analysis revealed the independent prognostic capacity of the prognostic model in relation to other clinical characteristics. The receiver operating characteristic (ROC) curve analysis confirmed the good performance of the prognostic model. Then, the prognostic model and the expression levels of the four genes were validated using the Gene Expression Omnibus (GEO) dataset. A nomogram comprising the prognostic model to predict the overall survival was established, and internal validation in the TCGA cohort was performed. The predictive model and the nomogram will enable patients with HCC to be more accurately managed in trials testing new drugs and in clinical practice.

Classification of gallbladder cancer by assessment of CD8+ TIL and PD-L1 expression.

BACKGROUND: Programmed death ligand 1/2 (PD-L1/PD-L2) expression has been established as a prognostic factor for various solid tumors and as a predictive factor for PD-1 blockade therapy, but scant data on its role in gallbladder cancer (GBC). The aims of this study were to assess the expression of PD-L1/PD-L2 and the density of CD8+ tumor-infiltrating lymphocytes (TIL) from GBC samples and to quantify the association between survival prognosis and these factors. METHODS: CD8+ TILs density and the expression of PD-1, PD-L1, PD-L2 and CD133 were assessed using immunohistochemistry in tumor specimens from 66 patients with gallbladder adenocarcinoma. These indexes were correlated with the clinicopathological features. RESULTS: The rate of PD-L1-positive (PD-L1+) was 54%, which included 18% positivity in tumor cells, and 36% in peritumoral immune stroma. High CD8+ TIL density (CD8high) was observed in PD-L1+ GBC, and PD-L1+ was positively associated with PD-L2+ expression. Regarding prognostic factors, PD-L1+ expression was related to worse overall survival (OS), and CD8high indicated better OS and progression-free survival (PFS). The combination of CD8high with PD-L1+ serves as a prognostic factor for improved OS (P < 0.001) and PFS (P = 0.014). CONCLUSION: Analysis of the tumor immune microenvironment based on CD8+ TIL and PD-L1 expression is a promising independent predictor for the clinical outcome of GBC patients.

PD-1/PD-L blockade in gastrointestinal cancers: lessons learned and the road toward precision immunotherapy.

Gastrointestinal (GI) malignancies are the most prevalent tumors worldwide, with increasing incidence and mortality. Although surgical resection, chemotherapy, radiotherapy, and molecular targeted therapy have led to significant advances in the treatment of GI cancer patients, overall survival is still low. Therefore, alternative strategies must be identified to improve patient outcomes. In the tumor microenvironment, tumor cells can escape the host immune response through the interaction of PD-1 and PD-L, which inhibits the function of T cells and tumor-infiltrating lymphocytes while increasing the function of immunosuppressive T regulatory cells. The use of an anti-PD-1/PD-L blockade enables reprogramming of the immune system to efficiently identify and kill tumor cells. In recent years, the efficacy of PD-1/PD-L blockade has been demonstrated in many tumors, and this treatment is expected to be a pan-immunotherapy for tumors. Here, we review the signaling pathway underlying the dysregulation of PD-1/PD-L in tumors, summarize the current clinical data for PD-1/PD-L inhibitors in GI malignancies, and discuss road toward precision immunotherapy in relation to PD-1/PD-L blockade. The preliminary data for PD-1/PD-L inhibitors are encouraging, and the precision immunotherapy of PD-1/PD-L inhibitors will be a viable and pivotal clinical strategy for GI cancer therapy.