COSMIC-based mutation database enhances identification efficiency of HLA-I immunopeptidome.

BACKGROUND: Neoantigens have emerged as a promising area of focus in tumor immunotherapy, with several established strategies aiming to enhance their identification. Human leukocyte antigen class I molecules (HLA-I), which present intracellular immunopeptides to T cells, provide an ideal source for identifying neoantigens. However, solely relying on a mutation database generated through commonly used whole exome sequencing (WES) for the identification of HLA-I immunopeptides, may result in potential neoantigens being missed due to limitations in sequencing depth and sample quality. METHOD: In this study, we constructed and evaluated an extended database for neoantigen identification, based on COSMIC mutation database. This study utilized mass spectrometry-based proteogenomic profiling to identify the HLA-I immunopeptidome enriched from HepG2 cell. HepG2 WES-based and the COSMIC-based mutation database were generated and utilized to identify HepG2-specific mutant immunopeptides. RESULT: The results demonstrated that COSMIC-based database identified 5 immunopeptides compared to only 1 mutant peptide identified by HepG2 WES-based database, indicating its effectiveness in identifying mutant immunopeptides. Furthermore, HLA-I affinity of the mutant immunopeptides was evaluated through NetMHCpan and peptide-docking modeling to validate their binding to HLA-I molecules, demonstrating the potential of mutant peptides identified by the COSMIC-based database as neoantigens. CONCLUSION: Utilizing the COSMIC-based mutation database is a more efficient strategy for identifying mutant peptides from HLA-I immunopeptidome without significantly increasing the false positive rate. HepG2 specific WES-based database may exclude certain mutant peptides due to WES sequencing depth or sample heterogeneity. The COSMIC-based database can effectively uncover potential neoantigens within the HLA-I immunopeptidomes.

Identification and validation of inflammatory subtypes in intrahepatic cholangiocellular carcinoma.

BACKGROUND: Inflammation plays a critical role in tumor development. Inflammatory cell infiltration and inflammatory mediator synthesis cause changes in the tumor microenvironment (TME) in several cancers, especially in intrahepatic cholangiocellular carcinoma (ICC). However, methods to ascertain the inflammatory state of patients using reliable biomarkers are still being explored. METHOD: We retrieved the RNA sequencing and somatic mutation analyses results and the clinical characteristics of 244 patients with ICC from published studies. We performed consensus clustering to identify the molecular subtypes associated with inflammation. We compared the prognostic patterns, clinical characteristics, somatic mutation profiles, and immune cell infiltration patterns across inflammatory subtypes. We performed quantitative real-time polymerase chain reaction (qRT-PCR) and immunohistochemistry (IHC) to confirm gene expression. We performed logistic regression analyses to construct a nomogram predicting the inflammatory status of patients with ICC. RESULTS: Our results confirmed that ICC can be categorized into an inflammation-high subtype (IHS) and an inflammation-low subtype (ILS). Patients from each group had distinct prognosis, clinical characteristics, and TME composition. Patients with ICC in the IHS group showed poorer prognosis owing to the immunosuppressive microenvironment and high frequency of KRAS and TP53 mutations. Cancer-associated fibroblast (CAF)-derived COLEC11 reduced myeloid inflammatory cell infiltration and attenuated inflammatory responses. The results of qRT-PCR and IHC experiments confirmed that COLEC11 expression levels were significantly reduced in tumor tissues compared to those in paracancerous tissues. Patients with ICC in the IHS group were more likely to respond to treatment with immune checkpoint inhibitors (ICIs) owing to their higher tumor mutational burden (TMB) scores, tumor neoantigen burden (TNB) scores, neoantigen counts, and immune checkpoint expression levels. Finally, we developed a nomogram to effectively predict the inflammatory status of patients with ICC based on their clinical characteristics and inflammatory gene expression levels. We evaluated the calibration, discrimination potential, and clinical utility of the nomogram. CONCLUSION: The inflammatory response in IHS is primarily induced by myeloid cells. COLEC11 can reduce the infiltration level of this group of cells, and myeloid inflammatory cells may be a novel target for ICC treatment. We developed a novel nomogram that could effectively predict the inflammatory state of patients with ICC, which will be useful for guiding individualized treatment plans.

Long-term survival and portal vein patency with novel PVTT surgery approach in advanced HCC patients with Vp3/4 PVTT following combination therapy of TKIs and PD-1 inhibitors.

BACKGROUND: It is controversial whether patients with hepatocellular carcinoma (HCC) with portal vein tumor thrombus (PVTT) should undergo salvage surgery following the combination therapy of tyrosine kinase inhibitors (TKIs) and programmed cell death protein 1 (PD-1) inhibitors. This study aimed to elucidate the efficiency and safety of salvage surgery following combination therapy, while also summarizing a novel surgical approach for Vp3/4 PVTT. METHODS: Between April 2019 and December 2022, a consecutive series of unresectable HCC patients with PVTT who received salvage surgery following combination therapy were enrolled. Evaluation included perioperative and long-term follow-up outcomes. The complete removal of Vp3/4 PVTT was achieved using a novel surgical approach characterized by "longitudinal incision and transverse suturing" and "angle-to-straight conversion". RESULTS: Forty patients including 22 patients with Vp3 and 18 patients with Vp4 were included. Long-term follow-up showed similar rates of portal vein patency (Vp3: 95.5%, Vp4:94.4%, p = 0.900), and 3-year portal vein patency rates were 95.0%. There were no significant differences observed in combination therapy-related adverse events (p = 0.253) and perioperative complications (p = 0.613) between the Vp3 and Vp4 groups. The recurrence patterns were similar between the two groups (p = 0.131). There were no significant differences in overall survival (OS) and recurrence-free (RFS) survival between the Vp3 and Vp4 groups (OS p = 0.457, RFS p = 0.985). Patients who achieved a pathological complete response had significantly better RFS (p = 0.011). CONCLUSION: Salvage surgery after combination therapy demonstrated favorable efficacy and safety. The novel surgical approach for PVTT can effectively achieve complete removal of PVTT and ensured long-term portal vein patency.

Integrating IASLC grading and radiomics for predicting postoperative outcomes in stage IA invasive lung adenocarcinoma.

BACKGROUND: The International Association for the Study of Lung Cancer (IASLC) Pathology Committee introduced a histologic grading system for invasive lung adenocarcinoma (LUAD) in 2020. The IASLC grading system, hinging on the evaluation of predominant and high-grade histologic patterns, has proven to be practical and prognostic for invasive LUAD. However, there are still limitations in evaluating the prognosis of stage IA LUAD. Radiomics may serve as a valuable complement. PURPOSE: To establish a model that integrates IASLC grading and radiomics, aimed at predicting the prognosis of stage IA LUAD. METHODS: We conducted a retrospective analysis of 628 patients diagnosed with stage IA LUAD who underwent surgical resection between January 2015 and December 2018 at our institution. The patients were randomly divided into the training set (n = 439) and testing set (n = 189) at a ratio of 7:3. Overall survival (OS) and disease-free survival (DFS) were taken as the end points. Radiomics features were obtained by PyRadiomics. Feature selection was performed using the least absolute shrinkage and selection operator (LASSO). The prediction models for OS and DFS were developed using multivariate Cox regression analysis, and the models were visualized through nomogram plots. The model's performance was evaluated using area under the curves (AUC), concordance index (C-index), calibration curves, and survival decision curve analysis (DCA). RESULTS: In total, nine radiomics features were selected for the OS prediction model, and 15 radiomics features were selected for the DFS prediction model. Patients with high radiomics scores were associated with a worse prognosis (p < 0.001). We built separate prediction models using radiomics or IASLC alone, as well as a combined prediction model. In the prediction of OS, we observed that the combined model (C-index: 0.812 ± 0.024, 3 years AUC: 0.692, 5 years AUC: 0.792) achieved superior predictive performance than the radiomics (C-index: 0.743 ± 0.038, 3 years AUC: 0.633, 5 years AUC: 0.768) and IASLC grading (C-index: 0.765 ± 0.042, 3 years AUC: 0.658, 5 years AUC: 0.743) models alone. Similar results were obtained in the models for DFS. CONCLUSION: The combination of radiomics and IASLC pathological grading proves to be an effective approach for predicting the prognosis of stage IA LUAD. This has substantial clinical relevance in guiding treatment decisions for early-stage LUAD.

Prediction Model for Immunotherapy Efficacy in Hepatocellular Carcinoma Based on Alternative Splicing Sequencing Data.

Background: Integrating immune checkpoint inhibitors with multi-target tyrosine kinase inhibitors presents an innovative and hopeful strategy in liver cancer treatment. Nonetheless, a degree of resistance to this treatment is noticeable in certain patients. Alternative splicing (AS) represents a common biological process that controls the variety of life functions via isoforms. Purpose: Investigating how gene AS affects the effectiveness of combined immunotherapy in treating hepatocellular carcinoma (HCC). Methods: Our retrospective examination focused on AS's effect on immune therapy effectiveness, utilizing accessible tissue sequencing and clinical records for HCC. For corroborating our results, we gathered samples of drug-resistant HCC tissue, nearby tissues, HCC tissue with high drug responsiveness, and healthy liver tissue from clinical studies. Results: The study revealed a link between the frequency of AS occurrences, the expression levels of programmed cell death 1 ligand 1, and the resistance to tumor medications. Our study detailed the AS occurrences in HCC, leading to the creation of a risk-assessment function and a predictive model using AS data. The results of our study revealed that the risk score effectively distinguished between various immune subtypes and the effectiveness of immune therapy. Additional examination of the chosen AS occurrences uncovered their effects on both the immune microenvironment and cellular immunity. Our investigation also delved into the regulatory framework of AS, uncovering the role of stringently controlled splicing factors in the emergence of tumors and the modulation of the body's immune response. Conclusions: Increased AS in HCC diminishes the efficacy of immunotherapy; conversely, more AS in peritumoral tissue elevates the likelihood of tumor immune evasion.

A combined model based on radiomics features of Sonazoid contrast-enhanced ultrasound in the Kupffer phase for the diagnosis of well-differentiated hepatocellular carcinoma and atypical focal liver lesions: a prospective, multicenter study.

OBJECTIVE: The objective of this study was to develop a combined model based on radiomics features of Sonazoid contrast-enhanced ultrasound (CEUS) during the Kupffer phase and to evaluate its value in differentiating well-differentiated hepatocellular carcinoma (w-HCC) from atypical benign focal liver lesions (FLLs). METHODS: A total of 116 patients with preoperatively Sonazoid-CEUS confirmed w-HCC or benign FLL were selected from a prospective multiple study on the clinical application of Sonazoid in FLLs conducted from August 2020 to March 2021. According to the randomization principle, the patients were divided into a training cohort and a test cohort in a 7:3 ratio. Seventy-nine patients were used for establishing and training the radiomics model and combined model. In comparison, 37 patients were used for validating and comparing the performance of the models. The diagnostic efficacy of the models for w-HCC and atypical benign FLLs was evaluated using ROCs curves and decision curves. A combined model nomogram was created to assess its value in reducing unnecessary biopsies. RESULTS: Among the patients, there were 55 cases of w-HCC and 61 cases of atypical benign FLLs, including 28 cases of early liver abscess, 16 cases of atypical hepatic hemangioma, 8 cases of hepatocellular dysplastic nodules (DN), and 9 cases of focal nodular hyperplasia (FNH). The radiomics model and combined model we established had AUCs of 0.905 and 0.951, respectively, in the training cohort, and the AUCs of the two models in the test cohort were 0.826 and 0.912, respectively. The combined model outperformed the radiomics feature model significantly. Decision curve analysis demonstrated that the combined model achieved a higher net benefit within a specific threshold probability range (0.25 to 1.00). A nomogram of the combined model was developed. CONCLUSION: The combined model based on the radiomics features of Sonazoid-CEUS in the Kupffer phase showed satisfactory performance in diagnosing w-HCC and atypical benign FLLs. It can assist clinicians in timely detecting malignant FLLs and reducing unnecessary biopsies for benign diseases.

Surgical treatment improves overall survival of hepatocellular carcinoma with extrahepatic metastases after conversion therapy: a multicenter retrospective study.

Systemic therapy is typically the primary treatment choice for hepatocellular carcinoma (HCC) patients with extrahepatic metastases. Some patients may achieve partial response (PR) or complete response (CR) with systemic treatment, leading to the possibility of their primary tumor becoming resectable. This study aimed to investigate whether these patients could achieve longer survival through surgical resection of their primary tumor. We retrospectively collected data from 150 HCC patients with extrahepatic metastases treated at 15 different centers from January 1st, 2015, to November 30th, 2022. We evaluated their overall survival (OS) and progress-free survival (PFS) and analyzed risk factors impacting both OS and PFS were analyzed. Patients who received surgical treatment had longer OS compared to those who did not (median OS 16.5 months vs. 11.3 months). However, there was no significant difference in progression-free survival between the two groups. Portal vein invasion (P = 0.025) was identified as a risk factor for poor prognosis in patients, while effective first-line treatment (P = 0.039) and surgical treatment (P = 0.005) were protective factors. No factors showed statistical significance in the analysis of PFS. Effective first-line treatment (P = 0.027) and surgical treatment (P = 0.006) were both independent protective factors for prolonging patient prognosis, while portal vein invasion was an independent risk factor (P = 0.044). HCC patients with extrahepatic metastases who achieve PR/CR with conversion therapy may experience longer OS through surgical treatment. This study is the first to analyze the clinical outcomes of patients receiving surgical treatment for HCC with extrahepatic metastases.

Discussion on the management strategy of patients aged over 70 years with esophageal cancer / 中国胸心血管外科临床杂志

@#Esophageal cancer (EC) is the eighth dangerous cancer in the world. As the global population ages, the management of elderly patients with EC poses a challenge as they have many aging-associated diseases and physiological changes. In addition, the data on the tolerability of cancer treatment and the use of combined therapies in the patients to guide their treatment are limited. In this paper, we reviewed the literatures and discussed the effect of surgical resection and the potential complications of elderly patients. We reviewed the basic principles of combined therapy and the potential benefits of chemotherapy or chemoradiotherapy for patients and focused on the management of elderly patients with EC as well as the role of comprehensive assessment for aging to provide treatment options for elderly patients.