Advancing immunotherapy for melanoma: the critical role of single-cell analysis in identifying predictive biomarkers.

Melanoma, a malignant skin cancer arising from melanocytes, exhibits rapid metastasis and a high mortality rate, especially in advanced stages. Current treatment modalities, including surgery, radiation, and immunotherapy, offer limited success, with immunotherapy using immune checkpoint inhibitors (ICIs) being the most promising. However, the high mortality rate underscores the urgent need for robust, non-invasive biomarkers to predict patient response to adjuvant therapies. The immune microenvironment of melanoma comprises various immune cells, which influence tumor growth and immune response. Melanoma cells employ multiple mechanisms for immune escape, including defects in immune recognition and epithelial-mesenchymal transition (EMT), which collectively impact treatment efficacy. Single-cell analysis technologies, such as single-cell RNA sequencing (scRNA-seq), have revolutionized the understanding of tumor heterogeneity and immune microenvironment dynamics. These technologies facilitate the identification of rare cell populations, co-expression patterns, and regulatory networks, offering deep insights into tumor progression, immune response, and therapy resistance. In the realm of biomarker discovery for melanoma, single-cell analysis has demonstrated significant potential. It aids in uncovering cellular composition, gene profiles, and novel markers, thus advancing diagnosis, treatment, and prognosis. Additionally, tumor-associated antibodies and specific genetic and cellular markers identified through single-cell analysis hold promise as predictive biomarkers. Despite these advancements, challenges such as RNA-protein expression discrepancies and tumor heterogeneity persist, necessitating further research. Nonetheless, single-cell analysis remains a powerful tool in elucidating the mechanisms underlying therapy response and resistance, ultimately contributing to the development of personalized melanoma therapies and improved patient outcomes.

Final analysis of camrelizumab plus chemotherapy for untreated advanced or metastatic esophageal squamous cell carcinoma: The ESCORT-1st trial.

BACKGROUND: The interim analysis of the randomized phase 3 ESCORT-1st study demonstrated significantly longer overall survival (OS) and progression-free survival (PFS) for camrelizumab-chemotherapy than placebo-chemotherapy in untreated advanced/metastatic esophageal squamous cell carcinoma (ESCC). Here, we present the final analysis of this study and investigate potential indicators associated with OS. METHODS: Patients were randomized 1:1 to receive camrelizumab (200 mg) or placebo, both in combination with up to six cycles of paclitaxel (175 mg/m2) and cisplatin (75 mg/m2). All treatments were administered intravenously every 3 weeks. The co-primary endpoints were OS and PFS assessed by the independent review committee. FINDINGS: As of April 30, 2022, the median OS was significantly longer in the camrelizumab-chemotherapy group compared to the placebo-chemotherapy group (15.6 [95% confidence interval (CI): 14.0-18.4] vs. 12.6 months [95% CI 11.2-13.8]; hazard ratio [HR]: 0.70 [95% CI 0.58-0.84]; one-sided p < 0.0001), with 3-year OS rates of 25.6% and 12.8% in the two groups, respectively. The 2-year PFS rates were 20.4% in the camrelizumab-chemotherapy group and 3.4% in the placebo-chemotherapy group. Adverse events were consistent with those reported in the interim analysis. Higher PD-L1 expression correlated with extended OS, and multivariate analysis identified sex and prior history of radiotherapy as independent indicators of OS. CONCLUSIONS: The sustained and significant improvement in efficacy with camrelizumab-chemotherapy compared to placebo-chemotherapy, along with the absence of accumulating or delayed toxicities, supports the long-term use of camrelizumab-chemotherapy as a standard therapy in untreated advanced/metastatic ESCC. FUNDING: This study was funded by Jiangsu Hengrui Pharmaceuticals Co., Ltd.

Exploring ALK fusion in colorectal cancer: a case series and comprehensive analysis.

Anaplastic lymphoma kinase (ALK) fusion-positive colorectal cancer (CRC) is a rare and chemotherapy-refractory subtype that lacks established and effective treatment strategies. Additionally, the efficacy and safety of ALK inhibitors (ALKi) in CRC remain undetermined. Herein, we examined a series of ALK-positive CRC patients who underwent various lines of ALKi treatment. Notably, we detected an ALK 1196M resistance mutation in a CRC patient who received multiple lines of chemotherapy and ALKi treatment. Importantly, we found that Brigatinib and Lorlatinib demonstrated some efficacy in managing this patient, although the observed effectiveness was not as pronounced as in non-small cell lung cancer cases. Furthermore, based on our preliminary analyses, we surmise that ALK-positive CRC patients are likely to exhibit inner resistance to Cetuximab. Taken together, our findings have important implications for the treatment of ALK-positive CRC patients.

Cetuximab plus FOLFOXIRI versus cetuximab plus FOLFOX as conversion regimen in RAS/BRAF wild-type patients with initially unresectable colorectal liver metastases (TRICE trial): A randomized controlled trial.

BACKGROUND: It remains unclear whether intensification of the chemotherapy backbone in tandem with an anti-EGFR can confer superior clinical outcomes in a cohort of RAS/BRAF wild-type colorectal cancer (CRC) patients with initially unresectable colorectal liver metastases (CRLM). To that end, we sought to comparatively evaluate the efficacy and safety of cetuximab plus FOLFOXIRI (triplet arm) versus cetuximab plus FOLFOX (doublet arm) as a conversion regimen (i.e., unresectable to resectable) in CRC patients with unresectable CRLM. METHODS AND FINDINGS: This open-label, randomized clinical trial was conducted from April 2018 to December 2022 in 7 medical centers across China, enrolling 146 RAS/BRAF wild-type CRC patients with initially unresectable CRLM. A stratified blocked randomization method was utilized to assign patients (1:1) to either the cetuximab plus FOLFOXIRI (n = 72) or cetuximab plus FOLFOX (n = 74) treatment arms. Stratification factors were tumor location (left versus right) and resectability (technically unresectable versus ≥5 metastases). The primary outcome was the objective response rate (ORR). Secondary outcomes included the median depth of tumor response (DpR), early tumor shrinkage (ETS), R0 resection rate, progression-free survival (PFS), overall survival (not mature at the time of analysis), and safety profile. Radiological tumor evaluations were conducted by radiologists blinded to the group allocation. Primary efficacy analyses were conducted based on the intention-to-treat population, while safety analyses were performed on patients who received at least 1 line of chemotherapy. A total of 14 patients (9.6%) were lost to follow-up (9 in the doublet arm and 5 in the triplet arm). The ORR was comparable following adjustment for stratification factors, with 84.7% versus 79.7% in the triplet and doublet arms, respectively (odds ratio [OR] 0.70; 95% confidence intervals [CI] [0.30, 1.67], Chi-square p = 0.42). Moreover, the ETS rate showed no significant difference between the triplet and doublet arms (80.6% (58/72) versus 77.0% (57/74), OR 0.82, 95% CI [0.37, 1.83], Chi-square p = 0.63). Although median DpR was higher in the triplet therapy group (59.6%, interquartile range [IQR], [50.0, 69.7] versus 55.0%, IQR [42.8, 63.8], Mann-Whitney p = 0.039), the R0/R1 resection rate with or without radiofrequency ablation/stereotactic body radiation therapy was comparable with 54.2% (39/72) of patients in the triplet arm versus 52.7% (39/74) in the doublet arm. At a median follow-up of 26.2 months (IQR [12.8, 40.5]), the median PFS was 11.8 months in the triplet arm versus 13.4 months in the doublet arm (hazard ratio [HR] 0.74, 95% CI [0.50, 1.11], Log-rank p = 0.14). Grade ≥ 3 events were reported in 47.2% (35/74) of patients in the doublet arm and 55.9% (38/68) of patients in the triplet arm. The triplet arm was associated with a higher incidence of grade ≥ 3 neutropenia (44.1% versus 27.0%, p = 0.03) and diarrhea (5.9% versus 0%, p = 0.03). The primary limitations of the study encompass the inherent bias in subjective surgical decisions regarding resection feasibility, as well as the lack of a centralized assessment for ORR and resection. CONCLUSIONS: The combination of cetuximab with FOLFOXIRI did not significantly improve ORR compared to cetuximab plus FOLFOX. Despite achieving an enhanced DpR, this improvement did not translate into improved R0 resection rates or PFS. Moreover, the triplet arm was associated with an increase in treatment-related toxicity. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT03493048.

Comparative investigation of neoadjuvant immunotherapy versus adjuvant immunotherapy in perioperative patients with cancer: a global-scale, cross-sectional, large-sample informatics study.

BACKGROUND: Neoadjuvant and adjuvant immunotherapies for cancer have evolved through a series of remarkable and critical research advances; however, addressing their similarities and differences is imperative in clinical practice. Therefore, this study aimed to examine their similarities and differences from the perspective of informatics analysis. METHODS: This cross-sectional study retrospectively analyzed extensive relevant studies published between 2014 and 2023 using stringent search criteria, excluding non-peer-reviewed and non-English documents. The main outcome variables are publication volume, citation volume, connection strength, occurrence frequency, relevance percentage, and development percentage. Furthermore, an integrated comparative analysis was conducted using unsupervised hierarchical clustering, spatiotemporal analysis, regression statistics, and Walktrap algorithm analysis. RESULTS: This analysis included 1,373 relevant studies. Advancements in neoadjuvant and adjuvant immunotherapies have been promising over the last decade, with an annual growth rate of 25.18% vs. 6.52% and global collaboration (International Co-authorships) of 19.93% vs. 19.84%. Respectively, five dominant research clusters were identified through unsupervised hierarchical clustering based on machine learning, among which Cluster 4 (Balance of neoadjuvant immunotherapy efficacy and safety) and Cluster 2 (Adjuvant immunotherapy clinical trials) (Average Publication Year [APY]: 2021.70±0.70 vs. 2017.54±4.59) are emerging research populations. Burst and regression curve analyses uncovered domain pivotal research signatures, including microsatellite instability (R2=0.7500, P=0.0025) and biomarkers (R2=0.6505, P=0.0086) in neoadjuvant scenarios, and the tumor microenvironment (R2=0.5571, P=0.0209) in adjuvant scenarios. The Walktrap algorithm further revealed that "neoadjuvant immunotherapy, non-small cell lung cancer (NSCLC), immune checkpoint inhibitors, melanoma" and "adjuvant immunotherapy, melanoma, hepatocellular carcinoma, dendritic cells" (Relevance Percentage: 100% vs. 100%, Development Percentage: 37.5% vs. 17.1%) are extremely relevant to this field but remain underdeveloped, highlighting the need for further investigation. CONCLUSION: This study identified pivotal research signatures and provided substantial predictions for neoadjuvant and adjuvant cancer immunotherapies. In addition, comprehensive quantitative comparisons revealed a notable shift in focus within this field, with neoadjuvant immunotherapy taking precedence over adjuvant immunotherapy after 2020; such a qualitative finding facilitate proper decision-making for subsequent research and mitigate the wastage of healthcare resources.

Combined anti-PD-1, HDAC inhibitor and anti-VEGF for MSS/pMMR colorectal cancer: a randomized phase 2 trial.

Epigenetic modifications of chromatin, including histone acetylation, and tumor angiogenesis play pivotal roles in creating an immunosuppressive tumor microenvironment. In the randomized phase 2 CAPability-01 trial, we investigated the potential efficacy of combining the programmed cell death protein-1 (PD-1) monoclonal antibody sintilimab with the histone deacetylase inhibitor (HDACi) chidamide with or without the anti-vascular endothelial growth factor (VEGF) monoclonal antibody bevacizumab in patients with unresectable chemotherapy-refractory locally advanced or metastatic microsatellite stable/proficient mismatch repair (MSS/pMMR) colorectal cancer. Forty-eight patients were randomly assigned to either the doublet arm (sintilimab and chidamide, n = 23) or the triplet arm (sintilimab, chidamide and bevacizumab, n = 25). The primary endpoint of progression-free survival (PFS) rate at 18 weeks (18wPFS rate) was met with a rate of 43.8% (21 of 48) for the entire study population. Secondary endpoint results include a median PFS of 3.7 months, an overall response rate of 29.2% (14 of 48), a disease control rate of 56.3% (27 of 48) and a median duration of response of 12.0 months. The secondary endpoint of median overall survival time was not mature. The triplet arm exhibited significantly improved outcomes compared to the doublet arm, with a greater 18wPFS rate (64.0% versus 21.7%, P = 0.003), higher overall response rate (44.0% versus 13.0%, P = 0.027) and longer median PFS rate (7.3 months versus 1.5 months, P = 0.006). The most common treatment-emergent adverse events observed in both the triplet and doublet arms included proteinuria, thrombocytopenia, neutropenia, anemia, leukopenia and diarrhea. There were two treatment-related fatalities (hepatic failure and pneumonitis). Analysis of bulk RNA sequencing data from the patients suggested that the triplet combination enhanced CD8+ T cell infiltration, resulting in a more immunologically active tumor microenvironment. Our study suggests that the combination of a PD-1 antibody, an HDACi, and a VEGF antibody could be a promising treatment regimen for patients with MSS/pMMR advanced colorectal cancer. ClinicalTrials.gov registration: NCT04724239 .

Phase II study of SOXIRI (S-1/oxaliplatin/irinotecan) chemotherapy in patients with unresectable pancreatic ductal adenocarcinoma.

BACKGROUND: To provide data on the safety and efficacy of a combination chemotherapy regimen consisting of S-1, oxaliplatin, and irinotecan (SOXIRI) as a first-line therapy in unresectable pancreatic ductal adenocarcinoma (UPDA) patients. METHODS: Patients with UPDA and no prior treatment chemotherapy in the UPDA setting were enrolled. The primary endpoint was the objective response rate (ORR). Secondary endpoints were overall survival (OS), progression-free survival (PFS) and adverse events. Patients received 80 mg/m2 S-1 twice a day for 2 weeks in an alternate-day administration cycle, 85 mg/m2 oxaliplatin on Day 1, and 150 mg/m2 irinotecan on Day 1 of a 2-week cycle. RESULTS: In these 62 enrolled patients, the ORR was 27.4 %, median OS was 12.1 months, and median PFS was 6.5 months. Major grade 3 or 4 toxicity included neutropenia (22.3 %), leucopenia (16.1 %), nausea (9.7 %), vomiting (9.7 %), thrombocytopenia (6.5 %), anorexia (8.5 %), anemia (4.8 %), and diarrhea (1.6 %). No treatment-related deaths occurred. In addition, the analysis of 32 patients suffering pain revealed that the rate of pain relief was 34.4 %. CONCLUSION: SOXIRI might be a standard regimen with an acceptable toxicity profile and favorable efficacy for use as chemotherapy in patients with UPDA.

The complementary and alternative roles of elemene injection in cancer: An umbrella review.

BACKGROUND: In the past, many meta-analyses (MAs) suggested that elemene injection (EI) played a complementary and alternative role in cancer treatment. However, some results were contradictory and a lot of evidences weren't classified. Thus, their clinical guidance effect was very limited. METHODS: Two reviewers independently retrieved 8 databases from their origin to May 19, 2023 and appropriate MAs were taken into consideration. A pooled analysis was conducted to merge results extracted from trials of included MAs. The methodological quality of MAs and the evidence certainty of pooled results were assessed. RESULTS: 31 MAs were taken into analysis with poor methodological quality. The main weaknesses were in the areas of heterogeneity analysis, bias risk, and literature selection. According to the present evidence, on the one hand, compared with conventional treatment (CT) alone, EI combined with CT may significantly enhance short-term or long-term efficacy and reduce adverse reactions caused by CT in multiple cancers. On the other hand, using EI alone also can improve ORR in the malignant (pleural) effusion and lessen the recurrence rate in bladder cancer obviously with fewer adverse reactions compared with CT alone. However, this evidence was rated as moderate to very low certainty mainly due to the risk of bias in clinical trials. CONCLUSION: EI may be a viable medication for the treatment of cancer although more convincing trials are still required to demonstrate its alternative and complementary benefits. Besides, it seems to have a broad potential for further development in immunotherapy, drug delivery technique, and predictive factor.

Long noncoding RNA Regulating ImMune Escape regulates mixed lineage leukaemia protein-1-H3K4me3-mediated immune escape in oesophageal squamous cell carcinoma.

BACKGROUND: Predictive biomarkers for oesophageal squamous cell carcinoma (ESCC) immunotherapy are lacking, and immunotherapy resistance remains to be addressed. The role of long noncoding RNA (lncRNA) in ESCC immune escape and immunotherapy resistance remains to be elucidated. METHODS: The tumour-associated macrophage-upregulated lncRNAs and the exosomal lncRNAs highly expressed in ESCC immunotherapy nonresponders were identified by lncRNA sequencing and polymerase chain reaction assays. CRISPR-Cas9 was used to explore the functional roles of the lncRNA. RNA pull-down, MS2-tagged RNA affinity purification (MS2-TRAP) and RNA-binding protein immunoprecipitation (RIP) were performed to identify lncRNA-associated proteins and related mechanisms. In vivo, the humanized PBMC (hu-PBMC) mouse model was established to assess the therapeutic responses of specific lncRNA inhibitors and their combination with programmed cell death protein 1 (PD-1) monoclonal antibody (mAb). Single-cell sequencing, flow cytometry, and multiplex fluorescent immunohistochemistry were used to analyze immune cells infiltrating the tumour microenvironment. RESULTS: We identified a lncRNA that is involved in tumour immune evasion and immunotherapy resistance. High LINC02096 (RIME) expression in plasma exosomes correlates with a reduced response to PD-1 mAb treatment and poor prognosis. Mechanistically, RIME binds to mixed lineage leukaemia protein-1 (MLL1) and prevents ankyrin repeat and SOCS box containing 2 (ASB2)-mediated MLL1 ubiquitination, improving the stability of MLL1. RIME-MLL1 increases H3K4me3 levels in the promoter regions of programmed death-ligand 1 (PD-L1) and indoleamine 2,3-dioxygenase 1 (IDO-1), constitutively increasing the expression of PD-L1/IDO-1 in tumour cells and inhibiting CD8+ T cells infiltration and activation. RIME depletion in huPBMC-NOG mice significantly represses tumour development and improves the effectiveness of PD-1 mAb treatment by activating T-cell-mediated antitumour immunity. CONCLUSIONS: This study reveals that the RIME-MLL1-H3K4me3 axis plays a critical role in tumour immunosuppression. Moreover, RIME appears to be a potential prognostic biomarker for immunotherapy and developing drugs that target RIME may be a new therapeutic strategy that overcomes immunotherapy resistance and benefits patients with ESCC.

Dynamic single-cell mapping unveils Epstein‒Barr virus-imprinted T-cell exhaustion and on-treatment response.

Epstein‒Barr virus (EBV)-associated gastric cancer (GC) manifests an intriguing immunotherapy response. However, the cellular basis for EBV-imprinted tumour immunity and on-treatment response remains undefined. This study aimed to finely characterize the dynamic tumour immune contexture of human EBV (+) GC treated with immunochemotherapy by longitudinal scRNA-seq and paired scTCR/BCR-seq. EBV (+) GC exhibits an inflamed-immune phenotype with increased T-cell and B-cell infiltration. Immunochemotherapy triggers clonal revival and reinvigoration of effector T cells which step to determine treatment response. Typically, an antigen-specific ISG-15+CD8+ T-cell population is highly enriched in EBV (+) GC patients, which represents a transitory exhaustion state. Importantly, baseline intratumoural ISG-15+CD8+ T cells predict immunotherapy responsiveness among GC patients. Re-emerged clonotypes of pre-existing ISG-15+CD8+ T cells could be found after treatment, which gives rise to a CXCL13-expressing effector population in responsive EBV (+) tumours. However, LAG-3 retention may render the ISG-15+CD8+ T cells into a terminal exhaustion state in non-responsive EBV (+) tumours. In accordance, anti-LAG-3 therapy could effectively reduce tumour burden in refractory EBV (+) GC patients. Our results delineate a distinct implication of EBV-imprinted on-treatment T-cell immunity in GC, which could be leveraged to optimize the rational design of precision immunotherapy.

The negative effect of concomitant medications on immunotherapy in non-small cell lung cancer: An umbrella review.

BACKGROUND: Conflicting results about the effect of concomitant medications on immunotherapy in non-small cell lung cancer (NSCLC) were reported by many meta-analyses (MAs), and the certainty of evidence linking concomitant medications with immunotherapy efficacy has not been quantified, which may cause some evidence to be misinterpreted. METHODS: Four databases including Embase, Cochrane Library, PubMed, and Web of Science were searched from inception to January 2023 in English. Based on prospective or retrospective clinical controlled trials including immunotherapy with concomitant medications or not in NSCLC, quantitative MAs reporting the efficacy of immunotherapy with binary direct comparison and enough extractable data were collected. The methodological quality, reporting quality, and risk of bias of included MAs were evaluated respectively. New meta-analyses were conducted and their evidence certainty was classified as nonsignificant, weak, suggestive, highly suggestive, or convincing. RESULTS: Fifteen MAs with 5 medications were included. After being assessed by AMSTAR-2, PRISMA, and ROBIS, the major shortcomings were focused on the registration of protocol, literature retrieval or data extraction, implementation of sensitivity analysis or evidence certainty assessment, and incomplete reporting in the section of method and result. New pooled analyses indicated that antibiotics (HR = 1.545[1.318-1.811]), steroids (HR = 1.784[1.520-2.093]), proton pump inhibitors (PPIs) (HR = 1.303[1.048-1.621]) and opioids (HR = 1.910[1.213-3.006]) could shorten overall survival (OS) in patients with NSCLC receiving immunotherapy. Besides, antibiotics (HR = 1.285[1.129-1.462]) and steroids (HR = 1.613[1.315-1.979]) were harmful to progression-free survival (PFS) in these patients significantly. No negative effect was found in nonsteroidal anti-inflammatory drugs and the objective response rate of all medications. High-level evidence suggested that using PPIs before or after the initiation of immunotherapy and using steroids during the first-course immunotherapy could weaken the OS of patients with NSCLC. Meanwhile, the negative effects of antibiotics and opioids on OS or PFS were only supported by moderate or low-level evidence. CONCLUSIONS: The concurrent usage of PPIs or steroids adversely affects the survival of patients with NSCLC receiving immunotherapy. Future investigations are required to ascertain whether these adverse effects are primarily attributed to the comorbidities or the concurrent medications.

Efferocytosis signatures as prognostic markers for revealing immune landscape and predicting immunotherapy response in hepatocellular carcinoma.

Background: Hepatocellular carcinoma (HCC) is a highly lethal liver cancer with late diagnosis; therefore, the identification of new early biomarkers could help reduce mortality. Efferocytosis, a process in which one cell engulfs another cell, including macrophages, dendritic cells, NK cells, etc., plays a complex role in tumorigenesis, sometimes promoting and sometimes inhibiting tumor development. However, the role of efferocytosis-related genes (ERGs) in HCC progression has been poorly studied, and their regulatory effects in HCC immunotherapy and drug targeting have not been reported. Methods: We downloaded efferocytosis-related genes from the Genecards database and screened for ERGs that showed significant expression changes between HCC and normal tissues and were associated with HCC prognosis. Machine learning algorithms were used to study prognostic gene features. CIBERSORT and pRRophetic R packages were used to evaluate the immune environment of HCC subtypes and predict treatment response. CCK-8 experiments conducted on HCC cells were used to assess the reliability of drug sensitivity prediction. Results: We constructed a prognostic prediction model composed of six genes, and the ROC curve showed good predictive accuracy of the risk model. In addition, two ERG-related subgroups in HCC showed significant differences in tumor immune landscape, immune response, and prognostic stratification. The CCK-8 experiment conducted on HCC cells confirmed the reliability of drug sensitivity prediction. Conclusion: Our study emphasizes the importance of efferocytosis in HCC progression. The risk model based on efferocytosis-related genes developed in our study provides a novel precision medicine approach for HCC patients, allowing clinicians to customize treatment plans based on unique patient characteristics. The results of our investigation carry noteworthy implications for the development of individualized treatment approaches involving immunotherapy and chemotherapy, thereby potentially facilitating the realization of personalized and more efficacious therapeutic interventions for HCC.

Precise microdissection of gastric mixed adeno-neuroendocrine carcinoma dissects its genomic landscape and evolutionary clonal origins.

Gastric mixed adenoneuroendocrine carcinoma (MANEC) is a clinically aggressive and heterogeneous tumor composed of adenocarcinoma (ACA) and neuroendocrine carcinoma (NEC). The genomic properties and evolutionary clonal origins of MANEC remain unclear. We conduct whole-exome and multiregional sequencing on 101 samples from 33 patients to elucidate their evolutionary paths. We identify four significantly mutated genes, TP53, RB1, APC, and CTNNB1. MANEC resembles chromosomal instability stomach adenocarcinoma in that whole-genome doubling in MANEC is predominant and occurs earlier than most copy-number losses. All tumors are of monoclonal origin, and NEC components show more aggressive genomic properties than their ACA counterparts. The phylogenetic trees show two tumor divergence patterns, including sequential and parallel divergence. Furthermore, ACA-to-NEC rather than NEC-to-ACA transition is confirmed by immunohistochemistry on 6 biomarkers in ACA- and NEC-dominant regions. These results provide insights into the clonal origin and tumor differentiation of MANEC.

The application of arsenic trioxide in cancer: An umbrella review of meta-analyses based on randomized controlled trials.

ETHNOPHARMACOLOGICAL RELEVANCE: Processed from natural minerals, arsenic trioxide (ATO) as an ancient Chinese medicine has been used to treat diseases for over 2000 years. And it was applied to treat acute promyelocytic leukemia (APL) since the 1970s in China. Summarizing the clinical evidence of ATO in cancer is conducive to further understanding, development, and promotion of its pharmacological research. AIM OF THE STUDY: It is the first time to comprehensively assess and summarize the evidence of ATO in cancer treatment via umbrella review. MATERIALS AND METHODS: 8 databases in English or Chinese from their inception to February 21, 2023 were searched by two reviewers separately and suitable meta-analyses (MAs) were included in this umbrella review. Their methodological quality and risk of bias were evaluated and data of outcomes was extracted and pooled again. The evidence certainty of pooled results was classified. RESULTS: 17 MAs with 27 outcomes and seven comparisons in three cancers were included in this umbrella review. However, their methodological quality was unsatisfactory with 6 MAs as low quality and 12 MAs as critically low quality. Their shortcomings were mainly focused on protocol, literature selecting, bias risk, small sample study bias, and conflicts of interest or funding. And they were all assessed as high risk in bias. It was suggested that ATO had an advantage in enhancing complete remission rate, event-free survival, and recurrence free survival and decreasing recurrence rate, cutaneous toxicity, hyper leukocyte syndrome, tretinoin syndrome, edema and hepatotoxicity in different comparisons of APL with low or moderate certainty. Besides, compared with transcatheter arterial chemoembolization (TACE) alone, ATO plus TACE also could improve objective response rate, disease control rate, survival rate (0.5, 1, 2, and 3-year) and life quality and reduce the level of alpha fetoprotein in primarily hepatocellular carcinoma with low or moderate certainty. However, no significant results were found in MM. Finally, key findings were as followed. ATO has potential broad-spectrum anticancer effects but the clinical transformation is rarely achieved. Route of administration may affect the antitumor effects of ATO. ATO can act synergistically in combination with a variety of antitumor therapies. The safety and drug resistance of ATO should be paid more attention to. CONCLUSIONS: ATO may be a promising drug in anticancer treatment although earlier RCTs have dragged down the level of evidence. However, high-quality clinical trials are expected to explore its broad-spectrum anticancer effects, wide application, appropriate route of administration, and compound dosage form.

Comprehensive DNA methylation profiling of COVID-19 and hepatocellular carcinoma to identify common pathogenesis and potential therapeutic targets.

BACKGROUND & AIMS: The effects of SARS-CoV-2 infection can be more complex and severe in patients with hepatocellular carcinoma (HCC) as compared to other cancers. This is due to several factors, including pre-existing conditions such as viral hepatitis and cirrhosis, which are commonly associated with HCC. METHODS: We conducted an analysis of epigenomics in SARS-CoV-2 infection and HCC patients, and identified common pathogenic mechanisms using weighted gene co-expression network analysis (WGCNA) and other analyses. Hub genes were identified and analyzed using LASSO regression. Additionally, drug candidates and their binding modes to key macromolecular targets of COVID-19 were identified using molecular docking. RESULTS: The epigenomic analysis of the relationship between SARS-CoV-2 infection and HCC patients revealed that the co-pathogenesis was closely linked to immune response, particularly T cell differentiation, regulation of T cell activation and monocyte differentiation. Further analysis indicated that CD4+ T cells and monocytes play essential roles in the immunoreaction triggered by both conditions. The expression levels of hub genes MYLK2, FAM83D, STC2, CCDC112, EPHX4 and MMP1 were strongly correlated with SARS-CoV-2 infection and the prognosis of HCC patients. In our study, mefloquine and thioridazine were identified as potential therapeutic agents for COVID-19 in combined with HCC. CONCLUSIONS: In this research, we conducted an epigenomics analysis to identify common pathogenetic processes between SARS-CoV-2 infection and HCC patients, providing new insights into the pathogenesis and treatment of HCC patients infected with SARS-CoV-2.

Molecular mechanism of Ganji Fang in the treatment of hepatocellular carcinoma based on network pharmacology, molecular docking and experimental verification technology.

Background: Hepatocellular carcinoma (HCC) is a malignant tumor harmful to human health. Ganji Fang (GJF) has good clinical efficacy in the treatment of HCC, but its mechanism is still unclear. Objective: The aim of this study was to investigate the mechanism of action of GJF in the treatment of HCC through network pharmacology, molecular docking and in vitro experiments. Methods: A series of network pharmacology methods were used to identify the potential targets and key pathways of GJF in the treatment of HCC. Then, molecular docking technology was used to explore the binding ability of key active ingredients and targets in GJF. Multiple external databases were used to validate the key targets. In in vitro experiments, we performed MTT assays, wound-healing assays, cell cycle assays, apoptosis assays and RT‒qPCR to verify the inhibitory effect of GJF on the Human hepatoma G2 (HepG2) cells. Result: A total of 162 bioactive components and 826 protein targets of GJF were screened, and 611 potential targets of HCC were identified. Finally, 63 possible targets of GJF acting on HCC were obtained. KEGG enrichment analyses showed that the top five pathways were the cell cycle, cellular senescence, p53 signaling pathway, PI3K/Akt signaling pathway, and progesterone-mediated oocyte maturation. Among them, we verified the PI3K/Akt signaling pathway. CCNE1, PKN1, CCND2, CDK4, EPHA2, FGFR3, CDK6, CDK2 and HSP90AAI were enriched in the PI3K/Akt pathway. The molecular docking results showed that the docking scores of eight active components of GJF with the two targets were all less than -5.0, indicating that they had certain binding activity. In vitro cell experiments showed that GJF could inhibit the proliferation and migration of HepG2 cells, block the cell cycle and induce apoptosis of HepG2 cells, which may be related to the PI3K/Akt signaling pathway. In summary, EPHA2 may be an important target of GJF in HCC, and pachymic acid may be an important critical active compound of GJF that exerts anticancer activity. Conclusion: In general, we demonstrated, for the first time, that the molecular mechanism of GJF in HCC may involve induction of G0/G1 phase cycle arrest through inhibition of the PI3K/Akt signaling pathway and promote apoptosis of hepatoma cell lines. This study provides a scientific basis for the subsequent clinical application of GJF and the in-depth study of its mechanism.

Safety and Clinical Activity of SHR7390 Monotherapy or Combined With Camrelizumab for Advanced Solid Tumor: Results From Two Phase I Trials.

BACKGROUND: SHR7390 is a novel, selective MEK1/2 inhibitor. Here, we report results from two phase I trials conducted to evaluate the tolerability, safety and antitumor activity of SHR7390 monotherapy for advanced solid tumors and SHR7390 plus camrelizumab for treatment-refractory advanced or metastatic colorectal cancer (CRC). PATIENTS AND METHODS: Patients received SHR7390 alone or combined with fixed-dose camrelizumab (200 mg every 2 weeks) in an accelerated titration scheme to determine the maximum tolerated dose (MTD). A recommended dose for expansion was determined based on the safety and tolerability of the dose-escalation stage. The primary endpoints were dose limiting toxicity (DLT) and MTD. RESULTS: In the SHR7390 monotherapy trial, 16 patients were enrolled. DLTs were reported in the 1.0 mg cohort, and the MTD was 0.75 mg. Grade ≥3 treatment-related adverse events (TRAEs) were recorded in 4 patients (25.0%). No patients achieved objective response. In the SHR7390 combination trial, 22 patients with CRC were enrolled. One DLT was reported in the 0.5 mg cohort and the MTD was not reached. Grade ≥3 TRAEs were observed in 8 patients (36.4%), with the most common being rash (n=4). One grade 5 TRAE (increased intracranial pressure) occurred. Five patients (22.7%) achieved partial response, including one of 3 patients with MSS/MSI-L and BRAF mutant tumors, one of 15 patients with MSS/MSI-L and BRAF wild type tumors, and all 3 patients with MSI-H tumors. CONCLUSIONS: SHR7390 0.5 mg plus camrelizumab showed a manageable safety profile. Preliminary clinical activity was reported regardless of MSI and BRAF status.

Comparison of response evaluation criteria in solid tumors and tumor regression grade in evaluating the effect of preoperative systemic therapy of gastric cancer.

BACKGROUND: Both Response Evaluation Criteria in Solid Tumors (RECIST) and tumor regression grade (TRG) play key roles in evaluating tumor response. We analyzed the consistency of TRG and RECIST 1.1 for gastric cancer (GC) patients and compared their prognostic values. METHODS: Patients with GC who received preoperative chemotherapy or chemoimmunotherapy and had records of TRG from December 2013 to October 2021 were enrolled retrospectively. TRG 0-1 and 2-3 are considered as corresponding to complete response (CR)/partial response (PR) and stable disease (SD)/progress disease (PD) in RECIST 1.1, respectively. The primary endpoints were disease-free survival (DFS) and overall survival (OS). The consistency of RECIST and TRG was examined by kappa statistics. Survival analysis was performed using the Kaplan Meier method. RESULT: One hundred fifty seven GC patients were enrolled, including 125 with preoperative chemotherapy and 32 with chemoimmunotherapy. Among them, 56 patients had measurable lesions. Only 19.6% (11/56) of the patients had consistent results between RECIST 1.1 and TRG. TRG was correlated with both OS and DFS (P = 0.02 and 0.03, respectively) while response according to RECIST1.1 was not (P = 0.86 and 0.23, respectively). The median DFS had not reached in the TRG 0-1 group and was 16.13 months in TRG 2-3 group. TRG 2-3 was associated with young age and peritoneal or liver metastasis. Besides, preoperative chemoimmunotherapy had a significantly higher pCR rate than chemotherapy alone (34.4% vs 8.0%, P < 0.001). CONCLUSION: TRG was in poor agreement with RECIST 1.1. TRG was better than RECIST 1.1 in predicting DFS and OS for GC patients who received preoperative therapy.