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Impact of BPA on HCC Immune Microenvironment and Progression

KEY TAKEAWAYS

  • The study aimed to assess BPA’s impact on the immune microenvironment and progression of HCC.
  • Researchers identified BPA’s impact on HCC immune microenvironment, suggesting it as a potential target for therapy.

This study explores the intricate relationship between bisphenol A (BPA), a widely-used synthetic compound, and the immune microenvironment of hepatocellular carcinoma (HCC). BPA has been linked to a variety of health issues, and emerging evidence suggests it may influence the progression of HCC.

Through a detailed analysis of the molecular and immunological landscape of this malignancy, the research aims to uncover how BPA interacts with immune cells within the tumor microenvironment, potentially influencing tumor growth, immune evasion, and therapeutic response.

Qi Liu and the team aimed to assess the role of BPA in modulating HCC progression and its implications for immunotherapy.

They performed an inclusive analysis using data from both The Cancer Genome Atlas and the Comparative Toxicogenomics Database, incorporating patient information to enhance the clinical relevance of the findings. Differential expression analyses were rigorously conducted, followed by Gene Ontology and Kyoto Encyclopedia of Genes and Genomes enrichment analyses to investigate potential functional pathways.

Single-sample gene set enrichment analysis, gene set enrichment analysis, and gene set variation analysis were applied to uncover molecular associations. Immune infiltration patterns were meticulously characterized, and a series of in vitro experiments using HCC cell lines were conducted to evaluate the direct effects of BPA exposure on cellular behavior.

The findings revealed a diverse range of active immune cells and functions within HCC. Notable correlations were observed between high immune-related scores, established markers of the tumor microenvironment, and the expression of immune checkpoint genes. A key discovery was the identification of specific genes linked to both immune-related pathways and BPA exposure.

Using these genes, researchers developed a prognostic model, providing predictive insights into patient outcomes in HCC. Additionally, in vitro studies indicated that BPA exposure may stimulate the proliferation of HCC cells.

The study concluded that the multifaceted nature of the HCC immune microenvironment is significantly influenced by BPA exposure, with potential modulatory effects on immune pathways.

The prognostic model developed through the research, if further validated, could become a valuable tool for risk stratification in HCC, aiding in the development of targeted therapeutic strategies.

The findings have important implications for immunotherapy, suggesting that BPA may play a role in enhancing treatment efficacy. As efforts to combat HCC progress, understanding the impact of environmental modulators like BPA is increasingly critical for improving patient outcomes.

No funding information was given for this source.

Source: https://pubmed.ncbi.nlm.nih.gov/39228142/

Liu Q, Niu R, Ye Y, et al. (2024). “Exploring the interplay between bisphenol A exposure, the immune microenvironment and hepatocellular carcinoma progression.” J Gene Med. 2024;26(9):e3723. doi:10.1002/jgm.3723

Pembrolizumab Combo Shows Promise in T4b ESCC Treatment

KEY TAKEAWAYS

  • The study aimed to investigate the safety and efficacy of pembrolizumab + cisplatin and 5-fluorouracil as 1L therapy in patients with T4b ESCC.
  • Researchers noted significant tumor reduction with fewer AEs, supporting pembrolizumab + chemo for T4b ESCC induction therapy.

Nobukazu Hokamura and the team aimed to focus on evaluating the safety and efficacy of pembrolizumab combined with cisplatin and 5-fluorouracil as first-line (1L) therapy in patients with advanced esophageal squamous cell carcinoma (ESCC).

Previous research has indicated that this regimen offers a better objective response and improved survival rates compared to conventional chemotherapy, while also resulting in fewer severe hematological adverse events. Given these promising outcomes, the study specifically targeted patients with T4b ESCC, a particularly advanced stage of the disease, to determine the potential benefits of this combination therapy.

They performed an inclusive analysis of 8 consecutive patients with T4b ESCC who received pembrolizumab combined with cisplatin and 5-fluorouracil as induction therapy, following the KEYNOTE-590 protocol. The patients were evaluated after receiving 1 to 3 courses of treatment.

In addition, the programmed death-ligand 1 (PD-L1) combined positive score (CPS) was assessed prior to the initiation of chemotherapy. The efficacy of the treatment on the primary tumor was determined using a specialized formula developed to calculate the tumor reduction rate.

The clinical outcomes, the numbers of patients with partial response (PR), stable disease, and progressive disease (PD) were 5, 1, and 2, respectively. The tumor reduction rate ranged from 69 to 87% in PR patients, and all PR patients experienced relief from T4b. Two patients underwent conversion surgery with R0 resection. The PD-L1 CPS was over 90 in 2 PR patients, but under 10 in 2 other PR patients.

PD-L1 CPS was under 10 in PD patients and 1 patient experienced hyperprogression, leading to the development of an esophago-pulmonary fistula. Adverse events (AEs) greater than grade 3 included a bleeding gastric ulcer in 1 patient (12.5%), neutropenia without G-CSF in 3 patients (37.5%), and hypopotassemia in 1 patient (12.5%). No patient developed febrile neutropenia.

The study concluded that marked tumor reduction was confirmed in 62.5% of patients receiving pembrolizumab + cisplatin and 5-fluorouracil, with fewer AEs compared to conventional treatments. This regimen demonstrates potential as an effective induction chemotherapy option for patients with T4b ESCC.

No funding information was given for this source.

Source: https://pubmed.ncbi.nlm.nih.gov/39223478/

Hokamura N, Fukagawa T, Fukushima R, et al. (2024). “Evaluation of pembrolizumab plus cisplatin and fluorouracil in radical treatment for patients with T4b esophageal squamous cell carcinoma.” BMC Gastroenterol. 2024;24(1):295. Published 2024 Sep 2. doi:10.1186/s12876-024-03382-w

Evaluating LODDS for Prognosis in GEC Post-Chemoradiation

KEY TAKEAWAYS

  • The study aimed to assess the prognostic value of the LODDS in staging GEC post-neoadjuvant chemoradiation.
  • Researchers found that TLODDSM better predicts prognosis and guides adjuvant therapy for patients with GEC post-neoadjuvant chemoradiation.

After neoadjuvant chemoradiation, the number of examined lymph nodes in resectable gastroesophageal cancer (GEC) often decreases, potentially compromising the accuracy of N staging.

Shuang Liu and the team aimed to evaluate the clinical relevance of a novel staging model based on the logarithmic odds of positive lymph nodes (LODDS) for patients with GEC who have undergone neoadjuvant chemoradiation.

They performed an inclusive analysis involving 1,130 patients with pathologically diagnosed GEC who received neoadjuvant chemoradiation between 2004 and 2019, sourced from the National Cancer Institute Surveillance, Epidemiology, and End Results (SEER) database. Lymph nodes were staged using both the AJCC TNM staging system (eighth edition) and the LODDS model.

Patient prognosis was assessed with the Kaplan-Meier method, and differences in node staging were evaluated using the Akaike Information Criterion and Bayesian Information Criterion. Additionally, 914 patients from the researchers’ center were used for external validation of the findings.

In comparison with the traditional TNM staging system, the new TLODDSM staging system, which includes stages I, II, IIIA, IIIB, and IVA, demonstrated higher benefits at various decision thresholds according to decision curve analysis.

The Akaike Information Criterion and Bayesian Information Criterion for the TLODDSM staging system were lower than those for the traditional TNM system, indicating improved sensitivity in predicting patient prognosis.

Additionally, patients classified as stage IIIB or IVA in the new system showed significant benefit from adjuvant chemotherapy. These findings were corroborated by externally validated data from the center.

The study concluded that the TLODDSM staging system offers significant advantages over the TNM staging system in predicting prognosis for patients with GEC who have completed neoadjuvant chemoradiation. This new system provides better guidance for adjuvant chemotherapy decisions, enhancing patient management and treatment outcomes.

The study was funded by the Department of Science and Technology of Jilin Province (No YDZJ202201ZYTS668).

Source: https://pubmed.ncbi.nlm.nih.gov/39210382/

Liu S, Wang Z, Ge Y, et al. (2024). “Prognostic significance of an innovative staging system based on the logarithmic odds of positive lymph nodes for resectable gastroesophageal cancer after neoadjuvant chemoradiation: a population-based study with external validation of data.” J Transl Med. 2024;22(1):801. Published 2024 Aug 29. doi:10.1186/s12967-024-05448-5

Efficacy of Axitinib + Avelumab in Pretreated Advanced GIST

Efficacy of Axitinib + Avelumab in Pretreated Advanced GIST

KEY TAKEAWAYS

  • The AXAGIST phase 2 trial aimed to investigate the synergy of axitinib and avelumab in advanced GIST after standard therapy failure.
  • The primary endpoint was to determine PFS.
  • Researchers noted significant efficacy and long-term benefit from the axitinib-avelumab combination in pretreated GIST.

The development of tyrosine kinase inhibitors (TKIs) has significantly advanced the treatment of unresectable or metastatic gastrointestinal stromal tumors (GISTs), yet resistance mechanisms continue to drive disease progression.

Piotr Rutkowski and the team considered the potential immunomodulatory effects of VEGF inhibitors and hypothesized that combining VEGF and PD-L1 inhibitors could have a synergistic effect and improve therapeutic outcomes.

They performed an inclusive analysis of AXAGIST (NCT04258956), a 2-centre, single-arm, phase II, 2-stage trial evaluating the efficacy and safety of avelumab (10 mg/kg IV Q2W) combined with axitinib (5 mg PO BID) in patients with unresectable or metastatic GIST after the failure of standard therapy. The primary endpoint was progression-free survival (PFS) at 3 months according to RECIST 1.1 criteria. Secondary endpoints included overall survival (OS), overall response rate (ORR), and safety.

About 58 patients were enrolled, with 56 evaluable for safety and efficacy. The median age was 60 years (range 18-80); 21 patients (37.5%) were female, and 30 patients (53.6%) had received prior treatment with 3 lines of TKIs. The median follow-up was 27.4 months (95% CI, 25.4-NA). The best response included partial response in 5 patients (8.9%), stable disease in 34 patients (60.7%), and progressive disease in 17 patients (30.4%).

Among patients with partial response, the median duration of response was 18.5 months (95% CI, 18.3-NA). The PFS rate at 3 months was 57.1%. Median PFS and OS were 4.6 months (95% CI, 2.9-6.4) and 14.2 months (95% CI, 9.2-26.3), respectively.

The 12-month PFS and OS rates were 22.8% (95% CI: 14-37.1) and 59.3% (95% CI: 47.5-74), respectively. Adverse events (AEs) occurred in 94.6% of patients, with 30.4% experiencing grade 3 or higher AEs, all of which were manageable.

The study concluded that the combination of targeted therapy and immunotherapy demonstrated significant efficacy in pretreated patients with GIST. A substantial subset of patients achieved long-term clinical benefit, with further biomarker correlations to be presented.

The trial was sponsored by Maria Sklodowska-Curie National Research Institute of Oncology.

Source: https://cslide.ctimeetingtech.com/esmo2024/attendee/confcal/show/session/47

Clinical Trial: https://clinicaltrials.gov/study/NCT04258956

Rutkowski P, Klimczak A, Teterycz P, et al. (2024). “Axitinib plus avelumab in patients with unresectable/metastatic gastrointestinal stromal tumor (GIST) after failure of standard therapy: Single-arm phase II study (AXAGIST).” Presented at ESMO 2024 (Abstract 1723MO).

Long-term Outcomes of LTG vs OTG in AGC After NACT

KEY TAKEAWAYS

  • The study aimed to compare long-term outcomes of laparoscopic vs. OTG after NACT in AGC.
  • Researchers noticed that LTG with D2 lymphadenectomy offers similar 3-year OS and DFS to OTG in patients with AGC post-NACT.

Yinkui Wang and the team aimed to evaluate and compare the long-term outcomes of laparoscopic total gastrectomy (LTG) vs open total gastrectomy (OTG) in patients with advanced gastric cancer (AGC) who underwent neoadjuvant chemotherapy (NACT).

By analyzing survival rates, including overall survival (OS) and disease-free survival (DFS), the research aimed to determine whether LTG could offer a viable alternative to OTG, particularly in terms of long-term efficacy. The outcomes were assessed over 3 years, focusing on the effectiveness and safety of LTG compared to the traditional open approach.

They performed an inclusive analysis involving patients with AGC who received NACT before surgery. Patients were enrolled into either the LTG or OTG group. To ensure comparability between the 2 groups, propensity score matching (PSM) was conducted using a 1:2 ratio, applying a 0.15 calliper width.

The study compared 3-year OS and DFS between the LTG and OTG groups before and after PSM. Survival rates were calculated using the Kaplan‒Meier method, and differences were evaluated through a log-rank test. Univariate and multivariate Cox proportional hazard analyses were utilized to estimate prognostic factors’ effects on survival and determine the hazard ratio (HR) between LTG and patients with OTG.

About 144 patients completed the follow-up, with 24 in the LTG group and 120 in the OTG group. After an average follow-up of 64.40 months, there were no significant differences observed in the 3-year OS or DFS rates between the two groups, both before (P = 0.453 and P = 0.362, respectively) and after PSM (P = 0.972 and P = 0.884, respectively). Multivariate Cox proportional hazards analysis identified the ypN stage as an independent risk factor for worse OS (P = 0.013).

The study concluded that LTG with D2 lymphadenectomy when performed by an experienced surgical team, provides comparable 3-year OS and DFS outcomes to OTG in patients with AGC following NACT.

This study was funded by the Beijing Municipal Health Commission (DFL20181103, ZYLX201701) and the Beijing Hospitals Authority Innovation Studio of Young Staff Funding Support (202123).

Source: https://pubmed.ncbi.nlm.nih.gov/39215275/

Wang Y, Lei X, Shan F, et al. (2024). “Long-term outcomes of laparoscopic versus open total gastrectomy in patients with advanced gastric cancer after neoadjuvant chemotherapy: a retrospective cohort study. BMC Cancer.” 2024;24(1):1074. Published 2024 Aug 30. doi:10.1186/s12885-024-12669-w

Role of DKC1 in Cuproptosis and Esophageal Cancer Progression

KEY TAKEAWAYS

  • The study aimed to investigate the impact of the cuproptosis-associated gene DKC1 on the malignant progression and prognosis of esophageal cancer.
  • Researchers noted that DKC1’s role in tumor progression highlights its potential as a diagnostic and therapeutic target.

Esophageal cancer is a prevalent malignancy of the digestive tract, with a poor overall prognosis despite advances in treatment. Cuproptosis, a type of programmed cell death, impacts tumor progression.

Daidi Zhang and the team aimed to evaluate the influence of the cuproptosis-associated gene DKC1 on esophageal cancer progression.

They performed an inclusive analysis using clinical and RNA sequencing data from patients with esophageal cancer sourced from The Cancer Genome Atlas (TCGA). Univariate Cox regression analysis was employed to identify cuproptosis-related differentially expressed genes linked to prognosis. The expression differences of DKC1 between tumor and normal tissues were validated through three-dimensional multiomics difference analysis.

The association between DKC1 expression and the tumor microenvironment (TME) was examined using the TIMER2.0 algorithm and further corroborated with 96 single-cell datasets from the TISCH database. Additionally, the functional role of DKC1 in pancarcinoma was explored through Gene Set Enrichment Analysis (GSEA).

A comprehensive pan-cancer survival map was constructed, and DKC1 expression across various molecular subtypes was verified. Drug sensitivity connections with DKC1 were established using the CellMiner, GDSC, and CTRP databases. Finally, the involvement of DKC1 in esophageal cancer progression was investigated through both in vivo and in vitro experiments.

About the copper death-related gene DKC1 identified in esophageal cancer, varying levels of DKC1 expression were observed across different tumor types. Analysis revealed a correlation between DKC1 expression and clinical features, associating it with common cell cycle pathways and multiple metabolic pathways. High DKC1 expression was found to predict poor prognosis in patients with various tumors and affect drug sensitivity.

Significant associations were also noted between DKC1 expression and molecules involved in immune regulation and lymphocyte subtype infiltration. The increased expression of DKC1 in esophageal cancer tissues was confirmed using clinical tissue samples. Additionally, DKC1-mediated promotion of esophageal cancer cell proliferation and migration was validated through both in vitro and in vivo experiments. Furthermore, it is suggested that DKC1 may play a role in the regulation of cuproptosis.

The study concluded that DKC1, through its systematic analysis and experimental validation, demonstrates strong diagnostic and prognostic potential across various cancers. Further research suggests that DKC1 may play a significant role in reshaping the TME, underscoring its potential as a target for cancer treatment and its usefulness in predicting responses to chemotherapy.

This study was funded by the National Natural Science Foundation of China and the Key Project of Science and Technology of Henan Province.

Source: https://pubmed.ncbi.nlm.nih.gov/39103487/

Zhang D, Zhu Q, Huang X, et al. (2024). “Identifying and validating the roles of the cuproptosis-related gene DKC1 in cancer with a focus on esophageal carcinoma.” J Cancer Res Clin Oncol. 2024;150(8):382. Published 2024 Aug 5. doi:10.1007/s00432-024-05870-8

Esophageal CSCs Evade NK Cells via ULBP-1 Suppression

KEY TAKEAWAYS

  • The study aimed to investigate how esophageal CSCs evade NK cell cytotoxicity via ULBP-1 downregulation.
  • Researchers found that esophageal CSCs evade NK cells by downregulating ULBP-1, suggesting a target for improved therapies.

Cancer stem-like cells (CSCs) are pivotal in the initiation and progression of aggressive cancers, including esophageal cancer, contributing to treatment resistance and tumor recurrence. Natural killer (NK) cells, vital components of innate immunity, can target and destroy various cancer cells, including CSCs, positioning NK cell-based therapy as a potential strategy to combat these resistant cells.

Bo Tang and the team aimed to examine the sensitivity of human esophageal CSCs to NK cell-mediated cytotoxicity, with a focus on understanding how these cells evade NK cell attacks.

They performed an inclusive analysis on CSCs enriched from human esophageal squamous cell carcinoma cell lines using sphere formation culture. Human NK cells were selectively expanded from the peripheral blood of healthy donors. Patients were assessed to understand the underlying mechanisms. qRT-PCR, flow cytometry, and ELISA assays were utilized to examine RNA expression and protein levels.

To evaluate the cytotoxicity of NK cells, CFSE-labeled target cells were co-cultured with human-activated NK cells, and flow cytometry was employed to detect and measure the extent of NK cell-mediated cytotoxicity.

About the results, researchers observed that esophageal CSCs were more resistant to NK cell-mediated cytotoxicity compared with their adherent counterparts. Consistently, esophageal CSCs exhibited down-regulated expression of ULBP-1, a ligand for the NK cell stimulatory receptor NKG2D. Knockdown of ULBP-1 led to significant inhibition of NK cell cytotoxicity against esophageal CSCs, while ULBP-1 overexpression resulted in the opposite effect.

Additionally, the pro-differentiation agent all-trans retinoic acid was found to enhance the sensitivity of esophageal CSCs to NK cell cytotoxicity.

The study concluded that esophageal CSCs exhibit increased resistance to NK cells due to the down-regulation of ULBP-1. This finding highlights a potential approach to enhance NK cell activity against esophageal CSCs, offering insights for developing more effective NK cell-based therapies.

This study was funded by the National Natural Science Foundation of China (82172704, 81773045) and the Medical Science and Technology Key Project of Henan Province, China (SBGJ202302038).

Source: https://pubmed.ncbi.nlm.nih.gov/39103915/

Tang B, Guo M, Zhai Y, et al. (2024). “Human esophageal cancer stem-like cells escape the cytotoxicity of natural killer cells via down-regulation of ULBP-1.” J Transl Med. 2024;22(1):737. Published 2024 Aug 5. doi:10.1186/s12967-024-05549-1

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