PD-L1 Expression Levels Research Articles

Current Status, Challenges, and Prospects of Combining Immune Checkpoint Inhibitors and Chemotherapy in Non-Small Cell Lung Cancer Treatment

In recent years, significant advancements have been made in the use of immune checkpoint inhibitors (ICIs) for treating non-small cell lung cancer (NSCLC). Nevertheless, their efficacy as monotherapy remains limited in certain patient populations, especially in patients with low levels of PD-L1 expression. The combination of ICIs with chemotherapy has gradually emerged as a novel strategy, aiming to leverage the immune-enhancing effects of chemotherapy to synergize with ICIs. This review provides a comprehensive analysis of the synergistic mechanisms, clinical trial outcomes, safety and toxicity issues, resistance challenges, and future directions of ICI-chemotherapy combination therapy for NSCLC. Clinical evidence suggests that this combination notably extends progression-free survival (PFS) and overall survival (OS), demonstrating promising efficacy, particularly in advanced squamous NSCLC patients with low PD-L1 levels. By inducing immune enhancement through chemotherapy and activating immune responses via ICIs, this combined approach effectively overcomes the limitations of single-agent therapies. Despite a range of challenges, this immunotherapy combination offers renewed hope for improving treatment outcomes in NSCLC patients.

Cost-effectiveness analysis of PD-L1 testing associated with pembrolizumab for first-line treatment of advanced non-small cell lung cancer in China.

Lung cancer is the leading cause of cancer-related deaths in China, and pembrolizumab shows differential efficacy in advanced non-small cell lung cancer (NSCLC) with different PD-L1 expression levels. To assess the cost-effectiveness of PD-L1 testing associated with pembrolizumab for first-line treatment of NSCLC from the perspective of Chinese healthcare system. Over a lifetime horizon, a three-state partitioned survival model was developed to assess the cost-effectiveness of PD-L1 testing and no PD-L1 testing. In the PD-L1 testing group, patients were stratified by PD-L1 tumor proportion score ≥ 50%, 1-49%, or < 1% and received pembrolizumab monotherapy, pembrolizumab plus chemotherapy, or chemotherapy alone, respectively. In the non-PD-L1 testing group, all patients received pembrolizumab plus chemotherapy. Model inputs were obtained from published literature and a healthcare price database, and clinical outcomes from two randomized clinical trials were used. The net monetary benefit (NMB) was estimated for the PD-L1 testing group versus the non-PD-L1 testing group. Deterministic and probabilistic sensitivity analyses, and scenario analyses were conducted to assess robustness of results. Using PD-L1 testing to guide treatment led to cost savings of $49,392.7 and a reduction in quality-adjusted life years (QALYs) of 0.234, resulting in a positive NMB of $46,421.7 at a willingness-to-pay (WTP) threshold of $12,680.8/QALY (GDP per capita in China, 2023). Findings were robust across sensitivity and scenario analyses. Using PD-L1 testing to guide first-line pembrolizumab treatment in patients with advanced NSCLC is a cost-effective strategy at a WTP threshold of $12,680.8/QALY for China.

Investigating the delivery of PD-L1-targeted immunoliposomes in a dynamic cervical cancer-on-a-chip model.

The recent approval of pembrolizumab in recurrent or metastatic cervical cancer warrants further investigations into the usefulness of immunotherapies for more durable and less radical interventions. In this study, the targeting potential of anti-PD-L1-functionalized immunoliposomes was tested in a 3D in vitro cervical cancer-on-a-chip model. Immunolipsomes were synthesized and decorated externally with monovalent anti-PD-L1 Fab' fragments of commercially available atezolizumab. Cervical cancer cell lines with varying levels of PD-L1 expression were cultured as spheroids embedded in a collagen I matrix, and treated under flow of culture media. Flow cytometry and live-cell confocal imaging were used to measure the interactions and uptake of untargeted liposomes and immunoliposomes in this panel of cell lines. The immunoliposomes retained specific functionality regardless of protein corona formation in high serum environments. As such, spheroids expressing high levels of PD-L1 preferentially internalized immunoliposomes in a 3D environment with extracellular matrix present, while low PD-L1-expressing cell lines showed no preference for either formulation. Importantly, treatments performed in monolayer cultures (on plastic) showed no differences between immuno- and untargeted liposome uptake, including the way in which the endocytosed liposomes are trafficked subcellularly. This study demonstrates the importance of both active and passive accumulation strategies to achieve nanoparticle targeting. Immunoliposomes remain a promising platform for the development of targeted nanotherapies against cervical cancers. However, initial functional tests did not translate directly to biological performance and this should be kept in mind for future formulations. Furthermore, the in vitro model developed appeared useful for visualizing liposome uptake in a 3D, live tissue environment and represents a cost-effective and reproducible model for future studies.

Correlation analysis of DLG5 and PD-L1 expression in triple-negative breast cancer

BackgroundTriple-negative breast cancer (TNBC) is among the most aggressive forms of breast cancer, characterized by a dismal prognosis. In the absence of drug-targetable receptors, chemotherapy remains the sole systemic treatment alternative. Recent advancements in immunotherapy, particularly immune checkpoint inhibitors (ICIs) that target programmed death 1/programmed death ligand 1 (PD-1/PD-L1) and cytotoxic T lymphocyte associated antigen 4 (CTLA-4), have provided renewed optimism for the treatment of patients with TNBC. Prior research has indicated that the expression level of the cell polarity protein discs large homolog 5 (DLG5) correlates with the malignant progression and prognosis of breast cancer; nevertheless, its influence on PD-L1 expression and its function in immunotherapy for TNBC require further investigation.MethodsThe hypoxia cell model was established by simulating the cell hypoxic microenvironment in the human SUM159 and MDA-MB-231 cell lines using cobalt II chloride (CoCl2). A combination of PD-L1 inhibitors and DLG5 RNA interference techniques was used, along with various methods including cell counting kit-8 (CCK-8), colony formation, wound healing, transwell migration, reverse transcription-quantitative real-time PCR (RT-qPCR), immunofluorescence, immunohistochemical staining (IHC), expression analysis from datasets and western blotting. These methods were employed to evaluate changes in cell proliferation, migration, and the expression levels of PD-L1 and DLG5. Additionally, the correlation between the expression of PD-L1 and DLG5 in clinical samples was analyzed.Results(1) In vitro experiments, a cellular hypoxia model was effectively established utilizing 150 µM CoCl₂. Under these conditions, cell clone formation, invasiveness, and migration rate were all significantly inhibited. (2) The expression levels of DLG5 and PD-L1 were significantly increased in both MDA-MB-231 and SUM159 cells following treatment with 150 µM CoCl₂. (3) Silencing DLG5 resulted in a considerable upregulation of PD-L1 expression in MDA-MB-231 and SUM159 cells under normoxic circumstances, but it was markedly downregulated under hypoxic settings. Inhibition of PD-L1 expression resulted in a considerable increase in DLG5 expression under normoxic conditions, but it decreased under hypoxic conditions. Correlation research demonstrated an inverse association between the expression of DLG5 and PD-L1 in TNBC tissues.ConclusionThis study provides new theoretical evidence and potential therapeutic targets for the immunotherapy strategies of TNBC, holding significant clinical application value.

Mogroside V protects Lipopolysaccharides-induced lung inflammation chicken via suppressing inflammation mediated by the Th17 through the gut-lung axis

Abstract Lipopolysaccharide (LPS) exposure triggers pulmonary inflammation, leading to compromised lung function in broiler. As amplified by policy restrictions on antibiotic usage, seeking antibiotic alternatives has become imperative. Mogroside V (MGV) has been reported to have a beneficial role in livestock and poultry production due to its remarkable anti-inflammatory effects. Despite evidence showcasing MGV's efficacy against LPS-triggered lung inflammation, its precise mechanism of action remains elusive. In this study, we transplanted normal fecal microbiota (CF), fecal microbiota modified by MGV (MF), and sterile fecal filtrate (MS) into broiler with LPS-induced pneumonia. The results showed that through fecal microbiota transplantation, transplanting MGV-induced microbial populations significantly mitigated tissue damage induced by LPS and enhanced the mRNA level of pulmonary tight junction proteins and mucoprotein (P &amp;lt; 0.01). The expression levels of RORα (P &amp;lt; 0.001), Foxp3 (P &amp;lt; 0.01) and PD-L1 (P &amp;lt; 0.01) were significantly increased in the MF group than CF group. The concentrations of IL-6 and IL-17 in broilers lung tissue of MF group were lower than those in broilers of CF group (P &amp;lt; 0.05). Furthermore, the concentration of TGF-β in broilers serum of MS and MF groups was higher than those in broilers of control group (P &amp;lt; 0.05). Microbial community analysis demonstrated that at genus level, the harmful bacterial populations Escherichia-shigella and Helicobacter following FMT treatment was significantly reduced in MF group (P &amp;lt; 0.05), potentially mediating its protective effects. Compared with CF group, valerate content and FFAR2 mRNA expression levels in MF group were significantly increased (P &amp;lt; 0.05). The study suggests that MGV via the gut-lung axis, attenuates Th17-mediated inflammation, offering promise as a therapeutic strategy against LPS-induced lung inflammation in chickens.

PHPS1 enhances PD-L1 serine phosphorylation by regulating ROS/SHP-2/AMPK activity to promote apoptosis of oral squamous cell carcinoma cells

To investigate the mechanism of PHPS1 for promoting apoptosis of oral squamous cell carcinoma cells and the role of AMPK in regulating tumor angiogenesis under hypoxic conditions. Human oral squamous cell carcinoma Ca9-22 cells cultured in hypoxic conditions (1% O2) were inoculated subcutaneously in 16 nude mice, which were divided into control group and PHPS1 group (n=8) for treatment with 10% DMSO and 10% PHPS1 respectively. Tumor growth in the mice was monitored till 14 days after the treatment, and the xenografts were examined pathologically using HE staining. In Ca9-22 cells cultured in 1% O2, the effect of PHPS1, compound C (an AMPK inhibitor), and their combination on expressions of SHP-2, AMPK, HIF-1α, PD-L1, caspase-8, caspase-3 and BAX were evaluated using Western blotting. In the tumor-bearing nude mice, PHPS1 treatment significantly inhibited tumor growth and neovascularization. HE staining showed significantly reduced tumor angiogenesis in PHPS1-treated mice. In Ca9-22 cells in hypoxic cultures, PHPS1 treatment significantly decreased the expression levels of SHP-2, HIF-1α, PD-L1, ERK2, STAT3 and VEGF and increased the expression of AMPK. The inhibitory effects of PHPS1 on HIF-1α and PD-L1 were obviously attenuated by the addition of compound C. PHPS1 also enhanced the expressions of caspase-3, caspase-8 and Bax proteins and increased the phosphorylation levels of PD-L1 and S195 in Ca9-22 cells, and these effects were effectively attenuated by compound C. PHPS1 can enhance PD-L1 serine phosphorylation by regulating SHP-2/AMPK activity to promote apoptosis of oral squamous cell carcinoma cells under hypoxic conditions.

The impact of neoadjuvant immunotherapy on the clinical efficacy of stage IIIA-N2 non-small cell lung cancer patients.

To explore the impact of neoadjuvant immunotherapy on the clinical efficacy of stage IIIA-N2 non-small cell lung cancer (NSCLC) patients. The retrospective study was conducted on 120 patients with stage IIIA-N2 NSCLC admitted to our hospital during April 2020 to April 2022. The control group received local chemotherapy, while the combination group received neoadjuvant immunotherapy on the basis of chemotherapy. The treatment efficacy, immune function, PD-1 and PD-L1 (SP142) expression levels, and changes in inflammatory factors were compared between the two groups. Kaplan Meier survival curve was used to analyze the overall survival rate. Total effective rate in the control group was 53.33% (15.00% recovery+16.66% significant effect+21.66% effective), and the combined group had a higher total effective rate of 85.00% (41.66% recovery+23.33% significant effective+20.00% effective) (P<0.001). After intervention, the combination group had largely increased immune indicators levels, including CD3+, CD4+ and CD4+/CD8+ (P<0.001), but reduced levels of CD8+, PD-1 and PD-L1 (SP142) than the control group (P<0.001). After intervention, the levels of inflammatory factors in the combination group were also reduced than the control group (P<0.001). Compared to the control group with an adverse reaction rate of 31.66% (8.33% gastrointestinal reaction+11.66% hair loss+6.66% proteinuria+5.00% diarrhea), the combined group had much lower adverse reaction rate of 11.66% (1.66% gastrointestinal reaction+5.00% hair loss+3.33% proteinuria+1.66% diarrhea) (P<0.05). After 24months of follow-up, the overall survival rate was 58.33% (35/60) and 40.00% (24/60) in the combination group and the control group, respectively. The Kaplan Meier survival curve analysis showed a statistically significant difference in overall survival rate between the two groups (P<0.05). Neoadjuvant immunotherapy had a more significant therapeutic effect on stage IIIA-N2 NSCLC patients by reducing immunosuppressive and inflammatory factors, improving immune function, and reducing the occurrence of adverse reactions.

Multiple Myeloma: Genetic and Epigenetic Biomarkers with Clinical Potential.

Multiple myeloma (MM) is characterized by the uncontrolled proliferation of monoclonal plasma cells and accounts for approximately 10% of all hematologic malignancies. The clinical outcomes of MM can exhibit considerable variability. Variability in both the genetic and epigenetic characteristics of MM undeniably contributes to tumor dynamics. The aim of the present study was to identify biomarkers with the potential to improve the accuracy of prognosis assessment in MM. Initially, miRNA sequencing was conducted on bone marrow (BM) samples from patients with MM. Subsequently, the expression levels of 27 microRNAs (miRNA) and the gene expression levels of ASF1B, CD82B, CRISP3, FN1, MEF2B, PD-L1, PPARγ, TERT, TIMP1, TOP2A, and TP53 were evaluated via real-time reverse transcription polymerase chain reaction in BM samples from patients with MM exhibiting favorable and unfavorable prognoses. Additionally, the analysis involved the bone marrow samples from patients undergoing examinations for non-cancerous blood diseases (NCBD). The findings indicate a statistically significant increase in the expression levels of miRNA-124, -138, -10a, -126, -143, -146b, -20a, -21, -29b, and let-7a and a decrease in the expression level of miRNA-96 in the MM group compared with NCBD (p < 0.05). No statistically significant differences were detected in the expression levels of the selected miRNAs between the unfavorable and favorable prognoses in MM groups. The expression levels of ASF1B, CD82B, and CRISP3 were significantly decreased, while those of FN1, MEF2B, PDL1, PPARγ, and TERT were significantly increased in the MM group compared to the NCBD group (p < 0.05). The MM group with a favorable prognosis demonstrated a statistically significant decline in TIMP1 expression and a significant increase in CD82B and CRISP3 expression compared to the MM group with an unfavorable prognosis (p < 0.05). From an empirical point of view, we have established that the complex biomarker encompassing the CRISP3/TIMP1 expression ratio holds promise as a prognostic marker in MM. From a fundamental point of view, we have demonstrated that the development of MM is rooted in a cascade of complex molecular pathways, demonstrating the interplay of genetic and epigenetic factors.

PD-L1 expression is mediated by microRNA processing, Wnt/β-catenin signaling, and chemotherapy in Wilms tumor.

Inhibition of immune checkpoint proteins is effective in adult cancers but has shown limited efficacy in pediatric cancers. While factors regulating expression of immune checkpoint proteins such as PD-L1 are well-documented in adult cancers, their regulation is poorly understood in pediatric cancers. Here, we show that PD-L1 is upregulated in distinct subsets of Wilms tumor, the most common pediatric kidney cancer. Specifically, chemotherapy-exposed Wilms tumor specimens exhibited higher levels of PD-L1 expression, and common chemotherapeutics upregulated PD-L1 in childhood cancer cell lines in vitro . Furthermore, mutations in CTNNB1 and DROSHA , the two most commonly mutated genes in Wilms tumor, correlated with higher PD-L1. Activation of Wnt/β-catenin signaling and knockdown of DROSHA or DICER1 both increase PD-L1 in vitro . Lastly, in adult cancers, DICER1 alterations are associated with immune gene expression signatures and improved survival in response to immune checkpoint inhibitors. Together, our results identify clinical and biological properties regulating PD-L1 in Wilms tumor that may inform precision therapy approaches in pediatric immuno-oncology.

PD-L2 act as an independent immune checkpoint in colorectal cancer beyond PD-L1.

Immunotherapy, especially immune checkpoint blockade (ICB), holds promise as a therapeutic strategy in colorectal cancer (CRC) by harnessing the patient's immune system to target malignant cells. Particularly, the PD-1/PD-L1 axis is widely recognized for its critical role in tumor microenvironment immunosuppression. Antibodies targeting PD-1 or PD-L1 have shown sustained efficacy against various cancers, including CRC. Nonetheless, many CRC patients exhibit limited responses to such immunotherapy, and the resistance mechanisms remain incompletely understood. We conducted experiments with C57BL/6 mice, and used the MC38 cell line for ICB treatment studies in syngeneic mouse models. Gene and protein analyses were performed using qPCR, Western Blot, and flow cytometry, with bioinformatics for clinical data survival analysis. In this study, we reveal that targeting PD-L2 emerges as a complementary therapeutic strategy to PD-1/PD-L1 blockade in CRC. Although PD-L2 is also inducible by IFNγ, like PD-L1, it displays a unique spatial distribution within the tumor microenvironment, implying discrete roles in immune evasion. Additionally, we uncovered a significant correlation between PD-L1 and PD-L2 expression levels and the infiltration of various immune cells, encompassing multiple dendritic cell (DC) subtypes. This correlation implies an enhanced antigen presentation process that may be unleashed by blocking these two immune checkpoints. Our results highlight the significance of PD-L2 as an essential immune checkpoint alongside PD-L1 and emphasize its potential as a target for bolstering antitumor immunity in colorectal cancer.

Neoadjuvant chemoradiotherapy up-regulates PD-L1 in radioresistant colorectal cancer.

Combining radiotherapy (RT) with immune checkpoint inhibitors (ICIs) is a promising strategy that can enhance the therapeutic efficacy of ICIs. However, little is known about RT-induced changes in the expression of immune checkpoints, such as PD-L1, and their clinical implications in colorectal cancer (CRC). This study aimed to investigate the association between responsiveness to RT and changes in PD-L1 expression in human CRC tissue and cell lines. Tissue specimens from preoperative biopsy via sigmoidoscopy and surgical resection were obtained from 24 patients with locally advanced rectal cancer (LARC) who underwent neoadjuvant chemoradiation therapy (CRT) between August 2016 and December 2017. Immunohistochemistry for PD-L1 in formalin-fixed paraffin-embedded tissue was performed from the endoscopic biopsy and surgical specimens. RNA sequencing was performed using 11 pairs of human LARC tissues before and after irradiation. After exposing human CRC cells to radiation, we investigated changes in the expression levels of PD-L1 and its regulatory signaling pathways. Patients were classified by tumor regression grade into responders (grade 2; 9 patients, 37.5%) and non-responders (grades 3, 4, or 5; 15 patients, 62.5%). In the non-responder group, 13 patients had low PD-L1 expression, but neoadjuvant CRT increased PD-L1 expression in 7 patients (53.9%) (McNemar's test, p=0.034). CRT up-regulated PD-L1 in non-responder LARC tissues. Similarly, radiation increased PD-L1 in radioresistant DLD-1 cells more than in radiosensitive HCT116 cells, also affecting PD-L1-regulating genes and immune checkpoints in CRC cells. Conventional fractionated radiation treatment further increased PD-L1 in DLD-1 cells compared to HCT116 cells. This study demonstrated that radiation induces an increase in PD-L1 expression, which is more pronounced in radioresistant CRC, proving the theoretical framework for a combined treatment strategy with a PD-L1 blockade for locally advanced rectal cancer.

Analysis of microsatellite instability in primary mediastinal large B-cell lymphoma: Focus on PD-L1/PD-L2 and CIITA

Introduction. Primary mediastinal large B-cell lymphoma (PMBCL) is a rare non-Hodgkin lymphoma. Considering the immunophenotype of PMBCL, which differs from diffuse large B-cell lymphoma (DLBCL), Microsatellite Repeat (MSR) aberrations in regions flanking PD-L1/PD-L2 and CIITA genes were investigated.Aim: to study the prevalence of MSR aberrations in 19 loci of the COrDIS Plus panel and in the regions of the PD-L1/PD-L2, CIITA genes in PMBCL and DLBCL, and to compare it with the expression level of PD-L1 and HLA-DR in PMBCL.Materials and methods. The study included 137 patients, 86 (62,8%) with PMBCL and 51 (37.2%) with DLBCL. The analysis was conducted using the standard COrDIS Plus panel, which includes a set of primers for 19 loci of tetranucleotide repeats. The allelic imbalance (AI) of MSR close to the PD-L1/PD-L2 genes (9p24.1) (n = 68/86 (79.1%) for PMBCL, n = 36/51 (70.6 %) for DLBCL) and CIITA (16p13.13) (n = 71/86 (82.6 %) for PMBCL, n = 29/51 (56.9 %) for DLBCL) was investigated using STR analysis. Patients with homozygous inheritance for each of the studied markers were excluded from further analysis due to the inability to assess loss of heterozygosity (LOH). The expression of PD-L1 and HLA-DR was assessed by immunohistochemistry in 27/86 (31.4 %) PMBCL patients.Results. Homozygosity for both markers near the PD-L1/PD-L2 genes was found in 5/68 (7.4 %) of PMBCL patients and 10/36 (27.8 %) of DLBCL patients (p = 0.008). Aberrations of MSR flanking the PD-L1/PD-L2 genes were detected in 33/63 (52.4%) of PMBCL patients and 5/26 (19.2 %) of DLBCL patients (p = 0.003; OR 5.8; 95% CI [2.8–18.7]). Homozygosity for both markers near the CIITA gene was identified in 8/71 (11.3%) of PMBCL patients and 7/29 (24.1%) of DLBCL patients (p = 0.13). AI near the CIITA gene was found in 24/63 (38.1 %) of PMBCL patients, while no changes in the CIITA region were observed in the DLBCL group (p = 0.0001; OR 14.3; 95% CI [2.8–262.5]). Using the COrDIS Plus panel, the frequencies of tetranucleotide repeat aberrations did not significantly differ between PMBCL and DLBCL (p = 0.78 for LOH, p = 0.17 for EMAST). No correlation was found between MSR aberrations near the PD-L1/PD-L2 and CIITA genes and the expression levels of PD-L1 and HLA-DR (p = 0.402 and 0.668, respectively).Conclusion. A statistically significant more frequent alteration in the MSR marker profile of the PD-L1/PD-L2 and CIITA gene regions was found in PMBCL patients compared to DLBCL. Chromosomal microarray analysis in 2 out of 3 PMBCL cases revealed genetic aberrations involving the PD-L1/PD-L2 and/or CIITA genes, and AI of these genes was observed simultaneously with the MSR profile evaluation. This confirms the different pathogenesis of these diseases and suggests that the presence of AI in these loci indicates the involvement of these genes in the pathogenesis. There is no correlation between AI in the PD-L1/PD-L2 and CIITA gene regions and the expression of PD-L1 and HLA-DR, respectively.

The predictive role of PD-L1 expression and CD8 + TIL levels in determining the neoadjuvant chemotherapy response in advanced ovarian cancer

ObjectiveTo analyze how the PD-L1 expression and CD8 + tumor infiltrating lymphocyte (TIL) levels in biopsy samples before neoadjuvant chemotherapy (NACT) can predict chemotherapy response score and survival for advanced high-grade serous ovarian cancer (HGSC).MethodsWe retrospectively analyzed 45 patients with advanced epithelial ovarian cancer between 2010 and 2018, who had received at least three cycles of NACT. PD-L1 expression and CD8 + TIL levels were evaluated by immunohistochemical staining in the pre-NAC tumor samples from which the patients had been diagnosed. The post-NACT tissue samples taken during interval debulking surgery (IDS) were used to evaluate the chemotherapy response score (CRS).ResultsAmong all the patients, CRS 1 (no response) was found in 8 patients, CRS 2 (partial response) in 28 patients, and CRS 3 (complete response) in 9 patients. A total of 20 (44.4%) patients had high intratumoral CD8 + TILs (iCD8 + TILs) levels, and 35 (77.8%) patients had high expression stromal CD8 + TILs (sCD8 + TILs). No statistically significant relationship was found between high and low expression of i/s CD8 + TILs levels with PFS and CRS. The study found that 33 (73.3%) patients had high levels of stromal PD-L1 (sPD-L1) expression and 28 (62.2%) patients had high levels of intratumoral PD-L1 (iPD-L1) expression. In the iPD-L1 group, patients with low expression had a PFS of 28 months, whereas those with high expression had a PFS of 17 months (p = 0.028). Among the patients with high iPD-L1 expression, 23 (82.1%) patients showed CRS2, 4 (14.3%) showed CRS3, and only 1 (3.6%) showed CRS1 (p < 0.001). However, high or low expression sPD-L1 did not significantly affect PFS and CRS (p = 0.928 and p = 0.305; respectively).ConclusionsWe found that iPD-L1 expression levels in diagnostic biopsy in ovarian cancer can predict the chemotherapy response score in interval debulking surgery.

Investigation the role of SIRT3, SIRT7, NFATC1, and PDL-1 genes in androgenetic alopecia

BackgroundAndrogenetic alopecia (AGA) stands as the most prevalent form of hair loss, affecting the hair follicles (HFs). Aging emerges as a prominent contributor in this condition. In this study, our aim is to elucidate the expression patterns of candidate genes—SIRT3, SIRT7, NFATC1, and PDL-1—known to exhibit differential expression levels during HF aging, and to underscore the role of aging in AGA.Material and methodsMesenchymal stem cells (MSCs) were isolated from the vertex and occipital regions of six men affected by AGA. The aim was to assess the expression levels of SIRT3, SIRT7, NFATC1, and PDL-1 genes. RNA extraction was performed followed by cDNA synthesis, and gene expression levels were quantified using real-time PCR. To validate the experimental findings, two different RNA-seq datasets relevant to the study were analyzed using R software.ResultsIn the present study, experimental tests revealed that the expression levels of SIRT3 and SIRT7, known to decrease during HF aging, were diminished in AGA-affected samples as well. Conversely, the mean value of NFATC1 and PDL-1 expression level, which are known to increase during HF aging, were found to be elevated in AGA-affected samples. Moreover, bioinformatic analyses provide additional support for the role of SIRT3, SIRT7 and NFATC1in AGA pathogenesis.ConclusionWhile SIRT3 and SIRT7 may play critical roles in AGA development, further research is needed to elucidate the significance of NFATC1 and PDL-1 in this context and to explore their potential as therapeutic targets for AGA treatment.

Baseline 18F FDG PET/CT imaging in NSCLC: Possible utility in predicting strong-positive PD-L1 expression

Background/Purpose: To assess whether 18F FDG PET/CT imaging can predict non-small cell lung cancer (NSCLC) patients with strong PD-L1 expression (≥50%). Methods: This retrospective study analyzed 149 NSCLC patients who had undergone baseline 18F FDG PET/CT imaging from June 2021 to May 2024. We recorded age, sex, smoking history, histopathology, TNM stage, metastasis, and PD-L1 expression levels. PET/CT parameters such as SUVmax, SUVmean, metabolic tumor volume (MTV), and total lesion glycolysis (TLG) were recorded. Patients were dichotomized based on two PD-L1 expression thresholds, as measured by immunohistochemistry: higher or lower than 1% (1%, n = 87) and higher or lower than 50% (

Two-Year Experience of a Center of Excellence for the Comprehensive Management of Non-Small Cell Lung Cancer at a Fourth-Level Hospital in Bogota, Colombia: Observational Case Series Study and Retrospective Analysis.

Background: This study aimed to provide a comprehensive analysis of 56 patients admitted to the Lung Cancer Clinical Care Center (C3) at Fundación Santa Fe de Bogotá (FSFB) between 2 May 2022 and 22 April 2024. The focus was on demographic characteristics, smoking history, comorbidities, lung cancer types, TNM classification, treatment modalities, and outcomes. Methods: This observational case series study reviewed medical records and included patients over 18 years with a confirmed diagnosis of non-small cell lung cancer (NSCLC). Data were collected and analyzed for demographics, comorbidities, treatment types, biomolecular profiling, and survival rates. Ethical approval was obtained, and data were anonymized. Results: The mean age was 71.8 years with a female predominance (53.6%). A history of smoking was present in 71.4% of patients. Adenocarcinoma was the most common type (75.0%), followed by squamous cell carcinoma (19.6%). At admission, the most frequent TNM stages were IA2 (17.9%) and IVA (16.1%). One-year survival was 68.8%, and 94.3% of stage I-IIIA patients underwent PET scans. Biomolecular profiling revealed 69.2% non-mutated EGFR, 90.4% ALK-negative, and various PDL-1 expression levels. Immunotherapy was received by 91.4% of patients, with Alectinib and Osimertinib being common. Grade III-IV pneumonitis occurred in 5.4% of patients. Conclusions: The study's findings align with existing literature, highlighting significant smoking history, common adenocarcinoma, and substantial use of immunotherapy. Limitations include the observational design, small sample size, and short follow-up period, impacting the generalizability and long-term outcome assessment. Future research should address these limitations and explore longitudinal outcomes and emerging therapies.

Role of immunohistochemical prognostic factors in various types of immunotherapy for metastatic melanoma: A retro-prospective study

Background. Anti-PD-1 immunotherapy (IT) is the standard of care for patients with metastatic melanoma. However, in the real world, IT is effective only in a fraction of patients. The lack of valid prognostic factors for various immunotherapy agents warrants a comprehensive and advanced study of this topic. Aim. To improve the outcomes of the first-line therapy for disseminated melanoma based on identifying immunohistochemical predictors of IT efficacy. Materials and methods. Data from 130 patients who were treated with immune checkpoint inhibitors nivolumab or prolgolimab in the first-line therapy for disseminated melanoma between 2017 and 2024 were analyzed. Results. The expression of PD-L110 on tumor cells was found to be a predictor of effective therapy: in the nivolumab group, the 2-year disease-free survival (DFS) with PD-L1 level 10% was high at 79% (95% confidence interval – CI 61–100); the 1-year DFS was 89% (95% CI 78–100) compared to 17% (95% CI 3.2–88) with a lower level of PD-L1 expression (p0.0001). In the prolgolimab group, the 2-year DFS with PD-L110% was also high at 78% (p0.0001; CI 54–100), the 1-year DFS was 94% (95% CI 84–100) compared to 35% (95% CI 17–73) with a lower level of PD-L1 expression (p0.0001). A less severe course of the disease was observed in patients with both peritumoral and intratumoral locations versus those with only peritumoral locations of the immune infiltrate. The study of the presence and form of lymphoid infiltration of the tumor showed the following direct relationship: in the nivolumab group, the 2-year DFS was 94% (95% CI 83–100) compared to 8.3% (95% CI 1.3–54), in the prolgolimab group, the 1-year DFS was 82% (95% CI 68–100) compared to 15% (95% CI 2.6–86); p0.0001. It was found that the predominance of CD8+ over CD4+ is associated with better results of IT: in the nivolumab group, the 2-year DFS was 87% (95% CI 74–100) compared to 19% (95% CI 4–91) in the absence of CD8+ predominance over CD4+; in the prolgolimab group, the 2-year DFS was 73% (95% CI 51–100) in patients with CD8+ predominance over CD4+ (p=0.0001). In patients without CD8 predominance over CD4, 2-year DFS was not achieved. The one-year DFS was 85% (95% CI 70–100) and 25% (95% CI 8.4–76), respectively; p=0.0001. Conclusion. The results of the study suggest that immunohistochemical characteristics such as a PD-L1 expression level 10%, the simultaneous presence of peri- and intratumoral lymphoid infiltration of the tumor, the ratio of the intensity of lymphoid infiltration with tumor-infiltrating lymphocytes (TILs), and the predominance of CD8+ over CD4+ can be considered predictors of IT efficacy with nivolumab and prolgolimab.

Effective treatment strategies and key factors influencing therapeutic efficacy in advanced SMARCA4-deficient non-small cell lung cancer

IntroductionSMARCA4/BRG1-deficient non-small cell lung cancer (SD-NSCLC) with high invasiveness and poor prognosis is associated with primary resistance to standard treatment, especially in late-stage patients. This study aimed to explore effective treatments and identify critical factors impacting therapeutic efficacy to enhance outcomes for SD-NSCLC patients. Methods103 SD-NSCLC patients in stage III/IV diagnosed by immunohistochemistry from May 2019 to March 2024 were included in this study. We assessed the patients’ clinical and genetic features, analyzed the clinical outcomes of local treatment and immunotherapy according to the TNM stage, and further evaluated the factors impacting therapeutic efficacy. ResultsIn stage III patients, no significant differences in the median progression-free survival (mPFS) and median overall survival (mOS) were observed between patients receiving local treatment at the primary site and those who did not (p > 0.05), while adding ICIs (immune checkpoint inhibitors) to local treatment significantly improved mPFS compared with non-ICIs (15.0 vs. 7.7 months, p = 0.033), though not mOS (p > 0.05). For stage IV patients, ICIs significantly improved mPFS (8.9 vs. 4.2 months, p = 0.006) and mOS (19.7 vs. 13.1 months, p = 0.007) compared to non-ICIs treatments. However, among ICIs-treated patients, the addition of local treatment to the primary lesion did not significantly affect mPFS and mOS (p > 0.05). Patients with STK11/KEAP1 mutations had significantly shorter mPFS (3.6 vs. 16.2 months, p = 0.001) and mOS (17.7 vs. 31.3 months, p = 0.002), while no significant difference was observed in mPFS and mOS in patients with different tumor mutation burden (TMB) and PD-L1 expression levels. ConclusionThe addition of ICIs to local treatment shows promising results for locally advanced patients with SD-NSCLC, and first-line ICIs are associated with improved survival in metastatic SD-NSCLC. STK11/KEAP1 mutations may be linked to reduced efficacy of immunotherapy.

TERT Gene Mutation in Gliomas Cross-Linked With (NTRK, PDL1, ALK, IDH, P53, EGFR, HER2): A Integrative Review TERT Gene Mutation in Gliomas.

Recent advancements in glioma treatment are largely driven by the identification of genetic alterations, which enhance diagnostic precision and prognostic assessments, and unveil potential therapeutic targets. TERT promoter mutations, in particular, are associated with a poorer prognosis and aggressive clinical behavior. This study explores the genetic interplay between TERT and other genes (ntrk, pdl1, alk, idh, p53, egfr, her2) in brain tumors through an integrative literature review. This method synthesizes evidence from selected articles spanning 2014 to 2023. The review identified 65 articles based on defined inclusion criteria, out of which 14 were analyzed in depth. Findings reveal that TERT, TP53, and IDH1 are the most frequently mutated genes in gliomas. The prognosis of glioma patients can be refined through the combined analysis of IDH and TERT mutations. Additionally, PD-L1 expression levels are associated with prognosis and may influence treatment responses, particularly, in immunotherapy. The study underscores the importance of molecular diagnostics, such as Next-Generation Sequencing (NGS), in detecting key genetic mutations. These advancements have paved the way for new therapeutic strategies and better patient outcomes. The findings highlight the crucial role of genetic markers in glioma treatment and prognosis, advocating for continued research to enhance clinical applications and patient care. The use of NGS is indispensable in identifying biomarkers associated with mutations in the TERT gene.

Pooled Long-Term Outcomes With Nivolumab Plus Ipilimumab or Nivolumab Alone in Patients With Advanced Melanoma.

Nivolumab (NIVO) + ipilimumab (IPI) combination and NIVO monotherapy have demonstrated durable clinical benefit in patients with unresectable/metastatic melanoma. This analysis describes long-term overall survival (OS) with the combination or monotherapy pooled across all major company-sponsored trials, as well as clinical factors associated with survival, in patients with immune checkpoint inhibitor (ICI) treatment-naïve unresectable/metastatic melanoma. Data were pooled from six CheckMate studies in ICI treatment-naïve patients receiving NIVO + IPI (NIVO 1 mg/kg + IPI 3 mg/kg or NIVO 3 mg/kg + IPI 1 mg/kg) or NIVO monotherapy (3 mg/kg). OS was assessed for each treatment, as well as in select subgroups. Cox proportional multivariate analysis (MVA) and classification and regression tree (CART) analyses were performed within treatment arms. Median follow-up for OS was 45.0 months for patients treated with NIVO + IPI (n = 839) and 35.8 months for patients treated with NIVO (n = 536). OS was longer with NIVO + IPI versus NIVO monotherapy (hazard ratio, 0.78 [95% CI, 0.67 to 0.91]), with 6-year OS rates of 52% versus 41%, respectively. Consistent benefit was observed in BRAF-mutant and BRAF-wild-type patients and those with normal and elevated lactate dehydrogenase (LDH). Numerical difference in OS was also observed across PD-L1 expression levels, although more pronounced with no/low PD-L1 expression. Clinical factors associated with decreased survival in both the MVA and CART analyses were LDH > upper limit of normal with either treatment, age ≥65 years with NIVO + IPI, and the presence of liver metastases with NIVO monotherapy. In this large, pooled nonrandomized retrospective analysis, we observed that NIVO + IPI provides longer OS than NIVO in patients with ICI treatment-naïve advanced melanoma and identifies clinical factors that appear to be associated with survival for each treatment, which may assist with treatment decision making.