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This study aimed to measure relative telomere length (RTL) in blood leukocytes of advanced-stage NSCLC patients either with or without Osimertinib-induced ADRs and determine whether RTL could serve as a biomarker of Osimertinib-induced ADRs. Blood leukocytes RTL were measured in 63 advanced-stage NSCLC patients and 62 age-matched healthy controls using real-time polymerase chain reaction. In patients with advanced-stage NSCLC, RTL was significantly shorter than that in healthy controls ( P  < 0.001). Compared to patients without ADRs and those with mild/moderate ADRs, patients with severe ADRs exhibited significantly decreased RTL ( P  < 0.001, P  < 0.001, respectively). ROC curve analysis uncovered a diagnostic value of RTL as a biomarker of Osimertinib-induced ADRs (AUC = 1.000, P  < 0.001). Kaplan-Meier analysis revealed a significant association between shorter RTL and increased cumulative incidence of Osimertinib-induced ADRs in patients with advanced-stage NSCLC ( P  < 0.001). Shorter RTL in blood leukocytes would reflect the occurrence of Osimertinib-induced ADRs and might emerge as a promising biomarker for identifying advanced-stage NSCLC patients who are at risk of experiencing Osimertinib-induced ADRs, particularly those with severe ADRs.

Cisplatin is a widely used chemotherapeutic drug for various cancers. One of the common adverse effects of cisplatin is nephrotoxicity including acute kidney injury (AKI) and acute kidney disease (AKD). Single Nucleotide Polymorphisms (SNPs) can be used to identify cancer patients who are susceptible to developing cisplatin-induced nephrotoxicity (CIN). In this study, we validated the association between 6 SNPs in the drug metabolizing enzyme genes, SLC22A2 (rs316019) & EPHX1 (rs1051740), and the DNA repair genes, ERCC1 (rs11615 & rs3212986) & ERCC2 (rs13181 & rs1799793), and CIN in the 169 Thai patients with head and neck, lung, or esophageal cancer. Effect of these SNPs on cumulative incidence of AKD, progression-free survival (PFS), and overall survival (OS) was also assessed. EPHX1 rs1051740 TC genotype was significantly associated with AKD in co-dominant [OR 2.894, 95% CI 1.091–7.680; P  = 0.033] and over-dominant [OR 2.793, 95% CI 1.333–5.851; P  = 0.006] models, and with an increased cumulative incidence of AKD ( P  = 0.021). Additionally, ERCC2 rs13181 and rs1799793 were significantly associated with OS ( P  = 0.002 and 0.004). Our results reveal an association between EPHX1 rs1051740 and AKD, and confirms the previously reported associations between ERCC2 SNPs and OS. These findings may help in predicting CIN in Thai cancer patients.

Background High prevalence of EGFRm lung cancer was found in the Asian population. Preclinical data suggest that inflammatory cytokines activated by PM2.5 affected EGFRm clone expansion. Here, we explored the correlation between inflammatory markers and EGFRm NSCLC. Methods Resected NSCLC patients (2016–2023) were enrolled. Tumor tissues and blood serum were retrieved from Ramathibodi tumor biobank. EGFR 19del and L858R mutations were performed by rt-PCR in cancerous tissue and dPCR in normal tissue in the same patient. NF-Kb and STAT3 protein signaling were measured by ELISA in both cancerous and normal tissue. Cytokines (IL-1ß, IL-6, IL-8, IL-10, IL-12 and TNF-α) were explored in serum by flow cytometry. Results Among 140 patients, EGFRm prevalence was 58% in cancerous tissue but only 5% in normal tissue. NF-kB and STAT3 were statistically higher in cancerous tissue than normal tissue [NF-kB median O.D.=0.82 (IQR; 0.07–2.82) vs. 0.32 (IQR; 0.05–2.48), P  < 0.001; STAT3 median O.D.=0.32 (IQR; 0.10–1.58) vs. 0.17 (IQR; 0.06–1.29, P  < 0.001]. STAT3 was significantly increased in EGFR m compared to EGFR wt [median O.D.=0.36 (IQR; 0.234–0.592) vs. 0.23 (IQR; 0.158–0.409), OR = 11.09 (95% CI; 2.17–56.58), P  = 0.004]. TNF-α, IL-10, and STAT3 in cancer cells were higher in EGFR m than EGFR wt ( P  = 0.003, 0.008, and < 0.001, respectively). None of cytokines was statistically different between EGFR m and EGFR wt patients. However, only STAT3 in cancer cells and non-smoker were associated with EGFRm NSCLC in multivariable analysis. Conclusion Inflammation could be one of the pathogenesis of both NSCLC and EGFR m lung cancer as we demonstrated in our pilot study. STAT3 is a potentially inflammatory-predictive biomarkers. Larger cohort is needed.

Background Breast cancer is the leading malignancy among Filipino women, with about 23.50% of cases characterized by human epidermal growth factor receptor-2 (HER2) overexpression. Trastuzumab, in addition to standard chemotherapy, is currently recommended as primary treatment for HER2-positive early-stage breast cancer (EBC) in the adjuvant settings, and has been listed in the Philippine National Formulary (PNF) since 2008, but with no current evidence yet on its value for money, to date. Hence, despite several policy enablers, its accessibility remains to be limited in the Philippines. We performed an economic evaluation to assess the cost-effectiveness and budget impact of adjuvant trastuzumab therapy for HER2-positive EBC in the Philippines, using healthcare system and societal perspectives, in aid of guiding coverage decisions. Methods A Markov model-based cost-utility and budget impact analyses were conducted to estimate the total costs incurred and outcomes gained in using 1 year of adjuvant trastuzumab added to standard chemotherapy versus standard chemotherapy alone, over a lifetime horizon. We discounted both costs and outcomes at 3.5% per annum. Parameters were estimated using country survival data, systematic review and meta-analysis of the relative treatment effect, local and international cost data, and published utility data. Univariate and probabilistic sensitivity analyses were used to account for parameter uncertainty. Results Trastuzumab therapy was dominated with an incremental cost-effectiveness ratio (ICER) at PHP 453,505 per QALY gained from a healthcare system perspective or PHP 458,686 per QALY gained from a societal perspective, with 10% cost-effectiveness probability at the country cost-effectiveness threshold of PHP 120,000 per QALY gained. National implementation will cost an additional amount of PHP 13,909 million in year one alone, plus about PHP 2000 to 3000 million annually for the succeeding fiscal years. Conclusion At its current cost, 1 year of adjuvant trastuzumab therapy compared to standard chemotherapy alone for HER2-positive EBC does not represent value for money in the Philippines. Its current cost will have to significantly lower down by one-half to achieve cost-effectiveness.

Genetic polymorphisms in drug metabolizing enzymes and drug transporters may affect irinotecan toxicity. Although genetic polymorphisms have been shown to influence the irinotecan toxicity, data are limited in Thai population. Thus, the aim of this study was to assess the allele and genotype frequencies and the relationship between CYP3A4/5 , DPYD , UGT1A1 , ABCB1 , and ABCC2 genetic variations and irinotecan-induced toxicity in Thai colorectal cancer patients . One hundred and thirty-two patients were genotyped, and the effect of genetic variations on irinotecan-induced toxicity was assessed in 66 patients who received irinotecan-based chemotherapy . Allele frequencies of ABCB1 c.1236C > T, ABCB1 c.3435C > T, ABCC2 c.3972C > T, ABCG2 c.421C > A, CYP3A4*1B , CYP3A4*18 , CYP3A5*3 , DPYD*5 , UGT1A1*28 , and UGT1A1*6 were 0.67, 0.43, 0.23, 0.27, 0.01, 0.02, 0.64, 0.19, 0.16, and 0.09, respectively. DPYD*2A and DPYD c.1774C > T variants were not detected in our study population. The ABCC2 c.3972C > T was significantly associated with grade 1–4 neutropenia ( P  < 0.012) at the first cycle. Patients carrying both UGT1A1*28 and *6 were significantly associated with severe neutropenia at the first (P < 0.001) and second (P = 0.017) cycles. In addition, patients carrying UG1A1*28 and * 6 had significantly lower absolute neutrophil count (ANC) nadir at first ( P  < 0.001) and second ( P  = 0.001) cycles. This finding suggests that UGT1A1*28, *6 , and ABCC2 c.3972C > T might be an important predictor for irinotecan-induced severe neutropenia.

Central nervous system (CNS) metastases are common in non-small-cell lung cancer (NSCLC) and associated with poor prognosis and high disease burden. Effective options are needed to treat CNS metastases, and delay or prevent their formation. For epidermal growth factor receptor mutation-positive (EGFRm) advanced NSCLC and brain metastases, upfront EGFR-tyrosine kinase inhibitors (TKIs) are recommended by the joint European Association of Neuro-Oncology–European Society for Medical Oncology and experts. While early-generation EGFR-TKIs have limited CNS efficacy, the third-generation, irreversible, EGFR-TKI osimertinib has potent efficacy in NSCLC CNS metastases. This review discusses the CNS data of osimertinib in the context of therapeutic strategies and future prospects based on expert review of published literature and relevant clinical, real-world, and ongoing studies in this setting. Osimertinib penetrates the blood–brain barrier and achieves greater exposure in the brain compared with other EGFR-TKIs. Osimertinib has demonstrated CNS efficacy, including in leptomeningeal metastases, in EGFRm advanced disease. In EGFRm stage IB–IIIA NSCLC, adjuvant osimertinib reduced CNS disease recurrence versus placebo. The burden and poor prognosis of CNS metastases necessitate more therapeutic options for their management and reduced risk of recurrence in patients with EGFRm NSCLC. Clinical studies are ongoing in advanced disease to investigate osimertinib combinations with chemotherapy/radiation therapy and optimal treatment post-CNS progression with osimertinib. Further prospective research evaluating treatments using CNS-specific endpoints and evaluating CNS resistance is needed to improve outcomes for patients with CNS metastases.

Background One-year of immune checkpoint inhibitor (ICI) treatment after concurrent chemoradiation (CCRT) in unresectable stage III non-small cell lung cancer (NSCLC) is a standard of care. The precise predictive biomarkers are under investigations either immunological markers or clinical characteristics. Here, we explored immune repertoire of T cell receptor β-chain (TCRβ) during ICI treatment. Methods During August 2019 and September 2021, stage III NSCLC, post CCRT patients from Ramathibodi Hospital was enrolled. All patients were treated by durvalumab after CCRT. Blood samples were collected together with clinical data and tumor assessment every 3–4 months until disease progression or discontinuation of treatment due to adverse events. CDR3 region and TCRΒ polymorphisms was explored by RNA sequencing using Next-Generation Sequencing (NGS) TCR beta short-read assay. Bioinformatic analysis was performed to analyze clonal diversity, TCR convergence frequency and the Shannon diversity from each timepoint. Immune repertoire and clinical correlation were explored using Spearman’s correlation and Pearson’s correlation. RStudio software version 2021 build 372 was used for analyses. A significance level was at P  < 0.05. Results Forty-four blood samples from 12 patients were analyzed. Mean duration of durvalumab treatment was 284 days. After durvalumab treatment, increasing of TCR convergence frequency was found compared to baseline ( R  = 0.36). Interestingly, it was also significantly higher in non-progressive disease (non-PD) patients compared with progressive disease (PD) patients ( P  = 0.011). Furthermore, Shannon diversity was higher increasing in PD patients compared with non-PD patients. Taken together, our study found that increasing of TCR convergence with less T-cell diversity in non-PD patients probably demonstrated a T cell-specific clonal expansion response to durvalumab treatment in this population. Conclusions TCRβ repertoire is the potential biomarker for predicting durvalumab treatment response in post CCRT stage III NSCLC patients. However, a larger cohort with long-read assay should be explored.

Background: Osimertinib has shown greater efficacy than standard epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) and fewer grade 3 or higher adverse drug reactions (ADRs) in patients with advanced non-small cell lung cancer (NSCLC) harboring epidermal growth factor receptor ( EGFR ) mutations. However, the clinical outcomes of osimertinib treatment vary depending on the patient’s ethnicity. Therefore, further research is necessary to evaluate the impact of single nucleotide polymorphisms (SNPs) in cytochrome P450 ( CYP450 ) and drug transporters on the therapeutic outcomes and ADRs to osimertinib in Thai patients, to provide improved pharmacological treatments for cancer patients. Methods: This retrospective and prospective cohort study enrolled 63 Thai patients with NSCLC treated with 80 mg of osimertinib once daily as monotherapy. Seventeen SNPs in candidate genes related to drug metabolism and transport pathways were analyzed in each patient. Chi-square or Fisher’s exact tests were used to evaluate the associations between SNPs and clinical outcomes, including ADR incidence and objective response rate (ORR). In addition, the correlation between the genotype and median time to treatment failure (TTF) or progression-free survival (PFS) was assessed using Kaplan-Meier analysis and a log-rank test. Results: We identified six SNPs (rs2231142 and rs2622604 in ABCG2 , rs762551 in CYP1A2 , rs1057910 in CYP2C9 , rs28371759 in CYP3A4 , and CYP2A6 deletion polymorphism ( CYP2A6 *4)) that significantly increased the incidence of ADRs. In addition, we found two SNPs (rs2069514 in CYP1A2 and rs1057910 in CYP2C9 ) that significantly decreased the median TTF, and two SNPs (rs28399433 in CYP2A6 and rs1057910 in CYP2C9 ) that significantly decreased the median progression-free survival (PFS). Specifically, we found that one of these SNPs (rs1057910 in CYP2C9 ) influenced ADRs, TTF, and PFS. Additionally, SNPs in the CYP2A6 heterozygous variant (non4/*4) significantly increased ADR incidence, leading to a high frequency of dose reduction (27.0%). Conclusion: Our study demonstrated significant SNPs associated with increased ADR incidence, decreased PFS, and decreased TTF in Thai patients with NSCLC treated with osimertinib. The CYP2C9 (*3) and CYP2A6 (*4) allele frequencies differed between ethnicities and were associated with an increased incidence of ADRs. These findings highlight the importance of considering genetic factors in NSCLC treatment and may facilitate personalized medicine approaches. Moreover, our study showed a higher incidence of ADRs than the previous trials, including FLAURA and AURA2, and a higher frequency of dose reduction than reported in the AURA 3 trial, possibly due to genetic differences among the study populations.

Introduction Difference in clinical responses to cancer therapy in each patient is from several factors. Gastrointestinal microbiota is one of the reasons. However, this correlation remains unknown. This study aims to explore correlation between gastrointestinal microbiota profile and clinical outcomes in Thai advanced non-small cell lung cancer (NSCLC) according to epidermal growth factor receptor ( EGFR ) status. Methods We enrolled 13 patients with advanced EGFR –wild-type (WT) NSCLC who received chemotherapy and 15 patients with EGFR -mutant NSCLC who received EGFR tyrosine kinase inhibitors. We collected fecal samples at baseline and first disease evaluation and performed 16S rRNA gene sequencing by NGS to assess microbiota profile. The correlations between gastrointestinal microbiota and clinical variables were studied. Results The clinical characteristics were balanced between the cohorts, excluding significantly higher albumin levels in the EGFR -mutant group. Albumin was the only significant clinical factor affecting the treatment response in multivariate analysis (ORR 15.6%, P  = 0.03). Proteobacteria counts were higher in the EGFR -WT group, whereas Bacteroidetes and Firmicutes counts were higher in the EGFR -mutant group. The alpha diversity of the gastrointestinal microbiome was significantly higher in the EGFR -mutant group (Shannon index: 3.82 vs. 3.25, P  = 0.022). Following treatment, Proteobacteria counts were lower and Bacteroidetes and Firmicutes counts were higher in both cohorts; the changes were more prominent in the EGFR -WT cohort. No significant correlation between microbiota profile and treatment response were demonstrated in our study. However, beta diversity was significantly different according to severity of adverse events. Enrichment of Clostridia and Bacteroidia was associated with higher adverse event risk in the EGFR -WT cohort. Conclusions Proteobacteria was dominant in Thai lung cancer patients both EGFR -WT and EGFR -mutant, and this phylum maybe associate with lung cancer carcinogenesis. Chemotherapy altered the gastrointestinal microbiota, whereas EGFR -TKIs had less effects. Our findings highlight the potential predictive utility of the gastrointestinal microbiota for lung cancer carcinogenesis. Studies with larger cohorts and comparison with the healthy Thai population are ongoing to validate this pilot study.

Chemotherapy is the main therapy for non-targetable advanced non-small cell lung cancer (NSCLC). Nevertheless, few biomarkers are currently available for predicting clinical outcomes and monitoring treatment response. The blood samples of 42 patients with non-targetable advanced NSCLC who received chemotherapy were collected before chemotherapy and after chemotherapy. The circulating immune cells and subpopulation Treg were investigated using flow cytometry, and human immune checkpoint biomarker levels were analysed by multiplex bead-based assay. After selecting the effective biomarkers for survival analysis, high pre-chemotherapy sCD25 (≥499.52 pg/mL; 4.52 vs 14.98 months, p = 0.030) and post-chemotherapy (≥515.23 pg/mL; 3.90 vs 21.25 months, p = 0.004) were associated with poorer median progression-free survival (PFS). An increase in pre-chemotherapy neutrophil to lymphocyte ratio (NLR) (ratio ≥ 6.9; 5.15 vs 21.54 months, p = 0.008) and post-chemotherapy NLR (ratio ≥ 3.1; 10-month OS 50.35% vs 83.57%, p = 0.014) was correlated with shorter overall survival (OS). Moreover, increased pre-chemotherapy %NKT cells (≥6.8%) were linked to improved clinical benefit rate (CBR) (2.72 vs 3.97 months, p = 0.013), while higher post-chemotherapy %NK cells (≥23.1%) were associated with rapid overall response rate (ORR) at 4 months (82.05% vs 25%, p = 0.035). Our findings suggest that sCD25 and NLR show potential as indicators of PFS and OS, respectively. Additionally, pre-chemotherapy %NKT and post-chemotherapy %NK cells may provide insight into monitoring chemotherapy response. This pilot study identified potential candidate biomarkers for further investigation to confirm their clinical utility.