면역관문억제제 치료한 신장암 환자에서 다중 면역조직화학검사를 이용한 종양미세환경 탐색 및 치료 반응 연관성 분석

Immune checkpoint inhibitors (ICIs) such as anti-programmed-death-1 (PD-1) and cytotoxic T lymphocyte protein-4 (CTLA4) inhibitors, are important treatment options for patients with advanced renal cell carcinoma (RCC). The tumor microenvironment (TME) in ICI-treated patients remains largely unknown. In this study, 71 patients were treated with ICIs between July 2015 and June 2020: 20 patients were treated with nivolumab plus ipilimumab as first-line therapy and 51 patients were treated with nivolumab monotherapy as second/third-line therapy. Multiplexed immunohistochemistry (mIHC) was performed to define the TME, which included various T cell subsets, B cells, macrophages, and dendritic cells. In the nivolumab plus ipilimumab group, the objective response rate (ORR) and disease control rate (DCR) were 47.1% and 64.7%, respectively. The density of CD8+ cytotoxic T cells (P=0.027), specifically CD103+ CD8+ tissue-resident T cells (P=0.046), CD137+ CD8+ T cells (P=0.005), Foxp3- CD4+ helper T cells (P=0.025), Foxp3+ CD4+ regulatory T cells (P=0.014), and CD68+ CD206- M1 macrophages (P=0.007) were significantly higher in responders than in non-responders. Patients who experienced initial disease progression had a lower infiltration of CD68+ CD206- M1 macrophages than those who did not (P=0.008). The median progression-free survival (PFS) was 11 months, and a high density of CD8+ cytotoxic T cells (P=0.030), Foxp3- CD4+ helper T cells (P=0.036), CD137+ CD8+ cytotoxic T cells (P=0.024), and CD68+ CD206- M1 macrophages (P=0.054) was associated with better PFS. In the nivolumab group, ORR and DCR were 38.8% and 61.2%, respectively, and median PFS was 6.3 months. Response to nivolumab monotherapy was not significantly associated with the infiltration of T cell subsets and B cells, but patients who had initial disease progression with nivolumab had a higher infiltration of CD68+ CD206+ M2 macrophages than those who did not (P=0.012). A high density of CD137+ CD8+ cytotoxic T cells (P=0.016), CD137+ CD4+ cytotoxic T cells (P=0.088), and a low density of CD68+ CD206+ M2 macrophages (P=0.067) were associated with better PFS. When quantifying the infiltration of immune cells according to the International Metastatic RCC Database (IMDC) risk groups, CD68+ CD206+ M2 macrophages were more highly infiltrated in high-risk patients than in intermediate- or favorable-risk patients. The density of T cell subsets significantly correlated with that of CD68+ CD206- M1 macrophages and CD20+ B cells, and the density of PD-L1+ cells significantly correlated with that of various immune cells. Therefore, through comprehensive TME analysis, CD137-expressing T cell subsets and M1/M2 macrophages were significantly associated with ICIs efficacy. This suggests that CD137 could be a predictive marker for selecting treatment options, and novel strategies targeting CD137 or macrophages should be further explored in advanced RCC.Docto

Real-world utility of next-generation sequencing for targeted gene analysis and its application to treatment in lung adenocarcinoma

Purpose This study investigated the clinical utility of next-generation sequencing (NGS) for detection of genetic alterations and its implications on treatment of lung adenocarcinoma in real-world practice. Patients and Methods Data were reviewed for 391 patients with lung adenocarcinoma who underwent NGS between March 2017 and October 2018. Formalin-fixed, paraffin-embedded archival samples were used for performing NGS targeting 382 genes, including all exons of 199 genes, 184 hotspots, and the partial introns of 8 genes often rearranged in cancer. Survival analysis was performed for stage IV disease. Results Among the 391 patients, at least one actionable mutation was identified in 294 patients (75.2%). The most commonly mutated gene was EGFR (n = 130, 33.2%), involving EGFR exon 19 deletion (n = 48, 12.3%), L858R (n = 47, 12%), and others (n = 35, 9%), followed by KRAS (n = 48, 12.3%), ALK (n = 40, 10.2%), RET (6%), MET (3%), ROS-1 (3%), and BRAF (2%) mutations. TP53 (46.9%) and CDKN2A (12.6%) mutations were common co-mutations in patients with AMs. With a median follow-up duration of 16.8 months, median overall survival was 36.8 months in patients with stage IV disease. Patients treated with the corresponding targeted therapy for AMs based on NGS reports lived significantly longer than those not treated with such therapy (p < 0.001). After multivariate analysis, targeted therapy for AM was a significantly favorable factor for survival (AM without targeted therapy vs. AM with targeted therapy, hazard ratio 2.58, 95% confidence interval 1.57-4.25; p < 0.001). Conclusion This study revealed that AMs could be comparably detected using NGS. Based on these NGS results, a suitable targeted therapy can be selected, which may improve survival in patients with lung adenocarcinoma. This NGS-based approach is useful in real-world practice to provide guidance when selecting targeted therapy

Use of Gemcitabine plus Carboplatin is Associated with Poor Outcomes in Urothelial Carcinoma Patients with Chronic Kidney Disease Stage 4-5

Abstract Purpose: This study aimed to investigate the clinical outcomes with gemcitabine-carboplatin (GCb), the standard treatment for patients with advanced urothelial carcinoma (UC) who are ineligible for cisplatin-based regimens, in advanced UC patients with a glomerular filtration rate (GFR) < 30 mL/min. Materials and methods: A retrospective cohort study involving GCb-treated advanced UC patients with GFR < 60 mL/min (n=89) was performed. Clinical outcomes were compared between subgroups with GFR < 30 mL/min and GFR ≥ 30 mL/min but < 60 mL/min. Results: Most baseline characteristics were comparable between the two subgroups. Patients with GFR < 30 mL/min had a significantly lower objective response rate (12.5%) compared to those with higher GFR levels (56.7%) (p=0.004). The number of GCb cycles was significantly lower in patients with GFR < 30 mL/min (median 2 cycles) than in those with higher GFR levels (median 6 cycles) (p=0.002). Compared to those with GFR ≥ 30 mL/min but < 60 mL/min, patients with GFR < 30 mL/min showed significantly worse progression-free survival (PFS) and overall survival (OS) (p < 0.001 for both). Further stratification of patient subgroups according to their GFR (i.e., GFR ≥ 45 mL/min but < 60 mL/min vs. GFR ≥ 30 mL/min but < 45 mL/min vs. GFR < 30 mL/min) revealed significantly different PFS and OS (p < 0.001 for both). Conclusion: The use of GCb is discouraged in advanced UC patients with GFR < 30 mL/min. Alternative therapeutic approaches with better efficacy are warranted for these patients. Keywords: Gemcitabine plus carboplatin; Glomerular filtration rate; Objective response rate; Urothelial carcinoma

Risk of tuberculosis in patients with cancer treated with immune checkpoint inhibitors: a nationwide observational study

Background While some recent studies have reported the development of tuberculosis (TB) in patients exposed to immune checkpoint inhibitors (ICIs), there is limited evidence to date. Therefore, we evaluated the risk of TB in patients with cancer exposed to ICIs using the National Health Insurance claims data in South Korea. Methods Patients with diagnostic codes for non-small cell lung cancer, urothelial carcinoma or melanoma between August 2017 and June 2019 were identified. The incidence rate and standardized incidence ratio (SIR) of TB were calculated for both the ICI exposure and non-exposure groups. The risk of TB according to ICI exposure was assessed using a multivariable Cox regression model. Results During the study period, 141 550 patients with cancer and 916 new TB cases were identified. Among the 5037 patients exposed to ICIs, 20 were diagnosed with TB at a median of 2.2 months after the ICI was initiated. The crude incidence rate of TB per 100,000 person-years was 675.8 (95% CI 412.8 to 1043.8) for the ICI exposure group and 599.1 (95% CI 560.5 to 639.6) for the non-exposure group. The SIR for TB was 8.1 (95% CI 8.0 to 8.2) in the ICI exposure group. After adjusting for potential confounding factors, ICI treatment was not significantly associated with an increased risk of TB (HR: 0.73; 95% CI 0.47 to 1.14). Conclusions While the incidence of TB in cancer patients exposed to ICIs was eightfold higher than in the general population, the risk of patients with cancer developing TB did not significantly differ according to ICI exposure

Reappraisal of the prognostic value of Epstein-Barr virus status in monomorphic post-transplantation lymphoproliferative disorders-diffuse large B-cell lymphoma

The role of the Epstein-Barr virus (EBV) status in the blood for predicting survival in post-transplantation lymphoproliferative disorders-diffuse large B-cell lymphoma (PTLD-DLBCL) is unknown. We evaluated the prognostic values of pre-treatment EBV-encoded small RNA (EBER) detected with in situ hybridization in tissues and EBV DNA in the whole blood (WB) and plasma in 58 patients with monomorphic PTLD-DLBCL after solid organ transplantation. There were no significant differences in the rates of overall response, complete response, and survival according to EBER EBV and WB EBV status. In contrast, patients with positive plasma EBV DNA had significantly lower rates of overall response (60.0% vs. 94.4%, P=0.043) and complete response (40.0% vs. 88.9%, P=0.019) as well as worse progression-free survival (PFS) (P=0.035) and overall survival (OS) (P=0.039) compared with patients with negative plasma EBV DNA. In multivariate analysis, plasma EBV DNA positivity was a significantly unfavorable prognostic factor for PFS [hazard ratio (HR) 4.92, 95% confidence interval (CI) 1.22-19.86, P=0.025] and OS (HR 4.48, 95% CI 1.14-17.63, P=0.032). Despite small number of 6 patients with plasma EBV positivity, plasma EBV DNA positivity might be more prognostic for survival than EBER or WB EBV DNA positivity in patients with monomorphic PTLD-DLBCL

Spatial Distribution and Prognostic Implications of Tumor-Infiltrating FoxP3(-) CD4(+) T Cells in Biliary Tract Cancer

Purpose The clinical implications of tumor-infittratingT cell subsets and their spatial distribution in biliary tract cancer (BTC) patients treated with gemcitabine plus cisplatin were investigated. Materials and Methods A total of 52 BTC patients treated with palliative gemcitabine plus cisplatin were included. Multiplexed immunohistochemistry was performed on tumor tissues, and immune infiltrates were separately analyzed for the stroma, tumor margin, and tumor core. Results The density of CD8(+) T cells, FoxP3(-) CD4(+) helper T cells, and FoxP3(+) CD4(-) regulatory T cells was significantly higher in the tumor margin than in the stroma and tumor core. The density of LAG3(-) or TIM3-expressing CD8(+) T cell and FoxP3(-) CD4(+) helper T cell infiltrates was also higher in the tumor margin. In extrahepatic cholangiocarcinoma, there was a higher density of T cell subsets in the tumor core and regulatory T cells in all regions. A high density of FoxP3(-) CD4(+) helper T cells in the tumor margin showed a trend toward better progression-free survival (PFS) (p=0.092) and significantly better overall survival (OS) (p=0.012). In multivariate analyses, a high density of FoxP3(-) CD4(+) helper T cells in the tumor margin was independently associated with favorable PFS and OS. Conclusion The tumor margin is the major site for the active infiltration of T cell subsets with higher levels of LAG3 and TIM3 expression in BTC. The density of tumor margin-infiltrating FoxP3(-) CD4(+) helper T cells may be associated with clinical outcomes in BTC patients treated with gemcitabine plus cisplatin