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Cancer-associated fibroblasts (CAFs) reside within the tumor microenvironment, facilitating cancer progression and metastasis via direct and indirect interactions with cancer cells and other stromal cell types. CAFs are composed of heterogeneous subpopulations of activated fibroblasts, including myofibroblastic, inflammatory, and immunosuppressive CAFs. In this study, we sought to identify subpopulations of CAFs isolated from human lung adenocarcinomas and describe their transcriptomic and functional characteristics through single-cell RNA sequencing (scRNA-seq) and subsequent bioinformatics analyses. Cell trajectory analysis of combined total and THY1 + CAFs revealed two branching points with five distinct branches. Based on Gene Ontology analysis, we denoted Branch 1 as “immunosuppressive”, Branch 2 as “neoantigen presenting”, Branch 4 as “myofibroblastic”, and Branch 5 as “proliferative” CAFs. We selected representative branch-specific markers and measured their expression levels in total and THY1 + CAFs. We also investigated the effects of these markers on CAF activity under coculture with lung cancer cells. This study describes novel subpopulations of CAFs in lung adenocarcinoma, highlighting their potential value as therapeutic targets.

miR-769-3p expression is suppressed in the stromal subtype of head and neck squamous cell carcinoma (HNSCC); however, its role in stromal HNSCC has not been fully elucidated. To investigate the biological relevance of miR-769-3p in the stromal phenotype, we established oral squamous cell cancer (OSCC) cell lines, namely CAL27, HSC3, and YD8, overexpressing miR-769-3p. miR-769-3p expression was positively and negatively correlated with interferon-gamma-related genes and MYC target gene sets, respectively. miR-769-3p decreased OSCC cell migration and invasion as well as mesenchymal marker expression and increased epithelial marker expression. Moreover, miR-769-3p enhanced OSCC cell sensitivity to 5-fluorouracil. High miR-769-3p expression was associated with good prognosis of HNSCC patients. Collectively, these results suggest that miR-769-3p suppression enhances stromal gene expression and promotes the epithelial-to-mesenchymal transition. Therefore, miR-769-3p may be a potential biomarker of the miRNA phenotype in OSCC patients.

Purpose Isoform 2 of tight junction protein claudin-18 (CLDN18.2) is a potential target for gastric cancer treatment. A treatment targeting CLDN18.2 has shown promising results in gastric cancer. We investigated the clinical significance of CLDN18.2 and other cell-adherens junction molecules (Rho GTPase-activating protein [RhoGAP] and E-cadherin) in metastatic diffuse-type gastric cancer (mDGC). Materials and Methods We evaluated CLDN18.2, RhoGAP, and E-cadherin expression using two-plex immunofluorescence and quantitative data analysis of H-scores of 77 consecutive mDGC patients who received first-line platinum-based chemotherapy between March 2015 and February 2017. Results CLDN18.2 and E-cadherin expression was significantly lower in patients with peritoneal metastasis (PM) than those without PM at the time of diagnosis (P=0.010 and 0.013, respectively), whereas it was significantly higher in patients who never developed PM from diagnosis to death than in those who did (P=0.001 and 0.003, respectively). Meanwhile, CLDN18.2 and E-cadherin expression levels were significantly higher in patients with bone metastasis than in those without bone metastasis (P=0.010 and 0.001, respectively). Moreover, we identified a positive correlation between the expression of CLDN18.2 and E-cadherin (P

Numerous long non-coding RNAs (lncRNAs) are differentially expressed in cancer cells compared with normal cells and are involved in tumor progression and metastasis. Metastasis is initiated by the epithelial-to-mesenchymal transition (EMT) process, which can also be regulated by lncRNAs. Given that ZEB1 is an important transcription factor inducing EMT, we screened lncRNAs controlled by ZEB1 using RNA sequencing in murine lung adenocarcinoma cells. Among several lncRNAs regulated by ZEB1, we selected lnc-Nr2f1. Lnc-Nr2f1 is upregulated by ZEB1 and TGF-β, a potent EMT signal. Growth, migration, and invasion of lung adenocarcinoma cells were decreased after lnc-Nr2f1 knockdown and increased after lnc-Nr2f1 overexpression. Interestingly, lnc-Nr2f1 was transcriptionally controlled by NR2F1, a transcription factor that is transcribed in the antisense direction. NR2F1 was also upregulated and positively correlated with ZEB1, forming a ZEB1/NR2F1/lnc-Nr2f1 axis. Lnc-Nr2f1, in turn, promoted Twist2 transcription through direct binding to its genomic DNA region. Collectively, lnc-Nr2f1 was upregulated by ZEB1 and NR2F1, and promoted migration and invasion of lung adenocarcinoma cells via TWIST2 regulation.

Vaccination with an adenoviral vector vaccine against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) can result in the rare development of thrombosis with thrombocytopenia mediated by platelet-activating antibodies against platelet factor 4 (PF4). This is a life-threating condition that may be accompanied by bleeding due to thrombocytopenia with thrombosis of the cerebral venous sinus or splanchnic vein. Herein, we describe the first fatal case of thrombosis with thrombocytopenia syndrome in Korea, presenting with intracranial hemorrhage caused by cerebral venous sinus thrombosis. A 33-year-old Korean man received the first dose of the ChAdOx1 nCoV-19 vaccination. He developed severe headache with vomiting 9 days after the vaccination. Twelve days after vaccination, he was admitted to the hospital with neurological symptoms and was diagnosed with cerebral venous sinus thrombosis, which was accompanied by intracranial hemorrhage. Thrombocytopenia and D-dimer elevation were observed, and the result of the PF4 enzyme-linked immunosorbent assay antibody test was reported to be strongly positive. Despite intensive treatment, including intravenous immunoglobulin injection and endovascular mechanical thrombectomy, the patient died 19 days after vaccination. Physicians need to be aware of thrombosis with thrombocytopenia syndrome (TTS) in adenoviral vector-vaccinated patients. Endovascular mechanical thrombectomy might be a useful therapeutic option for the treatment of TTS with cerebral venous sinus thrombosis., Graphical Abstract

The role of β-catenin and Dickkopf-1 (DKK1) is dependent on the specific immunobiology of T cell inflammation in biliary tract cancer (BTC). We aimed to analyze the role of DKK1 or β-catenin as a prognostic factor in BTC, and determine the clinical associations of ß-catenin and DKK1 with CD8 + tumor-infiltrating lymphocytes (TIL). We used data from The Cancer Genome Atlas Research Network and the clinicopathological data of 145 patients with BTC who had undergone primary radical resection between 2006 and 2016. CD8 + TIL expression was a significant predictor of favorable overall survival (OS) and relapse-free survival (RFS) (median OS, 34.9 months in high-TIL, 16.7 months in low-TIL, P

ObjectiveThe accurate estimation of expected survival in terminal cancer patients is important. The palliative performance scale (PPS) is an important factor in predicting survival of hospice patients. The purpose of this study was to examine how initial status of PPS and changes in PPS affect the survival of hospice patients in Korea.MethodWe retrospectively examined 315 patients who were admitted to our hospice unit between January 2017 and December 2018. The patients were divided based on the PPS of ≥50% (group A) and ≤40% (group B). We performed survival analysis for factors associated with the length of survival (LOS) in group A. Based on the hospice team's weekly evaluation of PPS, we examined the effect of initial levels and changes in group A on the prognosis of patients who survived for 2 weeks or more.ResultsAt the time of admission to hospice, 265 (84.1%) patients were PPS ≥50%, and 50 (15.9%) were PPS ≤40%. The median LOS of PPS ≥50% and PPS ≤40% were 15 (2–158 days) and 9 (2–43 days), respectively. Male, gastrointestinal cancer, and lower initial PPS all predicted poor prognosis in group A. Male, gastrointestinal cancer, and a PPS change of 10% or greater, compared with initial status 1 week and 2 weeks of hospitalization, were all predictors of poor prognosis in group A patients who survived for 2 weeks or longer.Significance of resultsOur research demonstrates the significance of PPS change at 1 week and 2 weeks, suggesting the importance of evaluating not only initial PPS but also change in PPS.

Background Small-cell lung cancer (SCLC) is a highly proliferative, rapidly growing tumor with a poor prognosis, even in cases of limited disease (LD). Timely and accurate high-intensity therapy is necessary. For concurrent chemoradiotherapy (CCRT), etoposide/platinum (EP)-based regimens are recommended, although irinotecan/platinum (IP)-based regimens are also effective with radiotherapy. This large-scale, retrospective, nationwide cohort study aimed to analyze the efficacy of CCRT in patients with LD-SCLC. Methods Population data registered between January 2008 and December 2018 was extracted from the Health Insurance Review and Assessment Service of Korea database. Survival outcomes of 4446 LD-SCLC patients who received CCRT were analyzed. Results Patients who received EP-CCRT (n = 4187) showed better time to first subsequent therapy (TFST: 11.2 months) and overall survival (OS: 22.2 months) than those who received IP-CCRT (n = 259; TFST: 9.6 months, P = 0.0477; OS: 16.4 months, P n = 925; OS: 9.1 months) provided a better survival benefit than single-agent chemotherapy (n = 815; OS: 7.5 months). IP-based chemotherapy resulted in better OS (9.6 months) than EP-based chemotherapy (7.1 months, P = 0.017) in platinum-resistant relapsed patients; the opposite was observed for platinum-sensitive relapsed patients (OS: EP, 17.2 months; IP, 6.6 months; P Conclusion In the Korean population, the effects of EP-CCRT on OS and TFST are significantly more favorable than those of IP-CCRT.

Background Immune checkpoint blockades (ICBs) are characterized by a durable clinical response and better tolerability in patients with a variety of advanced solid tumors. However, we not infrequently encounter patients with hyperprogressive disease (HPD) exhibiting paradoxically accelerated tumor growth with poor clinical outcomes. This study aimed to investigate implications of clinical factors and immune cell composition on different tumor responses to immunotherapy in patients with non-small cell lung cancer (NSCLC). Methods This study evaluated 231 NSCLC patients receiving ICBs between January 2014 and May 2018. HPD was defined as a > 2-fold tumor growth kinetics ratio during ICB therapy and time-to-treatment failure of ≤2 months. We analyzed clinical data, imaging studies, periodic serologic indexes, and immune cell compositions in tumors and stromata using multiplex immunohistochemistry. Results Of 231 NSCLC patients, PR/CR and SD were observed in 50 (21.6%) and 79 (34.2%) patients, respectively and 26 (11.3%) patients met the criteria for HPD. Median overall survival in poor response groups (HPD and non-HPD PD) was extremely shorter than disease-controlled group (SD and PR/CR) (5.5 and 6.1 months vs. 16.2 and 18.3 months, respectively, P = 0.000). In multivariate analysis, HPD were significantly associated with heavy smoker (p = 0.0072), PD-L1 expression ≤1% (p = 0.0355), and number of metastatic site ≥3 (p = 0.0297). Among the serologic indexes including NLR, PLR, CAR, and LDH, only CAR had constantly significant correlations with HPD at the beginning of prior treatment and immunotherapy, and at the 1st tumor assessment. The number of CD4+ effector T cells and CD8+ cytotoxic T cells, and CD8+/PD-1+ tumor-infiltrating lymphocytes (TIL) tended to be smaller, especially in stromata of HPD group. More M2-type macrophages expressing CD14, CD68 and CD163 in the stromal area and markedly fewer CD56+ NK cells in the intratumoral area were observed in HPD group. Conclusions Our study suggests that not only clinical factors including heavy smoker, very low PD-L1 expression, multiple metastasis, and CAR index, but also fewer CD8+/PD-1+ TIL and more M2 macrophages in the tumor microenvironment are significantly associated with the occurrence of HPD in the patients with advanced/metastatic NSCLC receiving immunotherapy.

Background Immune checkpoint blockers (ICBs) are characterized by a durable clinical response and better tolerability in patients with a variety of advanced solid tumors. However, we not infrequently encounter patients with hyperprogressive disease (HPD) exhibiting paradoxically accelerated tumor growth with poor outcomes. This study aimed to determine differences in factors among patients with non-small cell lung cancer (NSCLC) displaying different tumor responses to immunotherapy. Methods This study evaluated 231 NSCLC patients receiving ICBs between January 2014 and May 2018. HPD was defined as a > 2-fold tumor growth kinetics ratio during ICB therapy and time-to-treatment failure of ≤ 2 months. We analyzed clinical data, imaging studies, periodic serologic indexes, and immune cell compositions in tumors and stromata using multiplex immunohistochemistry. Results Twenty-six patients (11.3%) met the HPD criteria. HPD was more frequent in patients with oncogenic driver mutations, ≥ 3 metastatic sites, ≥ 4 prior systemic treatments, and low PD-L1 expression (

Epidermal growth factor receptor (EGFR) mutation testing is essential for individualized treatment using tyrosine kinase inhibitors. We evaluated two EGFR mutation tests, cobas v2 and PANAMutyper, for detection of EGFR activating mutations Ex19del, L858R, and T790M in tumor tissue and plasma from 244 non-small cell lung cancer (NSCLC) patients. The Kappa coefficient (95% CI) between the tests was 0.82 (0.74−0.92) in tumor samples (suggesting almost perfect agreement) and 0.69 (0.54−0.84) in plasma (suggesting substantial agreement). In plasma samples, both tests showed low to moderate sensitivity depending on disease stage but high diagnostic precision (86%−100%) in all disease stages (sensitivity: percentage of mutations in tumors that are also detected in plasma; precision: percentage of mutations in plasma which are also detected in tumors). Among the 244 patients, those previously diagnosed as T790M carriers who received osimertinib treatment showed dramatically better clinical outcomes than T790M carriers without osimertinib treatment. Taken together, our study supports interchangeable use of cobas v2 and PANAMutyper in tumor and plasma EGFR testing. Both tests have high diagnostic precision in plasma but are particularly valuable in late-stage disease. Our clinical data in T790M carriers strongly support the clinical benefits of osimertinib treatment guided by both EGFR mutation tests.

Cirrhosis can occur with the development of portal vein thrombosis (PVT). PVT may aggravate portal hypertension, and it can lead to hepatic decompensation. The international guideline recommends for anticoagulation treatment to be maintained for at least 3 months in all patients with acute PVT. Low-molecular-weight-heparin and changing to warfarin is the usual anticoagulation treatment. However, warfarin therapy is problematic due to a narrow therapeutic window and the requirement for frequent dose adjustment, which has prompted the development of novel oral anticoagulants for overcoming these problems. We report a 63-year-old female who experienced complete resolution of recurrent acute PVT in liver cirrhosis after treatment with rivaroxaban.

Afatinib is an oral tyrosine kinase inhibitor (TKI) that inhibit Endothelial Growth Factor Receptor (EGFR), Human Epidermal Growth Factor Receptor 2 (HER2), and HER4. The common side effects of EGFR TKI are rash, acne, diarrhea, stomatitis, pruritus, nausea, and loss of appetite. Drug induced pneumonitis is the less common adverse effects of EGFR TKI. Afatinib, 2nd generation EGFR TKI is anticipated to overcome drug resistance from 1st generation EGFR TKI according to preclinical study, and several studies are being conducted to compare clinical efficacy between 1st and 2nd EGFR TKI. Several cases of rug induced acute fatal pneumonitis were reported after use of erlotinib or gefitinib. However, a case of acute fatal pneumonitis associated with afatinib was note reported except drug induced pneumonitis in other clinical study. Here, we present a cases of acute severe pneumonitis related with afatinib in metastatic lung adenocarcinoma with literature review.

Simple Summary In this study, Sel-CapTM, a next-generation sequencing (NGS)-based genotyping platform, showed high sensitivity for detection of epidermal growth factor receptor (EGFR) gene mutations in plasma samples collected from 185 patients with non-small cell lung cancer (NSCLC). In the early-stage NSCLC, Sel-Cap liquid biopsy was able to detect more than half the EGFR mutations, which were detected in tumor tissue (sensitivity: 50% and 78% for Ex19del and L858R respectively, with tumor results as the references), while the conventional NGS could not detect any. Sel-Cap liquid biopsy was particularly sensitive for resistant mutation T790M (sensitivity: 88%). In addition, we conducted a retrospective study to monitor T790M using Sel-Cap in 34 patients who progressed on first-line tyrosine kinase inhibitors (EGFR-TKIs). The study suggested that the first appearance of T790M in plasma, ranging from at treatment baseline to over three years post-EGFR-TKI initiation, may be useful for prediction of disease progression (around 5 months in advance). Abstract Sel-CapTM, a digital enrichment next-generation sequencing (NGS)-based cancer panel, was assessed for detection of epidermal growth factor receptor (EGFR) gene mutations in plasma for non-small cell lung cancer (NSCLC), and for application in monitoring EGFR resistance mutation T790M in plasma following first-line EGFR-tyrosine kinase inhibitor (EGFR-TKI) treatment. Using Sel-Cap, we genotyped plasma samples collected from 185 patients for mutations Ex19del, L858R, and T790M, and compared results to those of PNAclampTM tumor biopsy (reference method, a peptide nucleic acid-mediated polymerase chain reaction clamping) and two other NGS liquid biopsies. Over two-thirds of activating mutations (Ex19del and L858R), previously confirmed by PNAclamp, were detected by Sel-Cap, which is 4–5 times more sensitive than NGS liquid biopsy. Sel-Cap showed particularly high sensitivity for T790M (88%) and for early-stage plasma samples. The relationship between initial T790M detection in plasma and progression-free survival (PFS) following first-line EGFR-TKIs was evaluated in 34 patients. Patients with T790M detected at treatment initiation (±3 months) had significantly shorter PFS than patients where T790M was first detected >3 months post treatment initiation (median PFS: 5.9 vs. 26.5 months; p < 0.0001). However, time from T790M detection to disease progression was not significantly different between the two groups (median around 5 months). In conclusion, Sel-Cap is a highly sensitive platform for EGFR mutations in plasma, and the timing of the first appearance of T790M in plasma, determined via highly sensitive liquid biopsies, may be useful for prediction of disease progression of NSCLC, around 5 months in advance.