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Abstract Progesterone (P4) is required for the preparation of the endometrium for a successful pregnancy. P4 resistance is a leading cause of the pathogenesis of endometrial disorders like endometriosis, often leading to infertility; however, the underlying epigenetic cause remains unclear. Here we demonstrate that CFP1, a regulator of H3K4me3, is required for maintaining epigenetic landscapes of P4-progesterone receptor (PGR) signaling networks in the mouse uterus. Cfp1 f/f;Pgr-Cre (Cfp1 d/d) mice showed impaired P4 responses, leading to complete failure of embryo implantation. mRNA and chromatin immunoprecipitation sequencing analyses showed that CFP1 regulates uterine mRNA profiles not only in H3K4me3-dependent but also in H3K4me3-independent manners. CFP1 directly regulates important P4 response genes, including Gata2, Sox17, and Ihh, which activate smoothened signaling pathway in the uterus. In a mouse model of endometriosis, Cfp1 d/d ectopic lesions showed P4 resistance, which was rescued by a smoothened agonist. In human endometriosis, CFP1 was significantly downregulated, and expression levels between CFP1 and these P4 targets are positively related regardless of PGR levels. In brief, our study provides that CFP1 intervenes in the P4-epigenome-transcriptome networks for uterine receptivity for embryo implantation and the pathogenesis of endometriosis.

Abstract Background Recently, we demonstrated that estrogen (E2) induces early growth response 1 (Egr1) to mediate its actions on the uterine epithelium by controlling progesterone receptor signaling for successful embryo implantation. EGR1 is a transcription factor that regulates the spectrum of target genes in many different tissues, including the uterus. E2-induced EGR1 regulates a set of genes involved in epithelial cell remodeling during embryo implantation in the uterus. However, only few target genes of EGR1 in the uterus have been identified. Result The expression of ADAM metallopeptidase with thrombospondin type 1 motif 1 (Adamts-1) was significantly downregulated in the uteri of E2-treated ovariectomized (OVX) Egr1(−/−) mice. Immunostaining of ADAMTS-1 revealed its exclusive expression in the uterine epithelium of OVX wild-type but not Egr1(−/−) mice treated with E2. The expression profiles of Adamts-1 and Egr1 were similar in the uteri of E2-treated OVX mice at various time points tested. Pre-treatment with ICI 182, 780, a nuclear estrogen receptor (ER) antagonist, effectively inhibited the E2-dependent induction of Egr1 and Adamts-1. Pharmacologic inhibition of E2-induced ERK1/2 or p38 phosphorylation interfered with the induction of EGR1 and ADAMTS-1. Furthermore, ADAMTS-1, as well as EGR1, was induced in stroma cells surrounding the implanting blastocyst during embryo implantation. Transient transfection with EGR1 expression vectors significantly induced the expression of ADAMTS-1. Luciferase activity of the Adamts-1 promoter containing EGR1 binding sites (EBSs) was increased by EGR1 in a dose-dependent manner, suggesting functional regulation of Adamts-1 transcription by EGR1. Site-directed mutagenesis of EBS on the Adamts-1 promoter demonstrated that EGR1 directly binds to the EBS at -1151/-1134 among four putative EBSs. Conclusions Collectively, we have demonstrated that Adamts-1 is a novel target gene of E2-ER-MAPK-EGR1, which is critical for embryo implantation in the mouse uterus during early pregnancy.

Abstract Background Aberration of estrogen (E2) and/or progesterone (P4) signaling pathways affects expression of their target genes, which may lead to failure of embryo implantation and following pregnancy. Although many target genes of progesterone receptors (PRs) have been identified in uterine stroma, only a few PR targets have been reported in the epithelium. Secretory phospholipase A2-(PLA2)-X, a member of the PLA2 family that releases arachidonic acids for the synthesis of prostaglandins that are important for embryo implantation, is dysregulated in the endometrium of patients suffering from repeated implantation failure. However, it is not clear whether sPLA2-X is directly regulated by ovarian steroid hormones for embryo implantation in the uterus. Result P4 induced the Pla2g10 encoding of secretory PLA2-X in the apical region of uterine LE of ovariectomized mice via PR in both time- and dose-dependent manners, whereas E2 significantly inhibited it. This finding is consistent with the higher expression of Pla2g10 at the diestrus stage, when P4 is elevated during the estrous cycle, and at P4-treated delayed implantation. The level of Pla2g10 on day 4 of pregnancy (day 4) was dramatically decreased on day 5, when PRs are absent in the LE. Luciferase assays of mutagenesis in uterine epithelial cells demonstrated that four putative PR response elements in a Pla2g10 promoter region are transcriptionally active for Pla2g10. Intrauterine delivery of small interfering RNA for Pla2g10 on day 3 significantly reduced the number of implantation sites, reinforcing the critical function(s) of Pla2g10 for uterine receptivity in mice. Conclusions Pla2g10 is a novel PR target gene whose expression is exclusively localized in the apical region of the uterine LE for uterine receptivity for embryo implantation in mice.

Cancer: Mediating metastatic migration A molecular mechanism underlying cell movement may contribute to the aggressive migration of metastatic tumor cells. A team led by Ki-Duk Song at Chonbuk National University, Jeonju-si, and Joong-Kook Choi at Chungbuk National University, Cheongju in South Korea investigated the function of a protein called p21-activated kinase 1 (PAK1). PAK1 is known to contribute to the reorganization of cellular structure. The researchers determined that it directly interacts with molecular machinery that controls the storage and release of stockpiled calcium ions at the periphery of the cell where migration takes place. These ions play an important role in enabling cell movement and attachment, and the researchers showed that they could disrupt cellular calcium ion accumulation by switching off the gene encoding PAK1. They now aim to investigate how this mechanism contributes to cancer cell migration.

Sparkling wine has widely been consumed because of its high added value. Sparkling wine is mainly produced using grape, however different fruits have been studied to ferment the wine. The objective of this study was to determine the quality characteristics and antioxidant potential of sparkling wine produced by using ripe persimmon with three strains of Saccharomyces, that is, S. bayanus, S. carlsbergensis, and S. cerevisiae. Persimmon sparkling wine samples were prepared by fermenting different amounts of persimmon fruit and water. Alcohol content was significantly varied in base wine with different proportion of persimmon fruit and water. Antioxidant potential in term of DPPH radical scavenging potential of the base wine prepared with 4:1 ratio of persimmon and water was significantly high. However, the tannin content of the wine samples was not significantly affected. Sensory characteristics in term of full-body was also significantly high for the wine prepared with 4:1 ratio of persimmon and water. Inoculation method also affected the ethanol content of persimmon sparkling wine. Results of this experiment showed that good quality persimmon sparkling wine could be prepared by fermenting 4:1 ratio of ripe persimmon and water during first fermentation.

Objective: To investigate the physicochemical properties of unripe peach-Prunus persica cv. Mibaekdo (Mibaekdo) and Prunus persica cv. Nagasawa Hakuho (Nagasawa Hakuho) as an alternative to food supplement while Japanese apricot (Prunus mume cv. Backaha) (Backaha) was used as a control sample. Methods: The unripe fruits were analyzed for soluble solid (°Brix), titratable acidity, pH, total polyphenol content, 1,1-diphenyl-2-picrylhydrazyl (DPPH) radical scavenging activity, amygdalin content, free amino acid content, organic acid content, free sugar content, and α-amylase activities. Results: Total polyphenol content of unripe peach ranged between 137.27-151.64 μg/g whereas that of apricot was 160.73 μg/g. DPPH radical scavenging activities of Backaha was the highest (89.16%) followed by Mibaekdo (85.05%) and Nagasawa Hakuho (41.50%). The highest amount of oxalic acid (612.8 mg/100 g) was observed in Mibaekdo while that of Nagasawa Hakuho and Backaha were (184.6±18.1) and (334.8±16.1) mg/100 g, respectively. Amygdalin contents of Mibaekdo, Nagasawa Hakuho and Backaha were 486.61, 548.60 and 174.28 μg/g, respectively. Conclusions: The results suggest that the unripe fruit of peach has a significant biochemical potential of using as a food supplement with potential health benefit for human health.

Spartalizumab (PDR001) is a humanized IgG4 monoclonal antibody targeting programmed cell death protein 1 (PD-1). We conducted a single-arm, phase 2 trial to investigate the efficacy and safety of spartalizumab in patients with refractory esophageal squamous cell carcinoma (ESCC). Patients with histologically confirmed ESCC who experienced disease progression after platinum-based chemotherapy received 300 mg of intravenous spartalizumab every three weeks until disease progression or occurrence of unacceptable toxicity. The primary endpoint was centrally assessed objective response according to the Response Evaluation Criteria in Solid Tumors, version 1.1. Adverse events were closely monitored throughout the study. From March 2020 through April 2021, 44 patients with ESCC were enrolled. Of the 44 patients, the objective response rate was 20.5% (95% confidence interval: 8.5–32.4). With a median follow-up of 10.9 months, median progression-free survival and overall survival were 3.2 months and 11.2 months, respectively. In addition, the median duration of response was 24.7 months. The most common grade 3 or 4 adverse event was grade 3 dysphagia (eight [18%] patients). Biomarker analyses explored programmed cell death ligand 1 and CD20 as potential predictive markers for PD-1 blockade. Spartalizumab showed promising activity with a manageable safety profile, indicating its potential as a new treatment option for patients with refractory ESCC.Trial registration The trial was registered at ClinicalTrials.gov under the identifier NCT03785496.

Intimate two-way interactions between the implantation-competent blastocyst and receptive uterus are prerequisite for successful embryo implantation. In humans, recurrent/repeated implantation failure (RIF) may occur due to altered uterine receptivity with aberrant gene expression in the endometrium as well as genetic defects in embryos. Several studies have been performed to understand dynamic changes of uterine transcriptome during menstrual cycles in humans. However, uterine transcriptome of the patients with RIF has not been clearly investigated yet. Here we show that several signaling pathways as well as many genes and microRNAs are dysregulated in the endometrium of patients with RIF (RIFE). Whereas unsupervised hierarchical clustering showed that overall mRNA and microRNA profiles of RIFE were similar to those of endometria of healthy women, many genes were significantly dysregulated in RIFE (cut off at 1.5 fold change). The majority (~75%) of differentially expressed genes in RIFE including S100 calcium binding protein P (S100P), Chemokine (C-X-C motif) ligand 13 (CXCL13) and SIX homeobox 1 (SIX1) were down-regulated, suggesting that reduced uterine expression of these genes is associated with RIF. Gene Set Enrichment analyses (GSEA) for mRNA microarrays revealed that various signaling pathways including Leukemia inhibitory factor (LIF) signaling and a P4 response were dysregulated in RIFE although expression levels of Estrogen receptor α (ERα) and Progesterone receptor (PR) were not significantly altered in RIFE. Furthermore, expression and phosphorylation of Signal transducer and activator of transcription 3 (STAT3) are reduced and a gene set associated with Janus kinase (JAK)-STAT signaling pathway is systemically down-regulated in these patients. Pairwise analyses of microRNA arrays with prediction of dysregulated microRNAs based on mRNA expression datasets demonstrated that 6 microRNAs are aberrantly regulated in RIFE. Collectively, we here suggest that dysregulation of several major signaling pathways and genes critical for uterine biology and embryo implantation may lead to uterine abnormalities in patients with RIF.

BackgroundSinonasal squamous cell carcinoma (SCC) is a rare disease entity, comprising less than 5% of malignancies of the head and neck. While surgery is the primary treatment approach, neoadjuvant and adjuvant therapies play crucial roles in enhancing the prognosis of patients undergoing treatment with the goal of cure. In this study, we aimed to explore the treatment outcomes of neoadjuvant chemotherapy (NAC) in patients with locally advanced sinonasal SCC.MethodsMedical records of patients diagnosed of locally advanced (cT3-4b, N0-3) sinonasal SCC treated with a definitive aim between January 2005 and March 2023 were retrospectively reviewed. Patients were categorized into the following groups based on the initial treatment: NAC followed by surgery, NAC followed by concurrent chemoradiotherapy (CCRT), definitive CCRT, or upfront surgery. Initial treatment plan was decided by a multidisciplinary team. Primary endpoint was overall survival (OS) and objective response rate, and secondary endpoints were progression free survival (PFS), cumulative incidence of local and distant failures, and treatment-related toxicity. The treatment response was assessed according to the RECIST criteria.ResultsTotal 126 patients were included, and the median follow-up period was 25.6 months. The objective response rate to NAC was 48.2%. The subsequent resection rate was 70%, 42.9%, and 16.7% for patients with stage T3, T4a, and T4b disease, respectively. Two-year progression-free survival did not differ significantly between the NAC followed by surgery and upfront surgery groups (53.6% vs. 60.6%, P = 0.615) or between the NAC followed by CCRT and definitive CCRT groups (26.7% vs. 37.4%, P = 0.506).ConclusionNAC may be a valuable treatment option for patients with locally advanced sinonasal SCC, as it provides an opportunity for curative surgery and exhibits non-inferior oncological outcomes compared with upfront definitive local treatments.

Abstract Background Next-generation sequencing (NGS) has been introduced to many Korean institutions to support molecular diagnostics in cancer since 2017, when it became eligible for reimbursement by the National Health Insurance Service. However, the uptake of molecularly guided treatment (MGT) based on NGS results has been limited because of stringent regulations regarding prescriptions outside of approved indications, a lack of clinical trial opportunities, and limited access to molecular tumor boards (MTB) at most institutions. The KOSMOS-II study was designed to demonstrate the feasibility and effectiveness of MGT, informed by MTBs, using a nationwide precision medicine platform. Methods The KOSMOS-II trial is a large-scale nationwide master observational study. It involves a framework for screening patients with metastatic solid tumors for actionable genetic alterations based on local NGS testing. It recommends MGT through a remote and centralized MTB meeting held biweekly. MGT can include one of the following options: Tier 1, the therapeutic use of investigational drugs targeting genetic alterations such as ALK, EGFR, ERBB2, BRAF, FH, ROS1, and RET, or those with high tumor mutational burden; Tier 2, comprising drugs with approved indications or those permitted for treatment outside of the indications approved by the Health Insurance Review and Assessment Service of Korea; Tier 3, involving clinical trials matching the genetic alterations recommended by the MTB. Given the anticipated proportion of patients receiving MGT in the range of 50% ± 3.25%, this study aims to enroll 1,000 patients. Patients must have progressed to one or more lines of therapy and undergone NGS before enrollment. Discussion This pragmatic master protocol provides a mass-screening platform for rare genetic alterations and high-quality real-world data. Collateral clinical trials, translational studies, and clinico-genomic databases will contribute to generating evidence for drug repositioning and the development of new biomarkers. Trial registration NCT05525858.

Background Oropharyngeal squamous cell carcinoma (OPSCC) induced by human papillomavirus (HPV-positive) is associated with better clinical outcomes than HPV-negative OPSCC. However, the clinical benefits of immunotherapy in patients with HPV-positive OPSCC remain unclear.Methods To identify the cellular and molecular factors that limited the benefits associated with HPV in OPSCC immunotherapy, we performed single-cell RNA (n=20) and T-cell receptor sequencing (n=10) analyses of tonsil or base of tongue tumor biopsies prior to immunotherapy. Primary findings from our single-cell analysis were confirmed through immunofluorescence experiments, and secondary validation analysis were performed via publicly available transcriptomics data sets.Results We found significantly higher transcriptional diversity of malignant cells among non-responders to immunotherapy, regardless of HPV infection status. We also observed a significantly larger proportion of CD4+ follicular helper T cells (Tfh) in HPV-positive tumors, potentially due to enhanced Tfh differentiation. Most importantly, CD8+ resident memory T cells (Trm) with elevated KLRB1 (encoding CD161) expression showed an association with dampened antitumor activity in patients with HPV-positive OPSCC, which may explain their heterogeneous clinical outcomes. Notably, all HPV-positive patients, whose Trm presented elevated KLRB1 levels, showed low expression of CLEC2D (encoding the CD161 ligand) in B cells, which may reduce tertiary lymphoid structure activity. Immunofluorescence of HPV-positive tumors treated with immune checkpoint blockade showed an inverse correlation between the density of CD161+ Trm and changes in tumor size.Conclusions We found that CD161+ Trm counteracts clinical benefits associated with HPV in OPSCC immunotherapy. This suggests that targeted inhibition of CD161 in Trm could enhance the efficacy of immunotherapy in HPV-positive oropharyngeal cancers.Trial registration number NCT03737968.

Abstract Background Advanced or metastatic esophageal squamous cell carcinoma (ESCC) is associated with poor prognosis; new first‐line systemic treatment options are needed. Combining immuno‐oncology therapies with standard chemotherapy may represent a promising approach for the treatment of solid tumors. Results from a Phase Ib study evaluating durvalumab with tremelimumab and chemotherapy in patients with advanced or metastatic ESCC are reported. Methods Adults with advanced or metastatic ESCC who were candidates for first‐line platinum‐based chemotherapy received durvalumab 1500 mg (Day 1), tremelimumab 75 mg (Day 1), cisplatin 80 mg/m2 (Day 1) and 5‐fluorouracil (5‐FU) 800 mg/m2 (Days 1–5) in 28‐day cycles until disease progression or discontinuation due to toxicity. The study consisted of safety run‐in (Part A) and expansion (Part B) periods. The primary endpoint was safety. Antitumor activity was an exploratory endpoint. Results Sixteen patients were enrolled, 6 in Part A and 10 in Part B, and received a median of 4.0 treatment cycles. All patients were Asian; median age was 65.0 years. All patients experienced adverse events (AEs) related to cisplatin and 5‐FU, and 8 (50.0%) patients experienced AEs related to durvalumab and tremelimumab. Grade ≥3 treatment‐related AEs occurred in 7 (43.8%) patients. There were no deaths associated with AEs. Six (37.5%) patients achieved an objective response. Median progression‐free survival was 3.75 months, and median overall survival was 9.69 months. Conclusions Durvalumab with tremelimumab and chemotherapy demonstrated manageable safety and antitumor activity in patients with advanced or metastatic ESCC, warranting further investigation in randomized trials. Registered with ClinicalTrials.gov: NCT02658214.

Abstract Background ONO‐4538‐52/TASUKI‐52 was performed in Japan, Korea, and Taiwan to determine the oncological effectiveness and safety of combining nivolumab or placebo with bevacizumab plus platinum chemotherapy for the initial (first‐line) treatment of patients with advanced non‐squamous non‐small cell lung cancer (nsNSCLC). At the interim analysis (minimum follow‐up, 7.4 months), the independent radiology review committee‐assessed progression‐free survival was significantly longer in the nivolumab arm, but overall survival (OS) data were immature. Methods Here, we present the updated OS data. Patients with treatment‐naïve stage IIIB/IV or recurrent nsNSCLC without driver mutations in ALK, EGFR, or ROS1, were randomized 1:1 to receive either nivolumab or placebo. Patients in both arms received paclitaxel, carboplatin, and bevacizumab, administered 3‐weekly for a maximum of 6 cycles. Nivolumab/placebo and bevacizumab were subsequently continued until disease progression or unacceptable toxicity. Results Overall, 550 patients were randomized. At the time of the analysis (minimum follow‐up: 19.4 months), the median OS was longer in the nivolumab arm than in the placebo arm (30.8 vs. 24.7 months; hazard ratio 0.74, 95% confidence interval 0.58–0.94). The 12‐month OS rates were 81.3% vs. 76.3% in the nivolumab vs. placebo arms, respectively. The respective 18‐month OS rates were 69.0% vs. 61.9%. Conclusion Nivolumab plus platinum chemotherapy and bevacizumab demonstrated longer OS vs. the placebo combination. We believe this regimen is viable as a standard, first‐line treatment for patients with advanced nsNSCLC without driver mutations in ALK, EGFR, or ROS1.

Background: The acute palliative care unit (APCU) bridges between active cancer treatment and hospice care. However, no study has proven the efficacy of APCU in Korea. Objective: To evaluate the first-year outcomes of the patients admitted to an APCU at a tertiary hospital in Korea. Design: The APCU admitted 205 patients between April 14, 2014, and April 30, 2015. Of these patients, 57 were evaluable for baseline and one-week follow-up Edmonton Symptom Assessment System (ESAS). Results: Of the 57 participants, 56.1% were male, with a median age of 60 years (range, 52.8?69.5 years). All patients had advanced cancer, and 42 out of 57 had terminal illnesses. The median APCU stay was 14 days (range, 10?17 days). The 42 (73.7%) patients were referred to the APCU after anticancer treatment was completed. Ten (17.5%) patients died during their stay, and 20 (35.1%) were discharged home. Among those who completed the ESAS, there were significant improvements in scores in the following symptoms: fatigue, depression, loss of appetite, and shortness of breath. Physical symptoms (pain, fatigue, nausea, drowsiness, appetite, and shortness of breath) and the total ESAS scores were significantly improved (p?=?0.002 and p?=?0.005, respectively). Each non-medical palliative care program, such as art and music therapy, yoga, foot massage, haircut, and body care, showed no significant differences between the group who received them and those who did not. Conclusion: During the APCU stay, the overall symptoms of inpatients were reduced. A comprehensive and multidisciplinary team approach is essential for patients who need palliative care.

Introduction: In the phase 3 KEYNOTE-604 study (NCT03066778), pembrolizumab plus etoposide and platinum chemotherapy (EP) significantly (p = 0.0023) improved progression-free survival versus placebo plus EP in previously untreated extensive-stage SCLC (ES-SCLC). We present health-related quality of life (HRQoL) results from KEYNOTE-604. Methods: Patients with stage IV SCLC were randomized 1:1 to pembrolizumab 200 mg or placebo every 3 weeks for 35 cycles plus four cycles of EP. Secondary end points included mean change from baseline to week 18 in the European Organisation for Research and Treatment of Cancer Quality-of-Life Questionnaire—Core 30 (QLQ-C30) global health status/quality of life (GHS/QoL) scale and time to deterioration in the composite outcome of cough, chest pain, or dyspnea from QLQ-C30 and QLQ—Lung Cancer Module 13. Two-sided, nominal p values are reported. Results: A total of 439 patients completed at least one QLQ-C30 and QLQ—Lung Cancer Module 13 assessment (pembrolizumab + EP, n = 221; placebo + EP, n = 218). GHS/QoL scores improved from baseline to week 18: least squares mean (95% confidence interval [CI]) changes were 8.7 (5.3–12.1) for pembrolizumab plus EP and 4.2 (0.9–7.5) for placebo plus EP. Between-group differences in least squares mean scores were improved for pembrolizumab plus EP (4.4 [95% CI: 0.2–8.7], p = 0.040]). Median time to deterioration for the composite end point was not reached and 8.7 (95% CI: 5.9–not reached) months, respectively (hazard ratio = 0.80 [95% CI: 0.56–1.14], p = 0.208). Conclusions: First-line pembrolizumab plus EP therapy maintained HRQoL in patients with ES-SCLC and may be associated with greater improvement than placebo plus EP. Together with the efficacy and safety findings in KEYNOTE-604, HRQoL data support the benefit of pembrolizumab in ES-SCLC.

Plasma-based next-generation sequencing (NGS) has demonstrated the potential to guide the personalized treatment of non-small cell lung cancer (NSCLC). Inherent differences in mutational genomic profiles of NSCLC exist between Asian and Western populations. However, the published mutational genomic data of NSCLC has largely focused on Western populations. We retrospectively analyzed results from comprehensive NGS of plasma (Guardant360®) from patients with advanced non-squamous NSCLC, as seen in clinical practice. Tests were ordered between January 2016 and December 2020 in Hong Kong, Korea, Taiwan, Japan and Southeast Asia. The assay identified single-nucleotide variants (SNV), insertions and deletions, and fusions and amplifications in 74 genes. In total, 1608 plasma samples from patients with advanced non-squamous NSCLC were tested. The median turnaround time for test results was 7 days. Of the samples with detectable ctDNA (85.6%), 68.3% had alterations in at least one NCCN-recommended NSCLC biomarker. EGFR driver mutations were most frequent (48.6%), followed by alterations of KRAS (7.9%), ERBB2 (4.1%) and ALK (2.5%). Co-mutations of EGFR and KRAS occurred in 4.7% of samples. KRAS G12C was identified in 18.6% of all samples with KRAS mutations. Common mutations, such as exon 19 deletions and L858R, accounted for 88.4% of EGFR driver mutations. Among the samples with any EGFR driver mutation, T790M was present in 36.9%, including 7.7% with additional alterations associated with osimertinib resistance (MET amplification, C797X). Comprehensive plasma-based NGS provided the timely and clinically informative mutational genomic profiling of advanced non-squamous NSCLC in East Asian patients.

Abstract Clinical benefit of ALK tyrosine kinase inhibitors (ALK‐TKIs) in ALK‐rearranged lung cancer has been limited by the inevitable development of acquired resistance, and bypass‐molecular resistance mechanisms remain poorly understood. We investigated a novel therapeutic target through screening FDA‐approved drugs in ALK‐TKI‐resistant models. Cerivastatin, the rate‐limiting enzyme inhibitor of the mevalonate pathway, showed anti‐cancer activity against ALK‐TKI resistance in vitro/in vivo, accompanied by cytoplasmic retention and subsequent inactivation of transcriptional co‐regulator YAP. The marked induction of YAP‐targeted oncogenes (EGFR, AXL, CYR61, and TGFβR2) in resistant cells was abolished by cerivastatin. YAP silencing suppressed tumor growth in resistant cells, patient‐derived xenografts, and EML4‐ALK transgenic mice, whereas YAP overexpression decreased the responsiveness of parental cells to ALK inhibitor. In matched patient samples before/after ALK inhibitor treatment, nuclear accumulation of YAP was mainly detected in post‐treatment samples. High expression of YAP in pretreatment samples was correlated with poor response to ALK‐TKIs. Our findings highlight a crucial role of YAP in ALK‐TKI resistance and provide a rationale for targeting YAP as a potential treatment option for ALK‐rearranged patients with acquired resistance to ALK inhibitors.

Background EML4-ALK is a distinct molecular entity that is highly sensitive to ALK tyrosine kinase inhibitors (TKIs). Immune checkpoint inhibitors (ICIs) have not proved efficacy in ALK-positive non-small cell lung cancer so far. In this study, we performed a mouse clinical trial using EML4-ALK transgenic mice model to comprehensively investigate immunomodulatory effects of ALK TKI and to investigate the mechanisms of resistance to ICIs.Methods EML4-ALK transgenic mice were randomized to three treatment arms (arm A: antiprogrammed death cell protein-1 (PD-1), arm B: ceritinib, arm C: anti-PD-1 and ceritinib), and tumor response was evaluated using MRI. Progression-free survival and overall survival were measured to compare the efficacy. Flow cytometry, multispectral imaging, whole exome sequencing and RNA sequencing were performed from tumors obtained before and after drug resistance.Results Mouse clinical trial revealed that anti-PD-1 therapy was ineffective, and the efficacy of ceritinib and anti-PD-1 combination was not more effective than ceritinib alone in the first line. Dynamic changes in immune cells and cytokines were observed following each treatment, while changes in T lymphocytes were not prominent. A closer look at the tumor immune microenvironment before and after ceritinib resistance revealed increased regulatory T cells and programmed death-ligand 1 (PD-L1)-expressing cells both in the tumor and the stroma. Despite the increase of PD-L1 expression, these findings were not accompanied by increased effector T cells which mediate antitumor immune responses.Conclusions ALK-positive tumors progressing on ceritinib is not immunogenic enough to respond to immune checkpoint inhibitors.

Purpose This study aimed to determine the role of local ablative radiotherapy (LART) in oligometastatic/oligoprogressive lung adenocarcinoma. Materials and Methods Patients (n=176) with oligometastatic lung adenocarcinoma treated with LART were identified, and those treated with LART at the initial diagnosis of synchronous oligometastatic disease (OMD group) or treated with LART when they presented with repeat oligoprogression (OPD group) were included. Results In the OMD group (n=54), the 1- and 3-year progression-free survival (PFS) were 50.9% and 22.5%, respectively, whereas the 1- and 3-year overall survival in the OPD group were 75.9% and 58.1%, respectively. Forty-one patients (75.9%) received LART at all gross disease sites. Tyrosine kinase inhibitor (TKI) use and all-metastatic site LART were significant predictors of higher PFS (p=0.018 and p=0.046, respectively). In patients treated with TKIs at the time of LART (n=23) and those treated with all-metastatic site LART, the 1-year PFS was 86.7%, while that of patients not treated with all-metastatic site LART was 37.5% (p=0.006). In the OPD group (n=122), 67.2% of the patients (n=82) maintained a systemic therapy regimen after LART. The cumulative incidence of changing systemic therapy was 39.6%, 62.9%, and 78.5% at 6 months, 1 year, and 2 years after LART, respectively. Conclusion Aggressive LART can be an option to improve survival in patients with oligometastatic disease. Patients with synchronous oligometastatic disease receiving TKI and all-metastatic site LART may have improved PFS. In patients with repeat oligoprogression, LART might potentially extend survival by delaying the need to change the systemic treatment regimen. [ABSTRACT FROM AUTHOR]

Purpose Precision oncology approach for recurrent and metastatic head and neck squamous cell carcinoma (HNSCC) is necessary due to its dismal prognosis. We performed a genomic profile-based umbrella trial of patients with platinum-refractory HNSCC (KCSGTRIUMPH). Here, we present an in-depth report of the the nintedanib arm (arm 3) of the current trial. Materials and Methods The TRIUMPH study was a multicenter, open-label, single-arm phase 2 trial, in which patients were assigned to treatment arms based on next-generation sequencing (NGS)-based, matching genomic profiles. Patients whose tumors harbor fibroblast growth factor receptor (FGFR) alteration were enrolled in the nintedanib arm (arm 3) as part of the TRIUMPH study. The primary endpoint was the overall response rate (ORR), and secondary endpoints included overall survival (OS), progression-free survival (PFS), safety, and biomarker analysis. Results Between October 2017 and August 2020, 207 were enrolled in the TRIUMPH study, and eight were enrolled in the nintedanib arm. ORR and disease control rate were 42.9% and 57.1%, respectively. The median PFS was 5.6 months and the median duration of response was 9.1 months. Median OS was 11.1 months. One patient maintained the partial response for 36 months. Overall, the toxicity profiles were manageable. Conclusion Single-agent nintedanib has demonstrated significant efficacy in FGFR-mutated, recurrent or metastatic HNSCC patients, with tolerable toxicity profiles. The results from the study have provided the basis for routine NGS screening and FGFR-targeted therapy. Because of the small number of patients due to slow accrual in this study, further studies with a larger cohort are warranted for statistical power. [ABSTRACT FROM AUTHOR]