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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.

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.

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 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.

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.

Background and Objective Obstructive sleep apnea (OSA) has significant effects on quality of life and may lead to cognitive impairments. Continuous positive airway pressure (CPAP) is the standard treatment for OSA and has been shown to improve sleep disturbances and daytime dysfunction. In this study, we aimed to assess the effects of CPAP on white matter (WM) integrity using longitudinal diffusion tensor imaging (DTI) tests. Methods Twenty-two male patients with moderate to severe OSA were recruited, and thepatients underwent DTI scanning before and 6–44 months after CPAP treatment. Sixteen male patients with untreated OSA who were not compliant with CPAP were included as a reference group. We compared the functional anisotropy (FA) values between baseline and follow-up magnetic resonance imaging in both the CPAP and untreated groups using tract-specific statistical analysis (TSSA) method. Results The TSSA analysis showed that FA values in the middle part of the right corticospinal tract were increased after treatment in the CPAP group. In the untreated group, no significant change in FA value was observed between baseline and follow-up. In the CPAP group, the post-treatment FA value in the anterior part of the right anterior thalamic radiation was significantly correlated with the duration of CPAP therapy, after controlling for age, body mass index, and baseline FA value. Conclusions Our study suggests that long-term CPAP treatment could gradually reverse OSA-induced injury to the WM microstructure, particularly WM associated with the motor and limbic systems. The study findings provide new insights into the mechanisms of cognitive improvement after CPAP treatment in patients with OSA.

Background/Aims The prognostic value of a comprehensive geriatric assessment (CGA) for the management of older small cell lung cancer (SCLC) patients remains to be established. Methods A retrospective cohort enrolled 21 SCLC patients over 65 years from March 2018 to 2019 at the Yonsei Cancer Center. The CGA included the following instruments: frailty, body mass index, sarcopenia (circumference of arm and calf, Timed Up and Go test, grip strength), comorbidity, polypharmacy, activities of daily living (ADL), Instrumental ADL, nutrition, depression, and cognitive function. The correlations of oncological and geriatric variables with overall survival (OS) were determined. The log-rank test with Cox model and Kaplan-Meier method were used for the analysis. Results The median age was 75 years (range, 67 to 85). All patients had the Eastern Cooperative Oncology Group performance status 0–2. The median survival was 9.93 months (range, 1.53 to 36.30). Among CGA parameters, ADL and nutritional status had significant differences in OS in univariate analysis. In multivariate analysis, only nutritional status was independently associated with survival (hazard ratio, 0.17; 95% confidence interval, 0.05 to 0.57). Median OS for low nutritional status was 5.63 months and the normal nutrition group was 15.5 months (p = 0.004). Conclusions Pre-treatment nutritional status measured by CGA appears to be a predictor of OS in older SCLC patients. However, for further generalization of the implication of CGA in SCLC, a larger scale study with prospective design is strongly needed.

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.

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.

Abstract Background Despite the dynamic treatment landscape for EGFR mutant-positive metastatic non-small cell lung cancer (EGFRm+ mNSCLC), most of the earlier studies have focused on US or Western populations. Objective The objective of this study was to explore real-world treatment patterns and outcomes of South Korean patients with EGFRm+ mNSCLC. Methods Retrospective chart review of adult patients with EGFRm+ mNSCLC who received systemic treatment between January-2019 and June-2019. Results A total of 162 patients were included from 21 hospitals, with a median follow-up of 15.6 months. Median age was 65.0 years, 22% had central nervous system metastasis, and 57% and 38% had exon 19 deletion and exon 21 L858R, respectively. Among 144 patients (89%) who received first-line EGFR-tyrosine kinase inhibitor, afatinib was most the common (44%), followed by gefitinib (28%) and erlotinib (13%). First-line chemotherapy was more common when an EGFR-mutation was detected after versus before first-line treatment initiation (31% vs 5%). Discontinuation of first-line treatment was mostly due to disease-progression (81%) and toxicity (7%). Among 58 (78%) patients who received second-line treatment, osimertinib was the most common (40%). Most (60%) patients reported ≥1 Grade ≥3 adverse event during first-line treatment. Following initiation of first-line treatment, physician visits and chest X-rays were the most frequent healthcare utilisation events. Rates of emergency-room visits and hospitalization were 12% and 16%, respectively, with a mean length-of-stay of 10.4 days. At 12 months, overall survival rate was 95%, and numerically worse for patients with exon 21 versus 19 mutations. Conclusions Characteristics and clinical outcomes of Korean patients with EGFRm+ mNSCLC in real-world practice were comparable to those observed in clinical trials. As osimertinib was not reimbursed for first-line treatment before study completion, further investigation is warranted to explore evolving treatment practice.

Abstract Background Human papillomavirus (HPV)-positive tonsil cancer has a better prognosis than HPV-negative tonsil cancer. Deintensification strategies to reduce or avoid radiotherapy (RT) for patients with HPV-associated tonsil cancer have been suggested. This study investigated the treatment outcomes of patients with HPV-associated tonsil cancer and suggested RT deintensification strategies. Methods A cohort of 374 patients with HPV-associated tonsil cancer treated with primary surgery or RT between 2008 and 2020 was retrospectively evaluated. Survival and locoregional control rates after primary surgery or RT were analyzed, and propensity score matching was performed to adjust for clinical factors. Pearson's chi-square or Fisher's exact test was used to compare categorical variables, and Student's t-test was used to compare continuous variables. The Kaplan–Meier method and log-rank test were used to assess overall survival, progression-free survival, and locoregional failure (LRF). Results No significant differences in survival or LRF were observed between the primary surgery and RT groups. Subgroup analysis was conducted for patients who underwent primary surgery. Advanced pathological N stage, negative contralateral nodes at diagnosis, abutting or positive surgical margins, and no adjuvant RT were independent risk factors for LRF. Advanced pathological T stage was an independent risk factor for LRF in patients who underwent primary surgery without subsequent adjuvant RT. None of the patients with pathological complete remission (CR) after induction chemotherapy died or experienced LRF. Conclusions Our study revealed that the outcomes of primary surgery and primary RT in HPV-positive tonsil cancer were similar after adjusting for clinical factors. Primary RT might be considered instead of surgery in patients with advanced pathological T stage. In the case of pathological CR after induction chemotherapy, deintensification for adjuvant RT should be considered.

Abstract Purpose Although postoperative radiotherapy (PORT) is demonstrably effective in local control of head and neck adenoid cystic carcinoma (HNACC), its application is controversial and the subset of patients who would benefit most from PORT is unknown. Herein, we analyzed the data of HNACC patients to clarify the role of PORT. Methods We retrospectively reviewed 187 patients with nonmetastatic HNACC who underwent surgical resection between 2005 and 2019. The study endpoints were locoregional failure-free survival (LRFFS), progression-free survival (PFS), and overall survival (OS). Subgroup analysis and recursive partitioning analysis (RPA) were performed to identify patients most likely to benefit from PORT. Results With a median follow-up of 84.7 months, the 5-year LRFFS, PFS, and OS were 70.0%, 52.6%, and 86.4%, respectively. Survival was significantly shorter in patients who experienced local failure than in those who did not (5-year OS: 88.1% vs. 80.5%, P = 0.001). The local failure rate was significantly lower in patients who underwent PORT (16.9% vs. 31.0%, P = 0.021), despite the high frequency of adverse factors. Especially, significant decreases in local failure and similar OS rates could be obtained after PORT among patients with positive margins, T2-4 stage disease, and minor salivary gland tumors. The RPA model for PFS categorized patients into four groups according to three prognostic factors (T-stage, location, and sex). The RPA model for LRFFS and OS suggested three groups based on two factors (T-stage, margin for LRFFS; T-stage, grade 3 for OS). Conclusion PORT could prevent dismal survival, while significantly reducing local failures in high-risk HNACC patients.

Introduction: Lorlatinib is a potent, third-generation inhibitor of ALK. In the planned interim analysis of the ongoing, phase 3, randomized, global CROWN trial (NCT03052608), lorlatinib resulted in significantly longer progression-free survival than crizotinib in patients with previously untreated, advanced, ALK-positive NSCLC. Here, we present a subgroup analysis of Asian patients in the CROWN study. Methods: Patients received lorlatinib 100 mg once daily or crizotinib 250 mg twice daily. The primary end point was progression-free survival assessed by blinded independent central review. Objective response rate (ORR), intracranial ORR, safety, and select biomarkers were secondary end points. Results: At data cutoff (September 20, 2021), 120 patients were included in the Asian intention-to-treat subgroup (lorlatinib n = 59; crizotinib n = 61). At 36 months, 61% (95% confidence interval [CI]: 47–72) and 25% (95% CI: 12–41) of patients in the lorlatinib and crizotinib groups, respectively, were alive without disease progression (hazard ratio for disease progression by blinded independent central review or death: 0.40; 95% CI: 0.23–0.71). ORR was 78% (95% CI: 65–88) versus 57% (95% CI: 44–70) for patients treated with lorlatinib and crizotinib, respectively. In patients with measurable, nonmeasurable, or both measurable and nonmeasurable brain metastases at baseline, intracranial ORR was 73% (95% CI: 39–94) versus 20% (95% CI: 4–48) for patients treated with lorlatinib and crizotinib, respectively. The definition of nonmeasurable brain metastases is: a brain lesion less than 10 mm in MRI scan is defined as nonmeasurable brain metastasi based on RECIST criteria (Clinical trial evaluation criteria). Hypercholesterolemia, hypertriglyceridemia, and edema were the most frequently reported adverse events with lorlatinib. Conclusions: Lorlatinib efficacy and safety in the Asian subgroup of CROWN were consistent with those in the overall population.

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.

Background/Aims Treatment decisions for locally advanced head and neck squamous cell carcinoma (LA-HNSCC) are complicated, and multi-modal treatments are usually indicated. However, it is challenging for older patients to complete treatments. Thus, we investigated disease characteristics, real-world treatment, and outcomes in older LA-HNSCC patients. Methods Older patients (aged ≥ 70 years) were selected from a large nationwide cohort that included 445 patients with stage III–IVB LA-HNSCC from January 2005 to December 2015. Their data were retrospectively analyzed and compared with those of younger patients. Results Older patients accounted for 18.7% (83/445) of all patients with median age was 73 years (range, 70 to 89). Proportions of primary tumors in the hypopharynx and larynx were higher in older patients and older patients had a more advanced T stage and worse performance status. Regarding treatment strategies of older patients, 44.5% of patients received concurrent chemoradiotherapy (CCRT), 41.0% underwent surgery, and 14.5% did not complete the planned treatment. Induction chemotherapy (IC) was administered to 27.7% (23/83) of older patients; the preferred regimen for IC was fluorouracil and cisplatin (47.9%). For CCRT, weekly cisplatin was prescribed 3.3 times more often than 3-weekly cisplatin (62.2% vs. 18.9%). Older patients had a 60% higher risk of death than younger patients (hazard ratio, 1.6; p = 0.035). Oral cavity cancer patients had the worst survival probability. Conclusions Older LA-HNSCC patients had aggressive tumor characteristics and received less intensive treatment, resulting in poor survival. Further research focusing on the older population is necessary.

Background: The clinical utility of plasma tumor mutational burden (pTMB) requires further validation. Herein, the pTMB and genetic alterations were investigated as predictive biomarkers for anti-PD-1 monotherapy outcome in metastatic non-small cell lung cancer (NSCLC). Methods: The GuardantOMNI panel (Guardant Health) was used to identify pTMB and genetic alterations. Data from 99 patients with metastatic NSCLC treated with pembrolizumab or nivolumab in first-, second-, or third-line settings between June 2016 and December 2020 were collected. Associations between pTMB and clinical benefit rate (CBR, stable disease ⩾6 months or partial response), progression-free survival (PFS), and overall survival (OS) were assessed. Results: Median pTMB in 84 patients was 10.8 mutations/megabase (mut/Mb). Histological analyses revealed that 61 and 36% of the patients had adenocarcinomas and squamous NSCLC, respectively. Most patients were treated with nivolumab (74%) and most anti-PD-1 agents were administered as second-line treatment (70%). The median follow-up duration was of 10.9 months (range, 0.2–40.7). Patients with high pTMB (⩾19 mut/Mb) had a higher CBR (69%) compared with low pTMB patients (33%; p = 0.01). ARID1A ( p = 0.007) and either ERBB2 or KIT mutations ( p = 0.012) were positive and negative determinants, respectively, for clinical benefit. Multivariate analysis further showed that high pTMB was an independent predictive biomarker for both PFS [hazard ratio (HR) = 0.44, 95% confidence interval (CI): 0.22–0.88, p = 0.02] and OS (HR = 0.37, 95% CI: 0.18–0.76, p = 0.007). Conclusion: High pTMB (⩾19 mut/Mb) is significantly associated with CBR in patients with NSCLC treated with anti-PD-1 agents.

Abstract Background In phase I studies, poziotinib has shown meaningful efficacy against various types of cancers. This phase 2 study aimed to investigate the efficacy and safety of poziotinib in recurrent and/or metastatic head and neck squamous cell carcinoma (R/M‐HNSCC). Methods Overall, 49 patients were enrolled (median age, 62 years; age range, 21–78 years). Patients received a median of two prior treatments including chemotherapy and others and received 12 mg poziotinib orally once daily as part of a 28‐day cycle. The primary endpoint was objective response rate (ORR), and the secondary endpoints were progression‐free survival (PFS) and overall survival (OS). Targeted capture sequencing was performed using available tissues to identify translational biomarkers related to clinical response. Results ORR was 22.4%, median PFS was 4.0 months (95% confidence interval [CI], 1.8–6.2 months), and median OS was 7.6 months (95% CI, 4.4–10.8 months). The most common treatment‐related adverse events were acneiform rash (85%) and mucositis (77%). A grade 3 or higher adverse event was acneiform rash (3%). Targeted capture sequencing was performed in 30 tissue samples. TP53 and PIK3CA were the most frequently mutated genes (43%), followed by CCND1 (33%) and EGFR (30%). Mutations in ERBB2, ERBB3, and ERBB4, which are HER family genes, were observed in 17%, 13%, and 10% samples, respectively. There was no difference in the frequency of somatic mutations in the HER family genes between the clinically benefitted and non‐benefitted groups. Conclusion Compared to other pan‐HER inhibitors, poziotinib showed clinically meaningful efficacy in heavily treated R/M‐HNSCC. Clinical trial registration number. NCT02216916.

EGFR mutant lung tumours do not respond favourably to immunotherapy. Here, using single cell sequencing, the authors find that tissue resident memory CD8+ T like cells are reduced in the immune landscape of EGFR mutant tumours in comparison to wild type tumours and the presence of these cells may predict response to immunotherapy.

Abstract Background Metagenome sampling bias for geographical location and lifestyle is partially responsible for the incomplete catalog of reference genomes of gut microbial species. Thus, genome assembly from currently under-represented populations may effectively expand the reference gut microbiome and improve taxonomic and functional profiling. Methods We assembled genomes using public whole-metagenomic shotgun sequencing (WMS) data for 110 and 645 fecal samples from India and Japan, respectively. In addition, we assembled genomes from newly generated WMS data for 90 fecal samples collected from Korea. Expecting genome assembly for low-abundance species may require a much deeper sequencing than that usually employed, so we performed ultra-deep WMS (> 30 Gbp or > 100 million read pairs) for the fecal samples from Korea. We consequently assembled 29,082 prokaryotic genomes from 845 fecal metagenomes for the three under-represented Asian countries and combined them with the Unified Human Gastrointestinal Genome (UHGG) to generate an expanded catalog, the Human Reference Gut Microbiome (HRGM). Results HRGM contains 232,098 non-redundant genomes for 5414 representative prokaryotic species including 780 that are novel, > 103 million unique proteins, and > 274 million single-nucleotide variants. This is an over 10% increase from the UHGG. The new 780 species were enriched for the Bacteroidaceae family, including species associated with high-fiber and seaweed-rich diets. Single-nucleotide variant density was positively associated with the speciation rate of gut commensals. We found that ultra-deep sequencing facilitated the assembly of genomes for low-abundance taxa, and deep sequencing (e.g., > 20 million read pairs) may be needed for the profiling of low-abundance taxa. Importantly, the HRGM significantly improved the taxonomic and functional classification of sequencing reads from fecal samples. Finally, analysis of human self-antigen homologs on the HRGM species genomes suggested that bacterial taxa with high cross-reactivity potential may contribute more to the pathogenesis of gut microbiome-associated diseases than those with low cross-reactivity potential by promoting inflammatory condition. Conclusions By including gut metagenomes from previously under-represented Asian countries, Korea, India, and Japan, we developed a substantially expanded microbiome catalog, HRGM. Information of the microbial genomes and coding genes is publicly available ( www.mbiomenet.org/HRGM/ ). HRGM will facilitate the identification and functional analysis of disease-associated gut microbiota.

Abstract Prior diffusion tensor imaging (DTI) studies have investigated white matter (WM) changes in patients with primary restless legs syndrome (RLS), but the results were inconsistent. Here, we proposed using tract-specific statistical analysis (TSSA) to find alterations in specific WM tracts to clarify the pathophysiological mechanisms of RLS. We enrolled 30 patients with RLS and 31 age- and sex- matched controls who underwent brain magnetic resonance imaging, neuropsychological tests, and polysomnography. Fractional anisotropy (FA) maps obtained from whole-brain diffusion tensor imaging and TSSA were used to localize WM changes in patients with RLS. Subsequently, a comparison of FA values for each tract between patients and controls was performed. The associations between FA values and clinical, polysomnographic, and neuropsychological parameters in RLS patients were assessed. RLS patients demonstrated decreased FA values in the left corticospinal tract (CST) and cingulum, and in the right anterior thalamic radiation (ATR) and inferior fronto-occipital fasciculus (IFO). Patients’ attention/executive function and visual memory scores positively correlated with FA values in the right ATR, and anxiety levels negatively correlated with FA values in the right IFO. Additionally, the number of periodic leg movements and movement arousal index were negatively correlated with FA values in the left CST. The TSSA method identified previously unknown tract-specific alterations in patients with RLS and significant associations with distinct clinical manifestations of RLS.

Abstract Targeting T-Cell Immunoreceptor with Ig and ITIM domain-poliovirus receptor (PVR) pathway is a potential therapeutic strategy in lung cancer. We analyzed the expression of PVR and programmed death ligand-1 (PD-L1) in surgically resected squamous cell lung carcinoma (SQCC) and determined its prognostic significance. We collected archival surgical specimens and data of 259 patients with SQCC at Yonsei Cancer Center (1998–2020). Analysis of variance was used to analyze the correlations between PVR and PD-L1 expression and patient characteristics. Kaplan–Meier curves were used to estimate recurrence-free survival (RFS) and overall survival (OS). Most patients were male (93%); the majority were diagnosed with stage 1 (47%), followed by stage 2 (29%) and stage 3 (21%). Overexpression of PVR resulted in a significantly shorter median RFS and OS (P = 0.01). PD-L1 expression was not significant in terms of prognosis. Patients were subdivided into four groups based on low and high PVR and PD-L1 expression. Those expressing high levels of PVR and PD-L1 had the shortest RFS (P = 0.03). PVR overexpression is associated with a poor prognosis in surgically resected SQCC. Inhibition of PVR as well as PD-L1 may help overcome the lack of response to immune checkpoint monotherapy.

Abstract We evaluated intracranial failure after hippocampus-avoidance-prophylactic cranial irradiation (HA-PCI) for limited-stage small-cell lung cancer (SCLC). Data of 106 patients who received PCI with 25 Gy were retrospectively reviewed. The patients were divided into two groups based on whether they underwent HA-PCI: the HA-PCI group (n = 48) and the conventional PCI (C-PCI) group (n = 58). Twenty-one patients experienced intracranial failure: 11 and 10 patients in the C-PCI and HA-PCI groups, respectively. Using the log-rank test, the intracranial failure rate was not significantly different between the groups (p = 0.215). No clinical factor was significantly associated with intracranial failure in multivariate Cox regression analysis, but HA-PCI tended to be associated with increased incidence of intracranial failure (HR 2.87, 95% CI 0.86–9.58, p = 0.087). Among patients who received HA-PCI, two developed peri-hippocampal recurrence. A higher thoracic radiotherapy dose (≥ 60 Gy) was significantly associated with DFS (HR 0.52, p = 0.048) and OS (HR 0.35, p = 0.003). However, HA-PCI was associated with neither DFS nor OS. Although HA-PCI may be associated with an increased risk of intracranial failure, HA-PCI did not impair disease control or survival. Future prospective randomized trials are needed to reach a definite conclusion.

AXL, along with MER and TYRO3, is a receptor tyrosine kinase from the TAM family. Although AXL itself is not thought to be a potent oncogenic driver, overexpression of AXL is known to trigger tumor cell growth, survival, invasion, metastasis, angiogenesis, epithelial to mesenchymal transition, and immune suppression. Overexpression of AXL is associated with therapy resistance and poor prognosis. Therefore, it is being studied as a marker of prognosis in cancer treatment or as a target in various cancer types. Recently, many preclinical and clinical studies on agents with various mechanisms targeting AXL have been actively conducted. They include small molecule inhibitors, monoclonal antibodies, and antibody-drug conjugates. This article reviewed the fundamental role of AXL in solid tumors, and the development in research of AXL inhibitors in recent years. Emphasis was placed on the function of AXL in acquired therapy resistance in patients with non-small cell lung cancer (NSCLC). Since clinical needs increase in NSCLC patients with acquired resistance after initial therapy, recent research efforts have focused on a combination treatment with AXL inhibitors and tyrosine kinase inhibitors or immunotherapy to overcome resistance. Lastly, we deal with challenges and limitations encountered in the development of AXL inhibitors.

Cancer: DNA modifications affecting response to treatment A study into natural regulatory DNA modifications that influence patient responses could guide strategies to help the roughly two-thirds of patients who respond poorly to treatment with anticancer drugs called PD-1 inhibitors. Researchers at Yonsei University in South Korea, led by Hye Ryun Kim and Insuk Lee, investigated the significance in lung cancer patients of pre-treatment levels of DNA methylation, in which methyl (CH3) groups are added to DNA. They identified > 1000 regions of DNA in which varying methylation levels were associated with differing responses to PD-1 inhibitors. These differences affected regions of DNA called enhancers and promoters, which have been implicated in controlling the activity of more than 1000 identified genes. The research could help predict response outcomes to potential treatments and suggest possibilities for new interventions that might improve responses.

Abstract Background By investigating treatment patterns and outcomes in locally advanced head and neck squamous cell carcinoma (LA-HNSCC), we aimed at providing valuable insights into the optimal therapeutic strategy for physicians in real-world practice. Methods This is a multi-institutional study enrolled the patients with stage III to IVB LA-HNSCC, except for nasopharyngeal carcinoma, from 2004 to 2015 in thirteen referral hospitals capable of multidisciplinary care. Results A total of 445 LA-HNSCC patients were analyzed. The median age was 61 years (range, 24–89). The primary tumor location was the oropharynx in 191 (43%), oral cavity in 106 (24%), hypopharynx in 64 (14%), larynx in 57 (13%) and other sites in 27 (6%). The most common stage was T2 in 172 (39%), and N2 in 245 (55%). Based on treatment intents, 229 (52%) of the patients received definitive concurrent chemoradiotherapy (CCRT) and 187 (42%) underwent surgery. Approximately 158 (36%) of the study population received induction chemotherapy (IC). Taken together, 385 (87%) of the patients underwent combined therapeutic modalities. The regimen for definitive CCRT was weekly cisplatin in 58%, 3-weekly cisplatin in 28% and cetuximab in 3%. The preferred regimen for IC was docetaxel with cisplatin in 49%, and docetaxel, cisplatin plus fluorouracil in 27%. With a median follow-up of 39 months, one-year and two-year survival rates were 89 and 80%, respectively. Overall survival was not significantly different between CCRT and surgery group (p = 0.620). Conclusions In patients with LA-HNSCC, the majority of patients received combined therapeutic modalities. Definitive CCRT, IC then definitive CCRT, and surgery followed by adjuvant CCRT or radiotherapy are the preferred multidisciplinary strategies in real-world practice.

Abstract Background We investigated whether head and neck squamous cell carcinoma (HNSCC) patient-derived xenografts (PDXs) reaffirm patient responses to anti-cancer therapeutics. Methods Tumors from HNSCC patients were transplanted into immunodeficient mice and propagated via subsequent implantation. We evaluated established PDXs by histology, genomic profiling, and in vivo anti-cancer efficacy testing to confirm them as the authentic in vivo platform. Results From 62 HNSCCs, 15 (24%) PDXs were established. The primary cancer types were tongue (8), oropharynx (3), hypopharynx (1), ethmoid sinus cancer (1), supraglottic cancer (1), and parotid gland (1); six PDXs (40%) were established from biopsy specimens from advanced HNSCC. PDXs mostly retained donor characteristics and remained stable across passages. PIK3CA (H1047R), HRAS (G12D), and TP53 mutations (H193R, I195T, R248W, R273H, E298X) and EGFR, CCND1, MYC, and PIK3CA amplifications were identified. Using the acquisition method, biopsy showed a significantly higher engraftment rate when compared with that of surgical resection (100% [6/6] vs. 16.1% [9/56], P

Abstract Background T cells exhibit heterogeneous functional states in the tumor microenvironment. Immune checkpoint inhibitors (ICIs) can reinvigorate only the stem cell-like progenitor exhausted T cells, which suggests that inhibiting the exhaustion progress will improve the efficacy of immunotherapy. Thus, regulatory factors promoting T cell exhaustion could serve as potential targets for delaying the process and improving ICI efficacy. Methods We analyzed the single-cell transcriptome data derived from human melanoma and non-small cell lung cancer (NSCLC) samples and classified the tumor-infiltrating (TI) CD8+ T cell population based on PDCD1 (PD-1) levels, i.e., PDCD1-high and PDCD1-low cells. Additionally, we identified differentially expressed genes as candidate factors regulating intra-tumoral T cell exhaustion. The co-expression of candidate genes with immune checkpoint (IC) molecules in the TI CD8+ T cells was confirmed by single-cell trajectory and flow cytometry analyses. The loss-of-function effect of the candidate regulator was examined by a cell-based knockdown assay. The clinical effect of the candidate regulator was evaluated based on the overall survival and anti-PD-1 responses. Results We retrieved many known factors for regulating T cell exhaustion among the differentially expressed genes between PDCD1-high and PDCD1-low subsets of the TI CD8+ T cells in human melanoma and NSCLC. TOX was the only transcription factor (TF) predicted in both tumor types. TOX levels tend to increase as CD8+ T cells become more exhausted. Flow cytometry analysis revealed a correlation between TOX expression and severity of intra-tumoral T cell exhaustion. TOX knockdown in the human TI CD8+ T cells resulted in downregulation of PD-1, TIM-3, TIGIT, and CTLA-4, which suggests that TOX promotes intra-tumoral T cell exhaustion by upregulating IC proteins in cancer. Finally, the TOX level in the TI T cells was found to be highly predictive of overall survival and anti-PD-1 efficacy in melanoma and NSCLC. Conclusions We predicted the regulatory factors involved in T cell exhaustion using single-cell transcriptome profiles of human TI lymphocytes. TOX promoted intra-tumoral CD8+ T cell exhaustion via upregulation of IC molecules. This suggested that TOX inhibition can potentially impede T cell exhaustion and improve ICI efficacy. Additionally, TOX expression in the TI T cells can be used for patient stratification during anti-tumor treatments, including anti-PD-1 immunotherapy.

Introduction: Osimertinib is a third-generation EGFR tyrosine kinase inhibitor (TKI) that is approved for the use of EGFR -mutant non-small cell lung cancer (NSCLC) patients. In this study, we investigated the acquired resistance mechanisms in NSCLC patients and patient-derived preclinical models. Methods: Formalin-fixed paraffin-embedded tumor samples and plasma samples from 55 NSCLC patients who were treated with osimertinib were collected at baseline and at progressive disease (PD). Next-generation sequencing was performed in tumor and plasma samples using a 600-gene hybrid capture panel designed by AstraZeneca. Osimertinib-resistant cell lines and patient-derived xenografts and cells were generated and whole exome sequencing and RNA sequencing were performed. In vitro experiments were performed to functionally study the acquired mutations identified. Results: A total of 55 patients and a total of 149 samples (57 tumor samples and 92 plasma samples) were analyzed, and among them 36 patients had matched pre- and post-treatment samples. EGFR C797S (14%) mutation was the most frequent EGFR- dependent mechanism identified in all available progression samples, followed by EGFR G824D (6%), V726M (3%), and V843I (3%). Matched pre- and post-treatment sample analysis revealed in-depth acquired mechanisms of resistance. EGFR C797S was still most frequent (11%) among EGFR-dependent mechanism, while among EGFR-independent mechanisms, PIK3CA, ALK , BRAF, EP300, KRAS , and RAF1 mutations were detected. Among Osimertinib-resistant cell lines and patient-derived models, we noted acquired mutations which were potentially targetable such as NRAS p.Q61K, in which resistance could be overcome with combination of osimertinib and trametinib. A patient-derived xenograft established from osimertinib-resistant patient revealed KRAS p.G12D mutation which could be overcome with combination of osimertinib, trametinib, and buparlisib. Conclusion: In this study, we explored the genetic profiles of osimertinib-resistant NSCLC patient samples using targeted deep sequencing. In vitro and in vivo models harboring osimertinib resistance revealed potential novel treatment strategies after osimertinib failure.

Background: Predictive markers for treatment response and survival outcome have not been identified in patients with advanced non-small-cell lung cancer (NSCLC) receiving chemoimmunotherapy. We aimed to evaluate whether imaging biomarkers of 18 F-fluorodeoxyglucose ( 18 F-FDG) positron emission tomography/computed tomography (PET/CT) and routinely assessed clinico-laboratory values were associated with clinical outcomes in patients with advanced NSCLC receiving pembrolizumab plus platinum-doublet chemotherapy as a first-line treatment. Methods: We retrospectively enrolled 52 patients with advanced NSCLC who underwent baseline 18 F-FDG PET/CT before treatment initiation. PET/CT parameters and clinico-laboratory variables, constituting the prognostic immunotherapy scoring system, were collected. Optimal cut-off values for PET/CT parameters were determined using the maximized log-rank test for progression-free survival (PFS). A multivariate prediction model was developed based on Cox models for PFS, and a scoring system was established based on hazard ratios of the predictive factors. Results: During the median follow-up period of 16.7 months (95% confidence interval: 15.7–17.7 months), 43 (82.7%) and 31 (59.6%) patients experienced disease progression and death, respectively. Objective response was observed in 23 (44.2%) patients. In the multivariate analysis, maximum standardized uptake value, metabolic tumour volume 2.5 , total lesion glycolysis 2.5 , and bone marrow-to-liver uptake ratio from the PET/CT variables and neutrophil-to-lymphocyte ratio (NLR) from the clinico-laboratory variables were independently associated with PFS. The scoring system based on these independent predictive variables significantly predicted the treatment response, PFS, and overall survival. Conclusion: PET/CT variables and NLR were useful biomarkers for predicting outcomes of patients with NSCLC receiving pembrolizumab and chemotherapy as a first-line treatment, suggesting their potential as effective markers for combined PD-1 blockade and chemotherapy.

Abstract Objectives AXL‐mediated activation of aberrant tyrosine kinase drives various oncogenic processes and facilitates an immunosuppressive microenvironment. We evaluated the anti‐tumor and anti‐metastatic activities of SKI‐G‐801, a small‐molecule inhibitor of AXL, alone and in combination with anti‐PD‐1 therapy. Methods In vitro pAXL inhibition by SKI‐G‐801 was performed in both human and mouse cancer cell lines. Immunocompetent mouse models of tumor were established to measure anti‐metastatic potential of SKI‐G‐801. Furthermore, SKI‐G‐801, anti‐PD‐1 or their combination was administered as an adjuvant or neoadjuvant in the 4T1 tumor model to assess their potential for clinical application. Results SKI‐G‐801 robustly inhibited pAXL expression in various cell lines. SKI‐G‐801 alone or in combination with anti‐PD‐1 potently inhibited metastasis in B16F10 melanoma, CT26 colon and 4T1 breast models. SKI‐G‐801 inhibited the growth of B16F10 and 4T1 tumor‐bearing mice but not immune‐deficient mice. An antibody depletion assay revealed that CD8+ T cells significantly contributed to SKI‐G‐801‐mediated survival. Anti‐PD‐1 and combination group were observed the increased CD8+Ki67+ and effector T cells and M1 macrophage and decreased M2 macrophage, and granulocytic myeloid‐derived suppressor cell (G‐MDSC) compared to the control group. The neoadjuvant combination of SKI‐G‐801 and anti‐PD‐1 therapy achieved superior survival benefits by inducing more profound T‐cell responses in the 4T1 syngeneic mouse model. Conclusion SKI‐G‐801 significantly suppressed tumor metastasis and growth by enhancing anti‐tumor immune responses. Our results suggest that SKI‐G‐801 has the potential to overcome anti‐PD‐1 therapy resistance and allow more patients to benefit from anti‐PD‐1 therapy.

Abstract Adequate preclinical model and model establishment procedure are required to accelerate translational research in lung cancer. We streamlined a protocol for establishing patient-derived cells (PDC) and identified effective targeted therapies and novel resistance mechanisms using PDCs. We generated 23 PDCs from 96 malignant effusions of 77 patients with advanced lung adenocarcinoma. Clinical and experimental factors were reviewed to identify determinants for PDC establishment. PDCs were characterized by driver mutations and in vitro sensitivity to targeted therapies. Seven PDCs were analyzed by whole-exome sequencing. PDCs were established at a success rate of 24.0%. Utilizing cytological diagnosis and tumor colony formation can improve the success rate upto 48.8%. In vitro response to a tyrosine kinase inhibitor (TKI) in PDC reflected patient treatment response and contributed to identifying effective therapies. Combination of dabrafenib and trametinib was potent against a rare BRAF K601E mutation. Afatinib was the most potent EGFR-TKI against uncommon EGFR mutations including L861Q, G719C/S768I, and D770_N771insG. Aurora kinase A (AURKA) was identified as a novel resistance mechanism to olmutinib, a mutant-selective, third-generation EGFR-TKI, and inhibition of AURKA overcame the resistance. We presented an efficient protocol for establishing PDCs. PDCs empowered precision medicine with promising translational values.

Abstract Background Regulatory T (Treg) cells have an immunosuppressive function in cancer, but the underlying mechanism of immunosuppression in the tumor microenvironment (TME) is unclear. Methods We compared the phenotypes of T cell subsets, including Treg cells, obtained from peripheral blood, malignant effusion, and tumors of 103 cancer patients. Our primary focus was on the expression of immune checkpoint (IC)-molecules, such as programmed death (PD)-1, T-cell immunoglobulin and mucin-domain containing (TIM)-3, T cell Ig and ITIM domain (TIGIT), and cytotoxic T lymphocyte antigen (CTLA)-4, on Treg cells in paired lymphocytes from blood, peritumoral tissue, and tumors of 12 patients with lung cancer. To identify the immunosuppressive mechanisms acting on tumor-infiltrating Treg cells, we conducted immunosuppressive functional assays in a mouse model. Results CD8+, CD4+ T cells, and Treg cells exhibited a gradual upregulation of IC-molecules the closer they were to the tumor. Interestingly, PD-1 expression was more prominent in Treg cells than in conventional T (Tconv) cells. In lung cancer patients, higher levels of IC-molecules were expressed on Treg cells than on Tconv cells, and Treg cells were also more enriched in the tumor than in the peri-tumor and blood. In a mouse lung cancer model, IC-molecules were also preferentially upregulated on Treg cells, compared to Tconv cells. PD-1 showed the greatest increase on most cell types, especially Treg cells, and this increase occurred gradually over time after the cells entered the TME. PD-1 high-expressing tumor-infiltrating Treg cells displayed potent suppressive activity, which could be partially inhibited with a blocking anti-PD-1 antibody. Conclusions We demonstrate that the TME confers a suppressive function on Treg cells by upregulating IC-molecule expression. Targeting IC-molecules, including PD-1, on Treg cells may be effective for cancer treatment.

Background: Head and neck cancer patients often suffer from dysphagia after surgery and radiotherapy. A singing-enhanced swallowing protocol was established to improve their swallowing function. This study aimed to evaluate the beneficial effects of therapeutic singing on dysphagia in head and neck cancer (HNC) patients. Methods: Patients who participated in this study were allocated to the intervention group (15 patients) and the control group (13 patients). Patients assigned to the intervention group received therapeutic singing 3 times per week for 4 weeks. Each group was divided into 2 subgroups, including the oral cavity cancer group and the pharyngeal cancer group. The patients’ vocal functions were evaluated in maximum phonation time, pitch, intensity, jitter, shimmer, harmonics to noise ratio, and laryngeal diadochokinesis (L-DDK). To evaluate swallowing function, videofluoroscopic swallowing study was done, and the results were analyzed by videofluoroscopic dysphagia scale (VDS) and dynamic imaging grade of swallowing toxicity (DIGEST). Results: Among the voice parameters, L-DDK of the intervention group significantly increased compared to that of the control group. Swallowing functions of the intervention group were significantly improved in VDS and DIGEST after the intervention. Detailed items of VDS and DIGEST showed improvements especially in the pharyngeal phase score of VDS, such as laryngeal elevation, pharyngeal transit time, and aspiration. In addition, the pharyngeal cancer group showed significant improvements in VDS and DIGEST scores after the intervention. Conclusions: Our outcomes highlight the beneficial effects of singing for HNC patients with dysphagia. The notable improvements in the pharyngeal phase suggest that therapeutic singing would be more appropriate for HNC patients who need to improve their intrinsic muscle movements of vocal fold and laryngeal elevation.

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.

Purpose Obesity is a well-known risk factor for central precocious puberty (CPP). Recently, elevated thyroid stimulating hormone (TSH) was reported in obese youth. However, few data regarding the relationship between CPP and TSH are available. The aim of this study was to evaluate thyroid function in girls with CPP and the relationship between CPP and serum TSH concentration. Methods This was a retrospective cross-sectional study. A total of 1,247 girls aged between 6.0 and 8.9 years who had undergone a gonadotropin-releasing hormone (GnRH) stimulation test to determine the presence of puberty were studied. Subjects were classified into CPP (n=554) and non-CPP (n=693) groups according to the results of the GnRH stimulation test. Characteristics and laboratory data of the CPP and non-CPP groups were compared and correlations between those characteristics and laboratory data and TSH concentration were evaluated. Serum TSH concentration in the CPP group was higher than that of the non-CPP group (3.19±1.55 mIU/L vs. 2.58±1.34 mIU/L, P

The success of immune checkpoint inhibitors (ICIs), notably anti-cytotoxic T lymphocyte associated antigen-4 (CTLA-4) as well as inhibitors of CTLA-4, programmed death 1 (PD-1), and programmed death ligand-1 (PD-L1), has revolutionized treatment options for solid tumors. However, the lack of response to treatment, in terms of de novo or acquired resistance, and immune related adverse events (IRAE) remain as hurdles. One mechanisms to overcome the limitations of ICIs is to target other immune checkpoints associated with tumor microenvironment. Immune checkpoints such as lymphocyte activation gene-3 (LAG-3), T cell immunoglobulin and ITIM domain (TIGIT), T cell immunoglobulin and mucin-domain containing-3 (TIM-3), V-domain immunoglobulin suppressor of T cell activation (VISTA), B7 homolog 3 protein (B7-H3), inducible T cell costimulatory (ICOS), and B and T lymphocyte attenuator (BTLA) are feasible and promising options for treating solid tumors, and clinical trials are currently under active investigation. This review aims to summarize the clinical aspects of the immune checkpoints and introduce novel agents targeting these checkpoints.

Background/PurposeSurgery followed by postoperative radiotherapy (RT) has been considered the standard treatment for oral cavity squamous cell carcinoma (OCSCC) of advanced stages or with adverse prognostic factors. In this study, we compared the outcomes in patients with OCSCC who received postoperative concurrent chemoradiotherapy (CCRT) or postoperative RT alone using modern RT techniques.MethodsA total of 275 patients with OCSCC treated between 2002 and 2018 were retrospectively analyzed. Adverse prognostic factor was defined as extranodal extension (ENE), microscopically involved surgical margin, involvement of ≥2 lymph nodes, perineural disease, and/or lymphovascular invasion (LVI). In total, 148 patients (54%) received CCRT and 127 patients (46%) received RT alone. More patients in the CCRT group had N3 disease and stage IVB disease (46.6% vs. 10.2%, p

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.

This nation-wide survey was conducted among Korean adults to examine the public interest in and attitudes toward establishing a citizen participation cohort model and to collect data to support and determine the future policy and research directions of the Resource Collection Project for Precision Medicine Research (RCP-PMR) before the project proceeds. The demographic framework of the survey population was established based on the statistical standards of the Ministry of the Interior and Safety. An online survey was carried out using web panels between 14 May 2018 and 23 May 2018. Sampling was performed using a simple proportional allocation method considering region, gender, and age. From this survey, the RCP-PMR received very high support (94.5%) and the intention to participate was as high as 83.5%. Respondents had a very positive attitude toward providing their samples and information to the study (84.5–89.9%). In terms of incentives to participate, respondents wanted to receive health information (80.2%), monetary compensation (51.4%), and smart devices (41.3%). Most participants responded that it was appropriate to carry out the project at governmental research institutes (66.9%). Respondents also had a positive attitude toward sharing their information and samples as long as it was only shared with the governmental researchers who run the project (88.0%). However, the survey participants expressed concerns about the study being time consuming or a hassle (38.1%), privacy breaches (33.6%), and the lack of returning benefits of participation (25.1%). Participants had a negative attitude toward sharing their data with researchers who are not directly involved in the RCP-PMR. Considering the future use of the database derived from this project, it will be important to communicate with the lay public as well as the RCP-PMR participants to understand their needs in participating in the forthcoming study and to improve their understanding of the goals of the project, and how data sharing can contribute to disease research and prevention. The RCP-PMR should consider building an efficient citizen-participation program and privacy protection for the research participants.

BackgroundA recent animal study showed that parathyroid hormone-related peptide (PTHrP) is associated with cancer cachexia by promoting adipose tissue browning, and we previously demonstrated that PTHrP predicts weight loss (WL) in patients with cancer. In this study, we investigated whether prediction of WL by PTHrP is influenced by clinical factors such as serum albumin, corrected calcium levels, cancer stage, and performance status (PS).MethodsA cohort of 219 patients with cancer whose PTHrP level was measured was enrolled and followed for body weight (BW) changes. Subjects were divided into two groups by serum albumin (cutoff value, 3.7 g/dL), corrected calcium (cutoff value, 10.5 mg/dL), cancer stage (stage 1 to 3 or 4), or PS (Eastern Cooperative Oncology Group 0 to 1 or 2 to 4), respectively. Clinically significant WL was defined as either percent of BW change (% BW)

PurposeSmall for gestational age (SGA) is confusingly defined as birth weight (BW) either below 3rd percentile or 10th percentile for infants. This study aimed to compare postnatal catch-up growth between SGA groups according to different definitions.MethodsData of 129 infants born with BW below the 10th percentile and admitted to Korea University Anam Hospital and Ansan Hospital were retrospectively reviewed. Height and weight were measured at 6, 12, and 24 months. Results were compared between group A (BW:

Purpose This study investigated the influence of obesity on the clinical course and effect of gonadotropin-releasing hormone analog (GnRHa) treatment in girls with central precocious puberty (CPP). Methods Medical records of 182 girls with CPP treated with GnRHa were reviewed. They were divided into 2 groups: normal weight (n=108) and overweight/obesity (n=74). Chronological age (CA), bone age (BA), difference between BA and CA (BA–CA), standard deviation score (SDS) of height, body mass index (BMI), predicted adult height (PAH), and laboratory findings were compared at baseline, after 1 year, and at the end of GnRHa treatment in both groups. Results Mean BMI SDS at baseline was 0.08±0.60 in the normal weight group and 1.55±0.36 in the overweight/obesity group. Initial CA, BA, midparental height, and PAH were similar between the 2 groups. BA–CA after treatment was significantly decreased compared to baseline in both groups (P

Abstract Background The aim of this study was to investigate the prevalence and prognostic significance of psychological distress in gastric cancer patients. Methods The study population included 229 gastric cancer patients visiting Yonsei Cancer Center between November 2009 and March 2011. The distress was measured by available tools including the Modified Distress Thermometer (MDT), Hospital Anxiety and Depression Scale (HADS), and Center for Epidemiologic Studies–Depression Scale (CES-D). Patients with psychological distress were defined as those who scored above the cut-off values in both the MDT and either one of the HADS or CES-D. Results The median age of patients was 56 (range, 20 to 86) and 97 (42.4%) patients were with stage IV disease status at enrollment. The overall prevalence of psychological distress was 33.6% (95% CI: 27.5–39.8%) in 229 gastric cancer patients. In multiple logistic regression analysis, lower education level (odds ratio [OR] 2.39; 95% confidence interval [CI] 1.11–5.17, P = 0.026) and higher disease stage (OR 2.72; 95% CI 1.47–5.03, P = 0.001) were associated with psychological distress. In stage I-III disease, patients with psychological distress had worse disease-free survival (DFS) (5-year DFS rate: 60% vs 76%, P = 0.49) compared with those without psychological distress. In stage IV disease (n = 97), patients with psychological distress showed poorer overall survival than those without psychological distress (median OS (Overall Survival): 12.2 vs. 13.8 months, P = 0.019). Conclusion Psychological distress is common in patients with all stages of gastric cancer and is associated with worse outcomes.

OBJECTIVES:Complete resection of thymic neoplasms is important for achieving a favorable prognosis; however, the efficacy of neoadjuvant therapy remains controversial. We investigated the effect of induction therapy on complete resection and survival using 3-dimensionally reconstructed images to measure tumor volume. METHODS:Eighty-nine patients who underwent surgical resection for Masaoka-Koga stage III-IV thymic neoplasms between January 2000 and December 2013 were enrolled, including 71 and 18 in the primary surgery and neoadjuvant therapy groups, respectively. Baseline characteristics, postoperative outcomes, and survival rates were analyzed. Moreover, baseline and post-neoadjuvant therapy tumor volumes were compared among patients in the neoadjuvant group. RESULTS:Adjacent mediastinal structure invasion was significantly rarer in the primary surgery group than in the neoadjuvant group (1.27±1.09 vs. 2.61±1.42, p