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Background: To identify the clinical and imaging characteristics of soft tissue sarcomas (STS) of the trunk and extremities that undergo unplanned excision. Methods: This retrospective study evaluated the data of patients with STS in the trunk or extremities between January 2008 and December 2021. Patients were divided into unplanned and planned excision groups based on their initial treatment. The distribution of histologic subtypes was analyzed, and the magnetic resonance imaging features were evaluated. Multivariable logistic regression was performed to identify variables independently associated with unplanned excision. Results: A total of 305 patients (mean age±standard deviation, 51±16.4 years; 179 males) were analyzed. The most prevalent subtype in the unplanned excision group was myxofibrosarcoma (22.3%). The unplanned excision group had a significantly smaller tumor size (p < 0.001) and more frequent superficial (p < 0.001) locations. Lobulated shape and peritumoral abnormalities were present in 70.0% and 50.0% of the unplanned excision group, respectively. Tumor size (adjusted odds ratio [OR], 0.87 per 1 cm increase; 95% confidence interval [CI], 0.77–0.98; p = 0.025) and superficial location (adjusted OR, 3.48; 95% CI, 1.57–7.72; p = 0.002) were independently associated with unplanned excision. Conclusion: Myxofibrosarcoma is associated with a high frequency of unplanned excision. A significant number of patients in the unplanned excision group demonstrated a lobulated shape and peritumoral abnormalities. Only small tumor size and superficial location were independently associated with unplanned STS excision. [ABSTRACT FROM AUTHOR]

Thyroid immune-related adverse events (irAEs) are associated with programmed cell death protein 1 (PD-1) blockade efficacy in non-small cell lung cancer (NSCLC). However, their independence from PD-L1 expression and quantitative impact on predicting PD-1 blockade efficacy remain unexplored. This multicenter, retrospective, longitudinal study from Korea included 71 metastatic NSCLC patients who underwent PD-L1 expression and thyroid function testing during PD-1 blockade. Disease progression by the Response Evaluation Criteria for Solid Tumors was the main outcome. Three-stage analyses were performed: (1) multivariate Cox regression models adjusted for PD-L1 expression according to thyroid irAEs; (2) subgroup analyses; (3) regrouping and comparing predictivity of current and alternative staging. Patients with thyroid irAE + exhibited a longer progression-free survival [7/20 vs. 34/51, adjusted HR 0.19 (0.07–0.47); P < 0.001] than those with thyroid irAE-, independent of PD-L1 expression; the results remained across most subgroups without interaction. The three groups showed different adjusted HR for disease progression (Group 1: PD L1 + and thyroid irAE + ; Group 2: PD-L1 + or thyroid irAE + : 5.08 [1.48–17.34]; Group 3: PD-L1− and thyroid irAE− : 30.49 [6.60–140.78]). Alternative staging (Group 1 in stage IVB → stage IVA; Group 3 in stage IVA → stage IVB) improved the prognostic value (PVE: 21.7% vs. 6.44%; C-index: 0.706 vs. 0.617) compared with the 8th Tumor–Node–Metastasis staging. Our study suggests thyroid irAEs and PD-L1 expression are independent biomarkers that improve predicting PD-1 blockade efficacy in NSCLC. Thyroid irAEs would be helpful to identify NSCLC patients who benefit from PD-1 blockade in early course of treatment. [ABSTRACT FROM AUTHOR]

Thyroid immune-related adverse events (irAEs) are associated with programmed cell death protein 1 (PD-1) blockade efficacy in non-small cell lung cancer (NSCLC). However, their independence from PD-L1 expression and quantitative impact on predicting PD-1 blockade efficacy remain unexplored. This multicenter, retrospective, longitudinal study from Korea included 71 metastatic NSCLC patients who underwent PD-L1 expression and thyroid function testing during PD-1 blockade. Disease progression by the Response Evaluation Criteria for Solid Tumors was the main outcome. Three-stage analyses were performed: (1) multivariate Cox regression models adjusted for PD-L1 expression according to thyroid irAEs; (2) subgroup analyses; (3) regrouping and comparing predictivity of current and alternative staging. Patients with thyroid irAE + exhibited a longer progression-free survival [7/20 vs. 34/51, adjusted HR 0.19 (0.07–0.47); P < 0.001] than those with thyroid irAE-, independent of PD-L1 expression; the results remained across most subgroups without interaction. The three groups showed different adjusted HR for disease progression (Group 1: PD L1 + and thyroid irAE + ; Group 2: PD-L1 + or thyroid irAE + : 5.08 [1.48–17.34]; Group 3: PD-L1− and thyroid irAE− : 30.49 [6.60–140.78]). Alternative staging (Group 1 in stage IVB → stage IVA; Group 3 in stage IVA → stage IVB) improved the prognostic value (PVE: 21.7% vs. 6.44%; C-index: 0.706 vs. 0.617) compared with the 8th Tumor–Node–Metastasis staging. Our study suggests thyroid irAEs and PD-L1 expression are independent biomarkers that improve predicting PD-1 blockade efficacy in NSCLC. Thyroid irAEs would be helpful to identify NSCLC patients who benefit from PD-1 blockade in early course of treatment. [ABSTRACT FROM AUTHOR]

PURPOSE: Evaluation of PD-L1 tumor proportion score (TPS) by pathologists has been very impactful but is limited by factors such as intraobserver/interobserver bias and intratumor heterogeneity. We developed an artificial intelligence (AI)–powered analyzer to assess TPS for the prediction of immune checkpoint inhibitor (ICI) response in advanced non–small cell lung cancer (NSCLC). MATERIALS AND METHODS: The AI analyzer was trained with 393,565 tumor cells annotated by board-certified pathologists for PD-L1 expression in 802 whole-slide images (WSIs) stained by 22C3 pharmDx immunohistochemistry. The clinical performance of the analyzer was validated in an external cohort of 430 WSIs from patients with NSCLC. Three pathologists performed annotations of this external cohort, and their consensus TPS was compared with AI-based TPS. RESULTS: In comparing PD-L1 TPS assessed by AI analyzer and by pathologists, a significant positive correlation was observed (Spearman coefficient = 0.925; P <.001). The concordance of TPS between AI analyzer and pathologists according to TPS ≥50%, 1%-49%, and <1% was 85.7%, 89.3%, and 52.4%, respectively. In median progression-free survival (PFS), AI-based TPS predicted prognosis in the TPS 1%-49% or TPS <1% group better than the pathologist's reading, with the TPS ≥50% group as a reference (hazard ratio [HR], 1.49 [95% CI, 1.19 to 1.86] v HR, 1.36 [95% CI, 1.08 to 1.71] for TPS 1%-49% group, and HR, 2.38 [95% CI, 1.69 to 3.35] v HR, 1.62 [95% CI, 1.23 to 2.13] for TPS <1% group). CONCLUSION: PD-L1 TPS assessed by AI analyzer correlates with that of pathologists, with clinical performance also being comparable when referenced to PFS. The AI model can accurately predict tumor response and PFS of ICI in advanced NSCLC via assessment of PD-L1 TPS. [ABSTRACT FROM AUTHOR]

Introduction: Numerous studies have suggested high concordance between tissue and circulating tumor DNA (ctDNA) comprehensive genomic profiling (CGP) tests but only few of them focused on fusions. In addition, atypical breakpoints occasionally detected from DNA-based fusion detection make interpretation difficult, and their clinical significance remains unclear. This study evaluated the clinical utility of ctDNA CGP for fusion detection. Methods: The results of ctDNA CGP tests performed on patients with stage IV non-small cell lung cancer during routine clinical care were retrospectively reviewed. The concordance between ctDNA CGP and combined tissue test results was analyzed using CGP, immunohistochemistry, fluorescence in situ hybridization, and reverse transcription polymerase chain reaction. The clinical significance of fusions detected by ctDNA CGP, including those with atypical breakpoints at the DNA level, was assessed. Results: In total, 264 patients were tested with ctDNA CGP. Fusions were detected in 27 patients (10.2%), and the fusion drivers were RET (n=12, 4.6%), ALK (n=9, 3.4%), ROS1 (n=4, 1.5%), and FGFR2 (n=2, 0.8%). The overall prevalence of fusion in tissue CGP was comparable to that in ctDNA CGP. A total of 371 ctDNA-tissue test pairs were available, and the overall positive and negative percent agreement rates were 92.9% (13/14) and 100.0% (357/357), respectively. One ALK IHC-positive and ctDNA CGP-negative case did not respond to ALK -targeted therapy. Response to targeted therapy was assessed in 16 patients, and a partial response was achieved in all patients, including four with atypical breakpoints. Conclusion: Fusion detection using ctDNA CGP showed high concordance with tissue tests and accuracy in predicting therapeutic responses in patients with non-small cell lung cancer. ctDNA CGP may provide an important diagnostic tool for fusion detection. [ABSTRACT FROM AUTHOR]

Background: Mitochondria are known to synthesize adenosine triphosphate (ATP) through oxidative phosphorylation. Understanding and accurately measuring mitochondrial ATP synthesis rate can provide insights into the functional status of mitochondria and how it contributes to overall cellular energy homeostasis. Traditional methods only estimate mitochondrial function by measuring ATP levels at a single point in time or through oxygen consumption rates. This study introduced the relative mitochondrial ATP synthesis response against inhibiting and stimulating substrates (MitoRAISE), designed to detect real-time changes in ATP levels as the cells respond to substrates. Methods: The sensitivity and specificity of the MitoRAISE assay were verified under various conditions, including the isolation of mitochondria, variations in cell numbers, cells exhibiting mitochondrial damage, and heterogeneous mixtures. Using peripheral blood mononuclear cells (PBMCs), we analyzed MitoRAISE data from 19 patients with breast cancer and 23 healthy women. Results: The parameters observed in the MitoRAISE data increased depending on the quantity of isolated mitochondria and cell count, whereas it remained unmeasured in mitochondrial-damaged cell lines. Basal ATP, rotenone response, malonate response, and mitochondrial DNA copy numbers were lower in PBMCs from patients with breast cancer than in those from healthy women. Conclusions: The MitoRAISE assay has demonstrated its sensitivity and specificity by measuring relative ATP synthesis rates under various conditions. We propose MitoRAISE assay as a potential tool for monitoring changes in the mitochondrial metabolic status associated with various diseases. [ABSTRACT FROM AUTHOR]

PURPOSE: Evaluation of PD-L1 tumor proportion score (TPS) by pathologists has been very impactful but is limited by factors such as intraobserver/interobserver bias and intratumor heterogeneity. We developed an artificial intelligence (AI)–powered analyzer to assess TPS for the prediction of immune checkpoint inhibitor (ICI) response in advanced non–small cell lung cancer (NSCLC). MATERIALS AND METHODS: The AI analyzer was trained with 393,565 tumor cells annotated by board-certified pathologists for PD-L1 expression in 802 whole-slide images (WSIs) stained by 22C3 pharmDx immunohistochemistry. The clinical performance of the analyzer was validated in an external cohort of 430 WSIs from patients with NSCLC. Three pathologists performed annotations of this external cohort, and their consensus TPS was compared with AI-based TPS. RESULTS: In comparing PD-L1 TPS assessed by AI analyzer and by pathologists, a significant positive correlation was observed (Spearman coefficient = 0.925; P <.001). The concordance of TPS between AI analyzer and pathologists according to TPS ≥50%, 1%-49%, and <1% was 85.7%, 89.3%, and 52.4%, respectively. In median progression-free survival (PFS), AI-based TPS predicted prognosis in the TPS 1%-49% or TPS <1% group better than the pathologist's reading, with the TPS ≥50% group as a reference (hazard ratio [HR], 1.49 [95% CI, 1.19 to 1.86] v HR, 1.36 [95% CI, 1.08 to 1.71] for TPS 1%-49% group, and HR, 2.38 [95% CI, 1.69 to 3.35] v HR, 1.62 [95% CI, 1.23 to 2.13] for TPS <1% group). CONCLUSION: PD-L1 TPS assessed by AI analyzer correlates with that of pathologists, with clinical performance also being comparable when referenced to PFS. The AI model can accurately predict tumor response and PFS of ICI in advanced NSCLC via assessment of PD-L1 TPS. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Aims: Programmed death‐ligand 1 (PD‐L1) expression is a predictive biomarker for adjuvant immunotherapy and has been linked to poor differentiation in lung adenocarcinoma. However, its prevalence and prognostic role in the context of the novel histologic grade has not been evaluated. Methods: We analysed a cohort of 1233 patients with resected lung adenocarcinoma where PD‐L1 immunohistochemistry (22C3 assay) was reflexively tested. Tumour PD‐L1 expression was correlated with the new standardized International Association for the Study of Lung Cancer (IASLC) histologic grading system (G1, G2, and G3). Clinicopathologic features including patient outcome were analysed. Results: PD‐L1 was positive (≥1%) in 7.0%, 23.5%, and 63.0% of G1, G2, and G3 tumours, respectively. PD‐L1 positivity was significantly associated with male sex, smoking, and less sublobar resection among patients with G2 tumours, but this association was less pronounced in those with G3 tumours. PD‐L1 was an independent risk factor for recurrence (adjusted hazard ratio [HR] = 3.25, 95% confidence intervals [CI] = 1.93–5.48, P < 0.001) and death (adjusted HR = 2.69, 95% CI = 1.13–6.40, P = 0.026) in the G2 group, but not in the G3 group (adjusted HR for recurrence = 0.94, 95% CI = 0.64–1.40, P = 0.778). Conclusion: PD‐L1 expression differs substantially across IASLC grades and identifies aggressive tumours within the G2 subgroup. This knowledge may be used for both prognostication and designing future studies on adjuvant immunotherapy. [ABSTRACT FROM AUTHOR]

Purpose Programmed death-1/programmed death-ligand 1 (PD-L1) inhibitors have shown efficacy in metastatic esophageal squamous cell carcinoma (ESCC) therapy. However, data is still limited regarding neoadjuvant immunotherapy for operable ESCC. Materials and Methods Patients with clinical stage T2 or T3 and N0 ESCC received three cycles of nivolumab therapy every two weeks before surgical resection. The primary endpoint is major pathologic responses (MPR) rate (= 10% of residual viable tumor [RVT]). Results Total 20 patients completed the planned nivolumab therapy. Among them, 17 patients underwent surgery as protocol, showing MPR in two patients (MPR rate, 11.8%), including one pathologic complete response, on conventional pathologic response evaluation. Pathologic response was re-evaluated using the immune-related pathologic response criteria based on immune-related RVT (irRVT). Three patients were classified as immunologic major pathologic response (iMPR; = 10% irRVT, iMPR rate: 17.6%), five as pathologic partial response (> 10% and < 90% irRVT), and nine as pathologic nonresponse (= 90% irRVT). The combined positive score (CPS) for PD-L1 in the baseline samples was predictable for iMPR, with the probability as 37.5% in CPS = 10 (3/8) and 0% in CPS < 10 (0/9). Conclusion Although the efficacy of neoadjuvant nivolumab therapy was modest in unselected ESCC patients, further researches on neoadjuvant immunotherapy are necessary in patients with PD-L1 expressed ESCC. [ABSTRACT FROM AUTHOR]

Background: Endocrine therapy resistance in hormone receptor-positive/HER2-negative (HR+/HER2−) breast cancer (BC) is a significant clinical challenge that poses several unmet needs in the management of the disease. This study aimed to investigate the prognostic value of c-MET-positive circulating tumor cells (cMET+ CTCs), ESR1/PIK3CA mutations, and cell-free DNA (cfDNA) concentrations in patients with hormone receptor-positive (HR+) metastatic breast cancer (mBC). Methods: Ninety-seven patients with HR+ mBC were prospectively enrolled during standard treatment at Samsung Medical Center. CTCs were isolated from blood using GenoCTC® and EpCAM or c-MET CTC isolation kits. PIK3CA and ESR1 hotspot mutations were analyzed using droplet digital PCR. CfDNA concentrations were calculated using internal control copies from the ESR1 mutation test. Immunocytochemistry was performed to compare c-MET overexpression between primary and metastatic sites. Results: The proportion of c-MET overexpression was significantly higher in metastatic sites than in primary sites (p = 0.00002). Survival analysis showed that c-MET+ CTC, cfDNA concentration, and ESR1 mutations were significantly associated with poor prognosis (p = 0.0026, 0.0021, and 0.0064, respectively) in HR+/HER2− mBC. By contrast, EpCAM-positive CTC (EpCAM+ CTC) and PIK3CA mutations were not associated with progression-free survival (PFS) in HR+/HER2− mBC. Multivariate analyses revealed that c-MET+ CTCs and cfDNA concentration were independent predictors of PFS in HR+/HER2− mBC. Conclusions: Monitoring c-MET+ CTC, rather than assessing c-MET expression in the primary BC site, could provide valuable information for predicting disease progression, as c-MET expression can change during treatment. The c-MET+ CTC count and cfDNA concentration could provide complementary information on disease progression in HR+ /HER2− mBC, highlighting the importance of integrated liquid biopsy. [ABSTRACT FROM AUTHOR]

Background: Invasive mucinous adenocarcinoma (IMA) is distinct from non-mucinous adenocarcinoma, but studies on recurrent IMA are scarce. Thus, this study aimed to evaluate the recurrence patterns of IMA and the role of pulmonary local therapy (LT) in resectable pulmonary recurrence of IMA. Methods: The study reviewed 403 patients with surgically resected IMA between 1998 and 2018. The recurrence patterns were categorized as solitary pulmonary recurrence (SPR), multiple pulmonary recurrence (MPR), and extra-pulmonary recurrence (EPR). The clinicopathologic characteristics, overall survival (OS), and post-recurrence survival (PRS) were analyzed according to the recurrence pattern and LT administration. Results: Recurrences were found in 91 (22.6%) patients, including 18 patients with SPR, 37 patients with MPR, and 36 patients with EPR. Compared with the MPR and EPR groups, the SPR group had a longer disease-free interval (32.5 vs. 9.6 vs. 10.1 months, respectively; p < 0.01) and a better OS (5-year OS: 88.5%, 41.5%, and 22.9%, respectively; p < 0.01). In case of resectable pulmonary recurrence, pulmonary LT was administered to 15 patients with SPR and 3 patients with MPR. These patients showed a better 5-year PRS than the other patients with pulmonary recurrence (86.3% vs. 30.4%; p < 0.01). Notably, long-term survival was observed for one patient with MPR undergoing LT and two patients with SPR undergoing a second LT for a second pulmonary recurrence. Conclusions: In this series, the patients with recurrent IMA showed different prognoses according to the recurrence pattern. The patients with pulmonary recurrence of IMA undergoing LT showed a favorable prognosis, suggesting the potential role of LT for resectable pulmonary recurrence of IMA. [ABSTRACT FROM AUTHOR]

Simple Summary: Lung cancer is a leading cause of death worldwide, and it's crucial to know severity of cancer and predict its prognosis. Our study focused on using a special type of scan known as FDG PET/CT to predict how well patients with a specific type of lung cancer, called adenocarcinoma, would fare after surgery. The study looked at 432 patients and analyzed various factors like age, sex, and certain imaging parameters of the tumors. Our key finding was that the metabolic tumor volume of tumor was powerful indicator of prognosis after surgery. This information was even more accurate when combined with TNM staging, existing methods used to stage cancer. Therefore, these scans could provide doctors with valuable information to plan better treatments. This development has the potential to improve survival rates and quality of life for lung adenocarcinoma patients. Introduction: FDG PET/CT is a robust imaging modality to diagnose and stratify prognoses for non-small cell lung carcinoma. However, the role of FDG PET/CT in operable lung adenocarcinoma patients has not been previously investigated in a large cohort with varying pathological stages. The prognostic value of volumetric parameters based on FDG PET/CT was investigated in patients with stage I–III lung adenocarcinoma receiving curative surgery. Methods: This retrospective study included 432 patients with lung adenocarcinoma undergoing preoperative FDG PET/CT between January 2016 and December 2017. Clinicopathologic variables, conventional image parameters, such as the maximum standardized uptake value (SUVmax) and mean SUV (SUVmean) of the primary tumor, and volumetric parameters, such as metabolic tumor volume (MTV) and total lesion glycolysis (TLG), were included in Cox regression analysis. Subgroup analysis was conducted to compare hazard ratios (HRs) based on MTV in each pathological stage. A new staging system including volumetric parameters was suggested. Results: A total of 432 patients (median age: 62 years; interquartile range: 56–70 years; 225 males) were evaluated. Sex, age, presence of EGFR mutation, pathological stage, MTV, and TLG of the primary tumor were selected as statistically significant prognostic factors for overall survival irrespective of other variables (OS; p < 0.05 for all). Pathological stage, MTV, and TLG of the primary tumor were selected as statistically significant prognostic factors for disease-free survival irrespective of other variables (p < 0.05 for all). The suggested new staging system including MTV as an additional criterion showed better discrimination and prediction for OS than the conventional pathological staging system despite statistical insignificance (concordance index: 0.698 vs. 0.673). Conclusions: The volumetric parameters of the primary tumor based on preoperative FDG PET/CT were independent prognostic factors in addition to pathological stage in patients with operable lung adenocarcinoma. The suggested new staging system considering MTV predicted the prognoses better than the conventional pathological staging system. [ABSTRACT FROM AUTHOR]

Aims: The prognostic role of EGFR mutations remains controversial. We aimed to evaluate the prognostic role of EGFR mutation in consideration of the IASLC histological grade in patients with resected early‐stage lung adenocarcinoma. Methods and results: A total of 3297 patients with stages I–IIA resected lung adenocarcinoma who had had EGFR mutation tests between January 2014 and December 2019 at the Samsung Medical Center, Seoul, Korea were included. Recurrence‐free survival (RFS) was compared by EGFR mutation status (EGFR‐M+ versus EGFR‐WT) and IASLC histological grade (G1, G2 and G3). Cox proportional hazards models were used to estimate the adjusted HRs (aHRs) and 95% confidence intervals (CIs). Results: Compared to the EGFR‐WT group, the EGFR‐M+ group had a significantly lower proportion of G3 tumour (16 versus 33%, P < 0.001). During a median follow‐up of 41.4 months, 376 patients experienced recurrence. After adjusting for histological grade, the aHR for recurrence comparing the EGFR‐M+ to the EGFR‐WT was 1.30 (95% CI = 1.04–1.62, P = 0.022). The EGFR‐M+ group had a significantly lower 5‐year RFS than the EGFR‐WT group among G3 patients (58.4 versus 71.5%, P < 0.001), but not among G1 and G2 patients. Conclusions: EGFR mutation status was associated with a risk of recurrence after consideration of the IASLC histological grading, especially in G3 tumours. The results of this study would be useful for developing a new staging system and identifying a subset of patients who may benefit from adjuvant targeted therapy. [ABSTRACT FROM AUTHOR]

The aim of this study was to evaluate the CT and PET-CT features of solitary pulmonary capillary hemangioma (SPCH) with clinicopathologic correlations. This retrospective study included 17 patients with histologically proven SPCH from four tertiary institutions. The clinical, pathological and imaging findings of SPCH were reviewed. The CT features assessed included lesion location, size, density, contour, margin, enhancement, presence of air bronchogram, perivascular lucency and pleural retraction, and 18F-fluorodeoxyglucose uptake on PET-CT. Changes in the size during the follow-up period were also evaluated. Imaging features were correlated with the clinicopathologic findings. The mean age of the patients was 47 years (range 30–60 years). All SPCHs were incidentally detected during screening CT examinations (n = 13, 76%) or during cancer work-up (n = 4, 24%). Most SPCHs appeared as part-solid nodules (n = 15, 88%), the remaining appeared as a pure ground-glass nodule or a pure solid nodule, respectively. Most had smooth contours (n = 16, 94%), while one had a lobulated contour. Nine SPCHs (53%) showed ill-defined margins. Air bronchogram was present in ten (59%) SPCHs, and perivascular lucency in two (12%). All SPCHs exhibited hypoattenuation on contrast-enhanced CT and hypometabolism on PET-CT. During the follow-up period (mean 14.8 ± 17.7 months), the lesions showed no change in size or density in ten SPCHs (59%), decreased or fluctuation in size and density in three (18%). SPCH is often incidentally detected in young and middle-aged adults, commonly as an ill-defined part-solid nodule that may accompany air bronchogram, perivascular lucency, and fluctuation in size or density on CT and hypometabolism on PET-CT. [ABSTRACT FROM AUTHOR]

Objectives: Ground-glass opacity (GGO) on computed tomography is associated with prognosis in early-stage non-small cell lung cancer (NSCLC) patients. However, the stratification of the prognostic value of GGO is controversial. We aimed to evaluate clinicopathologic characteristics of early-stage NSCLC based on the consolidation-to-tumor ratio (CTR), conduct multi-pronged analysis, and stratify prognosis accordingly. Methods: We retrospectively investigated 944 patients with clinical stage IA NSCLC, who underwent curative-intent lung resection between August 2018 and January 2020. The CTR was measured and used to categorize patients into six groups (1, 0%; 2, 0–25%; 3, 25–50%; 4, 50–75%; 5, 75–100%; and 6, 100%). Results: Pathologic nodal upstaging was found in 1.8% (group 4), 9.0% (group 5), and 17.4% (group 6), respectively. The proportion of patients with a high grade of tumor-infiltrating lymphocytes tended to decrease as the CTR increased. In a subtype analysis of patients with adenocarcinoma, all of the patients with predominant micro-papillary patterns were in the CTR > 50% groups, and most of the patients with predominant solid patterns were in group 6 (47/50, 94%). The multivariate analysis demonstrated that CTR 75–100% (hazard ratio [HR], 3.85; 95% confidence interval [CI], 1.58–9.36) and CTR 100% (HR, 5.58; 95% CI, 2.45–12.72) were independent prognostic factors for DFS, regardless of tumor size. Conclusion: We demonstrated that the CTR could provide various noninvasive clinicopathological information. A CTR of more than 75% is the factor associated with a poor prognosis and should be considered when making therapeutic plans for patients with early-stage NSCLC. [ABSTRACT FROM AUTHOR]

Simple Summary: Lung cancer is one of the leading causes of cancer-related mortality worldwide. The incidence of multiple primary lung cancers has been increasing. In addition to the identification of epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors, the evaluation of the EGFR mutation status in lung cancer is important to devise optimal treatment strategies. In this study, the EGFR mutation status in multiple primary lung cancers was examined, and its discordance rate in individual tumors was determined to be high. Our findings reveal the importance of EGFR mutation analysis in individual tumors of multiple primary lung cancers. The prevalence of multiple lung cancers has been increasing recently. Molecular analysis of epidermal growth factor receptor (EGFR) mutations in individual tumors of multiple lung cancers is essential for devising an optimal therapeutic strategy. The EGFR mutation status in multiple lung cancers was evaluated to determine its therapeutic implications. In total, 208 tumors from 101 patients who underwent surgery for multiple lung cancers were analyzed. Individual tumors were subjected to histological evaluation and EGFR analysis using a real-time polymerase chain reaction. Additionally, EGFR-wildtype tumors were subjected to next-generation sequencing (NGS). EGFR mutations were detected in 113 tumors from 72 patients, predominantly in females (p < 0.001) and non-smokers (p < 0.001). Among patients with at least one EGFR-mutant tumor, approximately 72% of patients (52/72) had different EGFR mutations in individual tumors. NGS analysis of EGFR-wildtype tumors from 12 patients revealed four and eight cases with concordant and discordant molecular alterations, respectively. These findings revealed a high proportion of discordant EGFR mutations among multiple lung tumors. Hence, EGFR analysis of individual tumors of multiple lung tumors is essential for the evaluation of clonality and the development of an optimal treatment strategy. [ABSTRACT FROM AUTHOR]

Simple Summary: Recently, there has been increasing interest in identifying NTRK fusions in various tumors, as they are therapeutically targetable driver mutations. In tumor types with low-frequency NTRK fusions, recent recommendations on NTRK testing recommend pan-Trk immunohistochemistry (IHC) as the initial screening test to validate pan-Trk expression cases with next- generation sequencing (NGS) assays. This retrospective study was conducted on 1113 solid tumor samples (510 non-small cell lung cancers, 503 colorectal cancers, and 100 inflammatory myofibroblastic tumors) to evaluate using pan-Trk IHC assay, and TRK expression cases were followed by validation with NGS. We investigated the accuracy of an IHC assay in detecting NTRK fusions and characterizing the clinicopathological and molecular features of NTRK-rearranged common tumors. Despite its rarity, this study confirms the importance of identifying potential target groups based on the pathological and immunohistochemical characteristics of NTRK fusion-driven solid tumors for effective targeted therapy. Most NTRK fusions occur at very low frequencies in various common cancers. Recent recommendations on NTRK testing recommend immunohistochemistry (IHC) as the initial test for tumor types with a low frequency of NTRK fusions. This study investigated the accuracy of an IHC assay to detect NTRK fusions and characterize the clinicopathological and molecular features of NTRK-rearranged tumors. This retrospective study was conducted on 1113 solid tumor samples known to harbor no oncogenic driver alterations, including 510 non-small cell lung cancers (NSCLC), 503 colorectal cancers (CRC), and 79 inflammatory myofibroblastic tumors (IMT). Additionally, 21 ALK expression-positive cases were included. TRK expression was evaluated using a pan-Trk IHC assay, and positive cases were validated using NGS. TRK expression was observed in three NSCLCs (0.6%), six CRCs (1.2%), and six IMTs (6%). NTRK fusions were finally detected in two NSCLCs (0.4%), six CRCs (1.2%), and one IMT (1%). In NSCLC and CRC, the majority of NTRK fusions were readily discernible due to diffuse moderate-to-strong cytoplasmic staining on pan-Trk IHC. In IMT, focal weak nuclear staining indicated the presence of NTRK fusion. Therefore, the utility of pan-Trk IHC should be assessed considering that the difference in performance depends on tumor type. [ABSTRACT FROM AUTHOR]

Background: The current standard treatment for patients with inoperable, locally advanced esophageal squamous cell carcinoma (ESCC) is definitive concurrent chemoradiotherapy (CCRT). Methods: Patients with locally advanced ESCC received 2 cycles of 5‐fluorouracil, cisplatin, durvalumab, and tremelimumab every 3 weeks with concurrent radiation therapy (60.2 or 64.5 grays). After completing CCRT plus immunotherapy, patients received 2 cycles of consolidative durvalumab and tremelimumab followed by durvalumab monotherapy every 4 weeks for 2 years after enrollment. Their survival outcomes were compared with those from a propensity score‐matched historical control group that had received CCRT alone. Results: In total, 40 patients were enrolled and analyzed. The 24‐month progression‐free survival (PFS) and overall survival rates were 57.5% and 75%, respectively. Compared with the historical control group (n = 75), the study population had significantly longer PFS (hazard ratio [HR], 0.52; 95% confidence interval [CI], 0.28‐0.97; P =.040) and overall survival (HR, 0.49; 95% CI, 0.25‐0.98; P =.043). In the study population, patients who had PD‐L1–positive tumors (n = 28) had significantly longer PFS (HR, 0.20; 95% CI, 0.07‐0.54; P <.001) and overall survival (HR, 0.16; 95% CI, 0.05‐0.56; P =.001) compared with those who had PD‐L1–negative tumors (n = 11). However, there was no difference in survival outcomes according to PD‐L1 status in the historical control group, indicating a strong interaction between PD‐L1–positive status and survival outcomes in the treatment groups (PFS, P for interaction =.003; overall survival, P for interaction =.002). Conclusions: Durvalumab and tremelimumab with definitive CCRT had promising efficacy in patients with locally advanced ESCC. In addition, PD‐L1 expression had strong predictive value in the study population. The clinical efficacy of durvalumab and tremelimumab with definitive chemoradiotherapy was studied in patients who had inoperable esophageal squamous cell carcinoma. Significantly longer progression‐free and overall survival were observed compared with a propensity scored‐matched historical control group, and PD‐L1 expression seemed to have a strong predictive role in patients who had positive PD‐L1 combined proportion scores. [ABSTRACT FROM AUTHOR]

Purpose: To evaluate the role of positron emission tomography/computed tomography (PET/CT) in predicting pathologic complete response (pCR) and identify relevant prognostic factors from clinico-imaging-pathologic features of locally advanced esophageal squamous cell carcinoma (eSCC) patients undergoing trimodality therapy. Methods: We evaluated 275 patients with eSCCs of T3-T4aN0M0 and T1-T4aN1-N3M0 who received trimodality therapy. We correlated volume-based PET/CT parameters before and after concurrent chemoradiation therapy with pCR after surgery, clinico-imaging-pathologic features, and patient survival. Results: pCR occurred in 75 (27.3%) of 275 patients, of whom 61 (80.9%) showed 5-year survival. Pre-total lesion glycolysis (pre-TLG, OR = 0.318, 95% CI 0.169 to 0.600), post-metabolic tumor volume (post-MTV, OR = 0.572, 95% CI 0.327 to 0.999), and % decrease of average standardized uptake value (% SUVavg decrease, OR = 2.976, 95% CI = 1.608 to 5.507) were significant predictors for pCR. Among them, best predictor for pCR was pre-TLG with best cutoff value of 205.67 and with AUC value of 0.591. Performance status (HR = 5.171, 95% CI 1.737 to 15.397), pathologic tumor size (HR = 1.645, 95% CI 1.351 to 2.002), pathologic N status (N1, HR = 1.572, 95% CI 1.010 to 2.446; N2, HR = 3.088, 95% CI 1.845 to 5.166), and post-metabolic tumor volume (HR = 1.506, 95% CI 1.033 to 2.195) were significant predictors of overall survival. Conclusion: Pre-TLG, post-MTV, and % SUVavg decrease are predictive of pCR. Additionally, several clinico-imaging-pathologic factors are significant survival predictors in locally advanced eSCC patients undergoing trimodality therapy. [ABSTRACT FROM AUTHOR]

Neurotrophic tropomyosin receptor kinase (NTRK) gene fusions are emerging tissue‐agnostic drug targets in malignancies including colorectal carcinomas (CRCs), but their detailed landscape in the context of various colorectal carcinogenesis pathways remains to be investigated. In this study, pan‐tropomyosin receptor kinase (TRK) protein expression was assessed by immunohistochemistry (IHC) in retrospectively collected colorectal epithelial tumor tissues, including 441 CRCs [133 microsatellite instability‐high (MSI‐high) and 308 microsatellite stable (MSS)] and 595 premalignant colorectal lesions (330 serrated lesions and 265 conventional adenomas). TRK‐positive cases were then subjected to next‐generation sequencing and/or fluorescence in situ hybridization to confirm NTRK rearrangements. TRK IHC positivity was not observed in any of the MSS CRCs, conventional adenomas, traditional serrated adenomas, or hyperplastic polyps, whereas TRK positivity was observed in 11 of 58 (19%) MLH1‐methylated MSI‐high CRCs, 4 of 23 (17%) sessile serrated lesions with dysplasia (SSLDs), and 5 of 132 (4%) sessile serrated lesions (SSLs). The 11 TRK‐positive MSI‐high CRCs commonly harbored CpG island methylator phenotype‐high (CIMP‐high), MLH1 methylation, BRAF/KRAS wild‐type, and NTRK1 or NTRK3 fusion (TPM3–NTRK1, TPR–NTRK1, LMNA–NTRK1, SFPQ–NTRK1, ETV6–NTRK3, or EML4–NTRK3). Both NTRK1 or NTRK3 rearrangement and BRAF/KRAS wild‐type were detected in all nine TRK‐positive SSL(D)s, seven of which demonstrated MSS and/or CIMP‐low. TRK expression was selectively observed in distorted serrated crypts within SSLs and was occasionally localized at the base of serrated crypts. NTRK fusions were detected only in SSLs of patients aged ≥50 years, whereas BRAF mutation was found in younger age‐onset SSLs. In conclusion, NTRK‐rearranged colorectal tumors develop exclusively through the serrated neoplasia pathway and can be initiated from non‐dysplastic SSLs without BRAF/KRAS mutations prior to full occurrence of MSI‐high/CIMP‐high. © 2021 The Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

The treatment of patients with advanced non-small-cell lung cancer (NSCLC) in recent years has been increasingly guided by biomarker testing. Testing has centered on driver genetic alterations involving the epidermal growth factor receptor (EGFR) and anaplastic lymphoma kinase (ALK) rearrangements. The presence of these mutations is predictive of response to targeted therapies such as EGFR tyrosine kinase inhibitors (TKIs) and ALK TKIs. However, there are substantial challenges for the implementation of biomarker testing, particularly in emerging countries. Understanding the barriers to testing in NSCLC will be key to improving molecular testing rates worldwide and patient outcomes as a result. In this article, we review EGFR mutations and ALK rearrangements as predictive biomarkers for NSCLC, discuss a selection of appropriate tests and review the literature with respect to the global uptake of EGFR and ALK testing. To help improve testing rates and unify procedures, we review our experiences with biomarker testing in China, South Korea, Russia, Turkey, Brazil, Argentina and Mexico, and propose a set of recommendations that pathologists from emerging countries can apply to assist with the diagnosis of NSCLC. [ABSTRACT FROM AUTHOR]

Background: Because of the growing number of actionable biomarkers in non–small cell lung cancer (NSCLC), sufficient tissue availability for testing is becoming a greater challenge. Liquid biopsy offers a potential solution by complementing standard tissue‐based methods. In this study, the authors analyzed the concordance of actionable genomic alterations sequenced from circulating tumor DNA (ctDNA; Guardant360) and tissue (Oncomine Focus Assay). Methods: From September 2015 to May 2018, 421 paired plasma and tissue samples from patients with advanced NSCLC who had previously undergone tissue testing by standard methods were collected. Both types of samples were available for 287 patients (262 in cohort 1 [treatment‐naive] and 25 in cohort 2 [treatment failure]), and only 1 sample type was available for 134 patients (50 in cohort 3 [plasma only] and 84 in cohort 4 [tissue only]). Results: In cohort 1, 198 samples (77.6%) showed concordance between tissue and plasma next‐generation sequencing (NGS). Among the discordant cases, plasma testing detected additional genomic alterations in 11 patients (4.2%). In 50 patients without tissue‐based NGS results (cohort 3), the ctDNA‐based test detected genomic alterations in 20 samples (40.0%). The median allele frequency (AF) of mutations identified with ctDNA‐based NGS (0.74%) was lower than that identified with the tissue‐based NGS test (13.90%). Clinical responses to matched targeted therapy occurred, regardless of the ctDNA AF. Upfront ctDNA‐based testing identified 60.4% of patients with genomic alterations. In addition, ctDNA‐based testing uncovered 12.0% more actionable alterations when it was performed after tissue‐based NGS testing. Conclusions: The results indicate that a ctDNA‐based test identifies additional patients with actionable genomic alterations and could, therefore, be used to complement traditional tissue‐based testing for NSCLC. Lay Summary: Circulating tumor DNA (ctDNA)–based next‐generation sequencing (NGS) testing is becoming essential as the number of actionable genomic biomarker increases for the treatment selection of non–small cell lung cancer.This study demonstrates the additive value of ctDNA‐based testing in addition to tissue‐based NGS and standard of care–based biomarker testing for detecting additional patients with actionable genomic alterations.Clinical responses have also been observed in patients with a low allele frequency detected by ctDNA‐based NGS testing. The results of this study support the benefit of circulating tumor DNA–based next‐generation sequencing (NGS) when it is used along with the tissue‐based standard of care and NGS to prevent undergenotyping in patients with non–small cell lung cancer at the time of the initial diagnosis and during later disease progression. [ABSTRACT FROM AUTHOR]

Background: Nuclear protein in testis (NUT) carcinoma is a rare tumor associated with NUT rearrangement that can present as poorly differentiated to undifferentiated carcinoma, with or without abrupt squamous differentiation. It is often misdiagnosed as poorly differentiated carcinoma or undifferentiated carcinoma if NUT is not suspected. In this study, we retrospectively analyzed pulmonary NUT carcinoma cases diagnosed with NUT immunohistochemical staining and discuss the differential diagnosis to provide information for this rare and aggressive entity. Methods: Cases, diagnosed as "NUT carcinoma" in lung pleura and "metastatic NUT carcinoma from the lung" in lymph nodes were diagnosed between 2017 and 2019 at the Samsung Medical Center (SMC). Clinical features such as age, sex, treatment and follow‐up period, and pathological reports were obtained by reviewing patients' electronic medical records. Results: A total of 10 NUT carcinoma cases were found in the SMC pathology database. Seven patients were men and six were non‐smokers. Tumor cells showed various cellular features such as round, squamoid, and spindle. Some cases had initially been misdiagnosed as spindle cell neoplasm, round cell sarcoma, squamous cell carcinoma and small cell carcinoma. All cases showed diffuse strong nuclear expression of NUT immunohistochemical staining, and some were positive for p63 staining and negative for CD56 staining. Conclusions: NUT carcinoma is often misdiagnosed because of its various morphologies. It is important to consider NUT as one of the differential diagnoses when encountering lung biopsy with undifferentiated morphology. Key points: Due to various morphological features, NUT carcinoma can be misdiagnosedIt is important to consider NUT carcinoma when diagnosing a poorly differentiated or undifferentiated tumor [ABSTRACT FROM AUTHOR]

Background: Treatment of human lung squamous cell carcinoma (LUSC) using current targeted therapies is limited because of their diverse somatic mutations without any specific dominant driver mutations. These mutational diversities preventing the use of common targeted therapies or the combination of available therapeutic modalities would require a preclinical animal model of this tumor to acquire improved clinical responses. Patient-derived xenograft (PDX) models have been recognized as a potentially useful preclinical model for personalized precision medicine. However, whether the use of LUSC PDX models would be appropriate enough for clinical application is still controversial.Methods: In the process of developing PDX models from Korean patients with LUSC, the authors investigated the factors influencing the successful initial engraftment of tumors in NOD scid gamma mice and the retainability of the pathological and genomic characteristics of the parental patient tumors in PDX tumors.Conclusions: The authors have developed 62 LUSC PDX models that retained the pathological and genomic features of parental patient tumors, which could be used in preclinical and co-clinical studies. Trial registration Tumor samples were obtained from 139 patients with LUSC between November 2014 and January 2019. All the patients provided signed informed consents. This study was approved by the institutional review board (IRB) of Samsung Medical Center (2018-03-110). [ABSTRACT FROM AUTHOR]

Background and Aim: Knowledge of lymph node metastasis (LNM) status is crucial to determine whether patients with superficial esophageal squamous cell carcinoma (ESCC) can be cured with endoscopic resection alone, without the need for additional esophagectomy. The present study aimed to identify predictive factors and develop a prediction model for LNM in patients with superficial ESCC. Methods: Clinicopathologic data from 501 patients with superficial ESCC treated with radical esophagectomy were reviewed. Stepwise logistic regression analysis determined the predictors of LNM. Using these predictors, a nomogram for predicting the risk of LNM was constructed and internally validated using a bootstrap resampling method. Results: LNM rates of tumors invading the lamina propria, muscularis mucosa, and SM1 layers were 3.7%, 15.5%, and 40.7%, respectively. Deep tumor invasion depth, moderately or poorly differentiated histology, and lymphovascular invasion were independent predictors of LNM. ESCC with muscularis mucosa and SM1 invasion had odds ratios of 3.635 and 11.834, respectively, compared with that for ESCC confined to the lamina propria. Large tumor size (>2.0 cm) and presence of tumor budding showed borderline significance for LNM prediction. These five variables were incorporated into a nomogram. A constructed nomogram showed good calibration and good discrimination with an area under the receiver‐operating characteristic curve (area under the curve [AUC]) of 0.812. After bootstrapping, AUC was 0.811. Conclusions: We developed a nomogram that can facilitate individualized prediction of risk of LNM in patients with superficial ESCC. This model can aid in decision‐making for the need for additional esophagectomy after endoscopic resection for superficial ESCC. [ABSTRACT FROM AUTHOR]

Advanced metastatic cancer poses utmost clinical challenges and may present molecular and cellular features distinct from an early-stage cancer. Herein, we present single-cell transcriptome profiling of metastatic lung adenocarcinoma, the most prevalent histological lung cancer type diagnosed at stage IV in over 40% of all cases. From 208,506 cells populating the normal tissues or early to metastatic stage cancer in 44 patients, we identify a cancer cell subtype deviating from the normal differentiation trajectory and dominating the metastatic stage. In all stages, the stromal and immune cell dynamics reveal ontological and functional changes that create a pro-tumoral and immunosuppressive microenvironment. Normal resident myeloid cell populations are gradually replaced with monocyte-derived macrophages and dendritic cells, along with T-cell exhaustion. This extensive single-cell analysis enhances our understanding of molecular and cellular dynamics in metastatic lung cancer and reveals potential diagnostic and therapeutic targets in cancer-microenvironment interactions. Understanding the mechanisms that lead to lung adenocarcinoma metastasis is important for identifying new therapeutics. Here, the authors document the changes in the transcriptome of human lung adenocarcinoma using single-cell sequencing and link cancer cell signatures to immune cell dynamics. [ABSTRACT FROM AUTHOR]

Objectives: To examine the correlation of diffusion-weighted and dynamic contrast-enhanced magnetic resonance imaging (MRI) parameters with Ki-67 labeling index (LI) in soft tissue sarcoma (STS).Methods: The institutional review board approved this retrospective study, and the requirement for informed consent was waived. Thirty-six patients with STS who underwent 3.0-T MRI, including diffusion-weighted and dynamic contrast-enhanced MRI, between July 2011 and February 2018, were included in this study. The mean and minimum apparent diffusion coefficients (ADCs) (ADCmean and ADCmin, respectively), volume transfer constant, reflux rate, and volume fraction of the extravascular extracellular matrix of each lesion were independently analyzed by two readers. Their relationship with the Ki-67 LI was examined using Spearman's correlation analyses. Differences between low- and high-proliferation groups based on Ki-67 LI were evaluated statistically. Optimal cut-off points were determined using the area under the curve analysis for significant parameters. Interobserver agreement was assessed with the intraclass correlation coefficient.Results: ADCmean (ρ = - 0.333, p = 0.047) was significantly and inversely correlated with Ki-67 LI. The high-proliferation group showed a significantly lower ADCmean than did the low-proliferation group (median, 1.08 vs. 1.20; p = 0.048). When a cut-off ADCmean value of 1.16 × 10-3 mm2/s was used, the sensitivity, specificity, and area under the curve for differentiating low- and high-proliferation groups were 75.0%, 60.0%, and 0.712, respectively. Interobserver agreements between the two readers were almost perfect for all parameters.Conclusions: ADCmean was correlated with Ki-67 LI and could help differentiate between STS with low and high proliferation potential.Key Points: • ADC meanwas significantly and inversely correlated with Ki-67 labeling index in soft tissue sarcoma. • In the high-proliferation group, ADC meanvalues were significantly lower than those of the low-proliferation group. [ABSTRACT FROM AUTHOR]

We previously showed that UBE2C mRNA expression is significantly associated with poor prognosis only in patients with hormone receptor (HR)+/human epidermal growth factor receptor 2 (HER2)– breast cancer. In this study, we further reanalyzed the correlation between UBE2C mRNA expression and clinical outcomes in patients with HR+/HER2– breast cancer, and we investigated the molecular mechanism underlying the role of UBE2C modulation in disease progression in this subgroup of patients. Univariate and multivariate analyses showed that high UBE2C expression was associated with significantly shorter survival of breast cancer patients with pN0 and pN1 tumors but not pN2/N3 tumors (P < 0.05). In vitro functional experiments in HR+/HER2– breast cancer cells showed that UBE2C expression is a tumorigenic factor, and that estrogen upregulated UBE2C mRNA and protein by directly binding to the UBE2C promoter region. UBE2C knockdown inhibited cell proliferation by affecting cell cycle progression, and UBE2C overexpression was associated with estrogen-independent growth. UBE2C depletion markedly increased the cytotoxicity of tamoxifen by inducing apoptosis. The present findings suggest that UBE2C overexpression is correlated with relapse and promotes estrogen-dependent/independent proliferation in early HR+/HER2– breast cancer. [ABSTRACT FROM AUTHOR]

With the increasing oncological potential of immunotherapy, several immune checkpoint modulators are being investigated. The value of immune markers, including programmed cell death ligand-1, programmed cell death-1 (PD-1), inducible co-stimulator (ICOS), lymphocyte activation gene-3, T-cell immunoglobulin, and mucin-dominant containing-3 (TIM-3), is not well known. Using tissue microarrays of 396 patients who underwent surgery for oesophageal squamous cell carcinoma (ESCC), infiltrated T-cell subsets (CD3, CD8, and Foxp3) and checkpoint protein expression were scored. With a median follow-up of 24.8 months, CD3+ TIL subsets (50.0%) had longer median recurrence-free survival (RFS, 55.0 vs 21.4 months) and overall survival (OS, 77.7 vs 35.8 months). Patients with high ICOS expression (46.5%) had longer median RFS (53.9 vs 25.3 months) and OS (88.8 vs 36.9 months). For PD-1, RFS (hazard ratio [HR] 0.67) and OS (HR 0.66) were significantly longer in the high-expression group (45.2%). In the multivariate analysis, high TIM-3 expression (50.8%) had a significant relationship with shorter RFS (HR = 1.52) and OS (HR = 1.60). High CD3+ TIL and T-cell ICOS expression were associated with favourable prognosis, whereas high TIM-3 expression suggested a poor prognosis. Our findings may confer new insights to improve ESCC outcomes beyond the application of PD-1 blockade. [ABSTRACT FROM AUTHOR]

Solitary fibrous tumors (SFTs) are NAB2-STAT6 fusion-associated neoplasms. There are several subtypes of NAB2-STAT6 fusions, but their clinical significances are still unclear. Moreover, the mechanisms of malignant progression are also poorly understood. In this study, using 91 SFT cases, we examined whether fusion variants are associated with clinicopathological parameters and also investigated the molecular mechanism of malignant transformation using whole-exome sequencing. We detected variant 1b (NAB2ex4-STAT6ex2) in 51/91 (56%) cases and variants 2a/2b (NAB2ex6-STAT6ex16/17) in 17/91 (19%) cases. The NAB2-STAT6 fusion variant types were significantly associated with their primary site (P < 0.001). In addition, a TERT promoter mutation was detected in 7/73 (10%) cases, and it showed a significant association with malignant SFTs (P = 0.003). To identify molecular changes during malignant progression, we selected an index patient to obtain parallel tissue samples from the primary and metastatic tumors. In the metastatic tissue, 10 unique molecular alterations, including those in TP53 and APAF1, were detected. In vitro functional experiments showed that APAF1 depletion increased the tumor potency of cells expressing NAB2-STAT6 fusion protein under treatment with staurosporine. We found that TP53 immunopositivity (P = 0.006) and loss of APAF1 immunoreactivity (P < 0.001) were significantly associated with malignant SFTs. Our study suggests that dysfunction of TP53 and APAF1 leads to impaired apoptotic function, and eventually contributes toward malignant SFT transformation. Key messages: We firstly found that the TERT promoter mutation was strongly associated with malignant SFTs (P = 0.003) and the representative 1b (NAB2ex4-STAT6ex2) or 2a (NAB2ex6-STAT6ex16) fusion variants similarly contribute to tumorigenicity. We also found that TP53 immunopositivity (P = 0.006) and loss of APAF1 immunoreactivity (P < 0.001) were significantly associated with malignant SFTs. Our study suggests that dysfunction of TP53 and APAF1 leads to impaired apoptotic function, and eventually contributes toward malignant SFT transformation. [ABSTRACT FROM AUTHOR]

Well‐differentiated liposarcoma (WDLPS) and dedifferentiated liposarcoma (DDLPS) are the most common types of liposarcoma. Although WDLPS and DDLPS patients receive intensive treatment including radical surgery and systemic therapy, their overall 5‐year survival rates are 90% and 30%, respectively, indicating that DDLPS is clinically more aggressive. We examined whether adipogenic stimulation induces adipogenesis in human WDLPS/DDLPS cells by using dexamethasone, indomethacin, insulin, and 3‐isobutyl‐1‐methylxanthine (IBMX), all putative medications or drugs. Functional in vitro experiments showed that treatment with these four compounds induced adipogenic potency by transcriptional and translational upregulation of genes related to the maintenance of stemness and adipogenic differentiation. Using in vivo xenograft models, we found that the induction of stemness and adipogenesis inhibited the tumorigenic potency of DDLPS. This study suggests a potential application of drug repositioning in which adipogenesis‐inducing compounds could be used to treat DDLPS patients in a clinical setting. [ABSTRACT FROM AUTHOR]

Introduction: The GenesWell Breast Cancer Test (BCT) is a recently developed multigene assay that predicts the risk of distant recurrence in patients with early breast cancer. Here, we analyzed the concordance of the BCT score with the Oncotype DX recurrence score (RS) for risk stratification in Asian patients with pN0-N1, hormone receptor-positive, human epidermal growth factor receptor 2 (HER2)-negative breast cancer. Methods: Formalin-fixed, paraffin-embedded breast cancer tissues previously analyzed using the Oncotype DX test were assessed using the GenesWell BCT test. The risk stratification by the two tests was then compared. Results: A total of 771 patients from five institutions in Korea were analyzed. According to the BCT score, 527 (68.4%) patients were classified as low risk, and 244 (31.6%) as high risk. Meanwhile, 134 (17.4%), 516 (66.9%), and 121 (15.7%) patients were categorized into the low-, intermediate-, and high-risk groups, respectively, according to the RS ranges used in the TAILORx. The BCT high-risk group was significantly associated with advanced lymph node status, whereas no association between RS risk groups and nodal status was observed. The concordance between the two risk stratification methods in the overall population was 71.9% when the RS low-risk, and intermediate-risk groups were combined into one group. However, poor concordance was observed in patients aged ≤50 years and in those with lymph node-positive breast cancer. Conclusions: The concordance between the BCT score and RS was low in women aged ≤50 years or with lymph node-positive breast cancer. Further studies are necessary to identify more accurate tests for predicting prognosis and chemotherapy benefit in this subpopulation. [ABSTRACT FROM AUTHOR]

Background: Liposarcoma (LPS) is a tumor derived from adipose tissue, and has the highest incidence among soft tissue sarcomas. Dedifferentiated liposarcoma (DDLPS) is a malignant tumor with poor prognosis. Recurrence and metastasis rates in LPS remain high even after chemotherapy and radiotherapy following complete resection. Therefore, the development of advanced treatment strategies for LPS is required. In the present study, we investigated the effect of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) treatment, and of combination treatment using TRAIL and a c-Met inhibitor on cell viability and apoptosis in LPS and DDLPS cell lines of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) treatment, and of combination treatment using TRAIL and a c-Met inhibitor.Methods: We analyzed cell viability after treatment with TRAIL and a c-Met inhibitor by measuring CCK8 and death receptor 5 (DR5) expression levels via fluorescence activated cell sorting (FACS) in both sarcoma cell lines and DDLPS patient-derived cells (PDCs). Moreover, we validated the effects of TRAIL alone and in combination with c-Met inhibitor on apoptosis in LPS cell lines and DDLPS PDCs via FACS.Results: Our results revealed that combination treatment with a c-Met inhibitor and human recombinant TRAIL (rhTRAIL) suppressed cell viability and induced cell death in both sarcoma cell lines and DDLPS PDCs, which showed varying sensitivities to rhTRAIL alone. Also, we confirmed that treatment with a c-Met inhibitor upregulated DR5 levels in sarcoma cell lines and DDLPS PDCs. In both TRAIL-susceptible and TRAIL-resistant cells subjected to combination treatment, promotion of apoptosis was dependent on DR5 upregulation.Conclusion: From these results, our findings validated that DR5 up-regulation caused by combination therapy with a c-Met inhibitor and rhTRAIL enhanced TRAIL sensitization and promoted apoptosis. We propose the use of this approach to overcome TRAIL resistance and serve as a novel treatment strategy for clinical trials. [ABSTRACT FROM AUTHOR]