The Prognostic Value of Sex-Determining Region Y-Box 2 and CD8+ Tumor-Infiltrating Lymphocytes in Limited-Stage Small-Cell Lung Cancer.

BACKGROUND: Sex-determining region Y-box 2 (SOX2) is a transcriptional factor that drives embryonic stem cells to neuroendocrine cells in lung development and is highly expressed in small-cell lung cancer (SCLC). However, the prognostic role of SOX2 and its relationship with tumor-infiltrating lymphocytes (TILs) has not been determined in SCLC. Herein, we assessed the expression of SOX2 and CD8+ TILs to obtain insights into the prognostic role of SOX2 and CD8+ TILs in limited-stage (LS)-SCLC. METHODS: A total of 75 patients with LS-SCLC was enrolled. The SOX2 expression and CD8+ TILs were evaluated by immunohistochemistry. RESULTS: High SOX2 and CD8+ TIL levels were identified in 52 (69.3%) and 40 (53.3%) patients, respectively. High SOX2 expression was correlated with increased density of CD8+ TILs (p = 0.041). Unlike SOX2, high CD8+ TIL numbers were associated with significantly longer progression-free survival (PFS; 13.9 vs. 8.0 months, p = 0.014). Patients with both high SOX2 expression and CD8+ TIL numbers (n = 29, 38.7%) had significantly longer PFS and overall survival (OS) compared to those from the other groups (median PFS 19.3 vs. 8.4 months; p = 0.002 and median OS 35.7 vs. 17.4 months; p = 0.004, respectively). Multivariate Cox regression analysis showed that the combination of high SOX2 expression and CD8+ TIL levels was an independent good prognostic factor for OS (HR = 0.471, 95% CI, 0.250-0.887, p = 0.02) and PFS (HR = 0.447, 95% CI, 0.250-0.801, p = 0.007) in SCLC. CONCLUSIONS: Evaluation of the combination of SOX2 and CD8+ TIL levels may be of a prognostic value in LS-SCLC.

The implications of clinical risk factors, CAR index, and compositional changes of immune cells on hyperprogressive disease in non-small cell lung cancer patients receiving immunotherapy.

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

Prognostic effects of histology-based tumour microenvironment scores in resected distal bile duct cancer.

AIMS: Histology-based tumour microenvironment (TME) scores are useful in predicting the prognosis of gastrointestinal cancer. However, their prognostic roles in distal bile duct cancer (DBDC) have not been previously studied. This study aimed to evaluate the prognostic significance of the TME scores using the Klintrup-Mäkinen (KM) grade, tumour stroma percentage (TSP) and the Glasgow microenvironment score (GMS) in resected DBDC. METHODS AND RESULTS: Eighty-one patients with DBDC who underwent curative resection were enrolled. DBDC was graded according to KM grade, TSP and GMS. A high KM grade was found in 19 patients (24%) and a high TSP was found in 47 patients (58%). A high TSP was significantly correlated with a low KM grade (P < 0.001). The distribution of the GMS, which was developed by combining the KM grade and TSP, was as follows: 0 (n = 19, 24%), 1 (n = 19, 24%) and 2 (n = 43, 52%). A low KM grade, high TSP and high GMS were significantly associated with short overall survival (OS) (P < 0.001) and relapse-free survival (RFS) (P < 0.001). Furthermore, multivariate analysis showed that a low KM grade [hazard ratio (HR) = 3.826; confidence interval (CI) = 1.650-8.869; P = 0.014], high TSP (HR = 2.193; CI = 1.173-4.100, P = 0.002) and high GMS (HR = 7.148; CI = 2.811-18.173) were independent prognostic factors for short RFS; a low KM grade (HR = 4.324; CI = 1.594-11.733) and high GMS (HR = 6.332; CI = 2.743-14.594) were independent prognostic factors for short OS. CONCLUSION: Histology-based TME scores, including the KM grade, TSP and GMS, are useful for predicting the survival of patients with resected DBDC.

Impact of Epidermal Growth Factor Receptor Mutation on Clinical Outcomes of Nintedanib Plus Docetaxel in Patients with Previously Treated Non-Small Cell Lung Cancer from the Korean Named Patient Program.

OBJECTIVES: Anti-angiogenic agents are reported to exert clinical activity on epidermal growth factor receptor (EGFR) mutant non-small-cell lung cancers. We evaluated the clinical outcomes of nintedanib and docetaxel in refractory NSCLC according to EGFR mutation status during the Korean nintedanib named patient program. METHODS: Docetaxel was administered either 75 or 37.5 mg/m2 on D1, D8 q every 3 weeks for 4-6 cycles plus nintedanib 200 mg orally twice daily until disease progression or unacceptable toxicity. RESULTS: Sixty-two patients were enrolled for study. Twenty-eight patients with activating EGFR mutations progressed after EGFR-tyrosine kinase inhibitors (TKI) therapy and 25 out of 28 patients showing progression after platinum doublet chemotherapy were enrolled. The objective response rate was 29% and median PFS and OS were 3.9 months and 11.7 months. Based on the EGFR mutation status, the objective response rate was 39.3 vs. 21.9% (EGFR mut(+) vs. EGFR mut(-), p = 0.142) and median PFS was 6.5 vs. 3.3 months (EGFR mut(+) vs. EGFR mut(-), p = 0.009). No treatment-related deaths were reported. The most frequent drug-related adverse events (AE) were neutropenia (53.2%) and diarrhea (37.1%). Treatment in 12 patients (19.3%) was permanently discontinued due to AEs without disease progression. CONCLUSIONS: Our data indicated that nintedanib-docetaxel combination could be considered to be effective treatment in EGFR TKI-resistant EGFR mutant NSCLC.

The effect of antibiotics on the clinical outcomes of patients with solid cancers undergoing immune checkpoint inhibitor treatment: a retrospective study.

BACKGROUND: This study aimed to assess the effect of antibiotics on the clinical outcomes of patients with solid cancers undergoing treatment with immune checkpoint inhibitors (ICIs). METHODS: The medical records of 234 patients treated with ICIs for any type of solid cancer between February 2012 and May 2018 at the Seoul St. Mary's Hospital were retrospectively reviewed. The data of patients who received antibiotics within 60 days before the initiation of ICI treatment were analyzed. The patients' responses to ICI treatment and their survival were evaluated. RESULTS: Non-small-cell lung carcinoma was the most common type of cancer. About half of the patients were treated with nivolumab (51.9%), and cephalosporin (35.2%) was the most commonly used class of antibiotics. The total objective response rate was 21%. Antibiotics use was associated with a decreased objective response (odds ratio 0.466, 95% confidence interval [CI] 0.225-0.968, p = 0.040). The antibiotics group exhibited shorter progression-free survival (PFS) and overall survival (OS) than the no antibiotics group (median PFS: 2 months vs. 4 months, p < 0.001; median OS: 5 months vs. 17 months, p < 0.001). In the multivariate analysis, antibiotics use was a significant predictor of patient survival (PFS: hazard ratio [HR] 1.715, 95% CI 1.264-2.326, p = 0.001; OS: HR 1.785, 95% CI 1.265-2.519, p = 0.001). CONCLUSIONS: The use of antibiotics may affect the clinical outcomes of patients with solid cancers treated with ICIs. Careful prescription of antibiotics is warranted in candidates who are scheduled for ICI treatment. TRIAL REGISTRATION: Not applicable (retrospective study).

Intracranial control and survival outcome of tyrosine kinase inhibitor (TKI) alone versus TKI plus radiotherapy for brain metastasis of epidermal growth factor receptor-mutant non-small cell lung cancer.

INTRODUCTION: The efficacy of tyrosine kinase inhibitors (TKIs) with and without radiotherapy (RT) has not been determined in patients with brain metastases from epidermal growth factor receptor-mutant TKI naïve non-small cell lung cancer (NSCLC). METHODS: Between 2008 and 2016, 586 patients were diagnosed with NSCLC and treated with TKIs at a hospital in Seoul, South Korea; 81 of these patients met the eligibility criteria for our study. Outcomes analyzed included intracranial progression (ICP), neurological death, and overall survival (OS). RESULTS: The 2-year cumulative incidence of ICP was 36.5% in the TKI plus RT group and 62.2% in the TKI alone group (P = 0.006). The chronological pattern analysis indicated that 64.3% of ICP developed within 12 months of the start of TKI treatment in the TKI alone group. The multivariate analysis revealed that treatment group (P = 0.003) and duration of TKI treatment ≤ 12 months (P < 0.001) were significantly associated with ICP. However, no significant differences were observed in the 2-year OS rate (P = 0.267) or the 2-year cumulative incidence of neurological death (P = 0.740). CONCLUSIONS: Cumulative incidence of ICP was significantly lower with TKI plus RT than with TKI alone; however, there was no significant difference in OS or neurological death. Deferring brain RT may not compromise neurologic and survival outcome in selected patients, but close magnetic resonance imaging follow-up is recommended for patients who defer brain RT.

Clinical Significance of C-MET Overexpression and Epidermal Growth Factor Receptor Mutation in Platinum-Based Adjuvant Chemotherapy Outcome in Surgically Resected Lung Adenocarcinoma.

PURPOSE: We retrospectively assessed the role of C-MET expression and epidermal growth factor receptor (EGFR) mutation on survival following platinum-based adjuvant chemotherapy. The impact of C-MET on survival was also investigated in relation to EGFR mutation status. METHODS: We enrolled 311 patients with resected lung adenocarcinoma (high-risk stage 1B-3A), and performed immunohistochemistry (IHC) using C-MET- and mutant EGFR (EGFRmut)-specific antibodies in tissue microarrays. RESULTS: Adjuvant chemotherapy was administered to 151 patients, 96 of whom relapsed and 85 died by the end of the study. On IHC, C-MET and EGFRmut were positive in 141 (45.3 %) and 88 (28.3 %) cases, respectively. On univariate analysis, adjuvant chemotherapy prolonged relapse-free survival (RFS) and overall survival (OS) in C-MET(+) patients (RFS p = 0.035; OS p = 0.013) but not in C-MET(-) patients. On multivariate analysis, adjuvant chemotherapy was a positive independent prognostic factor in C-MET(+) (RFS p = 0.013; OS p = 0.006) but not in C-MET(-) patients. In addition, univariate analysis showed no effect of EGFRmut status on RFS and OS after chemotherapy, whereas multivariate analysis revealed that adjuvant chemotherapy increased RFS in both EGFRmut(+) and EGFRmut(-) patients [EGFRmut(+) p = 0.033; EGFRmut(-) p = 0.030]. C-MET was a negative prognostic factor for RFS (p = 0.045) and OS (p = 0.007) in the EGFRmut(-) group but not in the EGFRmut(+) group, on multivariate analysis. CONCLUSIONS: Our data indicate that patients with C-MET overexpression should be considered for adjuvant chemotherapy, and that C-MET negatively correlates with survival in patients with wild-type, but not mutant, EGFR.

Serum lactate dehydrogenase levels at presentation in stage IV non-small cell lung cancer: predictive value of metastases and relation to survival outcomes.

This study aimed to evaluate the clinical correlations between serum lactate dehydrogenase (LDH) levels and tumor characteristics and to investigate the prognostic impact of serum LDH levels in advanced non-small cell lung cancer (NSCLC). A total of 394 patients were included in the present study between June 2007 and January 2013. All eligible patients had serum LDH levels available before treatment, and whole-body metastatic extent was measured using whole-body metastatic scores, as determined by 18(F)-fludeoxyglucose positron emission tomography scans from 1 to 7 as the sum of each metastatic region. The diagnostic cutoff value for an abnormal serum LDH level was 450 IU/L. The median serum LDH level was 477 IU/L (range, 113-2850), and 224 (56.9 %) patients had abnormal serum LDH levels. The serum LDH levels showed no significant associations with age, gender, histology, tumor differentiation, and smoking history. However, the proportion of patients with abnormal serum LDH levels was statistically significantly higher in the high total metastatic score group (scores 3-7) than in the low total metastatic score group (scores 1-2) (65.3 vs 50.4 %, p = 0.001). In a multivariate survival analysis, age (p = 0.001), gender (p = 0.001), histology (p = 0.003), tumor differentiation (p = 0.001), Eastern Cooperative Oncology Group (ECOG) performance status (p = 0.001), LDH levels (p = 0.046), and treatment factors (p = 0.001) proved to be independent prognostic factors for survival outcomes. The results of this study suggest that the serum LDH levels at presentation may be significantly correlated with whole-body tumor extent and might independently but modestly prognosticate OS in stage IV NSCLC.

A Randomized, Multicenter, Phase II Study of Cetuximab With Docetaxel and Cisplatin as Induction Chemotherapy in Unresectable, Locally Advanced Head and Neck Cancer.

BACKGROUND: We investigated the efficacy of cetuximab when added to induction chemotherapy followed by concurrent chemoradiotherapy (CCRT) in patients with locally advanced head and neck squamous cell carcinoma. METHODS: Patients were randomized to receive three cycles of docetaxel and cisplatin (TP regimen) with or without cetuximab (TP plus cetuximab [CTP] vs. TP) as induction chemotherapy. Patients in the CTP arm received CCRT with cetuximab and cisplatin, whereas patients in the TP arm received cisplatin alone. The primary endpoint was the objective response rate (ORR) after induction chemotherapy. RESULTS: Overall, 92 patients were enrolled. The ORRs for induction chemotherapy in the CTP and TP arms were not different (81% vs. 82%). Adding cetuximab lowered the completion rate of induction chemotherapy and CCRT and resulted in more frequent dose reductions of the induction chemotherapy, although this did not reach statistical significance. In the CTP and TP arms, respectively, the 3-year progression-free survival (PFS) rates were 70% and 56% (p = .359), and the overall survival (OS) rates were 88% and 74% (p = .313). When limited to patients who completed induction chemotherapy, 3-year PFS rates of 78% and 59% (p = .085) and OS rates of 94% and 73% (p = .045) were observed in the CTP and TP arms, respectively. CONCLUSION: Adding cetuximab to sequential treatment did not increase the treatment efficacy and resulted in greater toxicity. In the intent-to-treat population, neither PFS nor OS was improved by the addition of cetuximab to sequential treatment; however, a suggestion of improved survival outcomes was observed in patients completing cetuximab-containing induction chemotherapy.

Phase II study of gemcitabine and vinorelbine as second- or third-line therapy in patients with primary refractory or platinum-resistant recurrent ovarian and primary peritoneal cancer by the Korean Cancer Study Group (KCSG)_KCSG GY10-10.

OBJECTIVE: The main aim of this study was to evaluate the antitumor activity and safety of vinorelbine and gemcitabine combination chemotherapy in patients with primary refractory or recurrent platinum-resistant epithelial ovarian and primary peritoneal cancers. METHODS: Patients with platinum-resistant or primary refractory disease were eligible. Patients were allowed one prior chemotherapy for the treatment of platinum-resistant or refractory disease. Vinorelbine 25mg/m(2), followed by gemcitabine 1000mg/m(2), was administered intravenously on days 1 and 8 every 3weeks. Response Evaluation Criteria in Solid Tumors (RECIST) 1.0 and cancer antigen 125 test (CA-125 criteria) were adopted to classify responses. RESULTS: 44 patients received the median of 4 (range, 1-24) treatments with fifteen (34.1%) receiving six or more cycles. The overall objective response rate was 22.7%. One patient (2.3%) had complete while 9 patients (20.4%) had partial responses with median duration of response of 5.9months. 17 patients (38.6%) had stable disease for a median of 3.3months. Median progression-free survival (PFS) was 3.4months and overall survival (OS) was 14.5months. Four (9.1%) patients were not assessable. Neutropenia was the most frequently encountered toxicity, with grade 3 or 4 observed in 22 patients (50.0%). Fifteen patients (34.1%) needed immediate dose reduction. No treatment related death was reported. CONCLUSIONS: The combination chemotherapy with gemcitabine and vinorelbine achieved the primary end point of our clinical trial in management of platinum resistant recurrent ovarian cancer. However, further sophisticated dosing and scheduling of combination chemotherapy are needed because of a significant proportion of dose reduction.

New insights into ATR inhibition in muscle invasive bladder cancer: The role of apolipoprotein B mRNA editing catalytic subunit 3B.

Background: Apolipoprotein B mRNA editing catalytic polypeptide (APOBEC), an endogenous mutator, induces DNA damage and activates the ataxia telangiectasia and Rad3-related (ATR)-checkpoint kinase 1 (Chk1) pathway. Although cisplatin-based therapy is the mainstay for muscle-invasive bladder cancer (MIBC), it has a poor survival rate. Therefore, this study aimed to evaluate the efficacy of an ATR inhibitor combined with cisplatin in the treatment of APOBEC catalytic subunit 3B (APOBEC3B) expressing MIBC. Methods: Immunohistochemical staining was performed to analyze an association between APOBEC3B and ATR in patients with MIBC. The APOBEC3B expression in MIBC cell lines was assessed using real-time polymerase chain reaction and western blot analysis. Western blot analysis was performed to confirm differences in phosphorylated Chk1 (pChk1) expression according to the APOBEC3B expression. Cell viability and apoptosis analyses were performed to examine the anti-tumor activity of ATR inhibitors combined with cisplatin. Conclusion: There was a significant association between APOBEC3B and ATR expression in the tumor tissues obtained from patients with MIBC. Cells with higher APOBEC3B expression showed higher pChk1 expression than cells expressing low APOBEC3B levels. Combination treatment of ATR inhibitor and cisplatin inhibited cell growth in MIBC cells with a higher APOBEC3B expression. Compared to cisplatin single treatment, combination treatment induced more apoptotic cell death in the cells with higher APOBEC3B expression. Conclusion: Our study shows that APOBEC3B's higher expression status can enhance the sensitivity of MIBC to cisplatin upon ATR inhibition. This result provides new insight into appropriate patient selection for the effective application of ATR inhibitors in MIBC.

Clinical practice recommendations for the use of next-generation sequencing in patients with solid cancer: a joint report from KSMO and KSP.

In recent years, next-generation sequencing (NGS)-based genetic testing has become crucial in cancer care. While its primary objective is to identify actionable genetic alterations to guide treatment decisions, its scope has broadened to encompass aiding in pathological diagnosis and exploring resistance mechanisms. With the ongoing expansion in NGS application and reliance, a compelling necessity arises for expert consensus on its application in solid cancers. To address this demand, the forthcoming recommendations not only provide pragmatic guidance for the clinical use of NGS but also systematically classify actionable genes based on specific cancer types. Additionally, these recommendations will incorporate expert perspectives on crucial biomarkers, ensuring informed decisions regarding circulating tumor DNA panel testing.

Clear cell carcinomas of the ovary: a multi-institutional study of 129 cases in Korea with prognostic significance of Emi1 and Galectin-3.

Accurate diagnosis of ovarian clear cell carcinoma (CCC) is important because of its poor prognosis with chemoresistance and a high recurrent rate. The clinicopathologic characteristics and prognostic significance of the cell cycle regulator [early mitotic inhibitor-1 (Emi1)] and galactoside-binding protein (Galectin-3) were evaluated. Among 155 CCCs from 18 hospitals in Korea between 1995 and 2006, 129 pure CCCs were selected with consensus using immunohistochemical stains for hepatocyte nuclear factor-1ß, Wilms' tumor protein, and estrogen receptor. The expressions of Emi1, Galectin-3, p53, and Ki-67 labeling index were analyzed with clinicopathologic parameters and the patient's survival. The mean age of the patients was 49.6 yr; the tumors were bilateral in 10.9%, and the average size was 12 cm. Adenofibromatous component was found in 7%, and endometriosis in 48.1% of the cases. Psammoma body was seen in 16.3%. Disease-free survival and overall survival rates were 78.3% and 79.1%, respectively. The International Federation of Obstetrics and Gynecology (FIGO) stage was the most important prognostic indicator. Emi1 expression (>5%) was seen in 23.3% of CCCs, and associated with high FIGO grades and poor overall survival (P<0.05). High Galectin-3 (≥80%) expression was seen in 59.7% of CCCs, and associated with FIGO stages III and IV, and high Ki-67 labeling index. High Ki-67 labeling index (≥50%) and p53 expression (≥50%) were seen in 27.1% and 18.6% of CCCs, respectively, but there was no clinicopathologic and prognostic significance. On the basis of the fact that the expression of Emi1 in CCC was correlated with a high histologic grade and worse overall survival, target therapy using inhibitors of Emi1 may be tried in the management of CCC patients with Emi1 expression.

Treatment outcomes of systemic chemotherapy for peritoneal carcinomatosis arising from gastric cancer with no measurable disease: retrospective analysis from a single center.

BACKGROUND: Few studies of systemic chemotherapy have focused on gastric cancer with peritoneal carcinomatosis (PC) without measurable lesions. In the present study, we characterized the outcomes of systemic chemotherapy and prognostic factors for gastric cancer with PC, particularly in patients without measurable disease. METHODS: Clinical data from 211 gastric cancer patients with PC (137 without and 74 with measurable disease) who had received systemic chemotherapy between January 2003 and December 2010 at a single center were reviewed. RESULTS: The median overall survival (OS) rate of gastric cancer patients with PC with no measurable disease was significantly longer than that of patients with measurable disease (18.0 vs. 11.6 months, p = 0.010). On multivariate analysis, poor performance status [hazard ratio (HR) = 2.15, p < 0.001], the presence of metastatic lymphadenopathy (HR = 2.17, p < 0.001), and high-grade PC (HR = 1.83, p = 0.001) were associated with significantly decreased OS. When patients with low-grade PC were stratified by clinical PC grade, the median OS of those without measurable disease was 19.6 months. The median OS of patients with low-grade PC with no measurable disease was longer than those of patients with high-grade PC without measurable disease, patients with low-grade PC with measurable disease, and patients with high-grade PC with measurable disease (p = 0.001, p = 0.029, and p < 0.001, respectively). Among the patients with low-grade PC, patients who received a gastrectomy had longer survival than patients who did not receive a gastrectomy (p < 0.001). CONCLUSIONS: In our study, clinically low-grade PC without measurable disease was associated with better outcomes of systemic chemotherapy than the outcomes in the other groups examined. Clinical trials in patients with gastric cancer with PC should be stratified according to PC grade.

Glucose transporter 1 (GLUT1) of anaerobic glycolysis as predictive and prognostic values in neoadjuvant chemoradiotherapy and laparoscopic surgery for locally advanced rectal cancer.

PURPOSE: We investigated the relationships between biomarkers related to anaerobic glycolytic metabolism (GLUT1, LDH5, PDK1, and HIF-1α proteins), pathologic response, and prognosis. METHODS: All stage II and stage III rectal cancer patients had 50.4 Gy (1.8 Gy/day in 28 fractions) over 5.5 weeks, plus 5-fluorouracil (425 mg/m(2)/day) and leucovorin (20 mg/m(2)/day) bolus on days 1 to 5 and 29 to 33, and surgery was performed at 7 to 10 weeks after completion of all therapies. Expression of GLUT1, LDH5, PDK1, and HIF-1α proteins was determined by immunohistochemistry and was assessed in 104 patients with rectal cancer treated with neoadjuvant chemoradiotherapy. RESULTS: This study included stage II and III rectal cancer patients, and each stage accounted for each 50 % of the total cases. A high expression of GLUT1 protein was associated with a significantly lower rate of ypCR compared with low expression of GLUT1 protein (4.0 % vs. 27.8 %, respectively; p = 0.012). GLUT1 expression was also significantly higher in the poor response group (Grade 0, 1) than in the good response group (Grade 2, 3) (34.0 % vs. 14.8 %, respectively; p = 0.022). In recurrence analysis, the expression of GLUT1 protein demonstrated a significant correlation with time to recurrence, based on a log-rank method (p = 0.016). When analyzed by multiple Cox regression, the positive expression of GLUT1 was the most significant and independent unfavorable prognostic factor (p = 0.004). CONCLUSIONS: GLUT1 expression is a predictive and prognostic factor for pathologic complete response and recurrence in rectal cancer patients treated with 5-flurouracil and leucovorin neo-adjuvant chemoradiotherapy.

Effect of total intravenous versus inhalation anesthesia on long-term oncological outcomes in patients undergoing curative resection for early-stage non-small cell lung cancer: a retrospective cohort study.

BACKGROUND: Propofol-based total intravenous anesthesia (TIVA) improves long-term outcomes after cancer surgery compared with inhalation anesthesia. However, its effect on patients undergoing non-small cell lung cancer (NSCLC) surgery remains unclear. We aimed to compare the oncological outcomes of TIVA and inhalation anesthesia after curative resection of early-stage NSCLC. METHODS: We analyzed the medical records of patients diagnosed with stage I or II NSCLC who underwent curative resection at a tertiary university hospital between January 2010 and December 2017. The primary outcomes were recurrence-free survival (RFS) and overall survival (OS) according to anesthesia type. RESULTS: We included 1,508 patients with stage I/II NSCLC. The patients were divided into the TIVA (n = 980) and Inhalation (n = 528) groups. The two groups were well-balanced in terms of baseline clinical characteristics. The TIVA group demonstrated significantly improved RFS (7.7 years, 95% CI [7.37, 8.02]) compared with the Inhalation group (6.8 years, 95% CI [6.30, 7.22], P = 0.003). Similarly, TIVA was superior to inhalation agents with respect to OS (median OS; 8.4 years, 95% CI [8.08, 8.69] vs. 7.3 years, 95% CI [6.81, 7.71]; P < 0.001). Multivariable Cox regression analysis revealed that TIVA was an independent prognostic factor related to recurrence (hazard ratio [HR]: 1.24, 95% CI [1.04, 1.47], P = 0.014) and OS (HR: 1.39, 95% CI [1.12, 1.72], P = 0.002). CONCLUSIONS: Propofol-based TIVA was associated with better RFS and OS than inhalation anesthesia in patients with stage I/II NSCLC who underwent curative resection.

Enhanced Risk Stratification in Early-Stage Endometrial Cancer: Integrating POLE through Droplet Digital PCR and L1CAM.

AIM: In order to enhance risk stratification in early-stage endometrial cancer (EC), we conducted molecular classification using surrogate markers, including the POLE droplet digital polymerase chain reaction (ddPCR) and L1CAM immunohistochemistry (IHC). METHOD: We analyzed archival tumor tissue from 183 early-stage EC patients. POLE pathogenic mutations of P286R, V411L, S297F, A456P, and S459F within exons 9, 13, and 14 were detected using a ddPCR, while the mismatch repair (MMR) status was determined by MMR protein IHC and MSI tests. Additionally, we conducted IHC for p53 and L1CAM. RESULTS: The 183 ECs were categorized into four subgroups: POLE-mutated (15.9%), MMR-deficient (29.0%), p53-abnormal (8.7%), and non-specific molecular profile (NSMP, 46.4%). We further subcategorized the NSMP subgroup into NSMP-L1CAMneg (41.5%) and NSMP-L1CAMpos (4.9%), which we refer to as the molecular L1CAM classification. The molecular L1CAM classification was an independent prognostic factor for recurrence-free survival (RFS) and overall survival (OS) (p < 0.001, each). CONCLUSION: Integrating molecular L1CAM classification can enhance risk stratification in early-stage EC, providing valuable prognostic information to guide treatment decisions and improve patient outcomes. POLE ddPCR might be a cost-effective and easy-to-perform test as an alternative to POLE NGS.

Clinical Practice Recommendations for the Use of Next-Generation Sequencing in Patients with Solid Cancer: A Joint Report from KSMO and KSP.

In recent years, next-generation sequencing (NGS)-based genetic testing has become crucial in cancer care. While its primary objective is to identify actionable genetic alterations to guide treatment decisions, its scope has broadened to encompass aiding in pathological diagnosis and exploring resistance mechanisms. With the ongoing expansion in NGS application and reliance, a compelling necessity arises for expert consensus on its application in solid cancers. To address this demand, the forthcoming recommendations not only provide pragmatic guidance for the clinical use of NGS but also systematically classify actionable genes based on specific cancer types. Additionally, these recommendations will incorporate expert perspectives on crucial biomarkers, ensuring informed decisions regarding circulating tumor DNA panel testing.

Transcriptional Profiling Reveals Mesenchymal Subtypes of Small Cell Lung Cancer with Activation of the Epithelial-to-Mesenchymal Transition and Worse Clinical Outcomes.

While molecular subtypes of small cell lung cancers (SCLC) based on neuroendocrine (NE) and non-NE transcriptional regulators have been established, the association between these molecular subtypes and recently recognized SCLC-inflamed (SCLC-I) tumors is less understood. In this study, we used gene expression profiles of SCLC primary tumors and cell lines to discover and characterize SCLC-M (mesenchymal) tumors distinct from SCLC-I tumors for molecular features, clinical outcomes, and cross-species developmental trajectories. SCLC-M tumors show elevated epithelial-to-mesenchymal transformation (EMT) and YAP1 activity but a low level of anticancer immune activity and worse clinical outcomes than SCLC-I tumors. The prevalence of SCLC-M tumors was 3.2-7.4% in primary SCLC cohorts, which was further confirmed by immunohistochemistry in an independent cohort. Deconvoluted gene expression of tumor epithelial cells showed that EMT and increased immune function are tumor-intrinsic characteristics of SCLC-M and SCLC-I subtypes, respectively. Cross-species analysis revealed that human primary SCLC tumors recapitulate the NE-to-non-NE progression murine model providing insight into the developmental relationships among SCLC subtypes, e.g., early NE (SCLC-A and -N)- vs. late non-NE tumors (SCLC-M and -P). Newly identified SCLC-M tumors are biologically and clinically distinct from SCLC-I tumors which should be taken into account for the diagnosis and treatment of the disease.

EGFR-Tyrosine Kinase Inhibitors Induced Activation of the Autocrine CXCL10/CXCR3 Pathway through Crosstalk between the Tumor and the Microenvironment in EGFR-Mutant Lung Cancer.

CXCL10 is a cytokine that is elevated during EGFR-TKI treatment in the tumor microenvironment of lung cancer. Here, we report an original study that the impact of the CXCL10/CXCR3 pathway on EGFR-TKI resistance in EGFR-mutant lung cancer through a cytokine array analysis during in vitro coculture with tumor cells and activated PBMCs treated with EGFR-TKI, as well as the serial analysis of CXCL10 in EGFR-mutant lung cancer transgenic mice during EGFR-TKI treatment. In EGFR-mutant tumor cells cocultured with activated PBMCs, EGFR-TKI treatment increased CXCL10 in the supernatant; this activated CXCR3 in the tumor cells to induce the phosphorylation of Src and the NF-κB subunit, p65, and the expression of HIF-1α. CXCL10 siRNA treatment of EGFR-mutant tumor cells also decreased CXCL10 in the supernatant from coculturing with activated PBMCs, suggesting that the effects of CXCL10 occur via autocrine and paracrine pathways. Importantly, elevated CXCL10/CXCR3 signaling was recapitulated in a transgenic lung cancer mouse model. Our results show that increased CXCL10 levels during early EGFR-TKI treatment stimulate oncogenic signaling of persistent tumor cells to contribute to EGFR-TKI resistance via autocrine and paracrine pathways.