A multi-center, single-arm, phase II study of anlotinib plus paclitaxel and cisplatin as the first-line therapy of recurrent/advanced esophageal squamous cell carcinoma.

BACKGROUND: Anlotinib, a tyrosine kinase inhibitor, has shown encouraging anti-tumor activity in esophageal squamous cell carcinoma (ESCC). This study was designed to assess the efficacy and safety of anlotinib plus paclitaxel and cisplatin (TP) as first-line therapy for advanced ESCC. METHODS: In a multi-center, single-arm, phase II clinical trial, patients (aged > 18 years) with ESCC, which was judged to be locally advanced, recurrent, or metastatic, received 10 mg oral anlotinib once daily on days 1-14, 135 mg/m2 intravenous paclitaxel on day 1, and 60-75 mg/m2 intravenous cisplatin on days 1-3 every 3 weeks for a maximum of 4-6 cycles as the initial therapy in five centers in China. Subsequently, patients received anlotinib monotherapy (10 mg) as maintenance therapy until tumor progression or intolerable toxicity. The primary endpoint was progression-free survival (PFS). RESULTS: Forty-seven patients were enrolled in this study between October 2019 and March 2021. The median follow-up was 14.04 months (IQR, 9.30-19.38). Of 46 with assessable efficacy, the median PFS and median overall survival were 8.38 months (95% CI, 6.59-10.17) and 18.53 months (95% CI, 13.11-23.95), respectively. The objective response rate was 76.1% (95% CI, 61.2-87.4%), with 4 (8.7%) complete responses and 31 (67.4%) partial responses. The disease control rate was 91.3% (95% CI, 79.2-97.6%). The median duration of response was 6.80 months (95% CI, 4.52-9.08), and 1 patient had an ongoing response for 23 months. Subgroup analysis revealed no association between clinical factors and survival or response. Of the 47 patients with assessable safety, the main grade ≥ 3 treatment-emergent adverse events (TEAEs) were neutropenia (17.0%), bone marrow suppression (12.8%), and vomiting (10.6%). No treatment-related deaths or serious TEAEs were observed. Notably, higher c-Kit levels were an independent factor for superior PFS (HR = 0.032; 95% CI, 0.002-0.606; P = 0.022). CONCLUSIONS: The study demonstrated a manageable safety profile and durable clinical response of anlotinib plus TP as first-line therapy in advanced ESCC, which suggested a potential therapeutic option for this population. TRIAL REGISTRATION: ClinicalTrials.gov NCT04063683. Registered 21 August 2019.

Prophylactic cranial irradiation (PCI) versus active surveillance in patients with limited-stage small cell lung cancer: a retrospective, multicentre study.

BACKGROUND: The recommendation of PCI for limited-stage small cell lung cancer (LS-SCLC) is primarily based on evidence from the pre-magnetic resonance imaging (MRI) era. However, as MRI accuracy improves and stereotactic radiosurgery advances, the role of PCI for LS-SCLC has become uncertain. This study aims to compare the contemporary survival outcomes of patients with LS-SCLC treated with PCI versus active surveillance. METHODS: We conducted a retrospective cohort study in which 1068 patients with LS-SCLC who achieved a good response to first-line chemoradiotherapy were consecutively enrolled from 5 tertiary medical centres between June 2009 and June 2019. Of these patients, 440 received PCI, while 628 received surveillance without PCI. Propensity score matching with a 1:1 ratio was performed to balance the baseline characteristics of the two cohorts. The endpoints were overall survival (OS) and the incidence of brain metastasis (BM). RESULTS: In total, 648 patients were matched. The baseline characteristics were generally well balanced. At a median follow-up of 64.5 months (range 2-190), patients who underwent PCI had a significantly lower risk for BM than those who underwent surveillance. The 3-year cumulative incidence rate of BM was 28.2% (95% CI 22.5-33.8%) in the PCI cohort and 38.5% (32.6-44.5%) in the surveillance cohort (Gray's p = 0.002). However, the lower incidence of BM in the PCI cohort did not translate into a significant extension of OS. The median OS was 35.8 months (95% CI 27.6-44.0 months) in the PCI cohort versus 32 months (26.4-37.6 months) in the surveillance cohort (HR 0.90, 95% CI 0.74-1.10, p = 0.29). Multivariable analysis showed that disease stage, chemoradiotherapy sequence, and response to chemoradiotherapy were independent prognostic factors for BM or OS. CONCLUSIONS: Overall, PCI reduces the risk for BM but does not substantially prolong OS compared with active surveillance. A phase 3, prospective clinical trial (NCT04829708) we initiated is currently underway, which is expected to corroborate our results.

Comparison of Definitive Chemoradiotherapy in Locally Advanced Esophageal Squamous Cell Carcinoma.

BACKGROUND: This retrospective study was designed to estimate the efficacy and toxicity of definitive radiotherapy with concurrent or sequential docetaxel/S-1 for patients with locally advanced esophageal squamous cell carcinoma (ESCC). METHODS: Of the 62 eligible patients enrolled in this study during January 1, 2010 to December 31, 2014 from Qilu Hospital, Shandong University, Shandong Province, 39 patients received 3 cycles of docetaxel/S-1 during and after radiotherapy (concurrent chemoradiotherapy, CCRT), and 23 patients had radiotherapy followed by 3 cycles of docetaxel and S-1 (sequential chemoradiotherapy, SCRT). RESULTS: The CR of CCRT and SCRT groups were 48.72 and 21.74 %, respectively (p = 0.035). The median progress-free survival (PFS) of CCRT group (23.5 months) was significantly higher than SCRT group (11.7 months; p = 0.004). The median overall survival (OS) of CCRT group (33.5 months) also was significantly higher than SCRT group (24.0 months; p = 0.004). At 2 years, in this patient population, the rate of PFS of CCRT group was (44.2 ± 8.2 %), significantly higher than SCRT group (11.9 ± 9.6 %; p = 0.002). The 2-year OS rate of CCRT (68.6 ± 7.5 %) was significantly higher than SCRT group as well (42.0 ± 14.0 %; p = 0.002). The incidence of adverse events was higher in CCRT than SCRT group. No grade 4 or grade 5 adverse events occurred in our study. CONCLUSIONS: Definitive radiotherapy with concurrent or sequential docetaxel and S-1 for inoperable locally advanced ESCC was very well tolerated and remarkably active. In both CCRT and SCRT groups, acute toxicities were manageable. This regimen holds promises for treatment of esophageal carcinoma and warrants further investigation.

MiR-613: a novel diagnostic and prognostic biomarker for patients with esophageal squamous cell carcinoma.

MicroRNA-613 (miR-613) plays important roles in tumorigenesis and cancer progression. We aimed to evaluate its expression level and potential for diagnosis and prognosis in esophageal squamous cell cancer (ESCC). We examined miR-613 expression in 60 pairs of ESCC cancerous and matched paracancerous tissues, serum samples from 75 ESCC patients and 75 healthy volunteers, and 105 formalin-fixed paraffin-embedded (FFPE) tissue samples using quantitative reverse transcription polymerase chain reaction. Receiver-operating characteristic (ROC) curve analysis, Kaplan-Meier method, and Cox regression were applied to analyze its diagnostic and prognostic value. MiR-613 was significantly decreased in ESCC tissue compared with paracancerous tissue (P < 0.001). Moreover, the expression level of miR-613 was significantly reduced with increased T stage of ESCC. Statistically significant difference between ESCC patients and healthy controls in expression level of miR-613 (0.89 ± 0.73 vs. 1.71 ± 1.03, P < 0.001) was found. The area under the ROC curve (AUC) based on serum miR-613 was 0.767 ± 0.040. We also performed analysis on early-stage patients and revealed that the AUC value was 0.728 ± 0.052 (P < 0.001). The Kaplan-Meier curve revealed that the downregulation of miR-613 was related to worse overall survival (OS) and progression-free survival (PFS) of ESCC patients (P = 0.018 and P = 0.035, respectively). Furthermore, the multivariate analysis identified miR-613 to be an independent prognostic factor for OS and PFS (P = 0.031 and P = 0.006, respectively) In conclusion, miR-613 is significantly reduced in cancerous tissue and serum samples of ESCC patients. It can serve as an ideal indicator for the diagnosis and prognosis of ESCC.

Serum miR-1297: a promising diagnostic biomarker in esophageal squamous cell carcinoma.

We aimed to value the diagnostic potential of serum miR-1297 in esophageal squamous cell cancer (ESCC). Its expression level was detected in 156 pairs of patients with ESCC and healthy volunteers using quantitative real-time polymerase chain reaction (qRT-PCR) method. It was statistically decreased in ESCC patients compared with healthy controls. AUC based on serum miR-1297 was 0.840 ± 0.035 in discovery group and 0.837 ± 0.034 in validation group. Further analysis on early-stage patients revealed that the AUC was 0.819 ± 0.053 in discovery group and 0.814 ± 0.044 in validation group. Its sensitivity and specificity were promising. In conclusion, serum miR-1297 can serve as an ideal indicator for the diagnosis of ESCC.

The effect of socioeconomic status on health-care delay and treatment of esophageal cancer.

BACKGROUND: Socioeconomic status (SES) has been focused on as a key determinant of the incidence of cancer, cancer stage at diagnosis as well as treatment choices in western countries. However, to the authors' knowledge, little work has been done concerning the relationship of SES and esophageal cancer in China. METHODS: Patients diagnosed with primary esophageal cancer from January to December 2007 in Qilu hospital were included. Socioeconomic status was determined by a questionnaire including religion, years of schooling and high education, place of residence, occupation, annual household income, and insurance. RESULTS: A total of 238 cases were collected in this study. Linear-by-linear association testing revealed that health-care delay was significantly associated with SES (P = 0.009). Multivariable logistic regression analysis revealed that increased health-care delay (>2 months) was more frequently observed in patients with lower SES (OR 2.271; 95% CI 1.069-4.853). Patients diagnosed at TNM I and II were more frequently in higher SES groups (P = 0.017). The association test was statistically significant for undergoing surgical resection only (P = 0.015) and chemotherapy (P = 0.015). Multivariable logistic regression analysis revealed that surgical resection only was less performed in higher SES group compared with lower SES group (OR 0.372; 95% CI 0.188-0.734). For chemotherapy, higher SES patients had a three-fold higher likelihood compared with lower SES group (OR 3.042; 95% CI 1.335-6.928). CONCLUSION: Socioeconomic status was found to be associated with health-care delay, tumor stage and treatment modalities in esophageal cancer.

Prognostic significance of lymph node ratio in esophageal cancer.

N staging predicting esophageal cancer patient prognosis has been studied. Lymph node ratio, which is considered to show metastatic lymph node status more accurately, is found to have prognostic significance in several tumors. We investigated whether lymph node ratio (LNR) was associated with the prognosis of esophageal cancer in this study. Esophageal cancer patients who underwent esophagectomy at Qilu Hospital of Shandong University from January 2007 to December 2008 were studied. A total of 209 cases were evaluated in this study. The median disease-free survival (DFS) of this cohort was 35.2 months, and 5-year DFS rate was 32.1%. The median overall survival (OS) was 46.4 months, and 5-year OS rate was 40.0%. Kaplan-Meier survival analysis revealed that patients with LNR higher than 0.2 had significantly poorer DFS (p < 0.001) and OS (p < 0.001) than those with LNR less than 0.2. In a multivariate analysis, LNR was found to be an independent prognostic factor for DFS (p = 0.008, HR 1.863, 95% CI 1.180-2.942) and OS (p = 0.025, HR 1.708, 95% CI 1.068-2.731). N stage (p = 0.028, HR 1.626, 95% CI 1.055-2.506) was also found to be an independent prognostic factors for OS. Subgroups analysis revealed significant difference in OS and DFS rates between different LNR categories within the same N stages (p < 0.05) but not between different N stages within the same LNR category (p > 0.05). LNR was recognized as an independent factor in both OS and DFS in esophageal cancer. Besides, LNR showed a better prognostic value than N stage for esophageal cancer.

The clinical significance of preoperative plasma fibrinogen level and platelet count in resectable esophageal squamous cell carcinoma.

BACKGROUND: Patients with malignant disease frequently present with activated coagulation pathways, which are potentially associated with tumor progression and prognosis. The aims of the study were to investigate the clinical significance of preoperative plasma fibrinogen level and platelet count in esophageal squamous cell carcinoma (ESCC) treated by curative surgery. METHODS: A total of 119 patients with ESCC treated by curative surgery in Qilu Hospital of Shandong University were included in the study. RESULTS: The preoperative plasma fibrinogen levels in the patients with ESCC ranged from 2.2 to 6.91 g/L (mean ± SD, 3.85 ± 0.95 g/L). The incidence of hyperfibrinogenemia was 43.7% (52/119, cut-off value 4.0 g/L). Hyperfibrinogenemia was found to be positively correlated with increased tumor length (P = 0.027), increased depth of invasion (P = 0.013), advanced pathological stages (P = 0.011), and disease recurrence (P = 0.026). The platelet counts ranged from 78 × 10(9)/L to 936 × 10(9)/L (mean ± SD, 254.51 ± 89.26 × 10(9)/L). The incidence of thrombocytosis was 20.2% (24/119, cut-off value 300 × 10(9)/L). Thrombocytosis was more frequently seen in male gender (P = 0.029) and non-smokers (P = 0.008). Plasma fibrinogen levels were significantly correlated with platelet counts (r = 0.018, P = 0.048). Hyperfibrinogenemia was significantly associated with poor disease-free (P = 0.009, hazard ratio (HR) = 1.784, 95% confidence interval (CI) = 1.153 to 2.761) and overall (P = 0.003, HR = 1.992, 95% CI = 1.259 to 3.152) survivals in univariate analysis, but not an independent prognostic indicator in multivariate analysis. Thrombocytosis was not significantly associated with disease-free (P = 0.765, HR = 0.918, 95% CI = 0.524 to 1.608) or overall (P = 0.809, HR = 1.072, 95% CI = 0.618 to 1.891) survivals in univariate analysis. CONCLUSIONS: The study suggested that hyperfibrinogenemia is a valuable predictor for disease progression in ESCC. Anticoagulation therapy might be considered to control cancer progression in future studies.

The clinical significance of tumor-infiltrating neutrophils and neutrophil-to-CD8+ lymphocyte ratio in patients with resectable esophageal squamous cell carcinoma.

BACKGROUND: The interaction between tumor cells and inflammatory cells has not been systematically investigated in esophageal squamous cell carcinoma (ESCC). The main aims of the study were to investigate the clinical significance of tumor-infiltrating neutrophils and neturophil-to-CD8+ lymphocyte ratio (NLR), and to analyze the distribution of tumor-infiltrating neutrophils and CD8+ lymphocytes in ESCC treated by curative resection. METHODS: The expressions of CD66b and CD8 were assessed with double staining immunohistochemistry in the surgical specimens from 90 patients with ESCC treated by curative surgery. RESULTS: We showed that increased intratumoral neutrophils were significantly associated with lymph node metastasis (P = 0.016), and advanced pathological stages (P = 0.013). Decreased peritumoral CD8+ lymphocyte density was more frequently observed in patients with single positive lymph node (p = 0.045). Peritumoral NLR was significantly associated with advanced T stages (p < 0.001), lymph node metastasis (p = 0.041) and a trend towards advanced pathological stages (p = 0.053). Increased intratumoral neutrophils were significantly associated with decreased disease-free survival (p < 0.001) and overall survival (p < 0.001) in univariate analysis and were identified as an independent prognostic factor for disease-free survival (p = 0.006) and overall survival (p = 0.037) in multivariate analysis. Neither the density nor the distribution of tumor-infiltrating neutrophils was significantly correlated with that of CD8+ lymphocytes. The density of intratumoral CD8+ lymphocytes was significantly lower than (P < 0.001) and moderately correlated with (r = 0.434, p < 0.001) that in peritumoral area. CONCLUSIONS: Increased intratumoral neutrophils were an independent poor prognostic factor and peritumoral NLR was significantly associated with disease progression in ESCC treated by curative surgery, suggesting the possible effect of immune misbalance of tumor microenvironment in facilitating ESCC progression. Immunotherapy targeted to the above predictors should be considered in the future.

Down-regulation of stromal caveolin-1 expression in esophageal squamous cell carcinoma: a potent predictor of lymph node metastases, early tumor recurrence, and poor prognosis.

BACKGROUND: Recent studies have identified loss of stromal caveolin-1 (Cav-1) expression as a new prognostic histological characteristic in various types of human cancers. However, the clinical and pathological significance of stromal Cav-1 expression in esophageal squamous cell carcinoma (ESCC) remains largely unknown. We examined Cav-1 expression in both tumor and stromal cells in ESCC tissue by immunohistochemical analysis to evaluate its clinicopathological significance and prognostic value. METHODS: A total of 110 patients with ESCC who underwent surgical resection were included in this study. The expression of Cav-1 in both tumor and stromal cells in esophageal tumor tissues was examined immunohistochemically. RESULTS: Cav-1 expression was found in the cytoplasm of both tumor and stromal cells. Tumor Cav-1 overexpression was observed in 37.3 % tumors, which correlated to deeper tumor invasion (p = 0.038). Down-regulation of stromal Cav-1 expression was observed in 40.9 % tumors. The stromal Cav-1 down-regulation group had more lymph node metastases and more locoregional recurrences than those with higher expression (p = 0.020 and p = 0.002, respectively). In addition, down-regulation of stromal Cav-1 expression was associated with shorter disease-free survival (p < 0.001) and overall survival (p < 0.001). Multivariate analysis revealed that down-regulation of stromal Cav-1 expression was an independent prognostic factor for both disease-free survival (p = 0.028) and overall survival (p = 0.007). CONCLUSIONS: Down-regulation of stromal Cav-1 expression in ESCC had high malignant potential. It predicts high-risk of lymph node metastases and locoregional recurrence, and it could be a powerful prognostic marker for patients with ESCC.

Shorter dinner-to-bed time is associated with gastric cardia adenocarcinoma risk partly in a reflux-dependent manner.

BACKGROUND: Gastric cancer remains the second cause of cancer-related death worldwide. The aim of this study was to investigate the effects of shorter dinner-to-bed time, post-dinner walk, and obesity on gastric cardia adenocarcinoma (GCA) risk. METHODS: The study subjects consisted of 146 GCA patients and 166 healthy controls roughly matched by gender and age. Conditional logistic regression was used to calculated odds ratio (OR) and 95 % confidence intervals (CIs). RESULTS: The adjusted ORs of GCA for subjects with shorter dinner-to-bed time were 4.18 (95 % CI 2.10-8.33) compared with those with longer dinner-to-bed time. What is more, when reflux symptom was added into the multivariate models, risk estimate for shorter dinner-to-bed time decreased greatly, but still remained statistically significant (p = 0.007). Post-dinner walk was associated with a significantly decreased GCA risk (adjusted OR 0.54; 95 % CI 0.31-0.94). When subjects were analyzed according to post-dinner walk, the adjusted OR of GCA for shorter dinner-to-bed time relative to longer dinner-to-bed time was much higher for non-walking subjects (adjusted OR 20.21) than walking subjects (adjusted OR 1.39). We further found a significant interaction between shorter dinner-to-bed time and post-dinner walk regarding the risk of GCA (adjusted OR 0.07; p = 0.001). CONCLUSIONS: We found that shorter dinner-to-bed time was associated with significantly increased GCA risk, partly depending on reflux symptoms, while post-dinner walk was related to a significantly decreased GCA risk and could greatly attenuate the GCA risk attributable to shorter dinner-to-bed time.

Surgery versus radiotherapy for limited-stage small cell esophageal carcinoma: a multicenter, retrospective, cohort study in China (ChiSCEC).

BACKGROUND: There is no standard management for small cell esophageal carcinoma (SCEC). The purpose of this multicenter, retrospective study (ChiSCER) was to investigate the treatment, outcomes, and risk factors impacting survival endpoints in patients with limited-stage SCEC (LS-SCEC). MATERIALS AND METHODS: Consecutive patients with LS-SCEC from 14 institutions between 2000 and 2020 in China were enrolled. Survival curves were constructed using the Kaplan-Meier method and compared using a log-rank test. Univariate and multivariate Cox regression models and propensity score matching (PSM) analysis were adopted in the prognostic analysis. Results were reported as hazard ratio (HR), 95% confidence interval (CI), and P value. Statistical significance was set as P value <0.05 in a two-tailed test. RESULTS: Among 458 LS-SCEC patients, the median age was 63 [interquartile range (IQR), 57-68] years, and 318 (69%) were males. Eighty-four (18%), 167 (36%), and 207 (45%) patients received chemotherapy (CT) alone, CT plus definitive radiotherapy (CT+RT), and CT plus radical surgery (CT+S), respectively. With a median follow-up time of 58.7 (95% CI 48.9-68.6) months, the median overall survival (OS) and 3-year OS rate for all patients 24.3 (95% CI 21.6-27) months and 37.3% (95% CI 32.8-42.5%), respectively. Multivariate analysis indicated that treatment modes, Karnofsky performance status (KPS), TNM stage, and CT cycle were independent prognostic factors for OS ( P <0.05). Compared with CT alone, patients treated with CT+RT (HR 0.57, 95% CI 0.41-0.8, P =0.001) or CT+S (HR 0.59, 95% CI 0.42-0.82, P =0.002) had an improved OS, with no significant survival differences between CT+S and CT+RT groups after multivariate and PSM analyses ( P >0.05). Subgroup analysis indicated that compared with CT+RT, patients with tumor location at lower 1/3 (HR 0.59, 95% CI 0.37-0.93, P =0.03) or tumor length >5 cm (HR 0.52, 95% CI 0.3-0.9, P =0.02) could obtain significant OS benefit from CT+S. Patients with tumor location at middle 1/3 (HR 1.55, 95% CI 1.03-2.36, P =0.04) or tumor length ≤5 cm (HR 1.49, 95% CI 1.02-2.17, P =0.04) favored CT+RT. Distant metastasis accounted for 73.7% of all treatment failures after multidisciplinary treatments. CONCLUSION: Surgery and RT were equally effective local therapies for patients with LS-SCEC. The personalized decision of local therapy should be made after comprehensive considerations on tumor location, length, comorbidities, and organ preservation.

Prognostic value of body mass index for patients undergoing esophagectomy for esophageal squamous cell carcinoma.

OBJECTIVE: The correlation between high body mass index and outcomes after esophagectomy has not been systematically addressed. Some studies have shown that patients with a high body mass index had better overall survival and disease-free survival compared with those with a normal/low body mass index, whereas others have shown that the body mass index was not of prognostic value. METHODS: Ninety-nine patients with esophageal squamous cell carcinoma were retrospectively reviewed in this study. Patients' postoperative overall and disease-free survivals were compared between the two groups (body mass index <24.00 kg/m(2) and body mass index ≥24.00 kg/m(2)). RESULTS: There were 66 patients in the low/normal body mass index group (body mass index <24.00 kg/m(2)) and 28 patients in the high body mass index group (body mass index ≥24.00 kg/m(2)). Although disease recurrence were more frequent in the high body mass index group vs. the low/normal body mass index group, there was no significant difference noted (60.7%, 40.9%, P = 0.078). The 3-year overall survival rates were 60.6% in the low/normal body mass index group and 57.1% in the high body mass index group (P = 0.392). The 3-year disease-free survival rates were higher in the low/normal body mass index group vs. the high body mass index group (56.1%, 39.3%, P = 0.048). On multivariate analysis, the number of lymph node metastases (hazard ratio: 1.192, 95% confidence interval: 1.076-1.320, P = 0.001) was recognized as an independent prognostic factor for overall survival. Both body weight loss (hazard ratio: 2.153, 95% confidence interval: 1.027-4.511, P = 0.042) and the number of lymph node metastases (hazard ratio: 1.669, 95% confidence interval: 1.297-2.146, P < 0.001) were significantly and independently associated with disease-free survival. CONCLUSIONS: Our results suggest that high body mass index appears to shorten disease-free survival in esophageal squamous cell carcinoma patients and further studies are needed to detect the mechanism.

Irradiation Induces Gasdermin E-Triggered Tumor Immunity to Inhibit Esophageal Carcinoma Cell Survival.

Gasdermin E (GSDME), an executor of pyroptosis, can be activated by caspase-3 and has been recognized as a tumor suppressor in various human cancers. In addition, caspase-3/GSDME signal-induced pyroptosis is a form of immunogenic cell death (ICD). In this study, we aimed to understand the association between radiotherapy and caspase-3/GSDME signal-related ICD in esophageal carcinoma (EC) cells. The expression of caspase-3 and GSDME in two EC cell lines, ECA-109 and KYSE-150, was silenced or overexpressed by transfection with specific siRNAs or overexpression vectors. Cells were subjected to 0-8 Gy irradiation, and cell death was evaluated by CCK-8 assay, annexin V-FITC staining, lactate dehydrogenase (LDH) detection kit, Western blotting, and immunofluorescence. Irradiation in both EC cell lines promoted dose-dependent viability loss and apoptosis. More specifically, 8 Gy X-ray increased the apoptosis rate from 4.1 to 12.8% in ECA-109 cells and from 4.6 to 21.1% in KYSE-150 cells. In irradiated EC cells, the levels of LDH release and caspase-3/GSDME cleavage were increased. Caspase-3 silencing inhibited irradiation-induced GSDME cleavage and EC cell death. Furthermore, we identified the death of EC cells suppressed by caspase-3 siRNA, and the levels of CRT, HMGB1, HSP70, and HSP90 were also markedly downregulated by caspase-3 siRNA. Similarly, GSDME silencing diminished irradiation-induced EC cell death and the levels of ICD markers. Overexpression of caspase-3 and GSDME accelerated irradiation-induced ICD. In summary, irradiation in EC cells induces GSDME-mediated pyroptosis and activates ICD to inhibit esophageal carcinoma cell survival.

Real-world outcomes of PD-L1 inhibitors combined with thoracic radiotherapy in the first-line treatment of extensive stage small cell lung cancer.

BACKGROUND: The CREST study showed that the addition of thoracic radiotherapy (TRT) could improve the survival rate in patients with extensive stage small cell lung cancer (ES-SCLC), but whether TRT can bring survival benefit in the era of immunotherapy remains controversial. This study aimed to explore the efficacy and safety of adding TRT to the combination of PD-L1 inhibitors and chemotherapy. METHODS: The patients who received durvalumab or atezolizumab combined with chemotherapy as the first-line treatment of ES-SCLC from January 2019 to December 2021 were enrolled. They were divided into two groups, based on whether they received TRT or not. Propensity score matching (PSM) with a 1:1 ratio was performed. The primary endpoints were progression-free survival (PFS), overall survival (OS) and safety. RESULTS: A total of 211 patients with ES-SCLC were enrolled, of whom 70 (33.2%) patients received standard therapy plus TRT as first-line treatment, and 141 (66.8%) patients in the control group received PD-L1 inhibitors plus chemotherapy. After PSM, a total of 57 pairs of patients were enrolled in the analysis. In all patients, the median PFS (mPFS) in the TRT and non-TRT group was 9.5 and 7.2 months, respectively, with HR = 0.59 (95%CI 0.39-0.88, p = 0.009). The median OS (mOS) in the TRT group was also significantly longer than that in the non-TRT group (24.1 months vs. 18.5 months, HR = 0.53, 95%CI 0.31-0.89, p = 0.016). Multivariable analysis showed that baseline liver metastasis and the number of metastases ≥ 3 were independent prognostic factors for OS. Addition of TRT increased the incidence of treatment-related pneumonia (p = 0.018), most of which were grade 1-2. CONCLUSIONS: Addition of TRT to durvalumab or atezolizumab plus chemotherapy significantly improves survival in ES-SCLC. Although it may leads to increased incidence of treatment-related pneumonia, a majority of the cases can be relieved after symptomatic treatment.

The association of miR-146a rs2910164 and miR-196a2 rs11614913 polymorphisms with cancer risk: a meta-analysis of 32 studies.

MicroRNAs (miRNAs) are small non-coding RNA molecules, which act as post-transcriptional regulators of gene expression and have been implicated in initiation, progression and treatment outcome of diverse cancers. Single nucleotide polymorphisms (SNPs), as the most common type of genetic variation, also exist in miRNA genes and can lead to alteration in miRNA expression resulting in diverse functional consequences. Emerging studies have evaluated the association of miRNA SNPs with cancer risk, but the results remain inconclusive. To assess the relationship between miRNA SNPs and cancer risk, we performed a meta-analysis of 18 studies involving 20660 subjects for miR-146a rs2910164 polymorphism and 21 studies involving 26,018 subjects for miR-196a2 rs11614913 polymorphism. As for rs2910164, no significant association of cancer risk was found in the overall analysis. In subgroup analysis by cancer type, ethnicity, source of controls and sample size, significant association of cancer risk was mainly found in papillary thyroid carcinoma, primary liver cancer, cervical cancer, Caucasian population and small sample size studies. For rs11614913, significant results were found in all the tested genetic models and T allele or its carriers were associated with decreased cancer risk in overall analysis (T vs. C: OR = 0.888, 95% CI 0.84-0.938; TT+TC vs. CC: OR = 0.897, 95% CI 0.828-0.971). In stratified analysis by cancer type and ethnicity, significant association of cancer risk was observed in breast cancer, lung cancer, colorectal cancer and Asian population, but not in Caucasian population. During further stratified analysis by source of controls and sample size, results similar to those of overall analysis were found in all of the subgroups. Taken together, our results indicated that miR-196a2 rs11614913 T variant probably contribute to decreased susceptibility to cancer. However, limited evidence was found for association of miR-146a rs2910164 with cancer risk, and further well-designed studies with large sample size will be necessary to validate the effect of miR-146a rs2910164 on cancer susceptibility.

Dynamic Change of Amide Proton Transfer Imaging in Irradiated Nasopharyngeal Carcinoma and Related Histopathological Mechanism.

OBJECTIVE: To investigate the dynamic change of amide proton transfer (APT) imaging before and after irradiation in nasopharyngeal carcinoma (NPC) and the underlying histopathological mechanism. MATERIALS AND METHODS: Tumor-bearing BALB/C nude mouse models were established and randomly divided into three groups: high-dose group (20 Gy/2 fractions), low-dose group (10 Gy/2 fractions), and control group (0 Gy). MRI scanning was performed before irradiation and 3rd, 6th, and 9th day post-irradiation. Scanning sequence included T1 weighted, T2 weighted, and APT. HE staining and TUNEL immunofluorescence detection were performed to detect necrosis and apoptosis. RESULTS: After high-dose irradiation, the mean tumor APT values decreased significantly on the 3rd day and 6th day (from 3.83 before radiotherapy to 2.41%, P < 0.001, 3rd day; from 2.41 to 1.80%, P = 0.001, 6th day). For low-dose irradiation, the mean tumor APT values decreased slightly on the 3rd day and 6th day (from 3.52 to 3.13%, P = 0.109, 3rd day; from 3.13 to 3.05%, P = 0.64, 6th day). The mean APT values of nonirradiated tumor changed slightly. In contrast, the average volume of high-dose irradiated tumors did not decrease obviously until the 9th day post-irradiation (from 290 before radiotherapy to 208 mm3 on the 9th day). The low-dose irradiated tumors showed slow growth, and the nonirradiated tumors showed rapid growth. Subsequent HE staining and TUNEL staining showed obvious necrosis characteristics and higher proportion of positive apoptotic cell nucleus in high-dose irradiated tumors, but not nonirradiated tumors. CONCLUSION: The APT signal intensity decreased after irradiation, which is earlier than the change of tumor volume. What is more, the decrease of APT signal intensity is more significant in high-dose group. Histological analysis showed obvious apoptosis and necrosis histological characteristic in irradiated tumor, which may explain the decrease of APT signal intensity. These results indicate that APT imaging has the potential to serve as a reliable biomarker for response assessment in NPC.

Prognostic value of immune-related genes in the tumor microenvironment of lung adenocarcinoma and lung squamous cell carcinoma.

Non-small cell lung cancer (NSCLC), which consists mainly of lung adenocarcinoma (LUAD) and lung squamous cell carcinoma (LUSC), are the leading cause of cancer deaths worldwide. In this study, we performed a comprehensive analysis of the tumor microenvironmental and genetic factors to identify prognostic biomarkers for NSCLC. We evaluated the immune and stromal scores of patients with LUAD and LUSC using data from The Cancer Genome Atlas database with the ESTIMATE algorithm. Based on these scores, the differentially expressed genes were obtained and immune-related prognostic genes were identified. Functional analysis and protein-protein interaction network further revealed the immune-related biological processes in which these genes participated. Additionally, 22 subsets of tumor-infiltrating immune cells (TIICs) in the tumor microenvironment were analyzed with the CIBERSORT algorithm. Finally, we validated these valuable genes using an independent cohort from the Gene Expression Omnibus database. The associations of the immune and stromal scores with patients' clinical characteristics and prognosis were positive in LUAD but negative in LUSC and the correlations of TIICs with clinical characteristics were clarified. Several differentially expressed genes were identified to be potential immune-related prognostic genes. This study comprehensively analyzed the tumor microenvironment and presented immune-related prognostic biomarkers for NSCLC.

Yes-associated protein (YAP) predicts poor prognosis and regulates progression of esophageal squamous cell cancer through epithelial-mesenchymal transition.

The impact of yes-associated protein (YAP) on the prognosis of patients with esophageal squamous cell cancer (ESCC) and its mechanism of action has seldom been reported. In the present study, the role of YAP on the prognosis of patients with ESCC and the mechanism of action of YAP in promoting the progression of ESCC was investigated. Tumor tissue samples from patients with ESCC were collected and the level of YAP expression was detected using immunohistochemical staining. In addition, YAP was knocked-down in ESCC cell lines and the effects on cell migration and invasion were examined. The expression levels of vimentin, N-cadherin, and E-cadherin were further investigated to examine the association between YAP and epithelial-mesenchymal transition (EMT). Results showed that overexpression of YAP was associated with larger lymph node metastasis and poor disease-free survival and overall survival. Compared with patients in early stage ESCC, the association was more significant in patients with late stage ESCC. Univariate and multivariate analyses further indicated that YAP expression could be an independent prognostic factor for ESCC. Downregulation of YAP inhibited cell migration and invasion. Western blot analysis showed that when YAP was knocked down, expression levels of vimentin and N-cadherin were reduced, whereas that of E-cadherin was increased. In conclusion, the results indicates that YAP expression level could be a novel marker for predicting the prognosis of patients with ESCC, and YAP-promoted tumor migration and invasion might be through EMT in ESCC.

Prognostic significance of preoperative IKBKE expression in esophageal squamous cell carcinoma.

PURPOSE: IκB kinase epsilon (IKBKE; IKKε), a member of the nuclear factor-κB kinase inhibitor family, is upregulated in several human cancers, including breast cancer, prostate cancer, and ovarian cancer. Esophageal squamous cell carcinoma (ESCC) is one of the most common and most aggressively malignant cancers with dismal prognosis. However, the state of IKBKE expression in ESCC is still unknown and its potential value remains unexplored. PATIENTS AND METHODS: IKBKE protein expression was evaluated by immunohistochemistry in 118 paraffin specimens of ESCC treated by curative surgery. All patients were regularly followed up by telephone over 3 years after surgery. The chi-square test, Kaplan-Meier method, and Cox proportional hazard regression model were used to analyze the relationship of IKBKE expression, clinicopathological characteristics, and prognostic value for ESCC. RESULTS: IKBKE expression was 61.9% (73/118) in paraffin-embedded archived ESCC. Its expression was significantly associated with tumor differentiation grade (p=0.045) and advanced TNM (pathologic tumor node metastasis) stages (p=0.023). In univariate analysis, IKBKE expression was closely associated with decreased 3-year disease-free survival (HR 1.804, 95% CI 1.076-3.027; p=0.023) and overall survival (HR 2.118, 95% CI 1.189-3.773; p=0.009). Meanwhile, in multivariate analysis it was identified as an independent prognostic factor for 3-year disease-free survival (HR 1.777, 95% CI 1.034-3.054; p=0.037) and overall survival (HR 2.078, 95% CI 1.138-3.796; p=0.017). CONCLUSION: Our data indicated for the first time that IKKε expression is a highly recurrent event in ESCC and could play a pivotal role in the evaluation of prognosis. IKBKE upregulation is negatively associated with disease-free survival and overall survival. Therefore, IKBKE could serve as a prognostic variable and potential therapeutic target for this malignancy.