Metabolome and Transcriptome Analyses Reveal Flower Color Differentiation Mechanisms in Various Sophora japonica L. Petal Types.

Sophora japonica L. is an important landscaping and ornamental tree species throughout southern and northern parts of China. The most common color of S. japonica petals is yellow and white. In this study, S. japonica flower color mutants with yellow and white flag petals and light purple-red wing and keel petals were used for transcriptomics and metabolomics analyses. To investigate the underlying mechanisms of flower color variation in S. japonica 'AM' mutant, 36 anthocyanin metabolites were screened in the anthocyanin-targeting metabolome. The results demonstrated that cyanidins such as cyanidin-3-O-glucoside and cyanidin-3-O-rutinoside in the 'AM' mutant were the key metabolites responsible for the red color of the wing and keel petals. Transcriptome sequencing and differentially expressed gene (DEG) analysis identified the key structural genes and transcription factors related to anthocyanin biosynthesis. Among these, F3'5'H, ANS, UFGT79B1, bHLH, and WRKY expression was significantly correlated with the cyanidin-type anthocyanins (key regulatory factors affecting anthocyanin biosynthesis) in the flag, wing, and keel petals in S. japonica at various flower development stages.

X-ray inhibits FUT4-mediated proliferation in A549 cells by downregulating SP1 expression.

Objective: To identify the mechanism of down-regulation of Lewis Y antigen caused by X-ray irradiation. METHODS: The present original research study was conducted at Zhejiang University City College, Hangzhou, Republic of China, from 2020 to 2022. Western blotting, Co-immunoprecipitation (CO-IP), electrophoretic mobility shift assay and Cell Counting Kit-8 (CCK8) were performed to confirm the effect of X-ray irradiation on A549 cell proliferation and its mechanism. Data was analysed using Statistical Package for Social Sciences (SPSS) 11.5. RESULTS: The expressions of fucosyltransferase IV and Lewis Y were decreased after X-ray irradiation, thus inhibiting the proliferation of A549 lung cancer cells. Deoxyribonucleic acid damage caused by the irradiation caused higher level of poly- adenosinediphosphate-ribosylated Specific Protein 1(SP1), and translocation of SP1 from the nucleus, decreasing the expression of fucosyltransferase IV and Lewis Y. Conclusion: There was a significant role of glycosylation in radiation therapy for lung cancer.

Emodin reverses resistance to gemcitabine in pancreatic cancer by suppressing stemness through regulation of the epithelial­mesenchymal transition.

The present study aimed to explore the effects and underlying mechanisms of emodin (Emo) on gemcitabine (GEM)-resistant pancreatic cancer. GEM-resistant SW1990 cells (SW1990/GZ) were established by successively doubling the concentration of GEM. Cell viability was measured using the CCK-8 assay and flow cytometry was used to measure cell apoptosis. Cell migration was assessed using a Transwell assay. Sphere and colony-formation assays were used to evaluate cell self-renewal. The expression levels of epithelial-mesenchymal transition (EMT) and stem cell biomarkers were determined using western blotting. Snail family transcriptional repressor 1 gene (Snail) was overexpressed by transfecting cells with pcDNA3.1-Snail plasmids. A xenograft model was established in nude mice by using SW1990/GZ and Snail-overexpressing SW1990/GZ cells. Proliferation, migration, self-renewal and EMT progression of GEM-treated SW1990/GZ cells were significantly suppressed in vitro by Emo treatment, whereas the overexpression of Snail abolished the aforementioned effects. In in vivo, the antitumor activity of GEM and the inhibitory effect of GEM against EMT progression and stem-like characteristics were enhanced by treatment with Emo, whilst overexpression of Snail reversed these effects. In conclusion, Emo reversed GEM resistance in pancreatic cancer by suppressing stemness and regulating EMT progression.

A novel glycosylation-related gene signature predicts survival in patients with lung adenocarcinoma.

BACKGROUND: Lung adenocarcinoma (LUAD) is the most common malignant tumor that seriously affects human health. Previous studies have indicated that abnormal levels of glycosylation promote progression and poor prognosis of lung cancer. Thus, the present study aimed to explore the prognostic signature related to glycosyltransferases (GTs) for LUAD. METHODS: The gene expression profiles were obtained from The Cancer Genome Atlas (TCGA) database, and GTs were obtained from the GlycomeDB database. Differentially expressed GTs-related genes (DGTs) were identified using edge package and Venn diagram. Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), and ingenuity pathway analysis (IPA) methods were used to investigate the biological processes of DGTs. Subsequently, Cox and Least Absolute Shrinkage and Selection Operator (LASSO) regression analyses were performed to construct a prognostic model for LUAD. Kaplan-Meier (K-M) analysis was adopted to explore the overall survival (OS) of LUAD patients. The accuracy and specificity of the prognostic model were evaluated by receiver operating characteristic analysis (ROC). In addition, single-sample gene set enrichment analysis (ssGSEA) algorithm was used to analyze the infiltrating immune cells in the tumor environment. RESULTS: A total of 48 DGTs were mainly enriched in the processes of glycosylation, glycoprotein biosynthetic process, glycosphingolipid biosynthesis-lacto and neolacto series, and cell-mediated immune response. Furthermore, B3GNT3, MFNG, GYLTL1B, ALG3, and GALNT13 were screened as prognostic genes to construct a risk model for LUAD, and the LUAD patients were divided into high- and low-risk groups. K-M curve suggested that patients with a high-risk score had shorter OS than those with a low-risk score. The ROC analysis demonstrated that the risk model efficiently diagnoses LUAD. Additionally, the proportion of infiltrating aDCs (p < 0.05) and Tgds (p < 0.01) was higher in the high-risk group than in the low-risk group. Spearman's correlation analysis manifested that the prognostic genes (MFNG and ALG3) were significantly correlated with infiltrating immune cells. CONCLUSION: In summary, this study established a novel GTs-related risk model for the prognosis of LUAD patients, providing new therapeutic targets for LUAD. However, the biological role of glycosylation-related genes in LUAD needs to be explored further.

A combined predictive model based on radiomics features and clinical factors for disease progression in early-stage non-small cell lung cancer treated with stereotactic ablative radiotherapy.

Purpose: To accurately assess disease progression after Stereotactic Ablative Radiotherapy (SABR) of early-stage Non-Small Cell Lung Cancer (NSCLC), a combined predictive model based on pre-treatment CT radiomics features and clinical factors was established. Methods: This study retrospectively analyzed the data of 96 patients with early-stage NSCLC treated with SABR. Clinical factors included general information (e.g. gender, age, KPS, Charlson score, lung function, smoking status), pre-treatment lesion status (e.g. diameter, location, pathological type, T stage), radiation parameters (biological effective dose, BED), the type of peritumoral radiation-induced lung injury (RILI). Independent risk factors were screened by logistic regression analysis. Radiomics features were extracted from pre-treatment CT. The minimum Redundancy Maximum Relevance (mRMR) and the Least Absolute Shrinkage and Selection Operator (LASSO) were adopted for the dimensionality reduction and feature selection. According to the weight coefficient of the features, the Radscore was calculated, and the radiomics model was constructed. Multiple logistic regression analysis was applied to establish the combined model based on radiomics features and clinical factors. Receiver Operating Characteristic (ROC) curve, DeLong test, Hosmer-Lemeshow test, and Decision Curve Analysis (DCA) were used to evaluate the model's diagnostic efficiency and clinical practicability. Results: With the median follow-up of 59.1 months, 29 patients developed progression and 67 remained good controlled within two years. Among the clinical factors, the type of peritumoral RILI was the only independent risk factor for progression (P< 0.05). Eleven features were selected from 1781 features to construct a radiomics model. For predicting disease progression after SABR, the Area Under the Curve (AUC) of training and validation cohorts in the radiomics model was 0.88 (95%CI 0.80-0.96) and 0.80 (95%CI 0.62-0.98), and AUC of training and validation cohorts in the combined model were 0.88 (95%CI 0.81-0.96) and 0.81 (95%CI 0.62-0.99). Both the radiomics and the combined models have good prediction efficiency in the training and validation cohorts. Still, DeLong test shows that there is no difference between them. Conclusions: Compared with the clinical model, the radiomics model and the combined model can better predict the disease progression of early-stage NSCLC after SABR, which might contribute to individualized follow-up plans and treatment strategies.

Comparative Genomic Analysis Reveals Genetic Variations in Multiple Primary Esophageal Squamous Cell Carcinoma of Chinese Population.

Esophageal squamous cell carcinoma (ESCC) is one of the most common and lethal malignant tumors. The incidence of malignant transformation of esophageal mucosa increases greatly due to long-term exposure to factors such as smoking, drinking, and poor eating habits. Furthermore, multiple primary tumors could occur synchronously or asynchronously in the upper aerodigestive tract, especially in the esophagus, adding difficulty to the treatment of ESCC. Genetic mutations are important during the malignant transformation from normal mucosa to esophageal cancer, but the underlying mechanism has not been fully elucidated. In this study, we used whole-exome sequencing (WES) to profile genetic variations in physiologically normal mucosa (PNM) and ESCC tumors, as well as PNM of non-ESCC subjects. We found significant differences in mutation frequencies of NOTCH1 and NOTCH2, copy number variations (CNVs) at both gene and chromosomal arm levels, and cancer-related HIPPO, WNT, and NRF2 signaling pathways between ESCC tumors and normal mucosa. Our analysis of both primary tumors and paired PNM in bifocal ESCC revealed three different primary tumor evolution modes, and the most common mode exhibited a complete genomic divergence in all the samples from the same patient. Furthermore, the mutation frequency of TP53 was significantly higher in ESCC cases than that in non-ESCC cases. Overall, our results provide important evidence for further elucidating the mechanisms of genetic mutations underlying the cause of ESCC.

Effect of Different Reduction Intramedullary Nails on Spiral Fracture of Middle and Lower Tibia.

Objective: To compare the efficacy of different reduction and intramedullary nailing in the treatment of spiral fracture of middle and lower tibia. Method: A total of 96 patients with spiral fractures of middle and lower tibia treated with intramedullary nails were retrospectively analyzed. The patients were divided into closed functional reduction group, open anatomical reduction group, and closed anatomical reduction group according to different treatment methods. The operation time, intraoperative blood loss, intraoperative fluoroscopy times, fracture healing time, fracture nonunion, wound complications, and healing conditions of the three groups were compared. Results: The operation time and intraoperative fluoroscopy times of patients in the closed anatomical reduction group were significantly increased compared with those in the closed functional reduction group, while the fracture healing time was significantly reduced. However, patients in the open reduction group had significantly more intraoperative blood loss than those in the closed reduction group. The mean follow-up duration of patients was 15.81 ± 3.25 months. Open anatomical reduction was found to have a higher complication rate during follow-up. Specifically, a total of 3 cases recovered after 2 times of surgical treatment. 6 cases showed a small gap at the fracture end which did not affect the function. Conclusion: In the treatment of middle and lower spiral fracture of tibia, closed anatomical reduction and intramedullary nail internal fixation have shorter fracture healing time, less blood loss, and fewer complications, which can act as the first surgical choice. However, open reduction and intramedullary nailing have a high complication rate, which is not recommended.

Activation of PI3K/AKT Pathway Is a Potential Mechanism of Treatment Resistance in Small Cell Lung Cancer.

PURPOSE: Here, we have investigated treatment resistance mechanisms in small cell lung cancer (SCLC) by focusing on comparing the genotype and phenotype in tumor samples of treatment-resistant and treatment-sensitive SCLC. EXPERIMENTAL DESIGN: We conducted whole-exome sequencing on paired tumor samples at diagnosis and relapse from 11 patients with limited-stage (LS)-SCLC and targeted sequencing of 1,021 cancer-related genes on cell-free DNA at baseline and paired relapsed samples from 9 additional patients with LS-SCLC. Furthermore, we performed label-free mass spectrometry-based proteomics on tumor samples from 28 chemo-resistant and 23 chemo-sensitive patients with extensive-stage (ES)-SCLC. The main findings were validated in vitro in chemo-sensitive versus chemo-resistant SCLC cell lines and analyses of transcriptomic data of SCLC cell lines from a public database. RESULTS: Genomic analyses demonstrated that at relapse of LS-SCLC, genes in the PI3K/AKT signaling pathway were enriched for acquired somatic mutations or high-frequency acquired copy-number variants. Pathway analysis on differentially upregulated proteins from ES-SCLC cohort revealed enrichment in the HIF-1 signaling pathway. Importantly, 7 of 62 PI3K/AKT pathway genes containing acquired somatic copy-number amplifications were enriched in HIF-1 pathway. Analyses of transcriptomic data of SCLC cell lines from public databases confirmed upregulation of PI3K/AKT and HIF-1 pathways in chemo-resistant SCLC cell lines. Furthermore, chemotherapy-resistant cell lines could be sensitive to PI3K inhibitors in vitro. CONCLUSIONS: PI3K/AKT pathway activation may be one potential mechanism underlying therapeutic resistance of SCLC. This finding warrants further investigation and provides a possible approach to reverse resistance to chemo/radiotherapy.

Efficacy and safety evaluation of neoadjuvant immunotherapy plus chemotherapy for resectable non-small cell lung cancer in real world.

Objectives: The combination of immunotherapy and chemotherapy has shown great efficacy in stage IV non-small cell lung cancer (NSCLC) and is now widely used in clinical treatment strategy. This study retrospectively analyzed the efficacy and safety of neoadjuvant immunotherapy plus chemotherapy for resectable NSCLC in real world. Methods: We retrospectively analyzed patients with NSCLC who received neoadjuvant immunotherapy plus chemotherapy and underwent complete tumor resection in Zhejiang Cancer Hospital between January 2019 and January 2021. Tumor staging was based on the eighth TNM classification system of the American Joint Committee on Cancer staging criteria. The safety and toxicity (including operative and postoperative complications) and the efficacy [including objective response rate (ORR), disease control rate (DCR), tumor major pathological remission (MPR), and pathological complete response (pCR)] were evaluated. Results: In total, 368 patients with NSCLC were administered with neoadjuvant immunotherapy. Of them, 211 patients were included in this retrospective study. Most patients had stage II-III disease, with 75 (35.5%) and 88 (41.7%) patients diagnosed with clinical stages IIB and IIIA, respectively. A total of 206 patients (97.6%) received at least two doses of neoadjuvant immunotherapy plus chemotherapy. In addition, 121 patients (57.3%) have achieved MPR, and 80 patients (37.9%) have achieved pCR, with ORR at 69.2% and DCR at 97.7%. Treatment-related adverse events occurred in 46.4% of patients, and the incidence rate of grade 3 or 4 treatment-related adverse events was 13.3% (13/98). Moreover, adverse events of any grade of surgical complication occurred in 15.6% of patients. One-year disease-free survival was 80.6% (170/211). Conclusions: Neoadjuvant immunotherapy plus chemotherapy has significant efficacy with a high pCR and tolerable adverse effects for patients with resectable stage II-III NSCLC in real world.

Vascular endothelial cell-derived exosomal miR-30a-5p inhibits lung adenocarcinoma malignant progression by targeting CCNE2.

This study tried to explore the molecular mechanism underlying progression of lung adenocarcinoma (LUAD) and discuss the extracellular communication between cancer cells and vascular endothelial cells. Roughly, differential analysis was carried out to note that miR-30a-5p was lowly expressed in LUAD, whereas CCNE2 was highly expressed. Cell functional experiments demonstrated that overexpressed miR-30a-5p led to suppressed cell abilities in proliferation, migration and invasion. Dual-luciferase reporter gene assay and RNA immunoprecipitation verified the binding of miR-30a-5p and CCNE2, as well as decreased mRNA and protein expression of CCNE2 with miR-30a-5p overexpression. Simultaneous up-regulation of miR-30a-5p and CCNE2 reversed the promotion of CCNE2 on malignant behaviors of LUAD cells. In vivo mice experiments exhibited that high miR-30a-5p expression hindered tumor growth. Additionally, miR-30a-5p was localized on the Extracellular Vesicles microRNA (EVmiRNA) database. MiR-30a-5p was abundant in exosomes derived from vascular endothelial cells. To validate that miR-30a-5p could be delivered to LUAD cells via exosomes and then make an effect, exosomes from vascular endothelial cells were first extracted and identified by transmission electron microscopy and detection of exosomal marker proteins (Alix, CD63, TSG101). Sequentially, the extracted exosomes were labeled with DIO to note that exosomes could be internalized by cancer cells. Further experiments indicated that miR-30a-5p was increased in cancer cells co-cultured with exosomes, which in turn suppressed cell malignant behaviors and made cell cycle arrest. In all, our findings clarified that exosomes derived from vascular endothelial cells delivered miR-30a-5p to LUAD cells to affect tumor malignant progression via the miR-30a-5p/CCNE2 axis.

Neoadjuvant pembrolizumab with chemotherapy for the treatment of stage IIB-IIIB resectable lung squamous cell carcinoma.

BACKGROUND: Researches on programmed cell death (PD-1) as neoadjuvant immunotherapy for resectable non-small cell lung cancer is underway, which brings hope for individuals with the disease. However, a study dedicated to lung squamous cell carcinoma (LUSC) specifically has yet to be conducted. Now, data from our pilot prospective research neoadjuvant study provide new insights in the field of neoadjuvant regimen for LUSC. METHODS: Between June 2019 and July 2020, 37 adults with untreated, surgically resectable stage IIB-IIIB LUSC were enrolled into this prospective study. Patients received 2 cycles of pembrolizumab (2 mg/kg) with chemotherapy (albumin-bound paclitaxel 100 mg/m2 on days 1 and 8 + carboplatin AUC 5) via intravenous administration every 3 weeks, and underwent surgical treatment 3-4 weeks after the second cycle. The primary endpoint of the study was the tumor pathologic complete response (pCR) rate. The toxicity profile, tumor major pathological remission, complete resection rate, response rate, and operative and postoperative complications were also evaluated. RESULTS: The postoperative pathological specimens of 17 (45.9%) patients suggested pCR. Neoadjuvant pembrolizumab with chemotherapy had an acceptable side-effect profile, and no patients withdrew from the study preoperatively due to disease progression or toxicity. A major pathological response occurred in 24 (64.9%) resected tumors. All tumors were completely resected (R0, 100%). According to the Response Evaluation Criteria in Solid Tumors (RESIST), a response was evaluated before surgery in 32 (86.5%) patients by computed tomography. Twenty-five (67.6%) patients underwent thoracoscopic surgery. No deaths or postoperative major complications requiring reoperation occurred. Recurrence or metastasis was found in 2 patients during follow-up of 2-14 months. CONCLUSIONS: The early outcomes of pembrolizumab with chemotherapy in the neoadjuvant setting as a novel treatment for resectable stage IIB-IIIB LUSC showed a high pCR rate that has not been seen previously, as well as a high R0 resection rate and a low toxicity profile. The long-term efficacy of this novel treatment and the validity of the present findings should be confirmed with longer follow-up and prospective comparative trials.

A propensity-matched analysis of stereotactic body radiotherapy and sublobar resection for stage I non-small cell lung cancer in patients at high risk for lobectomy: the results in a Chinese population.

BACKGROUND: To investigate the comparative effectiveness of stereotactic body radiotherapy (SBRT) and sublobar resection (SLR) in patients with stage I non-small cell lung cancer (NSCLC) considered to be high-risk lobectomy patients. METHODS: From January 2012 to December 2015, patients who underwent SBRT or SLR for clinical stage I NSCLC were examined retrospectively. Propensity score matching (PSM) was performed to reduce selection bias in SBRT and SLR patients. RESULTS: Data from 86 SBRT and 79 SLR patients was collected. Median follow-up periods of the SBRT and SLR groups were 32 and 37 months, respectively. Patients treated with SBRT exhibited significantly higher age, higher likelihood of being male, larger tumor diameter, lower forced expiratory volume in 1 second (FEV1), and poorer performance status compared with SLR patients. There were no significant differences between SBRT and SLR patients for 3-year overall survival (OS) (80.3% and 82.3%, P=0.405), cause-specific survival (CSS) (81.3% and 83.4%, P=0.383), and local control (LC) (89.7% and 86.0%, P=0.501). Forty-nine patients were identified from each group after performing PSM. After patients were matched for age, gender, performance status, tumor characteristics and pulmonary function, no significant differences were observed in 3-year OS (85.4% and 73.3%, P=0.649), CSS (87.2% and 74.9%, P=0.637) and LC (95.6% and 82.1%, P=0.055). Prevalence of significant adverse events (grade 3 or worse) was 0% and 10.2% in the matched SBRT and SLR groups (P=0.056), respectively. CONCLUSIONS: Disease control and survival in the SBRT patients was equivalent to that seen in SLR patients with stage I NSCLC considered high-risk lobectomy candidates. SBRT could therefore be an alternative option to SLR in treating patients with a high operative risk.

Long-term outcomes and prognostic factor analysis of resected Siewert type II adenocarcinoma of esophagogastric junction in China: a seven-year study.

BACKGROUND: The incidence rate of adenocarcinoma of the esophagogastric junction (AEG) has significantly increased over the past two decades. Surgery remains the only curative treatment. However, there are currently few studies on Chinese AEG patients. The purpose of this study was to retrospectively analyze the survival and prognostic factors of AEG patients in our center. METHODS: Between January 2008 and September 2014, 249 AEG patients who underwent radical resection were enrolled in this retrospective study, including 196 males and 53 females, with a median age of 64 (range 31-82). Prognostic factors were assessed with the log-rank test and Cox univariate and multivariate analyses. RESULTS: The 5-year survival rate of all patients was 49%. The median survival time of all enrolled patients was 70.1 months. Pathological type, intraoperative blood transfusion, tumor size, adjuvant chemotherapy, duration of hospital stay, serum CA199, CA125, CA242 and CEA, pTNM stage, lymphovascular or perineural invasion, and the ratio of positive to negative lymph nodes (PNLNR) were significantly associated with overall survival when analyzed in univariate analysis. CONCLUSIONS: Our study found that adjuvant chemotherapy, PNLNR, intraoperative blood transfusion, tumor size, perineural invasion, serum CEA, and duration of hospital stay after surgery had significance in multivariate analysis and were independent risk factors for survival.

Prognostic impact of micropapillary component in patients with node-negative subcentimeter lung adenocarcinoma: A Chinese cohort study.

BACKGROUND: In this study, we investigated the prognostic significance of a micropapillary (MP) component in patients with subcentimeter lung adenocarcinoma. METHODS: A total of 311 patients with subcentimeter lung adenocarcinoma who underwent surgical resection between January 2009 to December 2012 from seven medical centers were included. Recurrence-free survival (RFS) and overall survival (OS) were analyzed. RESULTS: The five-year RFS was 79.8% in 97 (97/311, 31%) cases of adenocarcinoma with a MP component and 93.5% in the 214 (214/311, 69%) cases without. In multivariate analysis, MP was an independent risk factor for worse RFS (hazard ratio [HR], 3.73; 95% confidence interval [CI]: 1.87-7.42; P < 0.001) and OS (HR, 5.84; 95% CI: 2.20-15.49; P < 0.001). There was no significant difference among wedge resection, segmentectomy and lobectomy on RFS (P = 0.256) and OS (P = 0.103) in patients without MP. Regarding patients with a MP component, lobectomy achieved equivalent prognosis than segmentectomy, and both were better than wedge resection (P = 0.001). CONCLUSIONS: A MP component still suggest a poor prognosis in subcentimeter lung adenocarcinoma. Patients with subcentimeter lung adenocarcinoma with a MP component of 5% or greater treated with wedge resection were at higher risk of recurrence than patients treated with anatomical resection.

Impact of histological components on selecting limited lymphadenectomy for lung adenocarcinoma ≤ 2 cm.

OBJECTIVES: There is still some dispute regarding the performance of limited mediastinal lymphadenectomy (LML) even for lung adenocarcinoma ≤ 2 cm. We aimed to recognize the potential candidates who can benefit from LML based on the percentage of histological components (PHC). METHODS: We analyzed 1160 surgical patients with invasive lung adenocarcinoma ≤ 2 cm from seven institutions between January 2012 and December 2015. All histological subtypes were listed in 5% increments by pathological slices. To test the accuracy of frozen section in judging PHC, frozen section slides from 140 cases were reviewed by three pathologists. RESULTS: There were 882 patients with systematic mediastinal lymphadenectomy (SML) and 278 with LML. Multivariable analysis indicated that, the total percentage of micropapillary and solid components (PHCMIP+S) > 5 % was the independent predictor of N2 metastasis (P < 0.001). Overall, recurrence-free survival (RFS) and overall survival (OS) favored SML compared with LML, but the subgroup analysis revealed LML and SML had similar prognosis in the group of PHCMIP+S ≤ 5 %. Moreover, multivariable Cox analysis showed LML (vs. SML) was independently associated with worse prognosis for patients with PHCMIP+S > 5 % (RFS, HR = 2.143, P < 0.001; OS, HR=1.963, P < 0.001), but not for those with PHCMIP+S ≤ 5 % (RFS, P = 0.398; OS, P = 0.298). The sensitivity and specificity of frozen section to intraoperatively identify PHCMIP+S ≤ 5 % were 97.6 % and 84.2 %, respectively. CONCLUSIONS: PHCMIP+S showed the predictive value for N2 metastasis and procedure-specific outcome (LML vs. SML). It may serve as a feasible indicator for identifying proper candidates of LML by using intraoperative frozen section.

The classification and treatment strategies of post-esophagectomy airway-gastric fistula.

BACKGROUND: Airway-gastric fistulas (AGFs) are rare but life-threatening complications after esophagectomy for esophageal cancer. Their effective and reasonable management is challenging and still controversial. This study reports the classification and management strategies of post-esophagectomy AGF based on a retrospective analysis of 26 cases in two large volume centers in China. METHODS: Between January 2000 and December 2017, 6,316 consecutive patients with esophageal carcinoma underwent esophagectomy. AGF was verified in 26 patients. The patients with AGF were divided into two types based on the anatomic characteristics of the fistula. Type I was characterized by the presence of fistula orifices in digestive tract that were higher than those in the airway and were treated with conservative management. Type II had both fistula orifices located on the same horizontal plane and were treated with surgical management. Pearson Chi-Square (R software) was used to compare mortality rates. RESULTS: From January 2000 and December 2017, 26 cases occurred AGF in 6,316 consecutive patients with esophageal carcinoma underwent esophagectomy and the incidence of AGF was 0.4%. Ten of 12 patients with type I AGF survived. Nine of 14 patients with type II AGF died. There was a significantly difference in the mortality rates between patients with AGF type I and II, which was 16.7% (2/12) and 64.3% (9/14) (χ2=6.003, P=0.014), respectively. CONCLUSIONS: AGF may be classified into two types according to the anatomic characteristics. Type I patients may be cured by conservative management and type II patients, require surgical intervention with pedicled tissues flap wrapping of the airway.

Procedure-specific prognostic impact of micropapillary subtype may guide resection strategy in small-sized lung adenocarcinomas: a multicenter study.

BACKGROUND: Limited resection has gradually become an acceptable treatment for lung adenocarcinomas (ADCs) presenting as ground-glass nodules (GGNs). However, its role in lung ADCs presenting as pure solid nodules (PSN) remains unclear. In this study, we aimed to identify potential candidates for limited resection in lung ADCs presenting as PSN. METHODS: We retrospectively reviewed 772 patients from seven hospitals with lung ADCs ⩽2 cm, presenting as PSN on computed tomography scans, who had undergone surgery between 2009 and 2013. Histological subtypes were listed in 5% increments. To investigate the value of histological subtypes in surgical decision making, five pathologists prospectively evaluated the feasibility of identifying histological subtypes using frozen section (FS) in two cohorts. RESULTS: The percentage of micropapillary (MIP) subtype had a striking impact on recurrence-free survival (RFS) and overall survival (OS) for lung ADCs ⩽2 cm presenting as PSNs. In multivariable Cox analysis, segmentectomy was significantly associated with worse RFS and OS in patients with MIP >5% than lobectomy, but not in those with MIP ⩽5%. With wedge resection, worse RFS and OS were observed in patients with MIP >5% and those with MIP ⩽5% than lobectomy. The sensitivity and specificity for detecting MIP by FS were 74.2% and 85.6%, respectively, with substantial inter-rater agreement. CONCLUSION: Segmentectomy and lobectomy had similar oncological outcomes in patients with lung ADCs ⩽2 cm presenting as PSN with MIP ⩽5%. Randomized trials are necessary to validate the feasibility of intraoperative FS to choose candidates for segmentectomy.

Lepidic component identifies a subgroup of lung adenocarcinoma with a distinctive prognosis: a multicenter propensity-matched analysis.

BACKGROUND: Our aim was to investigate the prognostic impact of the lepidic component on T stage in patients with lung adenocarcinoma (LUAD). METHODS: A retrospective data set including 863 cases of LUAD with lepidic component and 856 cases without lepidic component was used to identify matched lepidic-positive and lepidic-negative cohorts (n = 376 patients per group) using a propensity-score matching. Primary outcome variables included recurrence-free survival (RFS) and overall survival (OS). Prognostic factors were assessed by Cox regression analysis and Kaplan-Meier estimates. RESULTS: Multivariate analysis revealed that lepidic component presence was an independent prognostic factor for prolonged RFS (p < 0.001) and OS (p < 0.001). Furthermore, lepidic ratio (LR) >25% or ⩽25% were confirmed to be independent prolonged survival predictors. No survival differences were observed between patients with LUAD with LR >25% or ⩽25% (RFS p = 0.333; OS p = 0.078). The 5-year OS rates of patients with LUAD with a lepidic component were 90% regardless of the T stage, and these survival rates were significantly better than those of patients with LUAD without a lepidic component in the corresponding T stage. Multivariate analysis confirmed that T stage was associated with survival only in patients with LUAD without a lepidic component. CONCLUSIONS: Lepidic component presence identifies a LUAD subgroup with an excellent prognosis independent of the LR, pathological T classification. Considering the lepidic component presence may improve prognostic predictions for patients with LUAD.

Final report of a prospective randomized study on thoracic radiotherapy target volume for limited-stage small cell lung cancer with radiation dosimetric analyses.

BACKGROUND: The thoracic radiotherapy (TRT) target volume for limited-stage small-cell lung cancer (SCLC) has been controversial for decades. In this report, the final results of a prospective randomized trial on the TRT target volume before and after induction chemotherapy are presented. METHODS: After 2 cycles of etoposide and cisplatin, patients arm were randomized to receive TRT to the postchemotherapy or prechemotherapy tumor volume in a study arm and a control arm. Involved-field radiotherapy was received in both arms. TRT consisted of 1.5 grays (Gy) twice daily in 30 fractions to up to a total dose of 45 Gy. Lymph node regions were contoured, and intentional and incidental radiation doses were recorded. RESULTS: The study was halted early because of slow accrual. Between 2002 and 2017, 159 and 150 patients were randomized to the study arm or the control arm, respectively; and 21.4% and 19.1% of patients, respectively, were staged using positron emission tomography/computed tomography (P = .31). With a median follow-up of 54.1 months (range, 19.9-165.0 months) in survivors, the 3-year local/regional progression-free probability was 58.2% and 65.5% in the study and control arms, respectively (P = .44), and the absolute difference was -7.3% (95% CI, -18.2%, 3.7%). In the study and control arms, the median overall survival was 21.9 months and 26.6 months, respectively, and the 5-year overall survival rate was 22.8% and 28.1%, respectively (P = .26). Grade 3 esophagitis was observed in 5.9% of patients in the study arm versus 15.5% of those in the control arm (P = .01). The isolated out-of-field failure rate was 2.6% in the study arm versus 4.1% in the control arm (P = .46), and all such failures were located in the supraclavicular fossa or contralateral hilum. The regions 7, 3P, 4L, 6, 4R, 5, and 2L received incidental radiation doses >30 Gy. CONCLUSIONS: TRT could be limited to the postchemotherapy tumor volume, and involved-field radiotherapy could be routinely applied for limited-stage SCLC.

Anti-TNF-α therapy alters the gut microbiota in proteoglycan-induced ankylosing spondylitis in mice.

Ankylosing spondylitis is a chronic, progressive disease, and its treatment is relevant to the gut microbiota. Anti-tumor necrosis factor-alpha (anti-TNF-α) therapy alters the gut microbiota in many diseases, including inflammatory bowel disease. However, little is known about the effect of TNF-α blocker treatment on the gut microbiota in ankylosing spondylitis. Herein, the effect of a TNF-α blocker on the gut microbiota in proteoglycan-induced arthritis was investigated. Proteoglycan-induced mice were treated with an rhTNFR:Fc solution of etanercept (5 µg/g) for 4 weeks. rhTNFR:Fc treatment attenuated the arthritis incidence and severity of arthritis in the proteoglycan-induced mice and decreased inflammation in the ankle joints and ameliorated ileal tissue destruction. Moreover, high gut permeability occurred, and zonula occludens-1 and occludin protein levels were reduced in proteoglycan-induced mice. These levels were significantly restored by the administration of rhTNFR:Fc. The serum TNF-α and IL-17 levels were also decreased. In addition, flora analysis via 16S rDNA high-throughput sequencing revealed that rhTNFR:Fc treatment restored the gut microbiota composition to a composition similar to that in control mice. In conclusion, anti-TNF-α therapy attenuated proteoglycan-induced arthritis progression and modulated the gut microbiota and intestinal barrier function. These results provide new insights for anti-TNF-α therapy strategies via regulating the gut microbiota in ankylosing spondylitis.