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Abstract Background Muscle atrophy can cause muscle dysfunction and weakness. Krüppel‐like factor 13 (KLF13), a central regulator of cellular energy metabolism, is highly expressed in skeletal muscles and implicated in the pathogenesis of several diseases. This study investigated the role of KLF13 in muscle atrophy, which could be a novel therapeutic target. Methods The effects of gene knockdown and pharmacological targeting of KLF13 on skeletal muscle atrophy were investigated using cell‐based and animal models. Clofoctol, an antibiotic and KLF13 agonist, was also investigated as a candidate for repurposing. The mechanisms related to skeletal muscle atrophy were assessed by measuring the expression levels and activation statuses of key regulatory pathways and validated using gene knockdown and RNA sequencing. Results In a dexamethasone‐induced muscle atrophy mouse model, the KLF13 knockout group had decreased muscle strength (N) (1.77 ± 0.10 vs. 1.48 ± 0.16, P

Abstract Multiple synchronous lung cancers (MSLCs) constitute a unique subtype of lung cancer. To explore the genomic and immune heterogeneity across different pathological stages of MSLCs, we analyse 16 MSLCs from 8 patients using single-cell RNA-seq, single-cell TCR sequencing, and bulk whole-exome sequencing. Our investigation indicates clonally independent tumours with convergent evolution driven by shared driver mutations. However, tumours from the same individual exhibit few shared mutations, indicating independent origins. During the transition from pre-invasive to invasive adenocarcinoma, we observe a shift in T cell phenotypes characterized by increased Treg cells and exhausted CD8+ T cells, accompanied by diminished cytotoxicity. Additionally, invasive adenocarcinomas exhibit greater neoantigen abundance and a more diverse TCR repertoire, indicating heightened heterogeneity. In summary, despite having a common genetic background and environmental exposure, our study emphasizes the individuality of MSLCs at different stages, highlighting their unique genomic and immune characteristics.

TGF-β stimulates CCN2 expression which in turn amplifies TGF-β signaling. This process promotes extracellular matrix production and accelerates the pathological progression of fibrotic diseases. Alternative splicing plays an important role in multiple disease development, while U2 small nuclear RNA auxiliary factor 2 (U2AF2) is an essential factor in the early steps of pre-mRNA splicing. However, the molecular mechanism underlying abnormal CCN2 expression upon TGF-β stimulation remains unclear. This study elucidates that SIRT4 acts as a master regulator for CCN2 expression in response to TGF-β by modulating U2AF2-mediated alternative splicing. Analyses of renal biopsy specimens from patients with CKD and mouse fibrotic kidney tissues revealed marked nuclear accumulation of SIRT4. The tubulointerstitial fibrosis was alleviated by global deletion or tubular epithelial cell (TEC)-specific knockout of Sirt4, and aggravated by adeno-associated virus-mediated SIRT4 overexpression in TECs. Furthermore, SIRT4 was found to translocate from the mitochondria to the cytoplasm through the BAX/BAK pore under TGF-β stimulation. In the cytoplasm, TGF-β activated the ERK pathway and induced the phosphorylation of SIRT4 at Ser36, which further promoted its interaction with importin α1 and subsequent nuclear translocation. In the nucleus, SIRT4 was found to deacetylate U2AF2 at K413, facilitating the splicing of CCN2 pre-mRNA to promote CCN2 protein expression. Importantly, exosomes containing anti-SIRT4 antibodies were found to effectively mitigate the UUO-induced kidney fibrosis in mice. Collectively, these findings indicated that SIRT4 plays a role in kidney fibrosis by regulating CCN2 expression via the pre-mRNA splicing.

Objectives Surgery is the mainstream treatment for early-stage esophageal squamous cell carcinoma (ESCC) and occult recurrent laryngeal nerve lymph node metastasis (RLNM) is not uncommon among those with R0 resection. The clinical value of postoperative radiotherapy (PORT) in patients with RLNM only is still controversial. Methods Consecutive patients with early-stage ESCC treated with R0 resection and pathologically confirmed RLNM only from June 2012 to July 2022 were retrospectively reviewed. PORT, covering the supraclavicular and superior mediastinum area (small T-field) at a dose of 50.4 Gy for 28 fractions, was performed in some patients. Propensity score matching (PSM) was performed to balance the baseline characteristics between patients with or without PORT. Pattern of failure, disease-free survival (DFS), and overall survival (OS) were compared. Results Among the 189 patients identified, 69 (35.5%) received PORT and the other 120 (63.5%) did not. After PSM, 154 patients were included in the matched cohort, including 62 in the PORT group and 92 in the non-PORT group. With a median follow-up of 48 (95% CI: 40.3-55.7) months, 69 patients developed their initial disease recurrence in the whole population and PORT significantly decreased the frequency of local recurrence (61.2% vs 21.4%) among those with recurrent disease. Additionally, in the PSM matched cohort, PORT significantly prolonged patients’ DFS (HR 0.393, P = 0.002) and OS (HR 0.462, P = 0.020). Moreover, PORT remained as the independent factor associated with improved DFS (HR 0.360, P = 0.001) and OS (HR 0.451, P = 0.021) after multivariate Cox analyses. In addition, tumor location and pathological TNM stage were found to be independent prognostic factors associated with survival outcomes. Conclusion PORT is associated with improved DFS and OS in ESCC patients with R0 resection and RLNM only, which warrants future validation.

Abstract Background Neoadjuvant chemoimmunotherapy (NCIT) for locally advanced esophageal squamous cell carcinoma (ESCC) is supported by increasing data, but the sample size is limited, and the findings are not completely consistent. We conducted a real‐world study and a meta‐analysis to evaluate the efficacy and safety of NCIT in locally advanced ESCC. Methods We retrospectively assessed the outcomes of patients with locally advanced ESCC who completed NICT and subsequent esophagectomy at our hospital between January 2019 and December 2022, including pathological complete response (pCR) rate, major pathological response (MPR) rate, 1‐, 2‐, and 3‐year overall survival (OS) rates, disease control rate (DCR), objective response rate (ORR), 1‐year recurrence rate, R0 resection rate and adverse events. Moreover, a meta‐analysis of 27 published literatures was also conducted for comparison. Results In the analysis, 128 patients were studied, with 25% achieving pCR, 46.1% MPR, and 99.2% R0 resection. The 1‐, 2‐, and 3‐year OS rates were 91.41% (95% CI: 85.15%–95.63%), 75.00% (95% CI: 66.58%–82.23%) and 64.84% (95% CI: 55.91%–73.07%).ORR and DCR were 31.2% (95% CI: 23.31–39.99) and 64.1% (95% CI: 55.15%–72.38%), and the 1‐year recurrence rate was 26.7% (95% CI: 22.5%–38.1%). Treatment‐related events occurred in 96.1% but were acceptable. In a meta‐analysis of 27 studies with 1734 patients, pooled rates for pCR, MPR, ORR, DCR, and R0 resection were 29%, 52%, 71%, 97%, and 98%, respectively, with a 1‐year recurrence rate of 12%. Conclusion NCIT is safe and provides potential survival benefits for patients with locally advanced ESCC. However, randomized phase 3 trial data is still needed.

Abstract Background Associations between adjuvant chemotherapy (ACT) and the improvement in survival for patients with pT2N0M0 non‐small cell lung cancer (NSCLC) who received R0 resection remain controversial. This study aimed to evaluate the value of ACT for patients with pT2N0M0 NSCLCs, and to identify the subgroups who could benefit from ACT. Methods Multivariable Cox proportional hazards regression models were used to estimate independent prognostic factors. High‐risk factor (HRF) included visceral pleural invasion (VPI), lymphovascular invasion (LVI) and poor differentiation/undifferentiated tumors. Results Of the 899 patients, 277 (30.8%) patients received ACT. More younger patients (p

Abstract Background Exercise mimetics is a proposed class of therapeutics that specifically mimics or enhances the therapeutic effects of exercise. Muscle glycogen and lactate extrusion are critical for physical performance. The mechanism by which glycogen and lactate metabolism are manipulated during exercise remains unclear. This study aimed to assess the effect of miR‐92b on the upregulation of exercise training‐induced physical performance. Methods Adeno‐associated virus (AAV)‐mediated skeletal muscle miR‐92b overexpression in C57BLKS/J mice, and global knockout of miR‐92b mice were used to explore the function of miR‐92b in glycogen and lactate metabolism in skeletal muscle. AAV‐mediated UGP2 or MCT4 knockdown in WT or miR‐92 knockout mice was used to confirm whether miR‐92b regulates glycogen and lactate metabolism in skeletal muscle through UGP2 and MCT4. Body weight, muscle weight, grip strength, running time and distance to exhaustion, and muscle histology were assessed. The expression levels of muscle mass‐related and function‐related proteins were analysed by immunoblotting or immunostaining. Results Global knockout of miR‐92b resulted in normal body weight and insulin sensitivity, but higher glycogen content before exercise exhaustion (0.8538 ± 0.0417 vs. 1.043 ± 0.040, **P = 0.0087), lower lactate levels after exercise exhaustion (4.133 ± 0.2589 vs. 3.207 ± 0.2511, *P = 0.0279), and better exercise capacity (running distance to exhaustion, 3616 ± 86.71 vs. 4231 ± 90.29, ***P = 0.0006; running time to exhaustion, 186.8 ± 8.027 vs. 220.8 ± 3.156, **P = 0.0028), as compared with those observed in the control mice. Mice skeletal muscle overexpressing miR‐92b (both miR‐92b‐3p and miR‐92b‐5p) displayed lower glycogen content before exercise exhaustion (0.6318 ± 0.0231 vs. 0.535 ± 0.0194, **P = 0.0094), and higher lactate accumulation after exercise exhaustion (4.5 ± 0.2394 vs. 5.467 ± 0.1892, *P = 0.01), and poorer exercise capacity (running distance to exhaustion, 4005 ± 81.65 vs. 3228 ± 149.8, ***P

Abstract Metabolic reprogramming to glycolysis is closely associated with the development of chronic kidney disease (CKD). Although it has been reported that phosphofructokinase 1 (PFK) is a rate-limiting enzyme in glycolysis, the role of the platelet isoform of PFK (PFKP) in kidney fibrosis initiation and progression is as yet poorly understood. Here, we investigated whether PFKP could mediate the progression of kidney interstitial fibrosis by regulating glycolysis in proximal tubular epithelial cells (PTECs). We induced PFKP overexpression or knockdown in renal tubules via an adeno-associated virus (AAV) vector in the kidneys of mice following unilateral ureteral occlusion. Our results show that the dilated tubules, the area of interstitial fibrosis, and renal glycolysis were promoted by proximal tubule-specific overexpression of PFKP, and repressed by knockdown of PFKP. Furthermore, knockdown of PFKP expression restrained, while PFKP overexpression promoted TGF-β1-induced glycolysis in the human PTECs line. Mechanistically, Chip-qPCR revealed that TGF-β1 recruited the small mothers against decapentaplegic (SMAD) family member 3-SP1 complex to the PFKP promoter to enhance its expression. Treatment of mice with isorhamnetin notably ameliorated PTEC-elevated glycolysis and kidney fibrosis. Hence, our results suggest that PFKP mediates the progression of kidney interstitial fibrosis by regulating glycolysis in PTECs.

Abstract Transforming growth factor-β (TGF-β) is the primary factor that drives fibrosis in most, if not all, forms of chronic kidney disease. In kidneys that are obstructed, specific deletion of Sirt2 in renal tubule epithelial cells (TEC) has been shown to aggravate renal fibrosis, while renal tubule specific overexpression of Sirt2 has been shown to ameliorate renal fibrosis. Similarly, specific deletion of Sirt2 in hepatocyte aggravated CCl4-induced hepatic fibrosis. In addition, we have demonstrated that SIRT2 overexpression and knockdown restrain and enhance TGF-β-induced fibrotic gene expression, respectively, in TEC. Mechanistically, SIRT2 reduced the phosphorylation, acetylation, and nuclear localization levels of SMAD2 and SMAD3, leading to inhibition of the TGF-β signaling pathway. Further studies have revealed that that SIRT2 was able to directly interact with and deacetylate SMAD2 at lysine 451, promoting its ubiquitination and degradation. Notably, loss of SMAD specific E3 ubiquitin protein ligase 2 abolishes the ubiquitination and degradation of SMAD2 induced by SIRT2 in SMAD2. Regarding SMAD3, we have found that SIRT2 interact with and deacetylates SMAD3 at lysine 341 and 378 only in the presence of TGF-β, thereby reducing its activation. This study provides initial indication of the anti-fibrotic role of SIRT2 in renal tubules and hepatocytes, suggesting its therapeutic potential for fibrosis.

Abstract Background The study aimed to fully understand small bowel necrosis, a rare but fatal complication after esophagectomy. Methods Patients who underwent esophagectomy for esophageal cancer at the Fudan University Shanghai Cancer Center from January 2013 to December 2021 were retrospectively reviewed. Clinical information on the demographics, presenting features, and outcomes of the cases were collected. Results Of the 6607 patients during the study period, 11 (0.2%) underwent reoperation due to bowel necrosis, including nine males (81.8%) and two females (18.2%). Among them, eight cases (72.7%) had hypertension and seven (63.6%) suffered from lower thoracic esophageal cancer. Eight (72.7%) and three (27.3%) patients underwent the Ivor‐Lewis and McKewon procedures, respectively. Jejunostomy was performed in nine patients (81.8%). The first signs of bowel necrosis appeared within 5 days after esophagectomy. Abdominal distension and deteriorating renal function were observed in seven patients (63.6%). There was no evidence of mesenteric vascular occlusion in any of the 11 cases, except for the hepatic portal venous gas found in seven patients on the computed tomography (CT) scan. Eight (72.7%) of the 11 patients underwent reoperation within 24 h due to the onset of the first symptoms. Eight (72.7%) had ileal necrosis, and three (27.3%) died. Conclusion Close attention should be paid to patients with abdominal distension, renal function damage, and portal hepatic venous gas after esophagectomy. These patients may suffer from small bowel necrosis, which may result in rapid disease progression. Exploratory laparotomy and bowel resection are effective treatments for such patients.

Abstract Purpose Esophageal squamous cell carcinoma (ESCC) metastasizes in an unpredictable fashion to adjacent lymph nodes, including those along the recurrent laryngeal nerves (RLNs). This study is to apply machine learning (ML) for prediction of RLN node metastasis in ESCC. Methods The dataset contained 3352 surgically treated ESCC patients whose RLN lymph nodes were removed and pathologically evaluated. Using their baseline and pathological features, ML models were established to predict RLN node metastasis on each side with or without the node status of the contralateral side. Models were trained to achieve at least 90% negative predictive value (NPV) in fivefold cross-validation. The importance of each feature was measured by the permutation score. Results Tumor metastases were found in 17.0% RLN lymph nodes on the right and 10.8% on the left. In both tasks, the performance of each model was comparable, with a mean area under the curve ranging from 0.731 to 0.739 (without contralateral RLN node status) and from 0.744 to 0.748 (with contralateral status). All models showed approximately 90% NPV scores, suggesting proper generalizability. The pathology status of chest paraesophgeal nodes and tumor depth had the highest impacts on the risk of RLN node metastasis in both models. Conclusion This study demonstrated the feasibility of ML in predicting RLN node metastasis in ESCC. These models may potentially be used intraoperatively to spare RLN node dissection in low-risk patients, thereby minimizing adverse events associated with RLN injuries.

Summary: Transforming growth factor β1 (TGFβ1) has been identified as a major pathogenic factor underlying the development of chronic kidney disease (CKD). This study investigated the role of miR-92b-3p in the progression of renal fibrosis in unilateral ureteral occlusion (UUO) and unilateral ischemia-reperfusion injury (uIRI) mouse models, as well as explored its underlying mechanisms in human proximal tubular epithelial (HK2) cells. We found that renal fibrosis increased in UUO mice after miR-92b knockout, while it reduced in miR-92b overexpressing mice. MiR-92b knockout aggravated renal fibrosis in uIRI mice. RNA-sequencing analysis, the luciferase reporter assay, qPCR analysis, and western blotting confirmed that miR-92b-3p directly targeted TGF-β receptor 1, thereby ameliorating renal fibrosis by suppressing the TGF-β signaling pathway. Furthermore, we found that TGF-β suppressed miR-92b transcription through Snail family transcriptional repressors 1 and 2. Our results suggest that miR-92b-3p may serve as a novel therapeutic for mitigating fibrosis in CKD.

Abstract Background To compare the efficacy and safety of postoperative extensive target volume irradiation with elevated radiation dose and concurrent chemotherapy with radiotherapy only for the postoperative treatment of esophageal squamous cell carcinoma. Methods This trial was a single-arm phase II trial. Patients who underwent a radical transthoracic resection with negative margins within 3 months and histologically confirmed esophageal squamous cell carcinoma (pT3-4N0M0 or pTxN + M0, AJCC 7th) were eligible for this study. Postoperative radiotherapy was performed at a total dose of 45 Gy in 25 fractions with clinical target volumes of the tumor bed, anastomosis, bilateral supraclavicular, mediastinal, left gastric and celiac trunk lymph node areas. Five cycles of weekly TC (paclitaxel 50 mg/m2, d1, carboplatin AUC = 2, d1) were given as concurrent chemotherapy. The primary endpoint was the 2-year local control rate, and the secondary endpoints were overall survival, disease free survival, local-regional recurrence free survival, distant metastasis free survival and adverse events. All endpoints were compared with those in ESO-Shanghai 8 study with postoperative radiotherapy alone (40 Gy/20Fx). Results A total of 70 patients were enrolled from 2016 to 2018. The 2-year local control rate was 87.9% (95% CI: 83.3–92.3) in this study, which achieved the hypothesized 2-year local control rate of at least 83%. Overall survival, disease free survival, local-regional recurrence free survival and distant metastasis free survival in this study were also longer than those in previous ESO-Shanghai 8 study while most toxicities were increased and two patients in this study died of radiation pneumonitis. Conclusions Postoperative extensive target volume irradiation with elevated radiation dose and concurrent chemotherapy was effective. Treatment related toxicity was increased due to higher treatment intensity. Trial registration clinicaltrials.gov: NCT02916511.

Summary: Transforming growth factor β (TGF-β) is the primary factor that drives fibrosis in most forms of chronic kidney disease. The aim of this study was to identify endogenous regulators of TGF-β signaling and fibrosis. Here, we show that tubulointerstitial fibrosis is aggravated by global deletion of KLF13 and attenuated by adeno-associated virus-mediated KLF13 overexpression in renal tubular epithelial cells. KLF13 recruits a repressor complex comprising SIN3A and histone deacetylase 1 (HDAC1) to the TGF-β target genes, limiting the profibrotic effects of TGF-β. Temporary upregulation of TGF-β induces KLF13 expression, creating a negative feedback loop that triggers the anti-fibrotic effect of KLF13. However, persistent activation of TGF-β signaling reduces KLF13 levels through FBXW7-mediated ubiquitination degradation and HDAC-dependent mechanisms to inhibit KLF13 transcription and offset the anti-fibrotic effect of KLF13. Collectively, our data demonstrate a role of KLF13 in regulating TGF-β signaling and fibrosis.

Diabetic kidney disease (DKD) is the leading cause of end-stage renal disease. Clinical features are traditionally used to predict DKD, yet with low diagnostic efficacy. Most of the recent biomarkers used to predict DKD are based on transcriptomics and metabolomics; however, they also should be used in combination with many other predictive indicators. The purpose of this study was thus to identify a simplified class of blood biomarkers capable of predicting the risk of developing DKD. The Gene Expression Omnibus database was screened for DKD biomarkers, and differentially expressed genes (DEGs) in human blood and kidney were identified via gene expression analysis and the Least Absolute Shrinkage and Selection Operator regression. A comparison of the area under the curve (AUC) profiles on multiple receiver operating characteristic curves of the DEGs in DKD and other renal diseases revealed that REG1A and RUNX3 had the highest specificity for DKD diagnosis. The AUCs of the combined expression of REG1A and RUNX3 in kidney (AUC = 0.929) and blood samples (AUC = 0.917) of DKD patients were similar to each other. The AUC of blood samples from DKD patients and healthy individuals obtained for external validation further demonstrated that REG1A combined with RUNX3 had significant diagnostic efficacy (AUC=0.948). REG1A and RUNX3 expression levels were found to be positively and negatively correlated with urinary albumin creatinine ratio and estimated glomerular filtration rate, respectively. Kaplan-Meier curves also revealed the potential of REG1A and RUNX3 for predicting the risk of DKD. In conclusion, REG1A and RUNX3 may serve as biomarkers for predicting the risk of developing DKD.

BackgroundImmune checkpoint inhibitors (ICI) improve survival in patients with late-stage esophageal squamous cell carcinoma (ESCC) but have not been fully evaluated in locally advanced ESCC.MethodWe retrospectively assessed outcomes of consecutive, treatment-naïve locally advanced ESCC (stage III or IVA) adults treated with neoadjuvant ICI plus chemotherapy followed by surgery, who refused or lacked access to radiotherapy, with regards to surgery feasibility, pathological response, and relapse-free survival (RFS).ResultsWe uneventfully treated 34 patients with the combined regimen in 2020. None reported grade III or higher toxic effects. All underwent surgery as planned: 32 received complete (R0) resections and 2 had microscopically positive margins (R1). Tumor downstaging occurred in 33 (97.1%) patients and 11 (32.4%) had pathologically complete response of the primary lesion. Median postoperative length of stay was 12 days (interquartile range: 11 to 17). All patients resumed a semi-liquid diet on discharge. The 90-day postoperative morbidity rate was 20.6% (7/34) with no mortalities. The 1-year RFS was 77.8% [95% CI, 64.2-94.2].ConclusionNeoadjuvant ICI plus chemotherapy was safe and resulted in significant downstaging, rendering inoperable tumors operable, relieving symptoms of dysphagia and prolonging survival for locally advanced ESCC patients who refused or lacked access to radiotherapy.

Nonalcoholic fatty liver disease (NAFLD) is defined as liver disease in which more than 5% of hepatocytes are steatotic with little or no alcohol consumption. NAFLD includes benign nonalcoholic fatty liver (NAFL) and nonalcoholic steatohepatitis (NASH). Importantly, NASH is an advanced progression of NAFL and is characterized by steatosis, hepatocyte ballooning, lobular inflammation, and fibrosis. However, to date, no drugs specifically targeting NAFLD have been approved by the FDA. Therefore, a new drug or strategy for NAFLD treatment is necessary. However, the pathogenesis of NAFLD is complex and no single-target drugs have achieved the desired results. Noticeably, traditional Chinese medicine formulations are a complex system with multiple components, multiple targets, and synergistic effects between components. The Ganweikang tablet is a compound formula based on traditional Chinese medicine theory and clinical experience. In this study, network pharmacology analysis indicates Ganweikang tablet as a candidate for NAFLD treatment. Furthermore, we evaluated the therapeutic effects of Ganweikang tablet on the NAFL and NASH and tried to clarify the underlying molecular mechanisms in animal models and cell experiments. As expected, Ganweikang tablet was found to improve NAFL and NASH by modulating inflammation, apoptosis, and fatty acid oxidation by inhibiting NFκB, caspase-8, and activating PPARα, which not only indicates that Ganweikang tablet as a drug candidate but also provides a theoretical basis of Ganweikang tablet for the treatment of NAFL and NASH.

Abstract Background 99mTc bone scintigraphy (BS) is still the most common approach for the evaluation of bone metastasis in China. The purpose of this study was to investigate the necessity of BS as part of a routine preoperative workup for patients with cT1N0 subsolid lung cancer. Methods This was a prospective multicenter clinical trial (NCT03689439). Patients with cT1N0 subsolid nodules who were candidates for surgical resection were consecutively enrolled into the study. BS was performed preoperatively. The surgical plan could be changed if a positive result was detected. The primary endpoint was the incidence rate of the surgical plan being changed because of positive BS results. The secondary endpoint was the rate of positive BS findings and the rate of related complications. Results From November 2018 to July 2019, 691 patients were enrolled into the study. None of the patients had positive BS results and no surgical plans were changed by BS findings. There were 222 male and 469 female patients. The average age was 54.8 ± 3.7 years old. The average tumor diameter was 14.9 ± 4.2 mm. There were 282 patients with pure GGO nodules and 409 with part‐solid nodules. A total of 470 patients had a single nodule, while 221 patients had multifocal lesions. The number of patients whose pathological diagnosis was invasive adenocarcinoma, minimally invasive adenocarcinoma, adenocarcinoma in situ and mucinous adenocarcinoma was 357, 293, 32 and nine, respectively. The number of patients who underwent lobectomy, segmentectomy and wedge resection was 234, 199 and 258, respectively. Conclusions 99mTc bone scintigraphy is unnecessary in the preoperative workup for patients with cT1N0 subsolid lung cancer. Key points Significant findings of the study In this prospective study of 691 patients with cT1N0 subsolid lung cancer, no surgical plans were affected by positive bone scan findings. What this study adds We suggest physicians consider canceling BS from preoperative workup for cT1 subsolid lung cancer patients. Clinical trial registry number: NCT03689439.

Diabetic kidney disease (DKD) is the leading cause of end-stage renal disease and has become a serious public health problem worldwide. Dipeptidyl peptidase-4 (DPP4) inhibitors, an emerging drug for the treatment of diabetes, have been found to have renoprotective effects in addition to glucose-lowering effects and therefore have the potential to be a treatment modality for DKD. Lobeliae Chinensis Herba (LCH), a traditional Chinese herb widely used in the treatment of diabetes, has recently been found to have a hypoglycaemic mechanism related to the inhibition of DPP4. Firstly, analysis of single-cell sequencing data from mouse kidneys in the National Center for Biotechnology Information (NCBI) database revealed that DPP4 was specifically upregulated in DKD podocytes and was associated with podocyte proliferation. Subsequently, the network pharmacology approach was applied to the screening of compounds. Twelve LCH active ingredients targeting DPP4 were extracted from the Traditional Chinese Medicine System Pharmacology (TCMSP) database. In addition, these 12 compounds and DPP4 were molecularly docked to predict the probability of them affecting DPP4 activity. In vitro, Quercetin, Methyl rosmarinate, Kaempferol, Diosmetin and Acacetin were demonstrated to retard podocyte proliferation by inhibiting DPP4 activity and were the top five compounds predicted by molecular docking to be the most likely to affect DPP4 activity. The half maximal inhibitory concentration (IC50) of the five compounds for DPP4 activity were as follows. Acacetin Log IC50 = −8.349, 95%CI (−9.266, −7.265), Diosmtrin Log IC50 = −8.419, 95%CI (−8.889, −7.950), Log IC50 = −8.349, 95%CI (−9.266, −7.265), Methyl rosmarinate Log IC50 = −8.415, 95%CI (−8.751, −8.085), Kaempferol Log IC50 = −8.297, 95%CI (−9.001, −7.615), Quercetin Log IC50 = −8.864, 95%CI (−9.107, −8.615). Finally, Quercetin, Methyl rosmarinate, Kaempferol, Diosmetin and Acacetin qualified for pharmacokinetic and drug similarity screening and have the potential to be the most promising oral agents for the treatment of DKD.

Background and purpose: FXR is a promising target for the treatment of human cholestatic liver disease (CLD). SIRT1 is a deacetylase which promotes FXR activity through deacetylating FXR. Pterostilbene (PTE) is an activator of SIRT1. However, the role of PTE in cholestasis has so far not been investigated. We examined whether PTE treatment alleviate liver injury in DDC or ANIT-induced experimental cholestasis, and explored the underlying mechanisms.Experimental approach: Mice with DDC- or ANIT-induced cholestasis were treated with different dose of PTE. Primary hepatocytes and bone marrow derived macrophages were used in vitro to assess the molecular mechanism by which PTE may improve CLD. Identical doses of UDCA or PTE were administered to DDC- or ANIT-induced cholestasis mice.Key results: PTE intervention attenuated DDC or ANIT-induced cholestasis. PTE inhibited macrophage infiltration and activation in mouse liver through the SIRT1-p53 signaling pathway, and it improved hepatic bile metabolism through the SIRT1-FXR signaling pathway. Compare with UDCA, the same doses of PTE was more effective in improving cholestatic liver injury caused by DDC or ANIT.Conclusion and implications: SIRT1 activation in macrophages may be an effective CLD treatment avenue. Using CLD models, we thus identified PTE as a novel clinical candidate compound for the treatment of CLD.

ObjectivesTo assess the association between common-used serum tumor markers and recurrence of lung adenocarcinoma and squamous cell carcinoma separately and determine the prognostic value of serum tumor markers in lung adenocarcinoma featured as ground glass opacities.MethodsA total of 2,654 non-small cell lung cancer patients undergoing surgical resection between January 2008 and September 2014 were analyzed. The serum levels of carcinoma embryonic antigen (CEA), cytokeratin 19 fragment (CYFRA21-1), neuron-specific enolase (NSE), carbohydrate antigen 125 (CA125), carbohydrate antigen 153 (CA153) and carbohydrate antigen 199 (CA199) were tested preoperatively. Survival analyses were performed with COX proportional hazard regression.ResultsAmong patients with lung adenocarcinoma, elevated preoperative serum CEA(HR=1.246, 95%CI:1.043-1.488, P=0.015), CYFRA21-1(HR=1.209, 95%CI:1.015-1.441, P=0.034) and CA125(HR=1.361, 95%CI:1.053-1.757, P=0.018) were significantly associated with poorer recurrence free survival (RFS). Elevated preoperative serum CA199 predicted worse RFS in patients diagnosed with lung squamous cell carcinoma (HR=1.833, 95%CI: 1.216-2.762, P=0.004). Preoperative serum CYFRA21-1(HR=1.256, 95%CI:1.044-1.512, P=0.016) and CA125(HR=1.373, 95%CI: 1.050-1.795, P=0.020) were independent prognostic factors for patients with adenocarcinoma presenting as solid nodules while serum CEA (HR=2.160,95%CI:1.311-3.558, P=0.003) and CA125(HR=2.475,95%CI:1.163-5.266, P=0.019) were independent prognostic factors for patients with adenocarcinoma featured as ground glass opacities.ConclusionsThe prognostic significances of preoperative serum tumor markers in non-small cell lung cancer were associated with radiological features and histological types.

The genomic and immune landscape of pre-invasive lung adenocarcinoma is poorly understood. Here, the authors perform exome and transcriptome sequencing on precursor legions and invasive lung adenocarcinomas, identifying recurrently mutated genes in pre/minimally invasive cases, and arm level alteration events linked to immune infiltration.

BackgroundSurgical resection is often the preferred treatment for non-small cell lung cancer (NSCLC) patients. Predictive biomarkers after surgery can help monitoring and treating patients promptly, so as to improve the clinical outcome. In this study, we evaluated one potential candidate biomarker, the folate receptor-positive circulating tumor cell (FR+CTC), by investigating its prognostic and predictive significance in NSCLC patients who underwent surgery.MethodsIn this prospective, observational study, we enrolled NSCLC patients who were eligible to receive surgery. Prior to operation, peripheral blood was collected from each patient for an FR+CTC analysis. FR+CTCs were isolated by negative enrichment using immunomagnetic beads to deplete leukocytes and then quantitatively detected by a ligand-targeted polymerase chain reaction (PCR) method. These patients were then given standard care and were actively followed up for seven years. At the end of the follow-up period, the association between the FR+CTC level and the prognosis in these patients was evaluated.ResultsOverall, preoperative FR+CTC level was not significantly different among NSCLC patients with adenocarcinoma or non-adenocarcinoma subtypes (P = 0.24). However, between patients with low- and high-risk pathological adenocarcinoma subtypes, the preoperative FR+CTC level was significantly different (P = 0.028). Further, patients with lower preoperative FR+CTC level had longer relapse-free survival (RFS) and overall survival (OS) than those with higher preoperative FR+CTC level (RFS: not reached vs. 33.3 months, P = 0.018; OS: not reached vs. 72.0 months, P = 0.13). In a multivariate COX regression analysis, FR+CTC level (HR = 4.10; 95% CI, 1.23–13.64; P=0.022) and pathological stage (HR = 3.16; 95% CI, 1.79–10.14; P = 0.0011) were independent prognostic factors of RFS. Moreover, FR+CTC level together with adenocarcinoma subtypes provided additional information on risk for disease recurrence compared with FR+CTC or adenocarcinoma subtype alone.ConclusionOur study demonstrated that the preoperative FR+CTC level was a potential predictor for the prognosis of NSCLC patients underwent surgery. Further, when preoperative FR+CTC level is considered together with primary tumor proliferation characteristics, its prognostic value supplements that of these conventional pathological features.

Here, we aimed to identify an immunohistochemical (IHC)‐based classifier as a prognostic factor in patients with esophageal squamous cell carcinoma (ESCC). A cohort of 235 patients with ESCC undergoing radical esophagectomy (with complete clinical and pathological information) were enrolled in the study. Using the least absolute shrinkage and selection operator (LASSO) regression model, we extracted six IHC features associated with progression‐free survival (PFS) and then built a classifier in the discovery cohort (n = 141). The prognostic value of this classifier was further confirmed in the validation cohort (n = 94). Additionally, we developed a nomogram integrating the IHC‐based classifier to predict the PFS. We used the IHC‐based classifier to stratify patients into high‐ and low‐risk groups. In the discovery cohort, 5‐year PFS was 22.4% (95% CI: 0.14–0.36) for the high‐risk group and 43.3% (95% CI: 0.32–0.58) for the low‐risk group (P = 0.00064), and in the validation cohort, 5‐year PFS was 20.58% (95% CI: 0.12–0.36) for the high‐risk group and 36.43% (95% CI: 0.22–0.60) for the low‐risk group (P = 0.0082). Multivariable analysis demonstrated that the IHC‐based classifier was an independent prognostic factor for predicting PFS of patients with ESCC. We further developed a nomogram integrating the IHC‐based classifier and clinicopathological risk factors (gender, American Joint Committee on Cancer staging, and vascular invasion status) to predict the 3‐ and 5‐year PFS. The performance of the nomogram was evaluated and proved to be clinically useful. Our 6‐IHC marker‐based classifier is a reliable prognostic tool to facilitate the individual management of patients with ESCC after radical esophagectomy.

Esophageal squamous cell carcinoma (ESCC) exhibits differences in incidence and survival patterns among races. Here, analysis of Chinese and TCGA ESCC patients reveals that Asian patients exhibit higher TP53, EP300 and NFE2L2 mutational frequencies, and mutated CSMD3 associates with better prognosis.

Appropriately manipulating macrophage M1/M2 phenotypic transition is a promising therapeutic strategy for tissue repair after myocardial infarction (MI). Here we showed that gene ablation of hypoxia-induced mitogenic factor (HIMF) in mice (Himf−/− and HIMFflox/flox;Lyz2-Cre) attenuated M1 macrophage-dominated inflammatory response and promoted M2 macrophage accumulation in infarcted hearts. This in turn reduced myocardial infarct size and improved cardiac function after MI. Correspondingly, expression of HIMF in macrophages induced expression of pro-inflammatory cytokines; the culturing medium of HIMF-overexpressing macrophages impaired the cardiac fibroblast viability and function. Furthermore, macrophage HIMF was found to up-regulate C/EBP-homologous protein (CHOP) expression, which exaggerated the release of pro-inflammatory cytokines via activating signal transducer of activator of transcription 1 (STAT1) and 3 (STAT3) signaling. Together these data suggested that HIMF promotes M1-type and prohibits M2-type macrophage polarization by activating the CHOP–STAT1/STAT3 signaling pathway to negatively regulate myocardial repair. HIMF might thus constitute a novel target to treat MI. [ABSTRACT FROM AUTHOR]

Cardiac function of the human heart changes with age. The age-related change of systolic function is subtle under normal conditions, but abrupt under stress or in a pathogenesis state. Aging decreases the cardiac tolerance to stress and increases susceptibility to ischemia, which caused by aging-induced Ca2+ transient impairment and metabolic dysfunction. The changes of contractility proteins and the relative molecules are in a non-linear fashion. Specifically, the expression and activation of cMLCK increase first then fall during ischemia and reperfusion (I/R). This change is responsible for the nonmonotonic contractility alteration in I/R which the underlying mechanism is still unclear. Contractility recovery in I/R is also attenuated by age. The age-related change in cardiac contractility influences the therapeutic effect and intervention timepoint. For most cardiac ischemia therapies, the therapeutic result in the elderly is not identical to the young. Anti-aging treatment has the potential to prevent the development of ischemic injury and improves cardiac function. In this review we discuss the mechanism underlying the contractility changes in the aged heart and age-induced ischemic injury. The potential mechanism underlying the increased susceptibility to ischemic injury in advanced age is highlighted. Furthermore, we discuss the effect of age and the administration time for intervention in cardiac ischemia therapies. [ABSTRACT FROM AUTHOR]

Background: Adjuvant chemotherapy in patients with resected esophageal squamous cell cancer (ESCC) remains controversial for its uncertain role in improving overall survival (OS). Nucleotide excision repair (NER) removes DNA-adducts in tumor cells induced by the platinum-based chemotherapy and thus may modulate efficacy of the treatment. The present study evaluated if single nucleotide polymorphisms (SNPs) of NER genes were prognostic biomarkers in ESCC patients treated with platinum-based adjuvant chemotherapy (PAC).Methods: The analysis included 572 patients, for whom six SNPs of NER genes [i.e., XPC (rs1870134 and rs2228001), ERCC2/XPD rs238406 and ERCC5/XPG (rs2094258, rs2296147 and rs873601)] were detected with the TaqMan assay. Kaplan-Meier analyses and Cox proportional hazards models were used to evaluate their associations with disease free survival (DFS) and OS of these ESCC patients receiving PAC. Receiving operating characteristic curve analysis was used to evaluate the role of the risk genotypes in the DFS and OS.Results: We found that ERCC5/XPG rs2094258 and rs873601 and ERCC2/XPD rs238406 SNPs were independently associated with poorer DFS and OS of ESCC patients [ERCC5/XPG rs2094258: CT+TT vs. CC: adjusted hazards ratio (adjHR) = 1.68 and P = 0.012 for DFS; adjHR = 1.99 and P = 0.0001 for OS; ERCC5/XPG rs873601: GA+GG vs. AA: adjHR = 1.59 and P = 0.024 for DFS; adjHR = 1.91 and P = 0.0005 for OS; ERCC2/XPD rs238406: TT vs. GG+GT: adjHR = 1.43 and P = 0.020 for DFS; adjHR = 1.52 and P = 0.008 for OS]. These HRs increased as the number of risk genotypes increased in the combined analysis. The model combining the risk genotypes with clinical characteristics or the TNM stage system was better in predicting outcomes in ESCC patients with PAC.Conclusion: SNPs of ERCC2/XPD and ERCC5/XPG may independently and jointly predict survival of ESCC patients treated with PAC in this study population. Further validation in other study populations is warranted. [ABSTRACT FROM AUTHOR]

Nimotuzumab (h-R3) is a humanized monoclonal antibody that is safe to use against epidermal growth factor receptor (EGFR). However, the available information is insufficient about the dose effect of monoclonal antibody against epidermal growth factor receptor for the treatment of esophageal squamous cell carcinoma (ESCC). We retrospectively recruited 66 patients with ESCC who were treated with h-R3 and chemoradiotherapy/radiotherapy. Patients who received more than 1,200 mg of h-R3 were classified as the high-dose group, and the remaining patients were classified as the low-dose group. The endpoint for efficacy was the overall survival. Differences in survival between the groups were analyzed using the log-rank test. The Cox proportional hazards model was used in multivariate analysis to identify independent prognostic factors. The low-dose and high-dose groups comprised 55 and eleven patients, respectively. The median follow-up time in the final analysis was 46 months. The high-dose group showed no increased incidence of toxicities compared to the low-dose group. The 1-, 2-, and 5-year overall survival rates in the low-dose and high-dose groups were 66.9%, 50.0%, 31.5% and 90.0%, 80.0%, 66.7%, respectively (P=0.04). Multivariate analyses showed that the high-dose group had better survival than the low-dose group (hazard ratio 0.28, 95% confidence interval 0.09-0.94, P=0.039). Taken together, high-dose h-R3 showed limited toxicity and improved survival in patients with ESCC. [ABSTRACT FROM AUTHOR]

Background: The epidermal growth factor receptor (EGFR) signaling pathway is important in regulating biological behaviors in many malignancies. We explored whether expression and activation of EGFR and several components on its downstream pathways have prognostic significance in patients with esophageal squamous cell carcinoma (ESCC). Methods: Expression of EGFR, phosphorylated (p)-EGFR, AKT1, p-AKT1, AKT2, p-AKT2, ERK1, ERK2, p-ERK1/2, STAT3, and p-STAT3 was assessed by immunohistochemical analysis of tissue microarrays for 275 ESCC patients who had undergone complete three-field lymphadenectomy. Spearman rank correlation tests were used to determine the relationships among protein expression, and Cox regression analyses were performed to determine the prognostic factors on overall survival (OS). Results: p-EGFR expression was correlated statistically with all of the other phosphorylated markers. Gender, N stage, and p-AKT1 expression were found to be independent prognostic factors for OS. Increased expression of p-AKT1 was associated with decreased patient survival. EGFR and p-EGFR expression was not significantly associated with patient survival. Conclusion: Activation of AKT1 was associated with poor prognosis in ESCC. [ABSTRACT FROM AUTHOR]

Background. Recent studies have revealed that clusterin is implicated in many physiological and pathological processes, including tumorigenesis. However, the relationship between serum clusterin expression and esophageal squamous cell carcinoma (ESCC) is unclear. Methods. The serum clusterin concentrations of 87 ESCC patients and 136 healthy individuals were examined. An independent-samples Mann-Whitney U test was used to compare serum clusterin concentrations of ESCC patients to those of healthy controls. Univariate analysis was conducted using the log-rank test and multivariate analyses were performed using the Cox proportional hazards model. Results. In healthy controls, the mean clusterin concentration was 288.8 ± 75.1 µg/mL, while in the ESCC patients, the mean clusterin concentration was higher at 412.3 ± 159.4 µg/mL (P < 0.0001). The 1-, 2-, and 4-year survival rates for the 87 ESCC patients were 89.70%, 80.00%, and 54.50%. Serum clusterin had an optimal diagnostic cut-off point (serum clusterin concentration = 335.5 µg/mL) for esophageal squamous cell carcinoma with sensitivity of 71.26% and specificity of77.94%. And higher serum clusterin concentration (>500 µg/mL) indicated better prognosis (P = 0.030). Conclusions. Clusterin may play a key role during tumorigenesis and tumor progression of ESCC and it could be applied in clinical work as a tumor marker and prognostic factor. [ABSTRACT FROM AUTHOR]

Clusterin is an enigmatic glycoprotein with a nearly ubiquitous tissue distribution. It plays important roles in various pathophysiological processes, including tissue remodeling, reproduction, lipid transport, complement regulation, and apoptosis. Clusterin appears to have two main isoforms that result from alternative splicing. The secreted and nuclear forms of clusterin have been reported to play different roles in human malignancies. The purpose of this study was to examine clusterin immunoexpression and its clinical significance in a group of Chinese patients with non-small cell lung cancer (NSCLC). Tissue samples from the primary tumors of 121 patients with completely resected NSCLC were obtained. Clusterin protein expression was evaluated by immunohistochemical staining with an antibody against all clusterin isoforms. Staining patterns were observed and graded based on intensity and density and were correlated with clinical and pathological data. Both cytoplasmic and nuclear clusterin immunostaining patterns were observed. Clusterin staining was observed only in the cytoplasm in 70 patients (57.9%), only in the nucleus in 27 patients (22.3%), and in both the cytoplasm and nucleus in 16 patients (13.2%). A significant association was observed between positive cytoplasmic clusterin expression and histologic type as indicated by adenocarcinomas that were more likely to have clusterin staining only in the cytoplasm. Clusterin immunostaining was neither associated with recurrence-free survival (RFS) nor overall survival of patients by univariate or multivariate analysis. For patients undergoing chemotherapy, those with only cytoplasmic clusterin staining had worse survival than other patients. In conclusion, both cytoplasmic and nuclear immunostaining patterns of clusterin were detected in the tumors of patients with NSCLC. Adenocarcinomas were more likely to have only cytoplasmic staining. The immunoexpression of clusterin was not associated with prognosis, and cytoplasm-only immunostaining of clusterin was inversely correlated with chemosensitivity in this group of patients. [ABSTRACT FROM AUTHOR]

The article discusses a study on the incidence, prognosis factors and treatment results of lung cancer patients between the age of 15 and 44 living in Shanghai, China. Demographic data including age and sex of patients with pathologically diagnosed lung cancer were taken from a Shanghai population-based cancer registry. The study showed that the survival of the middle-aged group is longer than the survival of the younger and older groups.

Background: Whether tumor size and stage distribution are correlated remains controversial. The objective is to assess the relationship between tumor size and disease stage distribution in non-small cell lung cancer (NSCLC). Methods: We conducted a retrospective analysis of 917 cases of NSCLC that were resected in the Cancer Hospital of Fudan University and Shanghai Sixth Hospital between January 2000 and February 2009. Tumor sizes were grouped into five categories: ≤20 mm, 21 to 30 mm, 31 to 50 mm, 51 to 70 mm and ≥71 mm. Results: Age and tumor size affected stage distribution: patients 60 years or older had a higher percentage of N0M0 disease than patients younger than 60 years (61.67% vs. 44.85%, p < 0.01). The smaller the tumor, the more likely the disease was N0M0 status (p < 0.05). For tumors ≤20 mm in diameter, the proportion of cases with N0M0 status was 70.79%, compared to 58.88% for 21 to 30 mm, 48.03% for 31 to 50 mm, 47.55% for 51 to 70 mm, 33.33% for ≥71 mm. The mean (± SD) tumor size of cases with N0M0 status was 37.17 ± 21.34 mm, compared to 45.75 ± 23.19 mm for cases with other status. Conclusions: There is a statistically significant relationship between tumor size and distribution of disease stage of primary NSCLC tumors: the smaller the tumor, the more likely the disease is N0M0 status. [ABSTRACT FROM AUTHOR]

Early efforts with minimally invasive esophagectomy (MIE) were hybrid approaches. No conclusive benefit was seen with this approach compared with the standard open procedure. Total MIE has demonstrated its advantages in single institution series. The drawbacks of total MIE include the steep learning curve and the high cost of the disposable instrumentation. We sought to determine the feasibility of modifying the surgical technique involved in the hybrid approach in an effort to decrease the cost of the surgery without compromising the outcome. From December 2007 to September 2008, the modified McKeown procedure (thoracoscopic esophageal mobilization three-incision esophagectomy) was performed in 30 cases. The median operative time was 225 minutes (range, 195 −290 minutes) and the median average time of VATS was 70 minutes (range, 50 −130 minutes). Median lymph node retrieval was 25.6 ± 4.8 nodes (15.1 ± 3.4 intrathoracic) per patient. The median postoperative hospital stay was 17.1 ± 6.3 days. There was no in-hospital (30 days) mortality. Postoperative complications occurred in 9 patients (30%), including 2 (6.7%) pneumonia, 1 (3.3%) chylothorax, 1 (3.3%) delayed gastric emptying ,1 (3.3%) vocal cord palsy, 2 (6.7%) neck anastomotic leaks, and 2 (6.7%) arrhythmias. This procedure is technically feasible and safe with lower mortality and mobility. The short-term surgical outcomes are comparable with most of the total MIE reports. Performing the gastric mobilization and spontaneous neck anastomosis first greatly facilitate and simplifies the VATS maneuver. [ABSTRACT FROM AUTHOR]

Background/Aims: Lymph nodes in patients with squamous cell carcinoma of the thoracic esophagus might be involved with metastases at cervical, mediastinal, and abdominal sites. The range of lymph node dissection is still controversial. The pattern of lymph node metastasis and factors that are correlated with lymph node metastasis affect the surgical procedure of lymph node dissection. The purpose of the present study was to explore the pattern of lymph node metastasis and factors that are correlated with lymph node metastasis in patients with esophageal cancer who underwent three-field lymphadenectomy. Methods: Lymph node metastases in 230 patients who underwent radical esophagectomy with three-field lymphadenectomy were analyzed. The metastatic sites of lymph nodes were correlated with tumor location by chi-square test. Logistic regression was used to analyze clinicopathological factors related to lymph node metastasis. Results:Lymph node metastases were found in 133 of the 230 patients (57.8%). The average number of resected lymph nodes was 25.3 ± 11.4 (range 11–71). The proportions of lymph node metastases were 41.6, 19.44, and 8.3% in neck, thoracic mediastinum, and abdominal cavity, respectively, for patients with upper thoracic esophageal carcinomas, 33.3, 34.7, and 14%, respectively, in those with middle thoracic esophageal carcinomas, and 36.4, 34.1, and 43.2%, respectively, for patients with lower thoracic esophageal carcinomas. We did not observe any significant difference in lymph node metastatic rates among upper, middle, and lower thoracic carcinomas for cervical or thoracic nodes. The difference in lymph node metastatic rates for nodes in the abdominal cavity was significant among upper, middle, and lower thoracic carcinomas. The lower thoracic esophageal cancers were more likely to metastasize to the abdominal cavity than tumors at other thoracic sites. A logistic regression model showed that depth of tumor invasion and lymphatic vessel invasion were factors influencing lymph node metastases. Conclusions: Based on our data, cervical and mediastinal node dissection should be performed independent of the tumor location. Abdominal node dissection should be conducted more vigorously for lower thoracic esophageal cancers than for cancers at other locations. Patients with deeper tumor invasion or lymphatic vessel invasion were more likely to develop lymph node metastases. Copyright © 2007 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Purpose The efficacy of neoadjuvant chemoradiotherapy (NCRT) plus surgery for locally advanced esophageal squamous cell carcinoma (ESCC) remains controversial. In this trial, we compared the survival and safety of NCRT plus surgery with surgery alone in patients with locally advanced ESCC. Patients and Methods From June 2007 to December 2014, 451 patients with potentially resectable thoracic ESCC, clinically staged as T1-4N1M0/T4N0M0, were randomly allocated to NCRT plus surgery (group CRT; n = 224) and surgery alone (group S; n = 227). In group CRT, patients received vinorelbine 25 mg/m 2 intravenously (IV) on days 1 and 8 and cisplatin 75 mg/m 2 IV day 1, or 25 mg/m 2 IV on days 1 to 4 every 3 weeks for two cycles, with a total concurrent radiation dose of 40.0 Gy administered in 20 fractions of 2.0 Gy on 5 days per week. In both groups, patients underwent McKeown or Ivor Lewis esophagectomy. The primary end point was overall survival. Results The pathologic complete response rate was 43.2% in group CRT. Compared with group S, group CRT had a higher R0 resection rate (98.4% v 91.2%; P = .002), a better median overall survival (100.1 months v 66.5 months; hazard ratio, 0.71; 95% CI, 0.53 to 0.96; P = .025), and a prolonged disease-free survival (100.1 months v 41.7 months; hazard ratio, 0.58; 95% CI, 0.43 to 0.78; P < .001). Leukopenia (48.9%) and neutropenia (45.7%) were the most common grade 3 or 4 adverse events during chemoradiotherapy. Incidences of postoperative complications were similar between groups, with the exception of arrhythmia (group CRT: 13% v group S: 4.0%; P = .001). Peritreatment mortality was 2.2% in group CRT versus 0.4% in group S ( P = .212). Conclusion This trial shows that NCRT plus surgery improves survival over surgery alone among patients with locally advanced ESCC, with acceptable and manageable adverse events.

Purpose: This study investigated the accuracy of intraoperative frozen section (FS) diagnosis for predicting the final pathology (FP) of peripheral small-sized lung adenocarcinoma and evaluated its usefulness in sublobar resection., Patients and Methods: The records of 803 patients with clinical stage I peripheral lung adenocarcinoma who underwent sublobar resection for FS diagnosis to guide surgical strategy were reviewed. The surgical extension was mainly based on FS. The FS were stratified into atypical adenomatous hyperplasia, adenocarcinoma in situ (AIS), minimally invasive adenocarcinoma (MIA), and invasive adenocarcinoma. The diagnostic accuracy of FS, the reasons for the discrepancy between FS and FP, and the clinical influence of the FS errors were evaluated. To assess the survival of patients with different subtypes after surgery, 301 patients were identified for prognosis evaluation., Results: The total concordance rate between FS and FP was 84.4%. When atypical adenomatous hyperplasia, AIS, and MIA were classified together as a low-risk group, the concordance rate was 95.9%. Most discrepant cases were the underestimation of AIS and MIA. The diagnostic accuracy of FS for tumors ≤ 1 cm and larger than 1 cm in diameter was 79.6% and 90.8%, respectively (P < .01). The FS errors had significant clinical impact on 0.9% of the 803 patients due to insufficient resection. The 5-year recurrence-free survival rate (100%) was significantly better for the patients with AIS/MIA than for patients with invasive adenocarcinoma (74.1%, P < .01)., Conclusion: Frozen pathology has a high concordance rate with FP. Precise diagnosis by intraoperative FS is an effective method to guide resection strategy for peripheral small-sized lung adenocarcinoma., (© 2015 by American Society of Clinical Oncology.)