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The process of oncogene-induced senescence (OIS) and the conversion between OIS and malignant transformation during carcinogenesis is poorly understood. Here, we show that following overactivation of oncogene Ras in lung epithelial cells, high-level transforming growth factor β1 (TGF-β1)–activated SMAD3, but not SMAD2 or SMAD4, plays a determinant role in inducing cellular senescence independent of the p53/p16/p15 senescence pathways. Importantly, SMAD3 binds a potential tumor suppressor ATOH8 to form a transcriptional complex that directly represses a series of cell cycle–promoting genes and consequently causes senescence in lung epithelial cells. Interestingly, the prosenescent SMAD3 converts to being oncogenic and essentially facilitates oncogenic Ras-driven malignant transformation. Furthermore, depleting Atoh8 rapidly accelerates oncogenic Ras-driven lung tumorigenesis, and lung cancers driven by mutant Ras and Atoh8 loss, but not by mutant Ras only, are sensitive to treatment of a specific SMAD3 inhibitor. Moreover, hypermethylation of the ATOH8 gene can be found in approximately 12% of clinical lung cancer cases. Together, our findings demonstrate not only epithelial cellular senescence directed by a potential tumor suppressor–controlled transcriptional program but also an important interplay between the prosenescent and transforming effects of TGF-β/SMAD3, potentially laying a foundation for developing early detection and anticancer strategies.

Background: Immune checkpoint (ICI) monotherapy and neoadjuvant immunochemotherapy has shown promising results in esophageal carcinoma. However, it is still unclear whether more courses in immunochemotherapy are better. We aimed to investigate the safety and efficacy of three courses of neoadjuvant treatment for patients with locally advanced esophageal squamous cell carcinoma (ESCC). Methods: This was a secondary analysis of the ChiCTR2000029807 clinical trial. Locally advanced ESCC patients have to receive three courses of camrelizumab (200mg every three weeks) plus nab-paclitaxel (260 mg/m2 every three weeks) and capecitabine (1250 mg/m2 every three weeks) before undergoing surgery. Patients received safety assessment, CT, and endoscopy (with endoscopic ultrasonography and mucosal biopsy) efficacy assessments before and in the second and third courses of treatment. We used the second and third courses' CT and endoscopic assessment results for comparison. Results: From May 2020 to December 2021, 47 patients were enrolled at Sun Yat-sen University Cancer Center. In our study, 43 patients completed three courses of preoperative chemotherapy combined with anti-PD-1 therapy and radical surgical resection. All Forty-three patients received safety assessments and CT efficacy assessments. Sixteen patients did not undergo an endoscopy examination during the second course of treatment because of esophageal stenosis or refused the endoscopy examination. The toxicity of the third course of immunochemotherapy was mild and well tolerated without increased treatment-related adverse events (TRAEs) and mortality compared with the second course of treatment. In terms of efficacy, an additional course of treatment after the second course of treatment was effective, which continued to increase the CT and endoscopy T downstaging rates by 16.3% and 25.9%, N downstaging rates by 7.0% and 11.1%, and ORR by 13.6 and 22.0%, respectively. Conclusions: No matter downstaging or ORR, three courses of immunochemotherapy appear to be superior to two courses of treatment without increasing TRAEs. (www.chictr.org.cn number, ChiCTR2000029807)

Background The current risk stratification system defined by clinicopathological features does not identify the risk of recurrence in early-stage (stage I-II) colorectal cancer (CRC) with sufficient accuracy. We aimed to investigate whether DNA methylation could serve as a novel biomarker for predicting prognosis in early-stage CRC patients. Methods We analyzed the genome-wide methylation status of CpG loci using Infinium MethylationEPIC array run on primary tumor tissues and normal mucosa of early-stage CRC patients to identify potential methylation markers for prognosis. The machine-learning approach was applied to construct a DNA methylation–based prognostic classifier for early-stage CRC (MePEC) using the 4 gene methylation markers FAT3, KAZN, TLE4, and DUSP3. The prognostic value of the classifier was evaluated in 2 independent cohorts (n = 438 and 359, respectively). Results The comprehensive analysis identified an epigenetic subtype with high risk of recurrence based on a group of CpG loci in the CpG-depleted region. In multivariable analysis, the MePEC classifier was independently and statistically significantly associated with time to recurrence in validation cohort 1 (hazard ratio = 2.35, 95% confidence interval = 1.47 to 3.76, P Conclusions We demonstrated the prognostic statistical significance of a DNA methylation profile in the CpG-depleted region, which may serve as a valuable source for tumor biomarkers. MePEC could identify an epigenetic subtype with high risk of recurrence and improve the prognostic accuracy of current clinical variables in early-stage CRC.

Objective. Histopathology image segmentation can assist medical professionals in identifying and diagnosing diseased tissue more efficiently. Although fully supervised segmentation models have excellent performance, the annotation cost is extremely expensive. Weakly supervised models are widely used in medical image segmentation due to their low annotation cost. Nevertheless, these weakly supervised models have difficulty in accurately locating the boundaries between different classes of regions in pathological images, resulting in a high rate of false alarms Our objective is to design a weakly supervised segmentation model to resolve the above problems. Approach. The segmentation model is divided into two main stages, the generation of pseudo labels based on class residual attention accumulation network (CRAANet) and the semantic segmentation based on pixel feature space construction network (PFSCNet). CRAANet provides attention scores for each class through the class residual attention module, while the Attention Accumulation (AA) module overlays the attention feature maps generated in each training epoch. PFSCNet employs a network model containing an inflated convolutional residual neural network and a multi-scale feature-aware module as the segmentation backbone, and proposes dense energy loss and pixel clustering modules are based on contrast learning to solve the pseudo-labeling-inaccuracy problem. Main results. We validate our method using the lung adenocarcinoma (LUAD-HistoSeg) dataset and the breast cancer (BCSS) dataset. The results of the experiments show that our proposed method outperforms other state-of-the-art methods on both datasets in several metrics. This suggests that it is capable of performing well in a wide variety of histopathological image segmentation tasks. Significance. We propose a weakly supervised semantic segmentation network that achieves approximate fully supervised segmentation performance even in the case of incomplete labels. The proposed AA and pixel-level contrast learning also make the edges more accurate and can well assist pathologists in their research.

Histopathology image analysis serves as the gold standard for cancer diagnosis. Efficient and precise diagnosis is quite critical for the subsequent therapeutic treatment of patients. So far, computer-aided diagnosis has not been widely applied in pathological field yet as currently well-addressed tasks are only the tip of the iceberg. Whole slide image (WSI) classification is a quite challenging problem. First, the scarcity of annotations heavily impedes the pace of developing effective approaches. Pixelwise delineated annotations on WSIs are time consuming and tedious, which poses difficulties in building a large-scale training dataset. In addition, a variety of heterogeneous patterns of tumor existing in high magnification field are actually the major obstacle. Furthermore, a gigapixel scale WSI cannot be directly analyzed due to the immeasurable computational cost. How to design the weakly supervised learning methods to maximize the use of available WSI-level labels that can be readily obtained in clinical practice is quite appealing. To overcome these challenges, we present a weakly supervised approach in this article for fast and effective classification on the whole slide lung cancer images. Our method first takes advantage of a patch-based fully convolutional network (FCN) to retrieve discriminative blocks and provides representative deep features with high efficiency. Then, different context-aware block selection and feature aggregation strategies are explored to generate globally holistic WSI descriptor which is ultimately fed into a random forest (RF) classifier for the image-level prediction. To the best of our knowledge, this is the first study to exploit the potential of image-level labels along with some coarse annotations for weakly supervised learning. A large-scale lung cancer WSI dataset is constructed in this article for evaluation, which validates the effectiveness and feasibility of the proposed method. Extensive experiments demonstrate the superior performance of our method that surpasses the state-of-the-art approaches by a significant margin with an accuracy of 97.3%. In addition, our method also achieves the best performance on the public lung cancer WSIs dataset from The Cancer Genome Atlas (TCGA). We highlight that a small number of coarse annotations can contribute to further accuracy improvement. We believe that weakly supervised learning methods have great potential to assist pathologists in histology image diagnosis in the near future.

Urachal carcinoma (UrC) is an exceedingly rare tumor and lacks effective treatment. Herein, we characterized an immune microenvironment characteristic of UrC in detail and identified its implications for prognosis and immunotherapy. In total, 37 resections of UrC were stained for CD20, CD3, CD4, CD8, FOXP3, CD68, HLA-DR, CD163, PD1, and PD-L1, as well as mismatch repair protein including MSH2, MSH6, MLH1, and PMS2 by immunohistochemistry. Intratumoral and peritumoral immune cell densities or the proportion of PD1 and PD-L1 expression alongside MSH2, MSH6, MLH1, and PMS2 status were manually evaluated using the whole slide. UrC patients with the number of tertiary lymphoid structures (TLS) per slide tended to be higher in tumors with dMMR (p = 0.1919), and tumors with higher number of TLS tended to have longer OS (p = 0.0940) and DFS (p = 0.0700). High densities of CD3+ T, CD8+ T, and CD68+ cells were significantly associated with worse OS and DFS (both pp = 0.0111) and peritumoral (p = 0.0485) CD8+ T cell densities were significantly associated with PD-L1 expression or increasing proportion of PD-L1 expression on immune cells. Similarly, increased intratumoral (p = 0.0008) and peritumoral (p = 0.063) CD8+ T cell densities were significantly associated with increasing proportion of PD1 expression on immune cells. Tumors with PD-L1 positive expression on immune cells had a significantly increased proportion of PD1 expression (p = 0.0121). High peritumoral CD8+ T cell density (>73.7/mm2) was significantly associated with worse OS (p = 0.0120) and DFS (p = 0.00095). The number of TLS seems to be considered not only as histopathological characteristics in predicting MMR status of UrC, but also as a prognostic or therapeutic biomarker, and we also provide some important suggestions for targeting PD-1/PD-L1 checkpoint in UrC.

Epstein–Barr virus-associated gastric cancer (EBVaGC) shows a robust response to immune checkpoint inhibitors. Therefore, a cost-efficient and accessible tool is needed for discriminating EBV status in patients with gastric cancer. Here we introduce a deep convolutional neural network called EBVNet and its fusion with pathologists for predicting EBVaGC from histopathology. The EBVNet yields an averaged area under the receiver operating curve (AUROC) of 0.969 from the internal cross validation, an AUROC of 0.941 on an external dataset from multiple institutes and an AUROC of 0.895 on The Cancer Genome Atlas dataset. The human-machine fusion significantly improves the diagnostic performance of both the EBVNet and the pathologist. This finding suggests that our EBVNet could provide an innovative approach for the identification of EBVaGC and may help effectively select patients with gastric cancer for immunotherapy.

The lungs are the second most common site of metastasis for colorectal cancer (CRC) after the liver. Rectal cancer is associated with a higher incidence of lung metastases compared to colon cancer. In China, the proportion of rectal cancer cases is around 50%, much higher than that in Western countries (nearly 30%). However, there is no available consensus or guideline focusing on CRC with lung metastases. We conducted an extensive discussion and reached a consensus of management for lung metastases in CRC based on current research reports and the experts’ clinical experiences and knowledge. This consensus provided detailed approaches of diagnosis and differential diagnosis and provided general guidelines for multidisciplinary therapy (MDT) of lung metastases. We also focused on recommendations of MDT management of synchronous lung metastases and initial metachronous lung metastases. This consensus might improve clinical practice of CRC with lung metastases in China and will encourage oncologists to conduct more clinical trials to obtain high-level evidences about managing lung metastases. Electronic supplementary material The online version of this article (10.1186/s13045-019-0702-0) contains supplementary material, which is available to authorized users.

Background: Mismatch repair deficient (dMMR) or microsatellite instability-high (MSI-H) serves as a predictor poor response to adjuvant chemotherapy in stage II colon cancer patients. Our objective was to investigate the efficacy of adjuvant chemotherapy in dMMR/MSI-H gastric cancer (GC). Methods: We searched literatures through December, 2020 to identify clinical studies that reported survival comparing adjuvant chemotherapy with surgery alone in dMMR/MSI-H GCs. Two approaches were used to pool the hazard ratio (HR) of survival: (1) If Kaplan-Meier curves and number at risk were provided, individual patient data were extracted. Cox models were used to calculate the HR with 95% confidence interval (CI); (2) for study-level data, pooled HR was estimated using fixed/random-effects models. Results: Six clinical studies were identified. For dMMR/MSI-H versus mismatch repair proficient (pMMR)/microsatellite stable (MSS)/microsatellite instability-low (MSI-L), the estimated 5-years DFS were 74.2% versus 51.5% (HR, 0.44; 95% CI, 0.32-0.62; P < 0.001); the estimated 5-years OS were 60.8% versus 50.1% (HR, 0.72; 95% CI, 0.60-0.88; P = 0.001). At study-level data, the pooled HRs were 0.42 for DFS (95% CI, 0.31-0.57; P < 0.001) and 0.66 for OS (95% CI, 0.32-1.38; P = 0.268). For adjuvant chemotherapy versus observation in dMMR/MSI-H, the estimated 5-years DFS were 76.1% versus 73.3% (HR, 0.72; 95% CI, 0.45-1.15; P = 0.171); the estimated 5-years OS were 74.9% versus 60.2% (HR, 0.60; 95% CI, 0.44-0.83; P = 0.001). Significant survival differences were also observed at study-level. Conclusions: This study further suggested adjuvant chemotherapy could be beneficial even in dMMR/MSI-H GC patients.

Despite the great success of immunotherapy in a small subset of cancer patients, most colorectal cancer (CRC) patients do not respond to programmed cell death receptor 1 (PD‐1) blockade immunotherapy. There is an urgent medical need to elucidate how cancer cells evade immune response and to develop novel means to boost the efficacy of immune checkpoint inhibitors. In this study, alcohol induces ligand programmed cell death receptor 1 (PD‐L1) expression of CRC cells in vitro and in vivo. Alcohol exposure is shown to induce aldehyde dehydrogenase 2 (ALDH2) expression that is a crucial enzyme involved in alcohol metabolism, and low level of lymphocytes infiltration in the murine CRC model and patients. Intriguingly, ALDH2 and PD‐L1 protein expression are positively correlated in tumor tissues from the CRC patients. Mechanistically, ALDH2 stabilizes PD‐L1 protein expression by physically interacting with the intracellular segment of PD‐L1 and inhibiting its proteasome‐dependent degradation mediated by an E3 ubiquitin ligase Speckle Type POZ Protein (SPOP). Importantly, inhibition of ALDH2 reduces PD‐L1 protein in CRC cells and promotes tumor‐infiltrating T cells (TILs) infiltration, presumably leading to the significant potentiation of anti‐PD‐1 antibody efficacy in a mouse CT26 CRC model. The findings highlight a crucial role played by ALDH2 to facilitate alcohol‐mediated tumor escape from immunity surveillance and promote tumor progression., Aldehyde dehydrogenase 2 (ALDH2) promotes alcohol‐mediated immune escape through stabilizing ligand programmed cell death receptor 1 (PD‐L1) protein expression by interacting with the intracellular segment of PD‐L1, thereby inhibiting its ubiquitination mediated by Speckle Type POZ Protein (SPOP). Silencing of ALDH2 significantly sensitizes tumors to PD‐1 blockade therapy.

Background: Small hepatocellular carcinoma (sHCC) is a special subtype of HCC with the maximum tumor diameter ≤ 3 cm and favorable long-term outcomes. Surgical resection or radiofrequency ablation offer the greatest chance for cure; however, many patients still undergo tumor recurrence after primary treatment. So far, there is no clinical applicable method to assess biological aggressiveness in solitary sHCC.Methods: In the present study, we retrospectively evaluated tumor necrosis of 335 patients with solitary sHCC treated with hepatectomy between December 1998 and 2010 from Sun Yat-sen University Cancer Center.Results: In the current study, the presence of tumor necrosis was observed in 157 of 335 (46.9%). Further correlation analysis showed that the presence of tumor necrosis in sHCC was significantly correlated with tumor size and vascular invasion (P = 0.026, 0.003, respectively). The presence of tumor necrosis was associated closely with poorer cancer-specific overall survival (OS) and recurrence-free survival (RFS) as evidenced by univariate (P < 0.001; hazard ratio, 2.821; 95% CI, 1.643-4.842) and multivariate analysis (P = 0.005; hazard ratio, 2.208; 95% CI, 1.272-3.833). More importantly, the combined model by tumor necrosis, vascular invasion and tumor size can significantly stratify the risk for RFS and OS and improve the ability to discriminate sHCC patients’ outcomes (P < 0.0001 for both).Conclusions: Our findings provide evidence that tumor necrosis has the potential to be a parameter for cancer aggressiveness in solitary sHCC. The combined prognostic model may be a useful tool for identifying solitary sHCC patients with worse outcomes.

e16004 Background: Mismatch repair deficient (dMMR) or microsatellite instability-high (MSI-H) serves as a predictor poor response to adjuvant chemotherapy in stage II colon cancer patients. Our objective was to investigate the efficacy of adjuvant chemotherapy in dMMR/MSI-H gastric cancer (GC). Methods: We searched literatures through December, 2020 to identify clinical studies that reported survival comparing adjuvant chemotherapy with surgery alone in dMMR/MSI-H GCs. Two approaches were used to pool the hazard ratio (HR) of survival: (1) If Kaplan-Meier curves and number at risk were provided, individual patient data were extracted. Cox models were used to calculate the HR with 95% confidence interval (CI); (2) for study-level data, pooled HR was estimated using fixed/random-effects models. Results: Six clinical studies were identified. For dMMR/MSI-H versus mismatch repair proficient (pMMR)/microsatellite stable (MSS)/microsatellite instability-low (MSI-L), the estimated 5-years DFS were 74.2% versus 51.5% (HR, 0.44; 95% CI, 0.32-0.62; P < 0.001); the estimated 5-years OS were 60.8% versus 50.1% (HR, 0.72; 95% CI, 0.60-0.88; P = 0.001). At study-level data, the pooled HRs were 0.42 for DFS (95% CI, 0.31-0.57; P < 0.001) and 0.66 for OS (95% CI, 0.32-1.38; P = 0.268). For adjuvant chemotherapy versus observation in dMMR/MSI-H, the estimated 5-years DFS were 76.1% versus 73.3% (HR, 0.72; 95% CI, 0.45-1.15; P = 0.171); the estimated 5-years OS were 74.9% versus 60.2% (HR, 0.60; 95% CI, 0.44-0.83; P = 0.001). Significant survival differences were also observed at study-level. Conclusions: This study further suggested adjuvant chemotherapy could be beneficial even in dMMR/MSI-H GC patients.

Background: The current study aimed to establish a novel nomogram to predict the overall survival of individual Chinese patients with gastroenteropancreatic neuroendocrine neoplasms (GEP-NENs). Furthermore, this study sought to externally validate this nomogram using the Surveillance, Epidemiology, and End Results (SEER) database. Methods: The records of 1183 patients with GEP-NENs treated at five high-capacity institutions in China between 2005 and 2015 were retrospectively analysed. In addition, 10 236 GEP-NEN cases from the SEER database were included as an external validation set. Results: A multivariate analysis using Cox proportional hazards (PHs) regression was performed, and a nomogram was constructed. Discrimination, calibration, and external validation were performed using the SEER data set. The multivariate Cox model indicated that age, tumour size, differentiation, lymph node metastases, and distant metastases were independent covariates associated with survival. With respect to the training set, the nomogram exhibited better discrimination power than TNM classification (Harrell’s concordance index (C-index): 0.837 vs 0.784, P=0.006). Discrimination was also excellent and superior to that of TNM classification for the SEER-based validation set (C-index: 0.808 vs 0.717, P

Objective To explore the feasibility and safety of using tissue-type plasminogen activator (t-PA) to prevent graft restenosis after coronary artery bypass grafting (CABG). Methods In this prospective observational study, 37 patients underwent CABG between June 2009 and May 2013. These patients were grouped according to the anti-coagulation strategy after surgery: t-PA (n = 12) and conventional treatments (n = 25). In the t-PA group, the patients received acetylsalicylic acid (ASA) and clopidogrel plus intravenous infusion of t-PA (0.25 mg/kg/day) starting at 24 h after surgery and that lasted for 3 days. In the conventional group, the patients received only ASA and clopidogrel. 64-row spiral computed tomographic coronary angiography was performed at 1 week, 1, and 3 months after surgery to evaluate the patency of the graft vessel. Results The mean stenosis severity of the saphenous vein grafts was lower in the t-PA group compared with the conventional group at 3 months after surgery (p 0.05). The patency rate of the grafts was not significantly different between the two groups at 1 week, 1, and 3 months after surgery (p > 0.05). Conclusion Early application of t-PA after CABG was feasible and safe, and might help prevent early restenosis of SV grafts. Additional clinical randomized trials are necessary to address this issue.

Purpose Early-stage hepatocellular carcinoma (E-HCC) is being diagnosed increasingly, and in one half of diagnosed patients, recurrence will develop. Thus, it is urgent to identify recurrence-related markers. We investigated the effectiveness of CpG methylation in predicting recurrence for patients with E-HCCs. Patients and Methods In total, 576 patients with E-HCC from four independent centers were sorted by three phases. In the discovery phase, 66 tumor samples were analyzed using the Illumina Methylation 450k Beadchip. Two algorithms, Least Absolute Shrinkage and Selector Operation and Support Vector Machine-Recursive Feature Elimination, were used to select significant CpGs. In the training phase, penalized Cox regression was used to further narrow CpGs into 140 samples. In the validation phase, candidate CpGs were validated using an internal cohort (n = 141) and two external cohorts (n = 191 and n =104). Results After combining the 46 CpGs selected by the Least Absolute Shrinkage and Selector Operation and the Support Vector Machine-Recursive Feature Elimination algorithms, three CpGs corresponding to SCAN domain containing 3, Src homology 3-domain growth factor receptor-bound 2-like interacting protein 1, and peptidase inhibitor 3 were highlighted as candidate predictors in the training phase. On the basis of the three CpGs, a methylation signature for E-HCC (MSEH) was developed to classify patients into high- and low-risk recurrence groups in the training cohort ( P < .001). The performance of MSEH was validated in the internal cohort ( P < .001) and in the two external cohorts ( P < .001; P = .002). Furthermore, a nomogram comprising MSEH, tumor differentiation, cirrhosis, hepatitis B virus surface antigen, and antivirus therapy was generated to predict the 5-year recurrence-free survival in the training cohort, and it performed well in the three validation cohorts (concordance index: 0.725, 0.697, and 0.693, respectively). Conclusion MSEH, a three-CpG–based signature, is useful in predicting recurrence for patients with E-HCC.

Classification of CRC lung metastases. (DOC 33 kb)

Human enhancer of filamentation 1 (HEF1), a scaffold protein, is highly expressed in a variety of cancer types and is involved cancer cell growth, migration and invasion. The prognostic value of HEF1 in hepatocellular carcinoma (HCC) remains to be elucidated. The aim of the present study was to assess the association between the expression of HEF1, the clinical/pathological parameters and survival in HCC. In the present study, immunohistochemistry was performed to investigate the protein expression of HEF1 in 123 hepatocellular carcinoma tissues and their adjacent normal liver tissues. Spearman's rank correlation, Kaplan-Meier plots and Cox regression model were used to analyze the data. Overexpression of HEF1 protein was observed in HCC tissue when compared with their adjacent non-malignant liver tissue. High expression of HEF1 correlated with higher advanced tumor, node, metastasis (TNM) stage and vascular invasion (P

Hepatocellular carcinoma (HCC) is the one of most common and deadly cancers, and is also highly resistant to conventional chemotherapy treatments. Mitochondrial phosphoglycerate mutase/protein phosphatase (PGAM5) regulates mitochondrial homeostasis and cell death, however, little is known about its roles in cancer. The aim of this study was to explore the clinical significance and potential biological functions of PGAM5 in hepatocellular carcinoma. For the first time, our results show that PGAM5 is significantly upregulated in HCC compared with corresponding adjacent noncancerous hepatic tissues and high PGAM5 expression is an independent predictor of reduced survival times in both univariate and multivariate analyses. Additionally, in vivo and in vitro studies showed that depleting PGAM5 expression inhibited tumor growth and increased the 5-fluorouracil sensitivity of HCC cells. Conversely, restoring PGAM5 expression in PGAM5-knockdown cells dramatically enhanced HCC cell resistance to 5-fluorouracil. Importantly, we demonstrated that the mechanism of 5-fluorouracil resistance conferred to HCC cells by PGAM5 was via inhibiting BAX- and cytochrome C-mediated apoptotic signaling by interacting and stabilizing Bcl-xL. Consistently, in the same cohorts of HCC patient tissues, Bcl-xL expression was positively correlated with PGAM5, and together predicted poor prognoses. In Conclusion, Our data highlight the molecular etiology and clinical significance of PGAM5 in HCC. Targeting the novel signaling pathway mediated by PGAM5/Bcl-xL may represent a new therapeutic strategy to improve the survival outcomes of HCC patients.

Background Body mass index (BMI) has been associated with the risk of esophageal cancer. But the influence of BMI on postoperative complications and prognosis has always been controversial. Methods Between 2000 and 2007, 424 patients with esophageal squamous cell carcinoma (ESCC) underwent R0 esophagectomy at our center without neoadjuvant therapy. We performed univariate and multivariate analyses to identify prognostic factors for survival. Results Patients were divided into three groups according to Asian-specific BMI cut-off value: underweight (n = 45), normal weight (n = 228), and overweight and obese (n = 151). Mean follow-up time was 39 months. The five-year overall survival (OS) rate was 19%, 34%, and 42% for underweight, normal weight, and overweight and obese, respectively (P < 0.001). The five-year disease-free survival (DFS) rate was 24%, 41%, and 74% for underweight, normal weight, and overweight and obese, respectively (P < 0.001). Multivariate analysis showed that pT, pN, and BMI were independent prognostic factors for DFS and OS. The C-index to the combined model showed improved predictive ability when compared to the pN classification (0.779 vs. 0.734). Conclusion Preoperative BMI was an independent prognostic factor for OS and DFS. The proposed new prognostic model with the pN classification supplemented by BMI might improve the ability to discriminate ESCC patients' outcome.

Hepatocellular carcinoma (HCC) is one of the most lethal malignancies, in which the NF-κB pathway plays an important role and is constitutively activated. Better understanding of the molecular pathogenesis of HCC and the NF-κB pathway are needed to improve patient outcomes. Herein, we identified an unappreciated protein involved in NF-κB-induced activation, Golgi phosphoprotein 3 (GOLPH3). The mRNA and protein expression levels of GOLPH3 were frequently up-regulated in HCC and GOLPH3 expression correlated closely with clinical stage and survival in both the testing and validation cohorts. Ectopic over-expression of GOLPH3 in PLC/PRF/5 (PLC) and Huh7 HCC cells protected against cisplatin-induced apoptosis, promoted angiogenesis and proliferation and increased the aggressiveness of HCC cells in vitro and in vivo, whereas inhibition of GOLPH3 led to decreased aggressiveness. Through analysis of two published HCC patient profiles, GOLPH3 expression significantly correlated with NF-κB signalling. Furthermore, we demonstrated that GOLPH3 promoted K63-linked polyubiquitination of tumour necrosis factor receptor-associated factor 2 (TRAF2), receptor interacting protein (RIP) and NF-κB essential modulator (NEMO) and substantially sustained the activation of NF-κB in HCC cells. Taken together, our findings provided evidence that GOLPH3 is a prognostic and/or potential therapeutic biomarker for HCC patients and plays an important role in activation of the NF-κB pathway during HCC progression.

International audience; Reduced expression of DICER, a key enzyme in the miRNA pathway, is frequently associated with aggressive, invasive disease, and poor survival in various malignancies. Regulation of DICER expression is, however, poorly understood. Here, we show that NF90/NF110 facilitates DICER expression by controlling the processing of a miRNA, miR-3173, which is embedded in DICER pre-mRNA. As miR-3173 in turn targets NF90, a feedback amplification loop controlling DICER expression is established. In a nude mouse model, NF90 overexpression reduced proliferation of ovarian cancer cells and significantly reduced tumor size and metastasis, whereas overexpression of miR-3173 dramatically increased metastasis in an NF90- and DICER-dependent manner. Clinically, low NF90 expression and high miR-3173-3p expression were found to be independent prognostic markers of poor survival in a cohort of ovarian carcinoma patients. These findings suggest that, by facilitating DICER expression, NF90 can act as a suppressor of ovarian carcinoma.

Malignant pleural mesothelioma (MPM) is a relative rare but highly aggressive neoplasm which is associated with asbestos exposure in most patients. The majority of patients are diagnosed in advanced stages so patients neither benefit from chemotherapy (e.g. pemetrexed-platinum combination) nor from surgery. It has been reported that cellular-mesenchymal to epithelial transition factor (MET) and epidermal growth factor receptor (EGFR) were critical for MPM cell proliferation. Moreover, targeting MET and EGFR drugs have gained promising results on anti-tumor therapy. Here, a striking difference in overall survival was observed between the MET and EGFR co-expression group (median survival time = 13.5 months) and non-co-expression group (median survival time = 20.5 months). In addition, treatment with combination of crizotinib and afatinib showed stronger inhibition on cell proliferation of MPM than the treatment by either one in vitro and in vivo. In conclusion, our data illustrated that crizotinib combined with afatinib may be a potentially effective strategy for treating MPM patients with over-expression of MET and EGFR.

// Yosuke Konno 1,* , Peixin Dong 2,* , Ying Xiong 3,* , Fumihiko Suzuki 4,* , Jiabin Lu 5 , Muyan Cai 5 , Hidemichi Watari 1 , Takashi Mitamura 1 , Masayoshi Hosaka 1 , Sharon J. B. Hanley 2 , Masataka Kudo 1 and Noriaki Sakuragi 1,2 1 Department of Gynecology, Hokkaido University, Sapporo, Japan 2 Department of Women’s Health Educational System, Hokkaido University, Sapporo, Japan 3 Department of Gynecology, State Key Laboratory of Oncology in South China, Sun Yat-sen University Cancer Center, Guangzhou, P. R. China 4 Department of Obstetrics and Gynecology, Tohoku University, Sendai, Japan 5 Department of Pathology, State Key Laboratory of Oncology in South China, Sun Yat-sen University Cancer Center, Guangzhou, P. R. China * These authors contributed equally to this work Correspondence: Peixin Dong, email: // Noriaki Sakuragi, email: // Keywords : microRNA-101, proliferation, EMT, EZH2, MCL-1, FOS Received : May 30, 2014 Accepted : July 1, 2014 Published : July 2, 2014 Abstract MicroRNA-101 has been implicated as a tumor suppressor miRNA in human tumors. However, its potential functional impact and the underlying mechanisms in endometrial cancer progression have not been determined. Here, we report that in aggressive endometrial cancer cells, re-expression of microRNA-101 leads to inhibition of cell proliferation and induction of apoptosis and senescence. Ectopic overexpression of microRNA-101 attenuates the epithelial-mesenchymal transition-associated cancer cell migration and invasion, abrogates the sphere-forming capacity and enhances chemosensitivity to paclitaxel. Algorithm and microarray-based strategies identifies potential microRNA-101 targets. Among these, we validated EZH2, MCL-1 and FOS as direct targets of miR-101 and silencing of these genes mimics the tumor suppressive effects observed on promoting microRNA-101 function. Importantly, further results suggest an inverse correlation between low miR-101 and high EZH2, MCL-1 and FOS expression in EC specimens. We conclude that, as a crucial tumor suppressor, microRNA-101 suppresses cell proliferation, invasiveness and self-renewal in aggressive endometrial cancer cells via modulating multiple critical oncogenes. The microRNA-101-EZH2/MCL-1/FOS axis is a potential therapeutic target for endometrial cancer.

Cytoplasmic polyadenylation element-binding protein 4 (CPEB4), a zinc-finger-containing sequence-specific RNA-binding protein, has been associated with tumor proliferation, invasion, and migration. Expression of CPEB4 and its prognostic significance in human colorectal cancer (CRC) have not been studied. The aim of the present study was to investigate expression of CPEB4 and its prognostic significance in CRC. Expression of CPEB4 in CRC tissues from two independent cohorts was examined by immunohistochemistry. Prognostic significance was analyzed using receiver operating characteristic curve analysis, Kaplan-Meier curves, and Cox regression analysis. High expression of CPEB4 was observed in 14.8 % of CRCs in the training cohort and 12.2 % of CRCs in the validation cohort. High expression of CPEB4 was significantly correlated with the pM classification, TNM stage, and poorer overall survival in both cohorts. Through multivariate Cox regression analysis, high expression of CPEB4 was found to be an independent prognostic biomarker for overall survival in CRC patients. High expression of CPEB4 may be an independent and useful biomarker for predicting the poor survival of patients with CRC.

Tumor-associated epigenetic alterations including DNA methylation and histone modifications are important determinants in the initiation and progression of hepatocellular cancer (HCC) and represent promising biomarkers and therapeutic targets. Locus-specific trimethylation of histone H3 lysine 4 (H3K4me) is a well-known modification linked to the enhanced transcriptional expression of many genes activated in HCC. Our aim was to assess the cellular expression pattern of H3K4me3 in HCC and its association with clinicopathologic variables and outcome. Expression of H3K4me3 and the histone methyltransferase (HMT) SET and MYND domain-containing protein 3 (SMYD3) was studied by Western blotting and immunohistochemistry in cell lines and tumor tissue microarray from a well-characterized series of HCC patients (n = 168). The optimal cut-point of H3K4me3 expression for prognosis was determined by the X-tile program. The prognostic significance was evaluated using Kaplan-Meier survival estimates and log-rank tests. Tumor tissue microarray from another independent HCC patients cohort (n = 147) was used for validation studies. Expression of H3K4me3 and SMYD3 were enhanced in HCC cell lines. In tumor specimens, enhanced expression of H3K4me3 was correlated with reduced overall survival (P < .0001), especially in early-stage HCC patients (TNM I/II). Furthermore, both univariate and multivariate analyses revealed that H3K4me3 level was a significant and independent predictor of poor survival (hazard ratio, 3.592; 95% confidence interval, 2.302-5.605). In addition, H3K4m3 expression was positively correlated with SMYD3 expression in both testing and validation cohorts (P < .0001). In conclusion, H3K4me3 level defines unrecognized subsets of HCC patients with distinct epigenetic phenotype and clinical outcome and can thus be a novel predictor for poor prognosis of HCC patients, especially at TNM I/II stage.

Objectives: We aimed to investigate the nature of endometrial stromal sarcoma (ESS) arising from endometriosis. Methods: The clinical data of 5 patients with ESS arising from endometriosis were reviewed retrospectively. The expression of CD117, HER2/neu, EGFR, VEGF, and PDGFR was analyzed by immunohistochemical staining. Results: The median age of the 5 patients was 45 years. The primary tumor sites were the ovary in 2, the pelvis in 2, and the cervical canal in 1 patient. Three patients had disseminated disease at diagnosis. Four patients underwent complete tumor resection. All of the 5 cases received adjuvant chemotherapy and 2 received progesterone therapy, while none were treated with radiotherapy. No recurrence occurred in the 4 cases who had complete tumor resection, and the only patient who progressed was the patient in whom the tumor was unresectable. Tumor cells in all cases exhibited positive staining for PDGFR and were negative for CD117 and HER2/neu. The expression of EGFR and VEGF was observed in 2 and 4 cases, respectively. Conclusion: ESS arising from endometriosis is rare. Complete tumor resection in ESS arising from endometriosis may reduce the recurrence rate.

Acylglycerol kinase (AGK) had been shown to contribute to cancer progression and unfavorable clinical outcomes of patients. Our study aimed to investigate the expression pattern and clinical significance of AGK in patients with early-stage cervical squamous cell cancer (CSCC). The protein and messenger RNA (mRNA) expression of AGK was analyzed in six cervical cancer cell lines and four paired early-stage CSCC specimens and normal cervical tissues (NCT), using Western blotting and real-time PCR (RT-PCR). And we investigated the AGK protein expression in paraffin-embedded specimens from 140 patients with early-stage CSCC and 30 cases of NCT by immunohistochemistry (IHC). Statistical analyses were performed to evaluate the clinicopathological significance of AGK expression. The expressions of AGK protein and mRNA were significantly up-regulated in cervical cancer cell lines and cancer tissues. IHC analyses revealed that AGK was highly expressed in 93 (66.4 %) of 140 early-stage CSCC specimens, but in none of the NCT. Moreover, AGK expression in early-stage CSCC was significantly correlated with tumor stage (P

It has been suggested that hexokinase 1 (HK1) is involved in tumorigenesis. However, the expression dynamics of HK1 and its prognostic significance in human colorectal cancer (CRC) still remain unclear. The aim of the present study was to investigate the expression of HK1 and its prognostic significance in CRC. In this study, immunohistochemical analysis was used to examine the expression dynamics of HK1 in CRC tissues from two independent cohorts. Receiver operating characteristic curve analysis, Kaplan-Meier curves, and Cox regression analysis were utilized to investigate the prognostic significance. Results showed that a high expression of HK1 was observed in 106 of 393 (27.0 %) and 69 of 229 (30.1 %) of CRC in the training cohort and validation cohort, respectively. Further correlation analyses indicated that the increased HK1 expression was strongly correlated with the pN classification and TNM stage. Both cohorts showed a close association between the overexpression of HK1 and poorer overall survival. Importantly, multivariate analysis identified HK1 expression in CRC as an independent prognostic factor. Overexpression of HK1 may act as a significant biomarker of poor prognosis for patients with CRC.

To investigate the frequency of different types of mature T- and NK-cell lymphomas diagnosed in a 4-year period at Sun Yat-sen University Cancer Center, and to study baseline CD30 for potential anti-CD30 targeted therapy in mature T- and NK-cell lymphoma.All cases of mature T- and NK-cell lymphoma diagnosed at Sun Yat-sen University Cancer Center from September 1, 2009 to August 31, 2013, were reviewed. Paraffin-blocks of available 164 consecutive cases were stained for CD30 immunohistochemistry using EnVision protocol.A total of 625 cases of mature T- and NK-cell lymphomas were diagnosed and the most common type was extranodal NK/T cell lymphoma (ENKTL), nasal type 319 (51.0%) cases, followed by angioimmunoblastic T-cell lymphoma (AITL) (119 cases, 19.0%), peripheral T-cell lymphoma, not otherwise specified (PTCL-NOS) (81 cases, 13.0%), and anaplastic large-cell lymphoma (ALCL), including 48 cases (7.7%) of systematic ALCL and 11 cases (1.8%) of primary cutaneous ALCL. Besides ALCL, ENKTL had the highest expression rate of CD30 among the 164 cases, with positivity observed in 41 cases (62.1%, 41/66). Only 1 case of PTCL-NOS was CD30 positive. CD30 was not expressed in all 28 cases of AITL and other rare types of mature T- and NK-cell lymphoma.The frequency of different types of mature T- and NK-cell lymphoma encountered at Sun Yat-sen University Cancer Center was similar to that seen in other areas of China and other Asia countries. CD30 expression is different among several types of mature T- and NK-cell lymphoma. In addition to ALCL, ENKTL has the highest expression rate of CD30, which may be a candidate disease for anti-CD30 targeted therapy.