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Bu W, Wang Z, Meng L, et al. Cancer Manag Res. 2019;11:3887–3898 The authors have advised that because of JilinUniversity’s rule that each paper can have only onefirst author and can’t have co-first authors, they wantto make a change in the author list. As a result, in theaffiliations section the asterisks should be removed fromthe author names Wenhuan Bu, Zilin Wang and LinMeng and the sentence “*These authors contributedequally to this work” should also be removed. Read the original article

Xiang Tan,1,* Huajian Peng,1,* Peixin Gu,2 Mingwu Chen,1 Yongyong Wang1 1Department of Thoracic Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, 530021, Guangxi Zhuang Autonomous Region, People’s Republic of China; 2Department of Neurology, The First Affiliated Hospital of Guangxi Medical University, Nanning, People’s Republic of China*These authors contributed equally to this workCorrespondence: Mingwu Chen; Yongyong Wang Department of Thoracic Surgery, The First Affiliated Hospital of Guangxi Medical University, Shuang Yong Road 6, Nanning, 530021, Guangxi Zhuang Autonomous Region, People’s Republic of ChinaEmail chen535@126.com; wangyongyong@stu.gxmu.edu.cnObjective: To evaluate the correlation between the advanced lung cancer inflammation index (ALI) and the L3 skeletal muscle index (L3SMI) and their prognostic value in elderly patients with esophageal cancer (EC).Materials and Methods: The clinical data of 158 elderly patients with EC were collected retrospectively. The L3SMI measures the area of skeletal muscle at the level of the third lumbar (L3) vertebra using computed tomography (CT). A high L3SMI and low L3SMI group were created using sex-based quartiles. The ALI, prognostic nutrition index (PNI), and geriatric nutrition risk index (GNRI) were calculated according to standard laboratory protocols.Results: The CT diagnostic criteria for senile sarcopenia in South China are height ≤ 32.96 cm2/m2 for females and height ≤ 35.4 cm2/m2 for males. The logistic regression analysis showed that a low L3SMI was significantly associated with a low ALI. Survival analysis revealed EC patients with a low L3SMI and a low ALI had poorer overall survival (OS) than patients with a high L3SMI and a high ALI. Univariate and multivariate Cox analyses showed that the L3SMI and ALI were independent predictors of EC prognosis in elderly individuals.Conclusion: There was a significant correlation between the PNI, GNRI, ALI, and L3SMI. Overall, our findings show the L3SMI and ALI are clinical indicators that can potentially be used to independently predict the prognosis of elderly EC patients and display good predictive value.Keywords: esophageal cancer, sarcopenia, L3 skeletal muscle index, survival, advanced lung cancer inflammation index

Hongchun Chen,1,2 Yuchen Huang,1,2 Ningning Yang,1,2 Wentian Yan,1,2 Ruxue Yang,3 Shan Zhang,4 Panpan Yang,5 Nan Li,1,2 Zhenzhong Feng1,2 1Department of Pathology, Bengbu Medical College, Bengbu, Anhui Province, 233000, People’s Republic of China; 2Department of Pathology, First Affiliated Hospital of Bengbu Medical College, Bengbu, Anhui Province, 233000, People’s Republic of China; 3Department of Pathology, First Affiliated Hospital of Anhui Medical University, Hefei, Anhui Province, 230000, People’s Republic of China; 4Department of Pathology, Second People’s Hospital of Hefei, Hefei, Anhui Province, 230000, People’s Republic of China; 5Department of Pathology, Second Affiliated Hospital of Anhui Medical University, Hefei, Anhui Province, 230000, People’s Republic of ChinaCorrespondence: Zhenzhong FengDepartment of Pathology, First Affiliated Hospital of Bengbu Medical College, No. 287 Changhuai Road, Longzihu District, Bengbu, Anhui, 233000, People’s Republic of ChinaTel +86 1 505 528 9508Email fzz18297301626@163.comPurpose: Solid-pseudopapillary neoplasm (SPN) of the pancreas, a rare tumor, has low malignant potential. However, some patients develop metastasis and recurrence after resection, with aggressive biological behaviors. This study aimed to explore the features and risk factors associated with the aggressive biological behaviors of SPNs.Patients and Methods: We retrospectively analyzed the clinicopathological and long-term follow-up data of 63 patients diagnosed with SPN at the First Affiliated Hospital of Bengbu Medical College between January 2007 and February 2019.Results: Sixty-three patients presented atypical clinical symptoms. The median tumor size was 7.0 cm (range, 2.4– 17 cm), and imaging features were solid and cystic or solid tumors with uneven density. Frequent and diffuse nuclear LEF1 protein expression (94.2%) was observed with LEF1 having a higher sensitivity and specificity. Overall survival significantly correlated with tumor size, Ki-67 index, and lymph node metastasis (P < 0.05).Conclusion: SPN is a rare low-grade malignancy with a specific pseudopapillary structure. LEF1 is an effective biomarker of SPNs. Although SPNs generally display indolent biological behavior, a large tumor size, high proliferation index, and lymph node metastasis may be risk factors for the aggressive behavior and poor prognosis of SPN.Keywords: pancreatic tumor, LEF1, retrospective study, overall survival, metastasis

Yingyun Zhang,1,2 Wei Wang,1,2 Xuedong Xu,1,2 Yankang Li,1,3 Hui Zhang,4 Jianbin Li,1,2 Zhenxiang Li1 1Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, 250117, People’s Republic of China; 2Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, People’s Republic of China; 3Cheeloo College of Medicine, Shandong University, Jinan, People’s Republic of China; 4Tumor Hospital of Xiangxi Tujia and Miao Autonomous Prefecture, Jishou, People’s Republic of ChinaCorrespondence: Jianbin Li; Zhenxiang LiDepartment of Radiation Oncology, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, 250117, People’s Republic of ChinaTel +86 13869135266; +86 18654536783Email lijianbin@msn.com; lizx0108@163.comIntroduction: The aim of this study was to investigate the role of local radiotherapy in the management of epidermal growth factor receptor (EGFR)-mutant non-small cell lung cancers (NSCLCs) treated with EGFR tyrosine kinase inhibitors (TKIs).Materials and Methods: Patients with stage IV EGFR-mutant NSCLC treated with radiotherapy concomitant to EGFR TKIs from May 2010 to December 2017 were retrospectively identified. Overall survival (OS) was the primary endpoints of the study.Results: A total of 205 patients were enrolled in the study. One hundred eleven patients received one-time single-site radiotherapy (SSR), and 94 patients received multiple-site radiotherapy (MSR). Patients who received MSR had longer OS (median OS, 40.0 months; 95% confidence interval [CI], 29.6 to 50.4) than those who received SSR (median OS, 28.9 months; 95% CI, 24.3 to 33.5; P=0.031). Thoracic radiotherapy was associated with prolonged median OS (41.7 months, 95% CI, 29.0 to 54.4 vs 27.1 months, 95% CI 22.7 to 31.5; log-rank P< 0.001). Multivariate analysis confirmed that thoracic radiotherapy was independently associated with improved OS (adjusted hazard ratio [HR], 0.514; 95% CI 32.3% to 81.8%; P=0.005).Conclusion: MSR improves survival outcomes in patients with advanced-stage, EGFR-mutant, lung adenocarcinoma, with thoracic radiotherapy having the most significant effect on prognosis.Keywords: advanced-stage lung cancer, adenocarcinomas, radiotherapy, EGFR

Zizhen Zhang,1– 3,* Fangyu Ju,1– 3,* Fei Chen,1– 3 Haoyue Wu,4 Jingyu Chen,1– 3 Jing Zhong,1– 3 Liming Shao,1– 3 Sheng Zheng,1– 3 Liangjing Wang,1– 3 Meng Xue1– 3 1Department of Gastroenterology, The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, 310020, People’s Republic of China; 2Institution of Gastroenterology, Zhejiang University, Hangzhou, 310000, People’s Republic of China; 3Zhejiang University Cancer Center, Hangzhou, 310000, People’s Republic of China; 4Institute of Genetics and Department of Genetics, Zhejiang University School of Medicine, Hangzhou, 310012, People’s Republic of China*These authors contributed equally to this workCorrespondence: Meng Xue; Liangjing Wang Email xuemeng@zju.edu.cn; wangljzju@zju.edu.cnAim: Chemoresistance to 5-fluorouracil (5-Fu) is common in colorectal cancer (CRC). Programmed necrosis (necroptosis) is an alternative form of programmed cell death regulated by receptor-interacting protein kinase (RIPK) 1 and 3, assumed as a novel target of cancer therapy. In this study, we aimed to explore whether a novel small molecular agent GDC-0326 could facilitate the effect of 5-Fu through necroptosis.Main Methods: Cell Counting Kit-8 (CCK-8) assay and colony formation were performed to confirm the function of GDC-0326 in CRC cells. Western blot and immunofluorescence were conducted to measure the altered expressions of RIPK1/RIPK3 induced by GDC-0326. Subcutaneous tumor models were used to evaluate the chemotherapeutic effects and concomitant side effects of GDC-0326 in vivo.Key Findings: We found that GDC-0326 effectively suppressed the growth of CRC cells in a dose-dependent manner. The induction of necroptosis by GDC-0326 was correlated with the modulation of RIPK1 and RIPK3. Necrostatin-1 and GSK-872, inhibitors of RIPK1 and RIPK3, respectively, could rescue the cell death induced by GDC-0326. In addition, in vitro and in vivo studies showed that 5-Fu plus GDC-0326 evinced a better antitumor efficacy by suppressing tumor growth and increasing tumor necrosis with no increased toxicity.Significance: This study demonstrates that GDC-0326 plus 5-Fu has augmented antitumor efficacy and acceptable safety, which might be a promising therapeutic strategy for CRC patients in the future.Keywords: GDC-0326, 5-fluorouracil, colorectal cancer, combination therapy

Wen Yang,1,* Xia Xu,2,* Ming Xu,1 Jun Zhou,1 Zihan Xi,1 Hui Guo,1 Jie Ming,1 Tao Huang1 1Department of Breast and Thyroid Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People’s Republic of China; 2Department of Pathology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People’s Republic of China*These authors contributed equally to this workCorrespondence: Tao Huang; Jie MingDepartment of Breast and Thyroid Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Jiefang Road No. 1277, Wuhan, Hubei Province, People’s Republic of ChinaTel +8613807112766; +8613905519049Fax +86 27-85726833Email huangtaowh@163.com; mingjiewh@126.comPurpose: Papillary thyroid cancer (PTC) patients could obtain poor prognosis if they have lymph node metastasis, identification of informative and robust biomarkers for predicting cervical lymph node metastasis is critical for improving clinical decision-making and patient prognosis.Materials and Methods: In this study, we analyzed the expression of X box binding protein 1 spliced-form (XBP1s) in 41 PTC tissue samples and extended our findings using public databases, then we investigated how XBP1s’ contributed to PTC progression in vitro.Results: We found that XBP1s’ expression was lower in PTC patients with cervical lymph node metastasis than non-metastasis patients by immunohistochemical analysis. With publicly accessible dataset, we showed that the XBP1 transcription was significantly decreased in thyroid cancer (TC) tissues with lymph node metastasis as compared to that without lymph node metastasis. Moreover, we also found that XBP1 expression was significantly correlated with patients’ gender, T classification, lymph node metastasis and PTC stages, and low XBP1 expression was associated with poor diseases free survival (DFS). In vitro, XBP1s overexpression could inhibit the invasion, migration, and wound healing capacity of PTC cells. Mechanistically, overexpression of XBP1s could enhance the expression of classical epithelial–mesenchymal transition (EMT) markers such as ZO-1 and E-cadherins, and downregulated N-cadherin in BCPAP cells.Conclusion: These findings suggest that XBP1s is a prognostic maker for thyroid carcinoma patients, and sustaining XBP1s expression might be a new strategy to control PTC progression.Keywords: XBP1s, lymph node metastasis, papillary thyroid cancer, EMT

Kewa Ma,* Jiannan Ye,* Lingling Wang, Chao Sun, Xin Zhou Department of Hematology, Affiliated Wuxi People’s Hospital, Nanjing Medical University, Wuxi, Jiangsu, People’s Republic of China*These authors contributed equally to this workCorrespondence: Chao Sun; Xin ZhouDepartment of Hematology, Affiliated Wuxi People’s Hospital, Nanjing Medical University, Wuxi, Jiangsu, 214000, People’s Republic of ChinaTel +86-15961806698; +86 51085350201Fax +86 51085350201Email 13057302309sun@163.com; zx89232@126.comPurpose: Recently, the British Myeloma Research Alliance put forward a Myeloma Risk Profile (MRP) for the first time to stratify the prognosis risk of non-transplanted patients with multiple myeloma. However, only limited studies have evaluated the applicability of this model in the Chinese population. This study aimed to estimate the prognostic value of MRP in newly diagnosed multiple myeloma patients without autologous stem cell transplantation in China.Patients and Methods: Patients with multiple myeloma in Wuxi People’s Hospital from January 1, 2007, to June 30, 2018 were evaluated based on the MRP score, and the relationship between the clinical outcome of patients with MM and the score was analyzed retrospectively.Results: First, significant differences were observed in the overall survival (OS) (P< 0.05) and progression-free survival (PFS) (P< 0.05) between the low-, middle-, and high-risk groups. Second, in the bortezomib treatment subgroup and complex chromosome karyotype subgroup, OS and PFS were significantly shorter in the high-risk group than in the low-risk group (P< 0.05). Third, the depth of remission still showed prognostic significance in the high-risk MRP group.Conclusion: MRP is also applicable in Chinese patients with newly diagnosed MM who did not undergo transplantation, as it is simple and cost effective; hence, it is worth popularizing.Keywords: multiple myeloma, myeloma risk profile, bortezomib, complex chromosome karyotype, prognosis

Yunhe Huang,* Lei Jiang,* Guangxia Wei Department of Thoracic Surgery, The First Affiliated Hospital of Nanchang University, Nanchang, 330006, People’s Republic of China*These authors contributed equally to this workCorrespondence: Guangxia WeiDepartment of Thoracic Surgery, The First Affiliated Hospital of Nanchang University, No. 17, Yongwaizheng Street, Donghu District, Nanchang, Jiangxi, People’s Republic of ChinaEmail uzbher@163.comBackground: Circular RNAs (circRNAs) exert important roles in carcinogenesis. Here, we aimed to uncover the working mechanism of circ_0006168 in esophageal squamous cell carcinoma (ESCC) development.Methods: Western blot assay and real-time quantitative polymerase chain reaction (RT-qPCR) were used to determine protein and RNA expression, respectively. Wound healing assay and transwell migration assay were performed to assess cell migration ability, whereas cell invasion ability was evaluated by transwell invasion assay. 3-(4,5-dimethyl-thiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay and colony formation assay were utilized to analyze cell proliferation ability. Xenograft tumor model was utilized to assess the role of X-box binding protein 1 (XBP1) in xenograft tumor growth in vivo. Dual-luciferase reporter assay, RNA immunoprecipitation (RIP) assay and RNA pull down assay were used to verify intermolecular interactions.Results: XBP1 silencing suppressed the migration, invasion and proliferation of ESCC cells in vitro and restrained the xenograft tumor growth in vivo. MicroRNA-516b-5p (miR-516b-5p) interacted with the 3ʹ untranslated region (3ʹUTR) of XBP1 in ESCC cells. MiR-516b-5p overexpression inhibited the proliferation and motility of ESCC cells. MiR-516b-5p was a molecular target of circ_0006168 in ESCC cells. The interference of circ_0006168 restrained the motility and proliferation of ESCC cells. Circ_0006168 acted as miR-516b-5p sponge to up-regulate XBP1 expression in ESCC cells. MiR-516b-5p silencing or the accumulation of XBP1 largely rescued the proliferation ability and motility in circ_0006168-silenced ESCC cells.Conclusion: In conclusion, circ_0006168 contributed to ESCC development through promoting the proliferation and motility of ESCC cells via mediating miR-516b-5p/XBP1 axis.Keywords: esophageal squamous cell carcinoma, circ_0006168, miR-516b-5p, XBP1

Mengwei Wang,* Tianwei Xu,* Wenyan Feng,* Junxia Liu, Zhaoxia Wang Cancer Medical Center, The Second Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, People’s Republic of China*These authors contributed equally to this workCorrespondence: Zhaoxia WangCancer Medical Center, The Second Affiliated Hospital of Nanjing Medical University, Jiangjiayuan Road 121#, Nanjing, People’s Republic of ChinaTel +86-25-58509810Fax +86-25-58509994Email wangzhaoxia@njmu.edu.cnAbstract: Long noncoding RNAs (lncRNAs) are a class of RNA molecules that are longer than 200 nucleotides and cannot encode proteins. Over the past decade, lncRNAs have been defined as regulatory elements of multiple biological processes, and their aberrant expression contributes to the development and progression of various malignancies. Recent studies have shown that lncRNAs are involved in key cancer-related signaling pathways, including the Hippo signaling pathway, which plays a prominent role in controlling organ size and tissue homeostasis by regulating cell proliferation, apoptosis, and differentiation. However, dysregulation of this pathway is associated with pathological conditions, especially cancer. Accumulating evidence has revealed that lncRNAs can modulate the Hippo signaling pathway in cancer. In this review, we elaborate on the role of the Hippo signaling pathway and the advances in the understanding of its lncRNA-mediated regulation in cancer. This review provides additional insight into carcinogenesis and will be of great clinical value for developing novel early detection and treatment strategies for this deadly disease.Keywords: lncRNAs, Hippo pathway, cancer, tumorigenesis, prognosis

Xinjian Xu,1,* Yiwen Ding,1,* Tianfan Pan,1 Feng Gao,1 Xiangzhong Huang,1 Qiulian Sun2 1Department of Interventional Radiology, Jiangyin People’s Hospital, Jiang Yin City, Jiangsu Province, 214400, People’s Republic of China; 2Department of Radiology, Zhejiangtaizhou Hospital, Taizhou City, Zhejiang Province, 317000, People’s Republic of China*These authors contributed equally to this workCorrespondence: Xiangzhong Huang; Qiulian Sun Email hxzdoc@163.com; sql947435865@163.comPurpose: To investigate the efficacy and safety of CT-guided 125I brachytherapy in the treatment of hepatocellular carcinoma (HCC) refractory to conventional transarterial chemoembolization (TACE).Methods: Nineteen patients with TACE-refractory HCC treated with CT-guided 125I brachytherapy between June 2017 and June 2020 at Jiangyin People’s Hospital were enrolled in this study. In addition, we used the modified Response Evaluation Criteria in Solid Tumors (mRECIST) criteria to evaluate the treatment response after 125I brachytherapy.Results: Twenty-one tumours were treated with CT-guided 125I brachytherapy in nineteen patients. Twelve tumours (57.1%) showed a complete response, and a partial response was observed in seven tumours (33.3%). The six-month objective response rate was 90.5% (19/21). The adverse effects of CT-guided 125I brachytherapy were tolerable.Conclusion: Our preliminary clinical experience demonstrated that CT-guided 125I brachytherapy was effective and well tolerated for the treatment of TACE-refractory HCC, suggesting that CT-guided 125I brachytherapy has the potential to become an effective alternative treatment for TACE-refractory HCC.Keywords: 125I brachytherapy, TACE, refractory, hepatocellular carcinoma

Jiangang Chen,1,2 Lin Hao,1,3 Shaoqi Zhang,1 Yong Zhang,2 Bingzheng Dong,1,3 Qianjin Zhang,1 Conghui Han1,3 1Medical College of Soochow University, Suzhou, Jiangsu Province, 215123, People’s Republic of China; 2Department of Urology, The Second Affiliated Hospital of Nantong University, Nantong, Jiangsu Province, 226001, People’s Republic of China; 3Department of Urology, Xuzhou Central Hospital, Xuzhou Clinical College Affiliated to Xuzhou Medical University, Xuzhou, Jiangsu Province, 221009, People’s Republic of ChinaCorrespondence: Conghui HanDepartment of Urology, Xuzhou Central Hospital, Xuzhou Clinical College Affiliated to Xuzhou Medical University, 199 Jiefang South Road, Xuzhou, Jiangsu, 221009, People’s Republic of ChinaEmail conghuihandoctor@163.comBackground: We conducted a two-center study to investigate the prognostic value of preoperative fibrinogen–albumin ratio (FAR) in patients undergoing radical cystectomy (RC).Methods: The clinical and survival data of 267 patients with bladder cancer (BCa) treated with RC were collected, of which 140 patients from Xuzhou Central Hospital were divided into training set and 127 patients from The Second Affiliated Hospital of Nantong University were divided into validation set. X-tile software was used to obtain the optimal cut-off values for preoperative platelet-to-lymphocyte ratio (PLR), neutrophil-to-lymphocyte ratio (NLR) and FAR. Receiver operating characteristic (ROC) curves were used to compare the predictive ability of PLR, NLR, FAR and modified Glasgow prognostic score (mGPS). Kaplan–Meier curves were used to assess overall survival (OS) and progression-free survival (PFS) of patients in different FAR groups. Univariate and multivariate Cox regression were used to assess patients’ independent risk factors, and R software was used to construct prognostic nomograms.Results: In the training set, the optimal cut-off values for PLR, NLR and FAR were 76.76, 3.97 and 0.08, respectively. Both in the training and validation sets, FAR had better ability to predict OS and PFS than PLR and NLR, and patients in the higher FAR group had worse OS and PFS. In the multivariate Cox regression analysis, FAR was an independent risk factor for OS [hazard ratio (HR) 3.569, 95% confidence interval (CI): 1.015– 12.546, P=0.047] and PFS [HR 5.071, 95% CI: 1.394– 18.451, P=0.014]. In addition, FAR-based prognostic nomograms had high predictive ability than TNM staging.Conclusion: Preoperative FAR is an independent prognostic factor for OS and PFS in BCa patients treated with RC, and a high FAR predicted a poor prognosis. In addition, a prognostic nomogram based on FAR can better predict individual survival.Keywords: fibrinogen–albumin ratio, bladder cancer, radical cystectomy, overall survival, progression-free survival

Qinge Wang,1 Min Gu,2 Yun Zhuang,1 Jianping Chen1 1Department of Digestive Disease, The First People’s Hospital of Changzhou, The Third Affiliated Hospital of Soochow University, Changzhou, Jiangsu, People’s Republic of China; 2Department of Pediatrics, Changzhou Children’s Hospital, Changzhou, Jiangsu, People’s Republic of ChinaCorrespondence: Jianping ChenDepartment of Digestive Disease, The First People’s Hospital of Changzhou, The Third Affiliated Hospital of Soochow University, Juqian Road, Tianning District, Changzhou, Jiangsu, 213003, People’s Republic of ChinaEmail Chenjianping123abc@126.comBackground: MAGI1-IT1 is a long non-coding RNA (lncRNA) previously reported to regulate several cancer types, but its functional role in gastric cancer (GC) remains to be defined. This study therefore explored the mechanistic role played by MAGI1-IT1 in the regulation of GC cell proliferation.Methods: 120 pairs of GC patient tumor, paracancerous tissues, human GES-1 control cells and human AGS, MKN-74, MKN-45, and MGC-803 GC cell lines were used to detected MAGI1-IT1, miR-302d-3p, and IGF1 expression by a qPCR approach. An shRNA approach was used to knock down MGI1-IT1 in order to examine the effect of such treatment on GC cell proliferation, and rescue experiments were subsequently conducted. In addition, the functional role of MAGI1-IT1 in GC in vivo was evaluated with a xenograft model system. P < 0.05 was the significance threshold.Results: Elevated MAGI1-IT1 expression was detected in GC cell lines and tissues, and was linked to poorer patient overall survival. Knocking down this lncRNA disrupted GC cell proliferation in vitro and in vivo, and miR-302d-3p was identified as a MAGI1-IT1 target. Notably, miR-302d-3p inhibition partially reversed the impact of MAGI1-IT1 knockdown on GC cell proliferation. IGF1 was subsequently identified as a miR-302d-3p target gene that was upregulated by MAGI1-IT1 through miR-302d-3p.Conclusion: Overall, these results indicated that MAGI1-IT1 controlled GC cell proliferation by modulating the miR-302d-3p/IGF1 axis, suggesting that this may be a viable treatment target in those with GC.Keywords: MAGI1-IT1, cell proliferation, gastric cancer, miR-302d-3p, IGF1

Yunning Huang,1,* Yuanyuan Yang,2,* Yuanyi Xu,2,* Qian Ma,3,4,* Fengying Guo,2 Yuan Zhao,2 Yuejia Tao,2 Mengqi Li,2 Jiaxin Guo2 1Department of Gastrointestinal Surgery, The Affiliated People’s Hospital of Ningxia Medical University, Yinchuan City, Ningxia Province, 750001, People’s Republic of China; 2Department of Pathology, Ningxia Medical University, Yinchuan City, Ningxia Province, 750004, People’s Republic of China; 3College of Life Sciences, Ningxia University, Yinchuan City, Ningxia Province, 750021, People’s Republic of China; 4College of Basic Medicine, Ningxia Medical University, Yinchuan City, Ningxia Province, 750004, People’s Republic of China*These authors contributed equally to this workCorrespondence: Yunning Huang; Yuanyi Xu Email nxhyncc@126.com; nxxyy@hotmail.comPurpose: Gastric cancer (GC) is one of the most fatal digestive tumors worldwide. Abnormal activation or accumulation of the nuclear factor-erythroid 2-related factor 2/heme oxygenase 1 (Nrf2/HO-1) axis is a malignant event in numerous solid tumors. However, its involvement in angiogenesis of GC remains unknown. This study investigated the role of the Nrf2/HO-1 axis in angiogenesis of GC.Methods: The expression of Nrf2, HO-1, and vascular endothelial growth factor (VEGF) in BGC-823 cells under hypoxia was analyzed using immunocytochemistry, immunofluorescence, Western blotting, and quantitative polymerase chain reaction. The effects of brusatol (Nrf2 inhibitor) and tert-butylhydroquinone (Nrf2 inducer) on these factors and angiogenesis were examined using immunofluorescence, Western blotting, quantitative polymerase chain reaction, and tube formation assay. Moreover, immunohistochemistry and Western blotting were used to determine these factors and microvessel density in tumor and normal tissues of tumor-bearing and tumor-free mice, respectively. Immunohistochemistry and Western blotting were employed to examine these factors and microvessel density in human paracancerous tissues, well-differentiated GC, and poorly differentiated GC. The correlations between Nrf2, HO-1, and VEGF gene expression in 375 patients with GC from The Cancer Genome Atlas cohort were analyzed.Results: The expression of Nrf2, HO-1, and VEGF was increased in hypoxic BGC-823 cells (P< 0.05). Although brusatol decreased their expression and angiogenesis (P< 0.05), tert-butylhydroquinone had the opposite effect (P< 0.05). Moreover, the expression of Nrf2, HO-1, and VEGF, and microvessel density in tumor tissues was higher than that recorded in normal tissues of nude mice (P< 0.05). Similarly, these parameters were low in paracancerous tissues, but high in GC tissues (P< 0.05). Also, they were weak in well-differentiated GC, but strong in poorly differentiated GC (P< 0.05). In addition, there was a significant correlation between Nrf2, HO-1, and VEGF (P< 0.05).Conclusion: The Nrf2/HO-1 axis may regulate the angiogenesis of GC via targeting VEGF. These findings provide a promising biomarker and potential treatment target for GC.Keywords: gastric cancer, angiogenesis, Nrf2, HO-1, VEGF

Jian Yang,1 Feng Bi,2 Hongfeng Gou1 1West China Hospital, Sichuan University, Chengdu, Sichuan Province, 610041, People’s Republic of China; 2Department of Medical Oncology, Laboratory of Molecular Targeted Therapy in Oncology, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan Province, 610041, People’s Republic of ChinaCorrespondence: Feng BiDepartment of Medical Oncology, Laboratory of Molecular Targeted Therapy in Oncology, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, 37# Wai Nan Guoxue Road, Chengdu, Sichuan Province, 610041, People’s Republic of ChinaTel +86-28-85423609(O)Fax +86-28- 85423609Email bifeng@scu.edu.cnHongfeng GouWest China Hospital, Sichuan University, 37# Wai Nan Guoxue Road, Chengdu, Sichuan Province, 610041, People’s Republic of ChinaEmail joan_gou1977@163.comAbstract: Due to specific genetic characteristics, therapeutic options for colorectal cancer (CRC) with DNA mismatch repair deficient (dMMR)/microsatellite instability-high (MSI-H) are limited. Although programmed death 1 (PD-1) blockade has been shown to be highly effective therapy for dMMR/MSI-H CRC, there is a need to develop new therapeutic paradigms to further improve survival rates of patients with dMMR/MSI-H CRC. So far, there is no case report on the use of immunotherapy combined with radiotherapy (RT) for the treatment of dMMR/MSI-H metastatic CRC (mCRC). Here, we report a 64-year-old patient diagnosed with mCRC who experienced a complete pathological response (pCR) after successfully conversion treatment with pembrolizumab and RT, and remains to be tumor-free during a follow-up of 11 months while off therapy. Immunohistochemical staining for MLH1, MSH2, MSH6, and PMS2 on the intestinal biopsy samples revealed loss of MLH1 and PMS2 protein expression. The present case report adds to the limited data on the safety and effectiveness of local RT combined with immunotherapy for patients with dMMR/MSI-H mCRC. This combination therapy appears to be a potential treatment for dMMR/MSI-H mCRC and deserves further exploration.Keywords: immunotherapy, radiotherapy, pembrolizumab, pathological complete response, colorectal cancer

Danfeng Li,1,* Yongming Zeng,1,* Peilin Shen,2,* Xiaosheng Lin,1 Tian Yang,1 Binlie Chen,1,3 Zhiyan Ma,1,3 Huaiming Wang1 1Department of Gastrointestinal Surgery, The First Affiliated Hospital of Shantou University Medical College, Shantou, 515041, People’s Republic of China; 2Department of Urology, The First Affiliated Hospital of Shantou University Medical College, Shantou, 515041, People’s Republic of China; 3Medical College, Shantou University, Shantou, Guangdong, People’s Republic of China*These authors contributed equally to this workCorrespondence: Huaiming WangDepartment of Gastrointestinal Surgery, The First Affiliated Hospital of Shantou University Medical College Email 13750417745@163.comPurpose: This study aimed to explore the function and clinical significance of AVL9 in colorectal cancer (CRC).Materials and Methods: The GEO, TCGA, and GEPIA databases were searched to evaluate the expression level of AVL9, while the SurvExpress online tool was used to explore its related clinical survival prognosis. The cBioPortal and LinkedOmics databases were used to identify AVL9 expression-related genes. Protein–protein interaction (PPI) networks were analyzed using Cytoscape 3.7.1 and DAVID6.8, which was used to perform Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genome (KEGG) signal pathway enrichment. The immunohistochemistry of AVL9 in CRC was detected using an online tool protein atlas. RNA isolation and reverse transcription–quantitative polymerase chain reaction (RT-qPCR) assays were used to detect AVL9 expression in tissue and plasma samples.Results: Our study confirmed that AVL9 was highly expressed in CRC lesions versus the adjacent normal tissues (P < 0.001). High AVL9 expression was negatively associated with survival outcomes (P < 0.05). GO analysis showed that AVL9 expression-related genes were enriched in single organismal cell–cell adhesion, post-transcriptional regulation of gene expression, and negative regulation of the vascular endothelial growth factor receptor signaling pathway (P < 0.05). On a KEGG pathway analysis, these genes were mainly involved in progesterone-mediated oocyte maturation, axon guidance, the insulin signaling pathway, and the ubiquitin-mediated proteolysis signaling pathways (P < 0.05). In the PPI analysis, the KBTBD2, KIAA1147, EPDR1, and RNF216 genes interacted with AVL9, and GEPIA predicted that their expression levels were all positively correlated with AVL9. Furthermore, a clinicopathological parameter analysis found that high AVL9 expression was positively correlated with differentiation and TNM stage. RT-qPCR analysis further showed that plasma AVL9 expression was upregulated in CRC patients versus healthy controls.Conclusion: AVL9 could serve as a potential biomarker and therapeutic target for CRC.Keywords: AVL9, biomarker, colorectal cancer, prognosis

Jin Li,1,* Yang Zhou,1,2,* Xinxin Wang,2 Yanyan Yu,2 Xueyan Zhou,3 Kuan Luan1 1College of Intelligent Systems Science and Engineering, Harbin Engineering University, Harbin, 150001, Heilongjiang Province, People’s Republic of China; 2Department of Radiology, Harbin Medical University Cancer Hospital, Harbin, 150001, Heilongjiang Province, People’s Republic of China; 3School of Technology, Harbin University, Harbin, 150001, Heilongjiang Province, People’s Republic of China*These authors contributed equally to this workCorrespondence: Kuan LuanCollege of Intelligent Systems Science and Engineering, Harbin Engineering University, Harbin, 150001, Heilongjiang Province, People’s Republic of ChinaEmail luankuan@hrbeu.edu.cnPurpose: This study investigated the predictive value of apparent diffusion coefficient (ADC) histogram parameters of the primary tumor for regional lymph node metastasis (LNM) in pathological T3 stage rectal cancer.Patients and Methods: We retrospectively studied 175 patients with T3 stage rectal cancer who underwent preoperative MRI, including diffusion-weighted imaging, between January 2015 and October 2017. Based on pathological analysis of surgical specimens, 113 patients were classified into the LN− group and 62 in the LN+ group. We analyzed clinical data, radiological characteristics and histogram parameters derived from ADC maps. Then, receiver operating characteristic curve (ROC) analyses were generated to determine the best diagnostic performance.Results: The mean (p=0.002, cutoff=1.08× 10– 3 s/mm2), coefficient of variation (CV) (p=0.040, cutoff=0.249) of the ADC map, carbohydrate antigen 199, and N stage with magnetic resonance (mrN stage) were independent factors for LNM. Combining these factors yielded the best diagnostic performance, with the area under the ROC curve of 0.838, 72.9% sensitivity, 79.1% specificity, 65.2% positive predictive value, and 84.5% negative predictive value.Conclusion: With the mean > 1.08× 10– 3 s/mm2 and CV < 0.249, the ADC improved the diagnostic performance of LNM in T3 stage rectal cancer, which could assist surgeons with neoadjuvant chemoradiotherapy.Keywords: diffusion-weighted magnetic resonance imaging, rectal cancer, lymph node metastasis, histogram analysis

Huajian Peng, Xiang Tan Department of Thoracic Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi Zhuang Autonomous Region, People’s Republic of ChinaCorrespondence: Xiang Tan Email tanxiang588@126.comObjective: To evaluate the correlation between systemic inflammation markers and sarcopenia in elderly patients with esophageal squamous cell carcinoma (ESCC) and their prognostic value.Materials and Methods: The clinical data of 121 elderly patients with ESCC were collected. The skeletal muscle area at the level of the third lumbar vertebrae (L3) was measured by computed tomography (CT), and then the skeletal muscle index (SMI) was calculated. The neutrophil-to-lymphocyte ratio (NLR), prognostic nutritional index (PNI) and Geriatric Nutritional Risk Index (GNRI) were calculated according to laboratory standards. Univariate and multivariate Cox proportional hazards models were used to determine prognostic factors for overall survival (OS).Results: A total of 121 elderly ESCC patients were enrolled. Among them, 65 patients had sarcopenia. NLR, PNI and GNRI are significantly related to sarcopenia. The OS of ESCC patients with sarcopenia and/or NLR> 2.24 was significantly worse.Conclusion: PNI, GNRI, NLR and sarcopenia were significantly related. Sarcopenia and NLR are independent prognostic factors for elderly ESCC, and when combined have better prognostic value.Keywords: esophageal squamous cell carcinoma, sarcopenia, neutrophil-to-lymphocyte ratio, survival, nutrition

Hussain Almasmoum Laboratory Medicine Department, Faculty of Applied Medical Science, Umm Al-Qura University, Makkah, 7607, Saudi ArabiaCorrespondence: Hussain AlmasmoumLaboratory Medicine Department, Faculty of Applied Medical Science, Umm Al-Qura University, Al Abdeyah, Makkah, 7607, Saudi ArabiaTel +966 125270000-ext4521Email haamasmoum@uqu.edu.saAbstract: Colorectal cancer (CRC) is one of the most common types of cancers. It is associated with a poor prognosis and high mortality. The role of mucins (MUCs) in colon tumorigenesis is unclear, but it might be significant in the progression of malignancy. Some mucins, such as MUC1 and MUC13, act as oncogenes, whereas others, such as MUC2 and MUC6, are tumor suppressors. However, there are still mucins with unidentified roles in CRC. In this review, we discuss the reported roles of mucins in CRC. Moreover, we review the capability of the mucin family to serve as a sensitive and specific histopathological marker for the early diagnosis of CRC. Lastly, the role of mucin genes clustered on chromosome 7q22 in CRC and other cancers is also discussed.Keywords: colorectal cancer, mucins, MUC3, MUC12, MUC17, chromosome 7q22.1

Qiuli Xu,1,* Liang Ye,2,* Litang Huang,1,* Li Zhou,3 Xi Chen,4 Mingxiang Ye,3 Guannan Wu,3 Ping Zhan,3 Tangfeng Lv,3 Yong Song1 1Department of Respiratory and Critical Care Medicine, Affiliated Jinling Hospital, Southeast University, Sch Med, Nanjing, Jiangsu, People’s Republic of China; 2Department of Respiratory Medicine, Nanjing First Hospital, Nanjing Medical University, Nanjing, Jiangsu, People’s Republic of China; 3Department of Respiratory and Critical Care Medicine, Affiliated Jinling Hospital, Medical School of Nanjing University, Nanjing, Jiangsu, People’s Republic of China; 4Department of Critical Care Medicine, Zhongda Hospital, School of Medicine, Southeast University, Nanjing, Jiangsu, People’s Republic of China*These authors contributed equally to this workCorrespondence: Tangfeng LvDepartment of Respiratory and Critical Care Medicine, Affiliated Jinling Hospital, Medical School of Nanjing University, #305, East Zhongshan Road, Nanjing, People’s Republic of ChinaTel/Fax +86 25-8086-3591Email bairoushui@163.comYong SongDepartment of Respiratory and Critical Care Medicine, Affiliated Jinling Hospital, Southeast University, Sch Med, Nanjing, Jiangsu, People’s Republic of ChinaTel/Fax +86 25-8086-3591Email yong.song@nju.edu.cnPurpose: The survival time of patients with leptomeningeal metastasis (LM) of lung cancer is very short, and the clinical characteristics of LM are varied, making the clinical diagnosis difficult. At present, a positive CSF fluid (CSF) cytology result remains the gold standard for diagnosing LM in lung cancer; however, the process of collecting CSF is traumatic and far less convenient than blood collection. With the development in technology, an increasing number of studies prefer to use liquid biopsy to diagnose or predict the occurrence of the disease. Therefore, we aimed to explore whether serum exosomal miRNA can replace miRNA from CSF to identify or predict the occurrence of LM.Patients and Methods: Herein, four pairs of serum and CSF samples were collected at four different time points from a patient with LM from non-small cell lung cancer (NSCLC). Serum and CSF exosomes were extracted. Western blot (CD63, TSG101) and electron microscope analyses were used to verify exosome extraction, after which exosomal miRNA sequencing was performed. Next, exosomal miRNA from serum and CSF samples from seven patients with LM and 30 patients without LM were collected for validation.Results: Sequencing results of serum exosomal miRNA and CSF exosomal miRNA showed that there were 44 exosomal miRNAs stably co-expressed at four different time points. Then, three common miRNAs related to LM were found (hsa-miR-483-5p, hsa-miR-423-5p, and hsa-miR-342-5p). Subsequently, exosomal miRNA was extracted from serum and CSF samples from seven patients with LM and 30 patients without LM for verification, and the expression of these exosomal miRNA was detected. The results showed that miRNA-483-5p and miRNA-342-5p significantly differed in LM−/+ patients (P = 0.0142 and P = 0.0031, respectively), whereas miRNA-423-5p had no difference (P = 0.0921). Additionally, as the symptoms improved, the expression of these miRNAs decreased or remained stable.Conclusion: Serum exosomal miRNA (hsa-miR-483-5p, and hsa-miR-342-5p) may be involved in LM of lung cancer and may replace CSF to predict LM in NSCLC.Keywords: non-small cell lung cancer, leptomeningeal metastasis, exosome, miRNA, liquid biopsy

Ming-Jing Yu,1,* Pei-Jun Li,2 Zong-An Liang2 1West China School of Medicine, Sichuan University, Chengdu, Sichuan, People’s Republic of China; 2Department of Respiratory and Critical Care Medicine, West China Hospital, Sichuan University, Chengdu, Sichuan, People’s Republic of China*These authors contributed equally to this workCorrespondence: Zong-An Liang Email liangza@scu.edu.cnAbstract: Pulmonary tuberculosis (TB) and lung cancer are both common diseases with poor prognosis and high mortality worldwide. The coexistence of the two diseases has rarely been reported while their relationship has been noted. Here we describe a patient diagnosed with both TB and squamous cell carcinoma in a single lesion. The patient had a cough for four months and polypnea for two months, with a smoking history of over 40 years. Chest computed tomography (CT) showed a lobular mass in the right hilar region, which was diagnosed as TB by transbronchial lung biopsy. The symptoms and CT findings indicated the possibility of lung cancer. So, the patient underwent a further lung biopsy at the periphery of the mass, which was confirmed as squamous cell carcinoma. This case illuminated that when the mass with cancer-like morphologic features and location instead of typical TB, even the initial pathological result shows TB, coexistence of the diseases should be considered.Keywords: pulmonary tuberculosis, squamous cell carcinoma, case report

Mingjiang Liu,* Jingjing Yu,* Hu Jin, Sifan Wang, Jin Ding, Hao Xing, Songqing He, Yonglian Zeng Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, 530021, Guangxi, People’s Republic of China*These authors contributed equally to this workCorrespondence: Songqing He; Yonglian ZengDepartment of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, 530021, Guangxi, People’s Republic of ChinaTel/Fax +86 771-5352512Email dr_hesongqing@163.com; zyl-lian@163.comBackground: Hepatocellular carcinoma (HCC) is a highly malignant and common tumor. Many biomarkers have been identified for HCC. However, the available ones are not accurate enough in term of prognostic value and new markers are needed for the prognosis of this disease. Sirtuins are NAD(+)-dependent histone deacetylases involved in many biological processes of cancers, consisting of family members SIRT1-SIRT7. However, the prognostic value of the SIRTs in HCC remains largely unknown.Methods: Differential expression of SIRTs and survival analysis were assessed in patients with HCC using Oncomine and UALCAN databases. Gene set enrichment analysis (GSEA) was used for pathway analysis. Metascape software was used to construct gene ontologies, metabolic pathways and protein-protein interaction networks. Moreover, a HCC murine model was used to validate the expression levels of SIRT3/6/7 expression.Results: Differential expression analysis suggested that SIRT2-7, not SIRT1, were expressed at higher levels in HCC tissues compared to adjacent normal tissues. These SIRTs showed some similarities, as revealed by GO and KEGG pathway. Higher SIRT3/6/7 mRNA expression levels were found to be significantly associated with shorter overall survival (OS) in HCC patients. Both SIRT3/6/7 mRNA and protein levels were highly expressed in HCC. In addition, over-expression of SIRT3/6/7 wasassociated with tumor stage and grade in HCC patients. Univariate analysis showed that SIRT 6/7 expressions were linked to a shorter OS of HCC patients. Multivariate analysis showed that SIRT7 levels were independently associated with a significantly shorter OS in HCC patients.Conclusion: Differentially expressed SIRT3/6/7 were significantly associated with tumor stage, grade and OS in HCC patients. In addition, SIRT7 were independently associated with a significantly shorter OS in HCC patients. Thus, SIRT3/6/7 can be used as prognostic biomarkers to predict the survival of HCC patients.Keywords: SIRT3, SIRT6, SIRT7, biomarker, hepatocellular carcinoma

Dehui Fu, Chao Li, Yongwang Huang Department of Ear-Nose-Throat (ENT), The Second Hospital of Tianjin Medical University, Tianjin, 300211, People’s Republic of ChinaCorrespondence: Yongwang HuangDepartment of Ear-Nose-Throat, The Second Hospital of Tianjin Medical University, No. 23 Pingjiang Road, Tianjin, 300211, People’s Republic of ChinaTel/Fax +86 22-88328701Email ywhuanghss@163.comPurpose: Nasopharyngeal carcinoma (NPC) is one of the most prevalent carcinomas among the Cantonese population of South China and Southeast Asia (responsible for 8% of all cancers in China alone). Although concurrent platinum-based chemotherapy and radiotherapy have been successful, metastatic NPC remains difficult to treat, and the failure rate is high.Methods: Thus, we developed stable lipid–polymer hybrid nanoparticles (NPs) containing cisplatin (CDDP) and afatinib (AFT); these drugs act synergistically to counter NPC. The formulated nanoparticles were subjected to detailed in vitro and in vivo analysis.Results: We found that CDDP and AFT exhibited synergistic anticancer efficacy at a specific molar ratio. NPs were more effective than a free drug cocktail (a combination) in reducing cell viability, enhancing apoptosis, inhibiting cell migration, and blocking cell cycling. Cell viability after CDDP monotherapy was as high as 85.1%, but CDDP+AFT (1/1 w/w) significantly reduced viability to 39.5%. At 1 μg/mL, AFT/CDDP-loaded lipid–polymer hybrid NPs (ACD-LP) were significantly more cytotoxic than the CDDP+AFT cocktail, indicating the superiority of the NP system.Conclusion: The NPs significantly delayed tumor growth compared with either CDDP or AFT monotherapy and were not obviously toxic. Overall, the results suggest that AFT/CDDP-loaded lipid–polymer hybrid NPs exhibit great potential as a treatment for NPC.Keywords: nasopharyngeal carcinoma, cisplatin, afatinib, nanoparticles, antitumor, apoptosis

Qingrong Li,1– 3,* Qiang Ma,1– 3,* Jibing Cheng,1– 3 Xi Zhou,1– 3 Wenjie Pu,1– 3 Xiaowu Zhong,1– 3 Xiaolan Guo1– 3 1Department of Clinical Laboratory, Affiliated Hospital of North Sichuan Medical College, Nanchong, 637000, People’s Republic of China; 2Translational Medicine Research Center, North Sichuan Medical College, Nanchong, 637000, People’s Republic of China; 3Department of Laboratory Medicine, North Sichuan Medical College, Nanchong, 637000, People’s Republic of China*These authors contributed equally to this workCorrespondence: Xiaolan GuoDepartment of Clinical Laboratory, Affiliated Hospital of North Sichuan Medical College Tel +86-817-2262302Fax +86-817-2282052Email alan5200@hotmail.comAbstract: Cancer is one of the major threats to human health. Although humans have struggled with cancer for decades, the efficacy of treatments for most tumors is still very limited. Dihydroartemisinin (DHA) is a derivative of artemisinin, a first-line antimalarial drug originally developed in China. Beyond the anti-malarial effect, DHA has also been reported to show anti-inflammatory, anti-parasitosis, and immune-modulating properties in vitro and in vivo. Furthermore, an increasing number of studies report that DHA possesses anticancer activities on a wide range of cancer types both in vitro and in vivo, as well as enhances the efficacy of chemotherapy, targeted therapy, and even radiotherapy. However, the mechanisms of DHA on different tumors differ in various ways. In this review, we intend to summarize how DHA sensitizes cancer cells to anti-cancer therapies, highlight its molecular mechanisms and pharmacological effects in vitro and in vivo as well as in current clinical trials, and discuss potential issues concerning DHA. Hopefully, more attention will be paid to DHA as a sensitizer for cancer therapy in the future.Keywords: dihydroartemisinin, anti-tumor drugs, sensitizer, molecular mechanism

Tao Guo,1 Xue Dong,2 Shanli Xie,3 Ling Zhang,4 Peibin Zeng,5 Lin Zhang6 1Department of Gynecology and Obstetrics, West China Second Hospital, Sichuan University, Chengdu, Sichuan, 610041, People’s Republic of China; 2Department of Gynecology, Cheng Du Shang Jin Nan Fu Hospital, West China Hospital, Sichuan University, Chengdu, Sichuan, 610041, People’s Republic of China; 3First People’s Hospital of Guangyuan, Guangyuan, Sichuan, 628000, People’s Republic of China; 4Department of Gynecology and Obstetrics, Guangyuan Central Hospital, Guangyuan, Sichuan, 628000, People’s Republic of China; 5West China School of Public Health and West China Fourth Hospital, Sichuan University, Chengdu, Sichuan, 610041, People’s Republic of China; 6Department of Forensic Biology, West China School of Preclinical and Forensic Medicine, Sichuan University, Chengdu, Sichuan, 610041, People’s Republic of ChinaCorrespondence: Peibin ZengWest China School of Public Health and West China Fourth Hospital, Sichuan University, Chengdu, Sichuan, 610041, People’s Republic of ChinaEmail zengpeibin@live.cnLin ZhangDepartment of Forensic Biology, West China School of Preclinical and Forensic Medicine, Sichuan University, Chengdu, Sichuan, 610041, People’s Republic of ChinaEmail zhanglin@scu.edu.cnAbstract: Ovarian cancer is a common and complex malignancy with poor prognostic outcome. Most women with ovarian cancer are diagnosed with advanced stage disease due to a lack of effective detection strategies in the early stage. Traditional treatment with cytoreductive surgery and platinum-based combination chemotherapy has not significantly improved prognosis and 5-year survival rates are still extremely poor. Therefore, novel treatment strategies are needed to improve the treatment of ovarian cancer patients. Recent advances of next generation sequencing technologies have both confirmed previous known mutated genes and discovered novel candidate genes in ovarian cancer. In this review, we illustrate recent advances in identifying ovarian cancer gene mutations, including those of TP53, BRCA1/2, PIK3CA, and KRAS genes. In addition, we discuss advances in targeting therapies for ovarian cancer based on these mutated genes in ovarian cancer. Further, we associate between detection of mutation genes by liquid biopsy and the potential early diagnostic value in ovarian cancer.Keywords: ovarian cancer, gene mutation, TP53, PIK3CA, BRCA1/2, KRAS, targeted therapy, liquids biopsy

Min Li,1 Tianqing Huang,2 Xiaolan Li,3 Zhiwei Shi,3 Yue Sheng,4 Mimi Hu,3 Kui Song3 1Department of Pharmacy, The First Affiliated Hospital of Jishou University, Jishou, Hunan, 416000, People’s Republic of China; 2Department of Neurology, The First Affiliated Hospital of Jishou University, Jishou, Hunan, 416000, People’s Republic of China; 3Department of Hematology, The First Affiliated Hospital of Jishou University, Jishou, Hunan, 416000, People’s Republic of China; 4Department of Pediatrics, The First Affiliated Hospital of Jishou University, Jishou, Hunan, 416000, People’s Republic of ChinaCorrespondence: Kui SongDepartment of Hematology, The First Affiliated Hospital of Jishou University, Century Avenue, Jishou City, Hunan Province, 416000, People’s Republic of ChinaEmail js_hematology@163.comBackground: Checkpoint kinase 1 (CHK1) plays an important role in DNA damage response and cell cycle progression. Thus, targeting CHK1 is an efficient strategy for cancer therapy.Purpose: The present study aimed to investigate the potential therapeutic effects of GDC-0575, a CHK1-specific inhibitor, in colitis-associated cancer (CAC) and colitis.Methods: We established a DSS-induced acute colitis model and an azoxymethane/dextran sodium sulfate (DSS)-induced CAC model using mice and tested the effect of GDC-0575 on them. Flow cytometry and immunofluorescence were employed to investigate the infiltration of immune cells, and inflammatory cytokine expression in the colon of mice with CAC or colitis was investigated using ELISA and qPCR. We also investigated the correlation between CHK1 and CCL2/CCR2 in human colorectal cancer (CRC) tissues.Results: Administration of GDC-0575 significantly inhibited CHK1 expression in the colon and dramatically impaired the development of CAC and colitis in mice. Moreover, the inhibition of CHK1 expression resulted in efficient inhibition of infiltration by iNOS-positive macrophages, but had no significant effect on CD4 T cells, CD8 T cells, and myeloid-derived suppressor cells (MDSCs). Significant downregulation of TNF-α, IL-6, and IL-1β and dramatic upregulation of IL-10 were observed in the colons of both mice with CAC and colitis treated with GDC-0575. CCL2 expression was also downregulated by GDC-0575 in both mice with CAC and colitis; this was followed by the inhibition of CCR2+ macrophage infiltration in the colon. Furthermore, we report a positive correlation between CHK1 expression and CCL2/CCR2 expression in the malignant tissues of patients with CRC.Conclusion: Taken together, we infer that GDC-0575 impairs the development of CAC and colitis by regulating cytokine expression and inhibiting CCR2+ macrophage infiltration in mice colon.Keywords: colitis, colitis-associated cancer, CHK1, macrophage

Łukasz Pietrzyk,1,2 Agnieszka Korolczuk,3 Małgorzata Matysek,4 Marcin B Arciszewski,4 Kamil Torres1 1Department of Didactics and Medical Simulation, Faculty of Medicine, Medical University of Lublin, Lublin, Poland; 2Department of General, Oncological and Minimally Invasive Surgery, 1st Military Clinical Hospital with the Outpatient Clinic in Lublin, Lublin, Poland; 3Department of Clinical Pathomorphology, Faculty of Medicine, Medical University of Lublin, Lublin, Poland; 4Department of Animal Anatomy and Histology, Faculty of Veterinary Medicine, University of Life Sciences in Lublin, Lublin, PolandCorrespondence: Łukasz PietrzykDepartment of Didactics and Medical Simulation, Faculty of Medicine, Medical University of Lublin, Chodźki 4, Lublin, 20-093, PolandTel +48 814485020Email lukasz.pietrzyk@wp.plBackground: Despite the continuous improvements in prevention and detection of colorectal cancer (CRC), there is an urgent need to find a sensitive, specific, and noninvasive biomarker to improve the early diagnosis and prognosis of CRC. We aimed to evaluate the tissue TEM8 expression and the serum TEM8 concentration in CRC patients.Methods: The study enrolled 42 CRC patients and 35 controls. Immunohistochemical staining was performed to assess the TEM8 tissue expression, whereas the serum TEM8 concentration was evaluated with the ELISA assay.Results: The expression of TEM8 observed in all primary colorectal tumor samples was significantly correlated with the TNM stages and the presence of lymphovascular invasion. The serum TEM8 concentration was significantly higher in CRC patients than in the controls. The TEM8 level was strongly associated with the TNM stage, depth of invasion, and lymph node and distant metastasis. Patients with a high serum TEM8 concentration had a worse overall survival (OS) rate than CRC patients with a low serum TEM8 level.Conclusion: TEM8 may serve as a biomarker for the diagnosis of CRC and it has value in predicting the prognosis of patients with CRC.Keywords: colorectal cancer, tumor endothelial marker 8, biomarker, ANTXR1, angiogenesis

Ming-Chao Wei,1 Yu-Min Wang,2 Da-Wei Wang3 1Department of Thoracic Surgery, Yantai Affiliated Hospital of Binzhou Medical University, Shandong, People’s Republic of China; 2Binzhou Medical University, Shandong, People’s Republic of China; 3Department of Thoracic Surgery, Yantai Mountain Hospital, Shandong, People’s Republic of ChinaCorrespondence: Da-Wei WangDepartment of Thoracic Surgery, Yantai Mountain Hospital, Yantai, Shandong, 264001, People’s Republic of ChinaTel +86-0535-6602183Email gebizhizhang44557@163.comBackground: The role of microRNA (miR) in tumors has been reported in numerous articles. Previous studies have found that miR-130a is low expressed in lung cancer, but the related mechanism has not been fully elucidated. This study mainly explores the mechanism of miR-130a in lung cancer, so as to provide potential therapeutic targets for clinical applications.Methods: Quantitative real-time polymerase chain reaction (qRT-PCR) was used to detect the expression of miR-130a and KLF3 in the tissues of lung cancer patients. The miR-130a-mimics and miR-130a-inhibit were constructed. Cell proliferation, invasion, migration and apoptosis were determined by CCK-8, transwell, scratch test and flow cytometry. Western Blot was used to determine the expression of KLF3 protein in cells, and the dual-luciferase reporter to determine the relationship between KLF3 and miR-130a.Results: miR-130a shows low expression in NSCLC patients, while KLF3 shows high expression, exhibiting a negative correlation. The 5-year survival rate of patients with low miR-130a expression and high KLF3 expression was reduced. Cox regression analysis showed that miR-130a was an independent prognostic factor for NSCLC patients. The dual-luciferase reporter revealed that miR-130a bound to KLF3 in a targeted manner, and cell experiments showed that miR-130a could inhibit the growth of lung cancer cells by regulating the expression of KLF3.Conclusion: miR-130a shows low expression in lung cancer and predicts a poor prognosis. In addition, up-regulation of miR-130a can down-regulate KLF3 and inhibit the growth of lung cancer.Keywords: miR-130a, KLF3, lung cancer, prognosis

Wenhui Chen,* Yucheng Wang,* Jie Zhu, Cunchuan Wang, Zhiyong Dong Department of Gastrointestinal Surgery, The First Affiliated Hospital of Jinan University, Guangzhou, 510630, People’s Republic of China*These authors contributed equally to this workCorrespondence: Zhiyong DongDepartment of Bariatric Surgery, The First Affiliated Hospital of Jinan University, No. 613 Huangpu Avenue West, Guangzhou, 510630, People’s Republic of ChinaTel/Fax +86 20 38688608Email dongzy2008@jnu.edu.cnIntroduction: Sleeve gastrectomy (SG) is the most commonly performed bariatric procedure. It has been shown that bariatric surgery reduces cancer risk. However, the risk of esophagogastric cancer after SG has not been defined yet and the development of cancer in the esophagus and stomach remains a matter of concern.Methods: Web of Science, PubMed and Embase databases were searched. Articles that described the diagnosis and management of esophageal or gastric cancer after SG were considered.Results: Seventeen esophagogastric cancer patients after SG were included. The age of the patients ranged from 21 to 64 years. Tumors were diagnosed after an interval of 33.9 ± 22.8 months from SG (range 4 months– 96 months). There were 4 esophageal cancers,4 gastroesophageal cancers and 9 gastric cancers; adenocarcinoma was the most frequent tumor histology (88.2%). The most commonly reported symptoms were food intolerance/dyspepsia (50.0%), vomiting/nausea/regurgitation (35.7%). Upper gastrointestinal endoscopy (UGIE) with biopsy was used for diagnosis in most of the patients. Surgery was performed in 10 patients (58.8%), while 4 patients were treated by endoscopic procedures (23.5%). The mean follow-up length was 12.2 months (range 3 months– 36 months) and the overall disease-free survival rate was 88.9%.Conclusion: The development of esophagogastric cancer after SG is still not well defined but it may occur at any time. Preoperative and follow-up UGIE are essential in order to allow for prevention, early diagnosis. Further epidemiologic studies are needed to investigate the post-SG-related risk of esophagogastric cancer development.Keywords: sleeve gastrectomy, esophageal cancer, gastric cancer, obesity

Rui Yang,1,2 Qiang Lu,1 Jinshun Xu,1,2 Jiayan Huang,1 Binyang Gao,1,2 Huan Zhang,1,2 Jie Zhou,1,2 Lanxin Du,1 Feng Yan2 1Ultrasound Department, West China Hospital of Sichuan University, Chengdu, Sichuan, People’s Republic of China; 2Laboratory of Ultrasound Imaging, West China Hospital of Sichuan University, Chengdu, Sichuan, People’s Republic of ChinaCorrespondence: Feng YanLaboratory of Ultrasound Imaging, West China Hospital of Sichuan University, No. 88 Keyuan Road South, Chengdu, Sichuan, 610041, People’s Republic of ChinaTel +86 18980606323Email yan_feng@scu.edu.cnPurpose: To identify and validate contrast-enhanced ultrasound (CEUS) features for differentiating malignant from benign splenic lesions.Patients and Methods: Splenic lesions in 123 patients who underwent conventional ultrasound (B-mode US) and CEUS were included in this study. Two radiologists evaluated the sonograms of B-mode and CEUS. Statistical analysis was performed to identify significant imaging predictors for splenic malignant lesions. Two other radiologists independently reviewed B-mode and CEUS sonograms and diagnosed the lesions based on proposed criteria as 1) benign, 2) probably benign, 3) probably malignant or 4) malignant. The diagnostic efficiency between B-mode US and CEUS was compared.Results: Common imaging findings of malignant lesions included hypoechoic, ill-defined margin, absence of cystic/necrotic portion, presence of splenomegaly on B-mode US, and hypoenhancement, rapid washout and presence of intralesional vessels on CEUS (P < 0.05). Among them, three independent features were identified using multivariate logistic regression analysis: hypoechoic pattern, hypoenhancement pattern and intralesional vessels. When three of these findings were combined as a predictor for splenic malignant lesions, 22 (55.0%) of 40 malignant splenic lesions were identified with a specificity of 100%. The diagnostic performance of two readers using receiver operating characteristic curve analysis was 0.622 and 0.533, respectively, for B-mode US, which was significantly improved to 0.908 and 0.906 for CEUS (P < 0.001). The degree of other diagnostic efficiency and inter-reader agreement also increased with CEUS compared to B-mode US.Conclusion: CEUS may provide more useful information than B-mode US and improve the diagnosis efficiency for distinguishing malignant from benign splenic lesions.Keywords: spleen, splenic diseases, contrast-enhanced ultrasound, conventional ultrasound

Krzysztof Kaliszewski,1 Dorota Diakowska,2 Marta Rzeszutko,3 Beata Wojtczak,1 Jerzy Rudnicki1 1Department of General, Minimally Invasive and Endocrine Surgery, Wroclaw Medical University, Wroclaw 50-556, Poland; 2Department of Nervous System Diseases, Faculty of Health Science, Wroclaw Medical University, Wroclaw 51-618, Poland; 3Department of Pathomorphology, Wroclaw Medical University, Wroclaw 50-368, PolandCorrespondence: Krzysztof KaliszewskiDepartment of General, Minimally Invasive and Endocrine Surgery, Wroclaw Medical University, Borowska Street 213, Wroclaw 50-556, PolandEmail krzysztofkali@wp.plPurpose: Although some prognostic variables and risk factors for thyroid cancer (TC) are age-related, the association between age and the risk of TC in patients with thyroid nodules (TNs) assigned to atypia of undetermined significance (AUS) and follicular lesion of undetermined significance (FLUS) is poorly estimated. The aim of this study was to assess the histopathology of AUS/FLUS and the risk of TC according to the age of the patients at the time of AUS/FLUS diagnosis.Patients and Methods: Among 5021 individuals treated for TNs at one institution from 2008 to 2018, 161 (3.2%) patients with 161 TNs assigned to the AUS/FLUS category (1 nodule per patient) were selected and stratified by age at initial diagnosis: < 55 years, 55– 75 years and > 75 years. Logistic regression analysis was used to estimate the association of age with the risk of TC diagnosis.Results: Ninety-one (56.52%) patients < 55 years old, 58 (36.02%) patients 55– 75 years old, and 12 (7.45%) individuals > 75 years old were identified. There were 130 (80.7%) females and 31 (19.3%) males with a mean age of 50.6 ± 16.12 years. Among the evaluated TNs, 142 (88.2%) were ultimately diagnosed as benign, and 19 (11.8%) were diagnosed as malignant. Younger age in patients was significantly related to malignancy outcome (p=0.024 for age < 55 years). Patients aged 55– 75 years had a significantly lower risk of TC than the other age categories (p=0.040). The risks of high vascularity and fast tumor growth were significantly higher in the youngest category than in the other categories (age < 55 years old: p=0.045 and p=0.002, respectively).Conclusion: Although patients with TNs classified as AUS/FLUS by ultrasound-guided fine needle aspiration biopsy (UG-FNAB) are not typically qualified for surgery, it is worth noting that younger patients with an AUS/FLUS diagnosis might be at a higher risk of TC.Keywords: age, risk factors, AUS/FLUS, thyroid cancer, surgery

Dandan Wang,1,2,* Kai Ma,3,* Wei Deng,4,* Jingyu Li,1 Shaohua Xiang,1 Yang Zhang,2 Ying Fu,2 Heng Dai,2 Bingding Huang1,2 1College of Big Data and Internet, Shenzhen Technology University, Shenzhen, Guangdong, 518118, People’s Republic of China; 2Department of Research and Development, Sinotech Genomics Inc., Shanghai, 230001, People’s Republic of China; 3Department of Thoracic Surgery, National Cancer Center, Cancer Hospital & Shenzhen Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Shenzhen, Guangdong, 518116, People’s Republic of China; 4Department of General Surgery, Beijing Friendship Hospital, Capital Medical University & National Clinical Research Center for Digestive Disease, Beijing, 100050, People’s Republic of China*These authors contributed equally to this workCorrespondence: Bingding HuangCollege of Big Data and Internet, Shenzhen Technology University, Shenzhen, Guangdong, 518118, People’s Republic of ChinaTel +86-755-23256024Email huangbingding@sztu.edu.cnBackground: The ability to rapidly, inexpensively, and accurately identify cancer patients based on actionable genomic mutations in tumour specimens is becoming critically important in routine clinical diagnostics. Targeted panel sequencing is becoming popular because it enables comprehensive and cost-effective diagnosis. However, the implementation of a next-generation sequencing (NGS) assay in clinical settings requires careful analytical validation to demonstrate its ability to detect multiple genomic variants.Materials and Methods: Here, we developed a custom-targeted NGS panel to identify actionable variants, including single nucleotide variants, insertions, and deletions; copy number variants; and gene fusions, across 73 genes for targeted cancer therapy. We implemented a practical validation strategy with diluted samples and reference standard samples that modelled key determinants of accuracy, including mutant allele frequency, insertion/deletion length, amplitude of copy number, and hotspot gene fusions.Results: The analytical validation results demonstrated that our panel can identify different types of genomic alterations in these test samples with high levels of accuracy, sensitivity, and reproducibility.Conclusion: Our panel could be deployed as a routine clinical test to comprehensively detect actionable variants in cancer patients to guide targeted therapy decisions.Keywords: next-generation sequencing, actionable mutations, targeted therapy

Xiao Yang,* Yuan Cheng,* Xingchen Li, Jingyi Zhou, Yangyang Dong, Boqiang Shen, Lijun Zhao, Jianliu Wang Department of Obstetrics and Gynecology, Peking University People’s Hospital, Beijing, People’s Republic of China*These authors contributed equally to this workCorrespondence: Jianliu WangDepartment of Obstetrics and Gynecology, Peking University People’s Hospital, No. 11 South Avenue, Xi Zhi Men Xicheng District, Beijing, 100044, People’s Republic of ChinaTel +86 10 8832 4474Fax +86 10-8832 4474Email wangjianliu@pkuph.edu.cnBackground: Endometrial cancer (EC) is a common malignancy of the female reproductive system worldwide. Increasing evidence has suggested that many transcription factors are aberrantly expressed in various cancers. This study aimed to develop a transcription factor-based prognostic signature for EC.Methods: Gene expression data and clinical data of EC patients were downloaded from The Cancer Genome Atlas (TCGA) database. Univariate Cox regression and Multivariate Cox regression analysis was used to construct a prognostic signature. Then, the efficacy of the prognostic signature was validated in a training cohort, testing cohort and then the entire cohort. Correlations between clinical features and the model were also analyzed, and a nomogram based on the multivariate Cox analysis was developed. Furthermore, we verified the effect of a key transcription factor, E2F1, on biological functions of EC in vitro.Results: We developed a nine-transcription factor (MSX1, HOXB9, E2F1, DLX4, BNC2, DLX2, PDX1, POU3F2, and FOXP3) prognostic signature. Compared with those in the low-risk group, patients in the high-risk group had worse clinical outcomes. The area under the curve (AUC) of this prognostic signature for 5-year survival was 0.806 in the training cohort, 0.710 in the testing cohort and 0.761 in the entire cohort. Gene set enrichment analysis (GSEA) revealed a correlation between the prognostic signature and various cancer signaling pathways, and a hub transcription factor regulatory network was constructed. The prognostic signature was confirmed to have independent predictive value. Finally, a nomogram based on the prognostic signature and clinical independent prognostic factors was also established and performed well according to the calibration curves. Further, knockdown of E2F1 inhibited invasion and metastasis of EC cells.Conclusion: Our study developed and validated a transcription factor-based prognostic signature that accurately predicts prognosis of EC patients. Moreover, E2F1 may represent a potential target for the treatment of EC.Keywords: endometrial cancer, transcription factor, prognostic signature, risk score, nomogram

Feng Chen,1,2 Lei He,2,3 Liman Qiu,2,3 Yang Zhou,2,3 Zhenli Li,2,3 Geng Chen,2,3 Fuli Xin,2,3 Xiuqing Dong,2,3 Haipo Xu,2,3 Gaoxiong Wang,4 Jingfeng Liu,2,3 Zhixiong Cai2,3 1College of Life Science, Fujian Agriculture and Forestry University, Fuzhou, 350002, People’s Republic of China; 2The United Innovation of Mengchao Hepatobiliary Technology Key Laboratory of Fujian Province, Mengchao Hepatobiliary Hospital of Fujian Medical University, Fuzhou, 350025, People’s Republic of China; 3Mengchao Med-X Center, Fuzhou University, Fuzhou, 350025, People’s Republic of China; 4Department of Hepatobiliary Surgery, The Second Affiliated Hospital of Fujian Medical University, Quanzhou, 362001, People’s Republic of ChinaCorrespondence: Gaoxiong WangDepartment of Hepatobiliary Surgery, The Second Affiliated Hospital of Fujian Medical University, Zhongshan North Road 34, Quanzhou, 362001, People’s Republic of ChinaTel/Fax +86 591 8370 5927Email wanggaoxiong2013@163.comZhixiong CaiThe United Innovation of Mengchao Hepatobiliary Technology Key Laboratory of Fujian Province, Mengchao Hepatobiliary Hospital of Fujian Medical University, Xihong Road 312, Fuzhou, Fujian, 350025, People’s Republic of ChinaTel/Fax +86 591 8370 5927Email caizhixiong1985@163.comBackground: Circular RNAs (circRNAs) could interact with miRNAs to regulate gene expression, participating in hepatocellular carcinoma (HCC) initiation and development. This work aimed to determine the potential function and molecular mechanism of circEPB41L2 (hsa_circ_0077837) during HCC progression.Materials and Methods: The expression of circEPB41L2 in HCC tissues and HCC cell lines was quantified using real-time quantitative PCR (qRT-PCR). CCK-8 assays and colony formation assays were utilized to detect the proliferation of HCC cells. Wound healing assay and transwell assay were performed to determine the capability of migration and invasion for HCC cells. Western blot was conducted to determine gene expression on protein levels. The effect of circEPB41L2 on HCC in vivo was investigated via xenograft experiment. Interaction between circEPB41L2 and miR-590-5p was predicted through bioinformatics methods and confirmed via luciferase reporter assay.Results: Extensive analysis of circRNA profiles in tumor and matched para-tumor tissues collected from 61 HCC patients identified that circEPB41L2 was significantly down-regulated in HCC, which was further confirmed in another HCC group by qRT-PCR analysis. The clinicopathological analysis revealed that down-regulation of circEPB41L2 was negatively associated with tumor size, vascular invasion and alpha-fetoprotein, while positively correlated with HCC prognosis. The biological function experiments showed that overexpression of circEPB41L2 could obviously inhibit the proliferation and metastasis of HCC cells in vitro, while knockdown of circEPB41L2 induced opposite results. Moreover, we also found that circEPB41L2 inhibited HCC migration and invasion though EMT signaling pathway. Similarly, overexpression of circEPB41L2 can also significantly inhibit the proliferation of HCC cells in vivo. Bioinformatic analysis and luciferase reporter assay revealed that circEPB41L2 interacts directly with miR-590-5p and the corresponding biological functions were also verified in miRNA rescue experiments.Conclusion: Our results suggest that circEPB41L2 might function as a tumor suppressor during HCC progression by sponging miR-590-5p.Keywords: circular RNA, circEPB41L2, hepatocellular carcinoma, miR-590-5p

Xingyue He,1 Xin Luo,2 Junjun Dong,1 Xing Deng,1 Feng Liu,1,2 Guanghui Wei1,2 1Department of Urology, Children’s Hospital of Chongqing Medical University, National Clinical Research Center for Child Health and Disorders, Ministry of Education Key Laboratory of Child Development and Disorders, Chongqing, People’s Republic of China; 2Chongqing Key Laboratory of Children Urogenital Development and Tissue Engineering; Chongqing Key Laboratory of Pediatrics, Chongqing, People’s Republic of ChinaCorrespondence: Feng Liu; Guanghui WeiDepartment of Urology, Children’s Hospital of Chongqing Medical University, National Clinical Research Center for Child Health and Disorders, Ministry of Education Key Laboratory of Child Development and Disorders, 136, Zhongshan 2nd Road, Yuzhong District, Chongqing, 400014, People’s Republic of ChinaTel +8613983693965; +8613883617398Email liuu_ff@163.com; u806806@cqmu.edu.cnPurpose: Although the long non-coding RNA (lncRNA) X inactive-specific transcript (XIST) has been reported to have an anti-tumor effect in multiple malignant tumors, its role in Wilms tumor (WT) progression has not been characterized. Thus, we investigated the underlying mechanism by which XIST regulates WT progression.Patients and Methods: We performed microarray analysis and real-time quantitative PCR (RT-qPCR) to detect the expression levels of XIST lncRNA, microRNA-194-5p (miR-194-5p), and YAP (yes-associated protein in Hippo pathway) in tumor and matched adjacent normal tissues and blood collected from 49 WT patients. We also conducted bioinformatics analyses to identify differentially expressed genes. We measured the effects of XIST overexpression and knockdown on cell proliferation, apoptosis, migration, and invasion, and its association with the miR-194-5p/YAP pathway in the rhabdoid G401cell line using flow cytometry, transwell assays, immunohistochemistry, Western blot analysis, and the dual luciferase reporter gene assay.Results: We found that XIST lncRNA levels were increased in blood and tissue samples of WT patients, and this upregulation was significantly correlated with TNM staging and shorter survival time. Notably, we found that XIST upregulation correlated with miR-194-5p downregulation and YAP upregulation in WT tissues, suggesting that XIST regulates the miR-194-5p/YAP pathway. Conversely, XIST downregulation inhibited WT cell proliferation, migration, and invasion and induced apoptosis. Our study revealed the oncogenic role of the lncRNA XIST in WT and demonstrated its role as a competitive endogenous RNA that regulates the miR-194-5p/YAP pathway.Conclusion: Our study demonstrates XIST’s potential as a clinical prognostic biomarker and therapeutic target for WT.Keywords: lncRNA, XIST, Wilms tumor, YAP

Yaqi Fan,1 Mingyuan Xu,2 Yulin Liang,2 Nanhui Wu,2 Feiyan Wang,3 Qian Du,2 Yun Bai,1 Yeqiang Liu1 1Department of Pathology, Shanghai Skin Disease Hospital, Tongji University School of Medicine, Shanghai, 200050, People’s Republic of China; 2Shanghai Skin Disease Hospital, Shanghai, 200443, People’s Republic of China; 3Shanghai Skin Disease Clinical College of Anhui Medical University, Shanghai Skin Disease Hospital, Shanghai, 200443, People’s Republic of ChinaCorrespondence: Yeqiang Liu; Yun BaiDepartment of Pathology, Shanghai Skin Disease Hospital, Tongji University School of Medicine, 1278 Bao’de Road, Shanghai, 200443, People’s Republic of ChinaTel/Fax +86 21 61833180Email lyqdoctor@163.com; baiyun@chgc.sh.cnPurpose: To investigate the clinicopathological characteristics and immunophenotype of desmoplastic melanoma (DM) in the Chinese population.Patients and Methods: We report three cases of DM diagnosed by the Pathology Department of Shanghai Dermatology Hospital. We describe the clinical and pathological characteristics of the three cases and examine molecular markers used in the diagnosis of DM. Finally, we summarize the current literature in the DM field.Results: Clinically, lesions in the three DM patients were characterized by non-pigmented nodules or papules. Microscopically, we observed an abundance of fibrous interstitium mixed with spindle cells exhibiting various degrees of atypia. Occasionally, these structures exhibited changes in lentigo maligna at the epidermal junction, accompanied by the presence of lymphoid follicular structures and neurophilic behavior. Diagnosis of DM was confirmed by immunohistochemical staining, which revealed high expression levels of S-100 and SOX-10. Melanocyte markers were focally positive or negative. Unlike DMs from other populations, our three patients were negative for WT-1 and P53. All three cases received surgical resection, which is the preferred treatment for DM, and none of the patients experienced recurrence.Conclusion: DM in these Chinese patients was similar to that observed in other DM populations in terms of immunophenotype and clinical and histological features. A notable absence in p53 staining was observed in the three cases reported here, suggesting that p53 negativity should not exclude the diagnosis of DM in the Chinese population.Keywords: desmoplastic melanoma, uneven pigmented nodules, histology, Chinese population, immunophenotypes

Lingzhu Wen,1,* Guochun Zhang,1,* Chongyang Ren,1,* Xuerui Li,1 Hsiaopei Mok,1 Minghan Jia,1 Yulei Wang,1 Bo Chen,1 Kai Li,1 Li Cao,1 Cheukfai Li,1 Weikai Xiao,1 Jianguo Lai,1 Jiali Lin,1 Guangnan Wei,1 Yingzi Li,1 Yuchen Zhang,1 Xiaoqing Chen,2 Ning Liao1 1Department of Breast Cancer, Guangdong Provincial People’s Hospital (Guangdong Academy of Medical Sciences), Guangzhou, Guangdong, People’s Republic of China; 2Department of Breast Surgical Oncology, Foshan Maternity and Children’s Healthcare Hospital Affiliated to Southern Medical University, Foshan, Guangdong, People’s Republic of China*These authors contributed equally to this workCorrespondence: Ning LiaoDepartment of Breast Cancer, Guangdong Provincial People’s Hospital (Guangdong Academy of Medical Sciences), No. 106, Zhongshan 2nd Road, Yuexiu District, Guangzhou, Guangdong, People’s Republic of ChinaTel/Fax +86 20-83827812Email syliaoning@scut.edu.cnPurpose: This study aimed to investigate AKT gene mutation status in Chinese breast cancer patients.Methods: The study included 411 breast cancer patients hospitalized in Guangdong Provincial People’s Hospital (GDPH) from June 1, 2017 to September 27, 2018. Mastectomy or breast conserving surgery was performed, and tissue samples were subjected to next-generation sequencing (NGS) to determine AKT gene mutation status. Meanwhile, the expression of human epidermal growth factor receptor 2 (Her2), progesterone receptor (PR), and estrogen receptor (ER) was analyzed by immunohistochemistry staining. The Cancer Genome Atlas (TCGA) database was used for comparative studies.Results: Patients in the GDPH cohort had an older age (P < 0.001), higher postmenopausal rate (P < 0.001), larger tumor size (P < 0.001), higher histologic type of infiltrating duct cancer (P < 0.001), higher metastatic rate (P < 0.001), higher expression of ER (P = 0.015) and HER2 (P < 0.001), and higher percentage of the HR/HER2 subtype (P < 0.001) than those in the TCGA cohort. The GDPH cohort displayed lower rates of overall AKT and AKT3 mutation (P < 0.001), but a higher AKT1 mutation rate (P < 0.0001) compared with the TCGA cohort. Notably, the NGS studies identified missense mutation and copy number amplification as the most common AKT variation type in the GDPH and TCGA cohorts, respectively. Specifically, E17K mutation in AKT1 was predominantly detected in GDPH cohort, while being absent in TCGA cohort. Moreover, in the GDPH cohort, AKT variation was correlated with a number of clinicopathological variables, including age over 50, HER2-, HR+/HER2-, and PR+.Conclusion: Patients in the GDPH cohort had lower rates of AKT and AKT3 mutation and higher AKT1 mutation rate than those in the TCGA cohort, while harboring missense mutations detected predominantly as E17K mutation in AKT1. In GDPH cohort, there were correlations between AKT mutation and the clinicopathological characteristics of patients.Keywords: AKT, next-generation sequencing, breast cancer, somatic mutations, population study

Yang Jiao,1,* Chen Fang,1,* Yuchen Yang,2 Lin Shao,2 Yi Huang,1 Qinying Sun,1 Yuchao Dong1 1Pulmonary and Critical Care Medicine, Changhai Hospital, The Naval Medical University, Guangzhou, People’s Republic of China; 2Burning Rock Biotech, Guangzhou, People’s Republic of China*These authors contributed equally to this workCorrespondence: Yuchao Dong; Qinying SunPulmonary and Critical Care Medicine, Changhai Hospital, The Naval Medical University, #168 Changhai Road, Yangpu District, Shanghai, 200433, People’s Republic of ChinaEmail dongyc1020@aliyun.com; sqy20031@163.comAbstract: MET exon 14 skipping variants have been identified as a novel type of oncogenic driver mutations in non-small-cell lung cancer (NSCLC), while the germline MET mutation, especially germline MET exon 14 skipping mutation rarely occurred in NSCLC. Herein, we present the first case of a 33-year-old NSCLC patient with a germline MET exon 14 skipping mutation, who also harbored a somatic EGFR exon 20 insertion. The patient was initially diagnosed with a stage IIB adenosquamous carcinoma. He underwent a thoracoscopic radical resection followed by four cycles of adjuvant chemotherapy but relapsed 2 months after completing the chemotherapy. Afatinib was then prescribed but disease progressed immediately. Subsequently, he received anlotinib but did not respond and died a month later with an overall survival of 9 months. Our case may provide an evidence for the pathogenicity of germline MET exon 14 skipping mutation in NSCLC and suggest it as an adverse prognostic factor.Keywords: MET exon 14 skipping mutation, rare germline mutation, next-generation sequencing, NGS, lung adenosquamous carcinoma, rapid disease progression

Angelo Dipasquale,1,2 Arianna Marinello,1,2 Armando Santoro1,2 1Department of Biomedical Sciences, Humanitas University, Pieve Emanuele, 20090, Italy; 2IRCCS Humanitas Research Hospital, Rozzano, 20089, ItalyCorrespondence: Armando SantoroIRCCS Humanitas Research Hospital, Via Manzoni 56, Rozzano, 20089, ItalyTel +39 28224 4080Fax +39 28224 4592Email armando.santoro@humanitas.itAbstract: Hepatocellular carcinoma (HCC) is the fifth most common malignancy across the world. Alongside improvement in local approaches for early stages, the prognosis of patients with advanced disease remains poor. The tyrosine kinase inhibitor sorafenib was the first drug approved for advanced HCC. During the past decade, this has been extensively explored in real-life settings, such as Eastern Cooperative Oncology Group performance status 2, Child-Pugh B liver function, chronic kidney disease, HIV infection, transplant recipients and the elderly. After 10 years, the multikinase inhibitor lenvatinib was approved in first-line setting. The Phase III REFLECT trial established the non-inferiority of lenvatinib compared with sorafenib in terms of overall survival, meanwhile exploratory analysis suggests a potential benefit over sorafenib for patients with HBV chronic infection and positive alpha-fetoprotein value. Experience with lenvatinib for patients not matching the REFLECT trial criteria remains promising but still retrospective. Indeed, the treatment sequence after lenvatinib still remains a crucial issue, considering that standard second-line options were tested only in patients who progressed to sorafenib. Overall, the choice between lenvatinib and sorafenib should take into account key selection criteria from randomized trials, evidence to date in special clinical situations, the physician’s experience and patient’s preference. Fast approval of atezolizumab plus bevacizumab as first-line treatment for advanced HCC brought an additional element in this scenario. Undoubtedly, lenvatinib and sorafenib remain available options for patients who are not suitable or those progressed to combination immunotherapy. It is conceivable that new systemic options will contribute to design a new treatment algorithm for HCC in the near future. Meanwhile, prospective studies and biomarker analysis are needed to help physicians in the choice between lenvatinib and sorafenib.Keywords: hepatocellular carcinoma, sorafenib, lenvatinib

Xianyun Xu,1,* Qiongjun Xie,2,* Mingfeng Xie,3 Yong Zeng,3 Qian Liu1 1Key Laboratory of Prevention and treatment of cardiovascular and cerebrovascular diseases of Ministry of Education, Jiangxi Provincial Clinical Research Center for Vascular Anomalies, Basic Medical School, Gannan Medical University, Ganzhou, Jiangxi, 341000, People’s Republic of China; 2Basic Medical School, Gannan Medical University, Ganzhou, Jiangxi, 341000, People’s Republic of China; 3Department of Pediatric Surgery, Jiangxi Provincial Clinical Research Center for Vascular Anomalies, Key Laboratory of Prevention and Treatment of Cardiovascular and Cerebrovascular Diseases of Ministry of Education, The First Affiliate Hospital of Gannan Medical University, Ganzhou, Jiangxi, 341000, People’s Republic of China*These authors contributed equally to this workCorrespondence: Qian LiuKey Laboratory of Prevention and treatment of cardiovascular and cerebrovascular diseases of Ministry of Education, Jiangxi Provincial Clinical Research Center for Vascular Anomalies, Basic Medical School, Gannan Medical University, Ganzhou, Jiangxi, 341000, People’s Republic of ChinaEmail liuqiangmu2017@126.comBackground: Small nucleolus RNA Host Gene 8 (SNHG8) belongs to a subgroup with long non-coding RNAs. LncRNA SNHG8 presents up-regulated in miscellaneous cancers, like gastric cancer, liver cancer, and esophageal squamous cell cancer. Nevertheless, the expression pattern and the pathological function of lncRNA SNHG8 in breast cancer remain obscure.Methods: We examined the expression levels of lncRNA SNHG8 in the tissue samples and cell lines from breast cancer via RT-qPCR in the present study. The functions of lncRNA SNHG8 on the progression of breast cancer cell were examined by CCK-8, EdU, Transwell chamber assays, and flow cytometry analyses. The expression of proteins was assessed using Western blot assay.Results: We found that proliferation, migration, and invasion of breast cancer cells were significantly inhibited due to knockdown of lncRNA SNHG8, while inducing apoptosis of these cells. Mechanistically, SNHG8 functioned as an inhibitor of miR-634 in tumor tissues.Conclusion: LncRNA SNHG8 sponged the miR-634 to increase the expression level of ZBTB20, thus further aggravating the malignancy of breast cancer. Hence, the lncRNA SNHG8-miR-634-ZBTB20 axis may be a promising therapeutic target to treat breast cancers.Keywords: small nucleolus RNA host gene 8, microRNA-634, breast cancer, ZBTB20

Tian Zhi, Weiling Zhang, Yi Zhang, Huimin Hu, Dongsheng Huang Department of Pediatrics, Beijing Tongren Hospital, Capital Medical University, Beijing, 100176, People’s Republic of ChinaCorrespondence: Dongsheng HuangDepartment of Pediatrics, Beijing Tongren Hospital, Capital Medical University, No. 1 Dongjiaominxiang Dongcheng District, Beijing, 100730, People’s Republic of ChinaTel/Fax +86 10 58266032Email huamgdomgshemg@163.comObjective: The present study aimed to summarize the clinical data of hepatoblastoma (HB) in infants under one year of age and to analyze the factors that affected the prognoses.Methods: The clinical data of 132 pediatric patients with a pathologically confirmed HB, aged less than one year and who had visited the Pediatric Single Center of Beijing Tongren Hospital from May 2005 to May 2019, were retrospectively analyzed to summarize the clinical outcomes and prognoses.Results: The male/female ratio was 1.27 and the median age was 8.40 months. The onset of HB was usually characterized by abdominal bulging (75.0%). The median level of AFP at the first visit was 154.7μg/mL, and the average platelet count was (405± 166)× 109/L. The epithelial type (57.6%) was the predominant pathological type, and stage III (54.5%) was the main PRETEXT staging. Distant metastases occurred in 45 cases, with pulmonary metastases (86.7%) being the most common site. At the time of visit, 24 cases (18.2%) had either portal vein, hepatic vein, or vena cava infiltration. Five cases (3.8%) had a hemorrhage of the ruptured tumor, and 26 cases (19.7%) had multiple intrahepatic foci. At the follow-up in May 2020, the overall survival (OS) rate at one, three, and five years of age was 94.3%, 88.8%, and 80.1%, respectively, and the event-free survival rate was 91.8%, 86.9%, and 77.5%, respectively, by the Kaplan–Meier survival analysis. According to the Log rank test, pediatric patients with an AFP < 100ng/mL, a PRETEXT stage IV, presence of distant metastases and multiple foci of the primary tumor at the initial diagnosis had poorer prognoses (P< 0.05).Conclusion: The prognosis of HB in infancy is relatively good, but is still vulnerable to multiple factors, such as tumor features leading to different AFP levels, PRETEXT stage, presence of distant metastases, and multiple intrahepatic foci.Keywords: hepatoblastoma, infant, AFP, chemotherapy, prognosis

Nan Jiang,1,2,* Xiao-Lin Ge,2,* Zhao-Yue Zhang,2 Jia Liu,2 Pei-Pei Wang,2 Xin-Chen Sun,1,2 Min Yang1 1The First School of Clinical Medicine, Nanjing Medical University, Nanjing, Jiangsu, 210000, People’s Republic of China; 2Department of Radiotherapy, Jiangsu Province Hospital, Nanjing, Jiangsu, 210000, People’s Republic of China*These authors contributed equally to this workCorrespondence: Min YangThe First School of Clinical Medicine, Nanjing Medical University, No. 818 of Tianyuan Road, Jiangning District, Nanjing, Jiangsu, 210000, People’s Republic of ChinaTel +86 13701516659Email yangmin@jsinm.orgXin-Chen SunDepartment of Radiotherapy, Jiangsu Province Hospital, No. 300 of Guangzhou Road, Gulou District, Nanjing, Jiangsu, 210000, People’s Republic of ChinaTel +86 13770662828Email sunxinchen2012@163.comPurpose: Intensity-modulated radiotherapy (IMRT) can improve the prognosis of patients with esophageal cancer. This study aimed to evaluate clinical factors relevant to the prognosis of patients with esophageal cancer who received intensity-modulated radiotherapy (IMRT) alone.Patient and Methods: Data of 103 patients with pathologically confirmed esophageal cancer who were admitted to our hospital between October 2011 and November 2017 were retrospectively reviewed. All patients had squamous cell carcinoma. All patients received IMRT. Patients with stage I–IVA tumors were included to represent the real-world clinical practice. We performed univariate and multivariate analyses to identify prognostic factors for overall survival (OS) and progression-free survival (PFS). In univariate analyses, the Kaplan–Meier method was used to estimate OS and PFS for various subgroups. In multivariate analyses, hazard ratios were calculated.Results: Single-factor analysis revealed that T stage (P=0.019), N stage (P =0.047), and lesion length (P =0.000) were associated with the prognosis of esophageal cancer patients who received IMRT. Cox regression analysis revealed that T stage (odds ratio [OR] = 4.68; P < 0.05), N stage (OR = 0.28; P < 0.05), and lesion length (OR = 0.09; P < 0.05) were independent factors relevant to prognosis.Conclusion: T stage, N stage, and lesion length influenced the long-term curative effects of IMRT for esophageal cancer and were prognostic factors for patients with esophageal cancer receiving definitive radiotherapy alone. The higher the stage and the longer the tumor, the lower the survival rate.Keywords: esophageal neoplasms, prognosis, intensity-modulated radiotherapy, retrospective studies

Yichao Wang,1,* Qianyi Zhong,1,* Zhaoyun Li,1 Zhu Lin,2 Hanjun Chen,1 Pan Wang1 1Department of Clinical Laboratory Medicine, Taizhou Central Hospital (Taizhou University Hospital), Taizhou, Zhejiang, 318000, People’s Republic of China; 2Department of Ultrasound, Taizhou Central Hospital (Taizhou University Hospital), Taizhou, Zhejiang, 318000, People’s Republic of China*These authors contributed equally to this workCorrespondence: Pan WangDepartment of Clinical Laboratory Medicine, Taizhou Central Hospital (Taizhou University Hospital), No. 999 Donghai Road, Jiaojiang District, Taizhou, Zhejiang, 318000, People’s Republic of ChinaTel +86 13586106875Email wangp9113@tzzxyy.comIntroduction: Breast cancer is the main reason for cancer-related deaths in women and the most common malignant cancer among women. In recent years, immunosuppressive factors have become a new type of treatment for cancer. However, there are no effective biomarkers for breast cancer immunotherapy. Therefore, exploring immune-related biomarkers is presently an important topic in breast cancer.Methods: Gene expression profile data of breast cancer from The Cancer Genome Atlas (TCGA) was downloaded. Scale-free gene co-expression networks were built with weighted gene co-expression network analysis. The correlation of genes was performed with Pearson’s correlation values. The potential associations between clinical features and gene sets were studied, and the hub genes were screened out. Gene Ontology and gene set enrichment analysis were used to reveal the function of hub gene in breast cancer. The gene expression profiles of GSE15852, downloaded from the Gene Expression Omnibus database, were used for hub gene verification. In addition, candidate biomarkers expression in breast cancer was studied. Survival analysis was performed using Log rank test and Kaplan–Meier. Immunohistochemistry was used to analyze the expression of CCNA2.Results: A total of 6 modules related to immune cell infiltration were identified via the average linkage hierarchical clustering. According to the threshold criteria (module membership > 0.9 and gene significance > 0.35), a significant module consisting of 13 genes associated with immune cells infiltration were identified as candidate hub genes after performed with the human protein interaction network. And 3 genes with high correlation to clinical traits were identified as hub genes, which were negatively associated with the overall survival. Among them, the expression of CCNA2 was increased in metastatic breast cancer compare with non-metastatic breast cancer, who underwent immunotherapy. Immunohistochemistry results showed that CCNA2 expression in carcinoma tissues was elevated compared with normal control.Discussion: CCNA2 identified as a potential immune therapy marker in breast cancer, which were first reported here and deserved further research.Keywords: breast cancer, immune infiltration, molecular markers, immunotherapy

Edyta Paczkowska,1,2 Michał Janowski,2 Katarzyna Karpińska,3 Małgorzata Ryłów,2 Barbara Zdziarska,2 Wojciech Poncyljusz,4 Bogusław Machaliński1 1Department of General Pathology, Pomeranian Medical University, Szczecin, Poland; 2Department of Hematology with Bone Marrow Transplantation Unit, University Hospital No. 1 of Pomeranian Medical University, Szczecin, Poland; 3Department of Pathomorphology, Pomeranian Medical University, Szczecin, Poland; 4Department of Diagnostic Imaging and Interventional Radiology, Pomeranian Medical University, Szczecin, PolandCorrespondence: Edyta PaczkowskaDepartment of General Pathology, Pomeranian Medical University, Al. Powstańców Wlkp. 72, Szczecin, 70-111, PolandEmail edyta.paczkowska@pum.edu.plIntroduction: Incidences of chronic myeloid leukaemia (CML) after treatment of Hodgkin lymphoma (HL) are well described. Here, we report a case of secondary HL in a patient with CML treated with dasatinib as a third-line treatment.Patient Information: A 64-year-old male was diagnosed with CML and initially treated with imatinib and then with nilotinib due to resistance. Finally, the patient experienced cardiovascular complications, and dasatinib was introduced. After 19 months of treatment, the patient experienced enlargement of lymph nodes that formed packs on the neck.Interventions: Based on histopathological examination of the lymph nodes, a diagnosis of classical Hodgkin lymphoma – mixed cellularity was established. The patient was successfully treated with 4 cycles of AVD (adriamycin, vinblastine, dacarbazine) chemotherapy.Outcomes: Complete metabolic remission of Hodgkin lymphoma is currently sustained, and the molecular response to dasatinib at a reduced dose of 50 mg daily corresponds with a deep molecular response.Conclusion: In this report, we demonstrate the efficacy and safety of the combination of dasatinib and AVD regimens in coexisting CML and HL. This case report emphasizes the importance of insightful evaluation and differential diagnosis in cases of lymphadenopathy during CML treatment.Keywords: chronic myeloid leukemia, Hodgkin lymphoma, dasatinib, lymphadenopathy, tyrosine kinase inhibitors

Han Bai,1 Jianjun Yu,2 Shidong Jia,2 Xiaoran Liu,1 Xu Liang,1 Huiping Li1 1Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Breast Oncology, Peking University Cancer Hospital and Institute, Beijing, 100142, People’s Republic of China; 2Huidu Shanghai Medical Sciences, Shanghai, 201499, People’s Republic of ChinaCorrespondence: Xu Liang; Huiping LiKey Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Breast Oncology, Peking University Cancer Hospital and Institute, No. 52, Fucheng Road, Haidian District, Beijing, 100142, People’s Republic of ChinaTel/Fax +86-10-88196739Email liangxu15@outlook.com; huipingli2012@hotmail.comPurpose: The status of TP53 mutations was measured in cell-free DNA from patients with metastatic breast cancer (MBC) to investigate disease characteristics and the prognostic role of different locations of the TP53 mutation site.Patients and Methods: Blood samples were taken from a total of 187 patients diagnosed with MBC who were treated at the Department of Breast Oncology, Peking University Cancer Hospital between January 2013 and March 2020. Next-generation sequencing was used to investigate the TP53 mutation spectra of circulating free DNA in these blood samples.Results: Among the 187 MBC patients, TP53-mutated patients had a significantly shorter median disease-free survival (DFS) and overall survival (OS) compared with TP53 wild-type patients (P=0.001 and P=0.006, respectively). Additionally, in hormone receptor positive/HER2 negative (HR+/HER2-) and triple negative (TNBC) cohorts, TP53-mutated patients had a significantly shorter median DFS than TP53 wild-type patients (P=0.038 and P=0.023, respectively). The 79 patients with TP53 mutations carried 87 somatic TP53 mutations, of which most (77.0%) mapped to the DNA-binding domain (DBD) of the protein encoded by TP53 exons 5– 8. In patients with TP53 mutations, those occurring in the non-DBD had a significantly shorter median DFS and OS than TP53 wild type (P< 0.001 and P=0.001, respectively). Additionally, patients with non-missense mutations in the DBD had a significantly shorter median DFS and OS than TP53 wild-type patients (P=0.001 and P< 0.001, respectively). TP53-mutated patients had a significantly shorter DFS than TP53 wild-type patients in the adjuvant endocrine therapy sensitive group (P=0.008), but differences in the endocrine therapy resistant group were not significant.Conclusion: TP53-mutated MBC patients had a significantly worse outcome than TP53 wild-type patients especially those in HR+/HER2– and TNBC cohorts. Of TP53-mutated patients, those with non-missense mutations in the DBD had worse breast cancer-related survival. TP53 mutations were also associated with endocrine resistance.Keywords: advanced breast cancer, TP53 mutation, NGS, adjuvant endocrine therapy, DNA-binding domain

Daniel Geh,1 Quentin M Anstee,2,3 Helen L Reeves2– 4 1Biosciences Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, UK; 2Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, UK; 3The Liver Unit, Newcastle Upon Tyne Hospitals NHS Foundation Trust, Freeman Hospital, Newcastle upon Tyne, UK; 4Hepatopancreatobiliary Multidisciplinary Team, Newcastle Upon Tyne Hospitals NHS Foundation Trust, Freeman Hospital, Newcastle upon Tyne, UKCorrespondence: Helen L ReevesTranslational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, NE2 4HH, UKTel +44 191 208 4423Fax +44 191 208 4301Email h.l.reeves@ncl.ac.ukAbstract: Due to an increase in the obesity-associated metabolic syndrome of epidemic proportions, nonalcoholic fatty liver disease (NAFLD) is becoming a leading cause of hepatocellular carcinoma (HCC) in western countries. This presents added challenges, as NAFLD-associated HCC tends to present at an advanced stage in older patients with co-morbidities. Their prognosis is generally poor with the benefits of standard therapies less certain. The pathogenesis of NAFLD-associated HCC is multifactorial and not well understood, although the risk of HCC developing undoubtedly increases as NAFLD progresses to steatohepatitis and cirrhosis. Recent advances in our understanding of the drivers of NAFLD and HCC will hopefully lead to the development of clinically relevant biomarkers, tools and strategies to aid the identification of high-risk patients, inform preventive measures, and introduction of better tolerated targeted therapies. Lifestyle modification and chemoprevention with drugs such as anti-platelets, statins and anti-diabetics are being evaluated for HCC prevention. The landmark IMBrave150 study introducing the combination of atezolizumab and bevacizumab has recently transformed the landscape of systemic therapies in HCC, with follow-up analyses and real-world data for patients with NAFLD-associated HCC eagerly anticipated. While responses may vary in ways not yet appreciated, the rate of discovery and progress suggests imminent change and opportunities.Keywords: hepatocellular carcinoma, HCC, nonalcoholic fatty liver disease, NAFLD, liver cirrhosis, biomarkers, prevention, systemic therapy, immunotherapy

Pan Hu,1,* Yu Ben,1,* Juan Liu,1 Weicheng Zheng,1 Xiyue Yan,1 Yaping Zhang,2 Wenyu Shi1,2 1Department of Oncology, Affiliated Hospital of Nantong University, Nantong, Jiangsu, 226001, People’s Republic of China; 2Department of Hematology, Affiliated Hospital of Nantong University, Nantong, Jiangsu, 226001, People’s Republic of China*These authors contributed equally to this workCorrespondence: Wenyu ShiDepartment of Oncology and Hematology, Affiliated Hospital of Nantong University, Nantong, Jiangsu, 226001, People’s Republic of ChinaTel +86-513-81160502Fax +86-513-85519820Email shiwenyu@hotmail.comYaping ZhangDepartment of Hematology, Affiliated Hospital of Nantong University, Nantong, Jiangsu, 226001, People’s Republic of ChinaTel +86-513-81160502Fax +86-513-85519820Email zzyaping@163.comAbstract: Epstein–Barr virus (EBV)-positive diffuse large B-cell lymphoma (DLBCL) complicated with angioimmunoblastic T-cell lymphoma (AITL) is extremely rare and typically shows an aggressive clinical course and unsatisfactory prognosis. Here, we describe the case of a 77-year-old man who was referred to the hospital because of repeated fever, night sweats, and weight loss. He was finally diagnosed with a discordant lymphoma consisting of AITL and DLBCL, with significantly different maximum standardized uptake values on positron emission tomography/computed tomography. Based on his complex illness and poor performance status, the patient received six cycles of lenalidomide combined with R-miniCHOP regimen and achieved complete remission with tolerable and controlled toxicity. He subsequently received lenalidomide maintenance therapy and achieved sustained remission. We consider the possible causes of this discordance involved AITL and EBV-positive DLBCL, and the possible mechanism of lenalidomide action in both T-cell and B-cell non-Hodgkin lymphomas. Lenalidomide-combination therapy may be a preferable choice in patients with an EBV-associated discordant lymphoma.Keywords: Epstein–Barr virus, diffuse large B-cell lymphoma, angioimmunoblastic T-cell lymphoma, discordant lymphoma, lenalidomide, positron emission tomography/computed tomography

Chuangkun Li,1,2,* Weiwen Liang,1,2,* Lili Chu,1,* Yingqi Wei,1,2 Xiusen Qin,1,2 Zifeng Yang,1,2 Wentai Guo,1,2 Hui Wang,1,2 Huaiming Wang,1,2 Rongkang Huang1,2 1Department of Colorectal Surgery, Sixth Affiliated Hospital, Sun Yat-Sen University, Guangzhou, Guangdong, 510655, People’s Republic of China; 2Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, Sixth Affiliated Hospital, Sun Yat-Sen University, Guangzhou, Guangdong, 510655, People’s Republic of China*These authors contributed equally to this workCorrespondence: Huaiming WangDepartment of Colorectal Surgery, Sixth Affiliated Hospital, Sun Yat-Sen University, Guangzhou, Guangdong, 510655, People’s Republic of ChinaEmail wanghm7@mail.sysu.edu.cnRongkang HuangDepartment of Colorectal Surgery, The Sixth Affiliated Hospital, Sun Yat-Sen University, Guangzhou, Guangdong, People’s Republic of ChinaTel +86-134-8021-8647Email huangrk3@mail.sysu.edu.cnPurpose: Anastomotic leakage after rectal cancer surgery in elderly patients is a critical challenge. Many risk factors have been found and many interventions tried, but anastomotic leakage in elderly patients remains difficult to deal with. This study aimed to create a nomogram for predicting anastomotic leakage after rectal surgery in elderly rectal cancer patients with dysfunctional stomata.Methods: We collected data from 326 consecutive elderly patients with dysfunctional stomata after rectal cancer surgery at the Sixth Affiliated Hospital, Sun Yat-Sen University from January 2014 to December 2019. Risk factors of anastomotic leakage were identified with multivariate logistic regression and used to create a nomogram. Predictive performance was evaluated by the area under the receiver-operating characteristic (ROC) curve.Results: American Society of Anesthesiologists score ≥ 3, male sex, and neoadjuvant radiotherapy were identified as significantly associated factors that could be combined for accurate prediction of anastomotic leakage on multivariate logistic regression and development of a nomogram.The area under the ROC curve for this model was 0.645. The C-index value for this model was 0.645, indicating moderate predictive ability of the risk of anastomotic leakage.Conclusion: The nomogram showed good ability to predict anastomotic leakage in elderly patients with rectal cancer after surgery, and might be helpful in providing a reference point for selection of surgical procedures and perioperative treatment.Keywords: nomogram, rectal cancer, anastomotic leakage, elderly patients

Jian Zheng,1 Xiaoxi Li,2 Cunwei Cai,3 Chengyu Hong,1 Bin Zhang4 1Department of Thoracic Medicine, Cancer Hospital of China Medical University, Liaoning Cancer Hospital & Insititute, Shenyang, Liaoning, 110042, People’s Republic of China; 2Central Laboratory, Cancer Hospital of China Medical University, Liaoning Cancer Hospital & Insititute, Shenyang, Liaoning, 110042, People’s Republic of China; 3Department of Pathology, Cancer Hospital of China Medical University, Liaoning Cancer Hospital & Insititute, Shenyang, Liaoning, 110042, People’s Republic of China; 4Department of Oncology, The First Affiliated Hospital of Dalian Medical University, Dalian, Liaoning, 116011, People’s Republic of ChinaCorrespondence: Jian ZhengDepartment of Thoracic Medicine, Cancer Hospital of China Medical University, Liaoning Cancer Hospital & Insititute, NO. 44 Xiaoheyan Road, Dadong District, Shenyang, Liaoning, 110042, People’s Republic of ChinaTel/ Fax +86-24-31916363Email zhengjian_2020@163.comBackground: The roles of microRNA (miR)-32 and miR-548a in non-small cell lung cancer (NSCLC) have been studied. But their influences on NSCLC cells to cisplatin (DDP) resistance remain elusive. This study estimated the mechanisms of miR-32 and miR-548a in NSCLC cells to DDP.Methods: Differentially expressed miRs in DDP-sensitive and resistant tissues were screened out using a GSE56036 chip. Then the predictive efficacies of miR-32 and miR-548a on DDP resistance were analyzed in NSCLC patients. The target mRNAs of miR-548a and miR-32 were predicted. miR-548a and miR-32 were knocked down to assess the influences of miR-32 and miR-548a on NSCLC growth. DDP-resistant cells were constructed and miR-32 and miR-548a expression was detected in resistant cells. After miR-32 and miR-548a knockdown, the IC50 value of DDP was detected. Then, the activation level of Wnt/β-catenin pathway was detected. The roles of miR-32 and miR-548a in NSCLC growth in vivo were detected by tumorigenesis experiment.Results: miR-32 and miR-548a were poorly expressed in DDP-resistant NSCLC. miR-32 and miR-548a mimic enhanced the DDP sensitivity of NSCLC cells. Both miR-32 and miR-548a targeted ROBO1, and overexpression of ROBO1 inhibited the promotion of miR-32 and miR-548a mimic on DDP sensitivity. ROBO1 activated the Wnt/β-catenin pathway, thus enhancing the DDP resistance.Conclusion: miR-32 and miR-548a target ROBO1 and inhibit Wnt/β-catenin activation, thus promoting the drug sensitivity of NSCLC cells to DDP.Keywords: non-small cell lung cancer, miR-32, miR-548a, cisplatin resistance, ROBO1, Wnt/β-catenin pathway

Zongying Liang, Baoshan Zhao, Jishen Hou, Jingxiong Zheng, Guohua Xin Department of Thoracic Surgery, The Affiliated Hospital of Chengde Medical University, Chengde, 067000, People’s Republic of ChinaCorrespondence: Guohua XinDepartment of Thoracic Surgery, The Affiliated Hospital of Chengde Medical University, No. 36, Nanyingzi Street, Shuangqiao District, Chengde, 067000, People’s Republic of ChinaEmail iqbqth@163.comBackground: Circular RNA hsa_circ_0003340 (circ-OGDH) has been uncovered to be involved in esophageal squamous cell carcinoma (ESCC) progression. However, the mechanism by which circ-OGDH regulates ESCC progression is unclear.Methods: Expression levels of circ-OGDH, microRNA (miR)-615-5p, and PDX1 (pancreatic and duodenal homeobox 1) mRNA were evaluated with quantitative real-time polymerase chain reaction (qRT-PCR). The proliferation, apoptosis, migration, invasion, and cell cycle progression of ESCC cells were analyzed by MTT (3-(4,5-Dimethylthiazol-2-yl)-2,5-Diphenyltetrazolium Bromide), colony formation, flow cytometry, and transwell assays. Measurement of glutamine consumption, α-KG (α-ketoglutarate) production, and ATP (Adenosine Triphosphate) content using corresponding kits. Protein levels were analyzed by Western blotting. The targeting relationship between circ-OGDH or PDX1 and miR-615-5p was verified by dual-luciferase reporter and RNA immunoprecipitation (RIP) assays. The function of circ-OGDH in ESCC was confirmed by animal experiments.Results: Circ-OGDH was upregulated in ESCC. Circ-OGDH inhibition reduced ESCC growth in vivo and accelerated cell apoptosis, cell cycle arrest, repressed cell proliferation, migration, invasion, and reduced cell glutamine metabolism in ESCC cells in vitro. MiR-615-5p was downregulated in ESCC, while PDX1 had an opposite result. Circ-OGDH sponged miR-615-5p to regulate PDX1 expression. MiR-615-5p inhibitor neutralized the repressive effect of circ-OGDH knockdown on malignancy and glutamine metabolism of ESCC cells. PDX1 overexpression counteracted the inhibitory impact of miR-615-5p mimic on malignancy and glutamine metabolism of ESCC cells.Conclusion: Circ-OGDH sponged miR-615-5p to elevate PDX1 expression, thus elevating glutamine metabolism and promoting tumor growth in ESCC. The study offered evidence to support circ-OGDH as a promising target for ESCC therapy.Keywords: ESCC, circ-OGDH, miR-615-5p, PDX1, glutamine

Wei-Dong Bao,1,* Qi Jia,2,* Tao Wang,2,3,* Yan Lou,2 Dong-Jie Jiang,2 Cheng Yang,2 Xinghai Yang,2 Quan Huang,2 Hai-Feng Wei,2 Jian-Ru Xiao1,2 1Department of Orthopedics, Longhua Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, 200032, People’s Republic of China; 2Department of Orthopedic Oncology, Spinal Tumor Center, Shanghai Changzheng Hospital, Second Military Medical University, Shanghai, 200003, People’s Republic of China; 3Department of Orthopeadics, Second Affiliated Hospital of Anhui Medical University, Hefei, 230000, People’s Republic of China*These authors contributed equally to this workCorrespondence: Hai-Feng Wei; Jian-Ru XiaoDepartment of Orthopedic Oncology, Spine Tumor Center, Changzheng Hospital, Second Military Medical University, #415 Fengyang Road, Shanghai, 200003, People’s Republic of ChinaTel +86-21-81886843Email gkxjl999@163.com; spine925@126.comPurpose: To investigate risk factors for instrumentation failure (IF) in titanium (Ti) mesh reconstruction for thoracic and lumbar tumors.Patients and Methods: The clinical data of patients with thoracic or lumbar tumors who received Ti mesh reconstruction via the posterior approach in our hospital from 2013 to 2018 were analyzed retrospectively. The observation indexes included sex, age, BMI, the vertebra resection mode, the number of resected vertebral segments, application of bone cement, radiotherapy, chemotherapy, revision or primary surgery, and primary tumor metastasis. Correlations between these factors and IF were analyzed by Kaplan–Meier survival and logistics regression analyses.Results: The 178 patients included 108 males and 70 females with a mean age of 48.09± 16.21 (6– 78) years and a mean follow-up period of 51.18 (24– 90) months. The data showed that 17 patients (9.55%) were inflicted with IF, involving the thoracic vertebra in 11 cases, thoracolumbar vertebrae (T12–L1) in 2 cases, and lumbar vertebrae in 4 cases. The mean interval between surgery to IF was 35.18± 14.17 (14– 59) months. Univariate analysis showed that total vertebral body resection, the number of resected vertebral segments, radiotherapy and multiple tumor resection were potential factors for IF, while multivariate analysis showed that only total vertebral body resection, the number of resected vertebral segments and radiotherapy were independent factors.Conclusion: Total vertebra resection, the number of resected vertebral segments (≥ 2) and radiotherapy before and after operation were significant risk factors related to IF.Keywords: instrumentation failure, titanium mesh, thoracic and lumbar tumors