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Whole-exome mutational landscape of neuroendocrine carcinomas of the gallbladder

Signal Transduction and Targeted Therapy 2021年第3期6卷 897-908页

作者： Fatao Liu Yongsheng Li Dongjian Ying Shimei Qiu Yong He Maoian Li Yun Liu Yijian Zhang Qin Zhu Yunping Hu Liguo Liu Guoqiang Li Weihua Pan Wei Jin Jiasheng Mu Yang Cao Yingbin Liu Department of General Surgery Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of MedicineYangpu DistrictShanghai 200092China Shanghai Key Laboratory of Biliary Tract Disease Yangpu DistrictShanghai 200092China State Key Laboratory of Oncogenes and Related Genes ShanghaiChina Shanghai Research Center of Biliary Tract Disease Yangpu DistrictShanghai 200092China Department of Biliary-Pancreatic Surgery Renji Hospital Affiliated to Shanghai Jiao Tong University School of MedicineShanghaiChina Department of Minimal Invasive Surgery Ningbo Medical Center Lihuili HospitalNingboZhejiang 315040China Department of hepatopancreatobiliary surgery Ganzhou hospital affiliated to Nanchang universityJiangxi 341000China Department of Pediatric Surgery Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of MedicineYangpu DistrictShanghai 200092China Information and Big Data Center Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of MedicineYangpu DistrictShanghai 200092China Department of Surgery Second Affiliated HospitalSchool of MedicineZhejiang UniversityHangzhouZhejiang 310009China Department of Gastric Surgery Cancer Hospital of the University of Chinese Academy of SciencesHangzhouZhejiang 310022China

Neuroendocrine carcinoma(NEC)of the gallbladder(GB-NEC)is a rare but extremely malignant subtype of gallbladder cancer(GBC).The genetic and molecular signatures of GB-NEC are poorly understood;thus,molecular targeting is currently unavailable.Inthe present study,we applied whole-exome sequencing(WES)technology to detect gene mutations and predicted somatic singlenucleotide variants(SNVs)in 15 cases of GB-NEC and 22 cases of general GBC.in 15 GB-NECs,the C>T mutation was predominantamong the 6 types of SNVs.TP53 showed the highest mutation frequency(73%,11/15).Compared with neuroendocrine carcinomasof other organs,signifcantly mutated genes(SMGs)in GB-NECs were more similar to those in pulmonary large-cell euroendocrinecarcinomas(LCNECs),with drver roles for TP53 and RB1.Iin the COSMIC database of cancer-related genes,211 genes were mutated.Strikingly,RB1(4/15,27%)and NAB2(3/15,20%)mutations were found specifically in GB-NECs;in contrast,mutations in 29 genes,including ERB82 and ERBB3,were identified exclusively in GBC.Mutations in RB1 and NAB2 were significanty related to downregulation of the RB1 and NAB2 proteins,respectively,according to immunohistochemical(IHC)data(p values=0.0453 and0.0303).Clinically actionable genes indicated 23 mutated genes,including ALK,BRCA1,and BRCA2.Iin addition,potential somaticSNVs predicted by ISowN and SomVarlUS constituted 6 primary coSMIC mutation signatures(1,3,30,6,7,and 13)in GB-NEC.Genes carrying somatic SNVs were enriched mainly in oncogenic signaling pathways involving the Notch,WNT,Hippo,and RTK-RASpathways.In summary,we have systematically identified the mutation landscape of GB-NEC,and these findings may providemechanistic insights into the specifc pathogenesis of this deadly disease.

关键词： gallbladder carcinomas organs

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Clinicopathological,treatment,and prognosis study of 43 gastric neuroendocrine carcinomas

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World Journal of Gastroenterology 2017年第3期23卷 516-524页

作者： De-Jun Liu Xue-Liang Fu Wei Liu Lu-Ying Zheng Jun-Feng Zhang Yan-Miao Huo Jiao Li Rong Hua Qiang Liu Yong-Wei Sun Department Biliary-Pancreatic Surgery Ren Ji HospitalSchool of MedicineShanghai Jiao Tong UniversityShanghai 200127China Department Pathology Ren Ji HospitalSchool of MedicineShanghai Jiao Tong UniversityShanghai 200127China

AIM To provide more information and therapeutic methods about gastric neuroendocrine carcinomas(G-NECs) which occur rarely but are highly malignant and clinically challenging.METHODS We retrospectively analyzed the clinicopathological characteristics, treatments, and prognosis of 43 G-NEC patients at our hospital between January 2007 and December 2014. The diagnosis was based on the 2010 World Health Organization criteria.RESULTS Forty-three G-NECs containing 39 small cell carcinomas and 4 large cell NECs with Ki67 > 60% were included in this study, accounting for only 0.95% of all gastric carcinomas. The median patient age was 62 years (range, 33-82) and the male-to-female ratio was 4.4:1. All patients underwent surgery, including 38 curative resections and 5 palliative resections. Among these 43 patients, nearly half(48.84%) of these tumors were located in the cardiac region of the stomach, regional lymph node metastasis was found in 31 cases(72.09%), and liver metastasis was found in 6 cases(13.95%). Follow-up information was got for 40 patients. Twentythree die of this disease with a median survival of 31 mo(range 1-90). The 1-year, 2-year, 3-year, and 5-year survival rate was 77.50%, 57.04%, 44.51%, and 35.05%, respectively. Survival was better in patients with tumor located in the cardiac region of the stomach, less than 7 lymph nodes metastasis and no liver metastasis. Five patients did not undergo postoperative chemotherapy, and the median survival time for these patients was 15 mo. For the remaining 34 patients who received postoperative chemotherapy, the median survival time was 44 mo and those received etoposide, cisplatin, and Paclitaxel survived the best. One patient with resected liver metastasis who received postoperative Capecitabine plus Oxaliplatin and Paclitaxel systemic chemotherapy plus octreotide LAR(30 mg intramuscularly, every 4 wk, for 2 years) has survived for 74 mo with no recurrence.CONCLUSION G-NECs are mostly nonfunctioning, which lead to a delay in detection. Local and/or distant me

关键词： Gastric neuroendocrine carcinomas Liver metastasis Medical treatment Surgery Prognosis

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Clinical significance of programmed death 1/programmed death ligand 1 pathway in gastric neuroendocrine carcinomas

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World Journal of Gastroenterology 2019年第14期25卷 1684-1696页

作者： Min-Wei Yang Xue-Liang Fu Yong-Sheng Jiang Xiao-Jing Chen Ling-Ye Tao Jian-Yu Yang Yan-Miao Huo Wei Liu Jun-Feng Zhang Pei-Feng Liu Qiang Liu Rong Hua Zhi-Gang Zhang Yong-Wei Sun De-Jun Liu Department of Biliary-Pancreatic Surgery Ren Ji Hospital School of Medicine Shanghai Jiao Tong University Central Laboratory Ren Ji Hospital School of MedicineShanghai Jiao Tong University Department of Pathology Ren Ji Hospital School of Medicine Shanghai Jiao Tong University State Key Laboratory of Oncogenes and Related Genes Shanghai Cancer Institute Shanghai Jiao Tong University

BACKGROUND Recently, more and more studies have demonstrated the pivotal role of programmed death 1/programmed death ligand 1(PD-1/PD-L1) pathway in the immune evasion of tumors from the host immune system. However, the role of PD-1/PD-L1 pathway in gastric neuroendocrine carcinomas(G-NECs) remains unknown.AIM To investigate the expression of PD-1/PD-L1 and role of PD-1/PD-L1 pathway in G-NECs, which occur rarely but are highly malignant and clinically defiant.METHODS We investigated the expression of PD-L1 on tumor cells and PD-1^+, CD8^+, and FOXP3^+ T cell infiltration by immunohistochemistry in 43 resected G-NEC tissue specimens. The copy number alterations of PD-L1 were assessed by qRT-PCR.RESULTS Most of the G-NECs tumor cells exhibited a near-uniform expression pattern of PD-L1, while some showed a tumor-stromal interface enhanced pattern. Of the 43G-NECs, 21(48.8%) were classified as a high PD-L1 expression group, and the high expression of PD-L1 was associated with poor overall survival(OS). The high expression of PD-L1 was correlated with abundant PD-1^+ tumor infiltrating lymphocytes(TILs) instead of CD8^+ TILs and FOXP3^+ regulatory T cells(Tregs).Our analysis also suggested that the infiltration of CD8^+ TILs tended to be a favorable factor for OS, although the difference did not reach the statistical significance(P = 0.065). Meanwhile, PD-L1 was significantly overexpressed in cases with copy number gain as compared with those without.CONCLUSION Our data demonstrated for the first time that high expression of PD-L1 in GNECs is associated with a poor prognosis, while the high expression may be due to the copy number variation of PD-L1 gene or stimulation of TILs. These results provide a basis for the immunotherapy targeting PD-1/PD-L1 pathway in GNECs.

关键词： Programmed death 1 Programmed death ligand 1 Gastric neuroendocrine carcinomas Prognosis Tumor infiltrating lymphocytes

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Analyses of publicly available genomics resources define FGF-2-expressing bladder carcinomas as EMT-prone, proliferative tumors with low mutation rates and high expression of CTLA-4, PD-1 and PD-L1

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Signal Transduction and Targeted Therapy 2017年第1期2卷 258-265页

作者： Elizabeth A McNiel Philip N Tsichlis Molecular Oncology Research Institute Tufts Medical CenterBostonMAUSA Cummings School of Veterinary Medicine Tufts UniversityNorth GraftonMAUSA.

Fibroblast growth factor 2(FGF-2)is overexpressed in a subset of invasive bladder carcinomas and its overexpression correlates with poor prognosis.Analyses of publicly available databases addressing the molecular mechanisms that may be responsible for the poor prognosis of these tumors,revealed that FGF-2 expression correlates positively with the expression of epithelial to mesenchymal transition(EMT)-promoting transcription factors and with changes in gene expression that are characteristic of EMT.The same analyses also revealed that FGF-2 correlates negatively with the expression,mutation and copy number variations of FGFR-3,all of which are associated with noninvasive bladder carcinomas.Finally,they showed that FGF-2 expression correlates with the expression of FGFR-1,the expression of the IIIc variant of FGFR-2 and with the expression of Akt3.The latter observation is significant because our earlier studies had shown that Akt3 regulates FGFR-2 alternative splicing,shifting the balance toward the IIIc relative to the IIIb FGFR-2 splice variant.As the IIIc variant is recognized by FGF-2,while the IIIb variant is not,we conclude that Akt3 may facilitate the FGF-2 response.FGF-2 is known to promote the expression of KDM2B,which functions in concert with EZH2 to repress the EZH2-targeting microRNA miR-101,activating a switch,which stably upregulates EZH2.The cancer genome atlas(TCGA)data showing a correlation between KDM2B and EZH2 expression and Oncomine data,showing a correlation between KDM2B and tumor progression,strongly support the role of the FGF-2/KDM2B/miR-101/EZH2 pathway in bladder cancer.These observations combined,suggest a model according to which FGF-2 induces EMT,cell proliferation and cancer stem cell self-renewal by coupling the Akt3 and KDM2B-controlled pathways outlined above,in bladder carcinomas.Further analyses of publicly available databases,revealed that FGF-2-expressing bladder carcinomas carry fewer genetic alterations and they tend to express high levels of CTLA-4,PD-1 and PD-L1,which s

关键词： bladder carcinomas alterations

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Predictive value of tumor volume reduction rates before and after induction chemotherapy in determining the radiosensitivity and prognosis of locally advanced nasopharyngeal carcinomas

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Oncology and Translational Medicine 2019年第1期5卷 12-18页

作者： Yang Song Ge Wang Chuan Chen Yun Liu Bin Wang Cancer Center Institute of Surgery Research Third Affiliated Hospital Army Medical University (Third Military Medical University)

Objective This study investigated the predictive value of tumor volume reduction rates(TVRRs) before and after induction chemotherapy in determining the radiosensitivity and prognosis of patients with locally advanced nasopharyngeal carcinomas(NPCs). Methods The clinical data of 172 patients with locally advanced primary NPCs who were treated from January 2009 to December 2012 were collected. Tumor regression was evaluated based on the results of the computed tomography scan or magnetic resonance imaging studies. Data about the tumor diameters before and after induction chemotherapy and after radiotherapy as well as the survival times of the patients were obtained. Results All 172 patients had NPCs. After radiotherapy, the TVRR in patients without residual tumor cells was higher than that in patients with residual tumor cells after induction chemotherapy(median values: 47.7% and 15.1%, respectively), and the 5-year survival rates were 80.3% and 45.6%, respectively. Neck lymph node metastasis was observed in 161 of 172 patients, and the TVRRs were similar(median values: 46.8% in 161 patients without residual tumor cells and 11.1% in 161 patients with residual tumor cells). The 5-year survival rate of the 161 patients without residual tumor cells was 84.5%, and that of patients with residual tumor cells was 37.3%. As shown by the receiver operating characteristic(ROC) curve, the area under the curve(AUC) of the ROC curve for TVRRs in patients with primary NPCs but without residual tumors was 0.851, whereas that for TVRRs in patients with neck lymph node metastasis but without residual tumors was 0.784. This result indicates that TVRR has a high diagnostic performance. The univariate Cox regression analysis showed that clinical stage, TVRR in primary NPCs, neck lymph node metastatic lesions before and after induction chemotherapy, presence or absence of residual tumor cells in primary NPCs, and neck lymph node metastatic lesions after radiotherapy were significantly correlated to overall survival(OS). Results of the

关键词： nasopharyngeal carcinomas induction chemotherapy radiosensitivity prognosis

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Bartholin’s Gland carcinomas: A 20 plus-year experience from Queensland

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Open Journal of Obstetrics and Gynecology 2012年第4期2卷 385-388页

作者： Ian S. C. Jones Alex Crandon Karen Sanday Queensland Centre for Gynaecological Cancer University of Queensland Brisbane Australia

Objective: To review the records of cases of Bartholin’s Gland Carcinoma referred to the Queensland Centre for Gynaecological Cancer (QCGC) between mid 1993 and mid 2012. Methods: Bartholin’s Gland Carcinoma case data from QCGC were reviewed and analysed using the computer software Statistical Package for the Social Sciences 11.0. Results: Of the 12 cases four died of their disease, seven are still alive and disease free and one is alive with recurrent disease. The mean age at diagnosis was 52.8 years. Time from onset of symptoms to diagnosis averaged 5.8 months. All diagnoses were confirmed histologically. Presenting symptoms included a lump and pain. The most common presenting complaint was a lump. Treatment included surgical excision, occasional biopsy followed by radiotherapy with or without chemotherapy. In some cases radiation and chemotherapy was followed by vulvectomy of various extent. Conclusions: Bartholin’s Gland Carcinoma is a rare condition with outcome dependent on duration of symptoms, including delay in diagnosis, cell-type, cellular differentiation and the International Federation of Gynecology and Obstetrics (FIGO) classification. A Bartholin’s gland mass in a woman aged 40 years or more should be considered malignant until a biopsy proves otherwise.The incidence of Bartholin’s Gland Carcinoma in Queensland is less than that reported elsewhere but a higher proportion of squamous cell carcinomas was found in this small series.

关键词： Bartholin’s Gland carcinomas Cancer Diagnosis Management Outcome Follow Up

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Spontaneous Mammary carcinomas in Female Dogs:Association between the Immunohistochemical Degree of Aggressiveness of Tumors,Intensity of DNA Damage and Residues of Pyrethroids

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Open Journal of Pathology 2013年第3期3卷 133-137页

作者： Yara de Oliveira Brandao Marcia Moleta Colodel Glenda Nicioli da Silva Stephane Cássia Vexenat Isabelle Ferreira Yame Fabres Robaina Sancler da Silva Camilo Bulla Noeme Sousa Rocha Department of Clinical Veterinary Medicine Laboratory of Investigative and Comparative PathologySchool of Veterinary Medicine and Animal ScienceSao Paulo State UniversityBotucatuBrazil Departament of Pathology School of MedicineSao Paulo State UniversityBotucatuBrazil Laboratory of Biomedical Vibrational Spectroscopy(LEVB) Institute of Research and DevelopmentUniversidade do Vale do ParaíbaUrbanovaBrazil Department of Reproduction Sao Paulo State UniversityBotucatuBrazil Department of Pathobiology and Population Medicine College of Veterinary MedicineMississippi State UniversityStarkvilleUSA

Diagnosis and biological behavior of breast cancer of female dog represent one of the biggest challenges facing the Veterinarian in recent years. Due to its exponential growth and the degree of aggressiveness, the exact cause of this tumor is probably multifactorial and it is believed that may suffer influence from environmental factors. Among the suspected environmental contaminants are the pyrethroids. Aiming to investigate the participation of pyrethroids in tumorigenesis in female dogs, a study was conducted using 50 female dogs, 22 were positive for simple breast carcinoma (Group I), 18 with a diagnosis of complex breast carcinoma (Group II) and 10 negative (Group III) for breast cancer. In order to detect DNA damage, the Comet assay was performed on mammary samples of these animals, which also had samples submitted to the technique of High Performance Liquid Chromatography (HPLC), which aimed to quantify the concentration of pyrethroids. The results of HPLC of each animal were compared with those obtained by the Comet assay analysis of variance and the means were compared by the test groups “Student T” at the significance level of p ￡ 0.05. Despite presenting correlation between the amount of DNA damage and tumor aggressiveness, no statistical differences were found in the DNA damage of different histologic types of breast carcinoma. As for pyrethroids, even these were detected in 22% of tumor tissues and peritumoral fat, there was no difference in DNA damage between cells exposed and not exposed to environmental contaminant.

关键词： Mammary carcinomas DNA Damage Pyrethroids

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^(12)C^(6+)重离子束治疗皮肤鳞状细胞癌临床疗效分析

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临床军医杂志 2010年第5期38卷 762-764页

作者：魏世华刘倩张红李莎岳养军田种泽赵瑞陈小华朱向辉解放军兰州军区总医院放射治疗科甘肃兰州730050 中国药物生物制品检定所北京100053 中国近代物理研究所甘肃兰州730000

目的通过应用重离子加速器产生的12C6+束治疗皮肤鳞状细胞癌,评价高线性能量传递在临床治疗的应用。方法 15例经病理证实的皮肤鳞状细胞癌患者,应用80~100 meV/U12C6+重离子束分别给予总剂量43.5~120.6 Gy/5~13次照射,相对生物效应(RBE... 详细信息

目的通过应用重离子加速器产生的12C6+束治疗皮肤鳞状细胞癌,评价高线性能量传递在临床治疗的应用。方法 15例经病理证实的皮肤鳞状细胞癌患者,应用80~100 meV/U12C6+重离子束分别给予总剂量43.5~120.6 Gy/5~13次照射,相对生物效应(RBE)等于3。结果 12例患者3月后病变完全消失,达临床治愈(CR);2例缩小75%,达临床部分缓解(PR);总有效率达100%(1例中途终止照射)。治疗中及治疗后照射野皮肤无破溃等放射性损伤。结论 12C6+重离子束具有治疗精度高,疗程短,对肿瘤周围正常组织损伤小等特点。

关键词：重离子束治疗精度皮肤鳞状细胞癌临床疗效分析 squamous cell carcinomas 重离子加速器正常组织损伤照射野相对生物效应线性能量传递放射性损伤总有效率临床治愈临床治疗癌患者病理证实总剂量临床部肿瘤特点

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Expression and clinical significance of vascular endothelial growth factor-C and nm23-H1 in stage Ⅱ and Ⅲ colorectal carcinomas

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China Medical Abstracts(Internal Medicine) 2013年第3期30卷 168-169页

作者：耿倩倩 Dept Med Oncol 1st Affil HospMed CollXi'an Jiaotong Univ

Objective To discuss the expression and clinical significance of VEGF-C and nm23-H1 in stageⅡandⅢcolorectal carcinomas.Methods SP immunohistochemical staining was employed to determine the expression of vascular end... 详细信息

关键词： colorectal and carcinomas staining median prognosis metastasis mucosal gender judgment

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The correlation between BRAF mutations, RET/PTC rearrangements and platelet-derived growth factor B expression in papillary thyroid carcinomas

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China Medical Abstracts(Internal Medicine) 2013年第1期30卷 25-26页

作者：王萍 Dept Endocrinol Affil HospMed CollQingdao Univ

Objective To investigate the prevalence of BRAF T1799A mutation and RET/PTC rearrangement in Qingdao and detect the expression of platelet-derived growth factor B(PDGF-B) in order to investigate the

关键词： thyroid papillary carcinomas mutation Qingdao neoplasm rearrangement prevalence incidence pression

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