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Ultra-sensitive Nanoprobe Modified with Tumor Cell Membrane for UCL/MRI/PET Multimodality Precise Imaging of triple-negative Breast Cancer

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Nano-Micro Letters 2020年第5期12卷 64-77页

作者： Hanyi Fang Mengting Li Qingyao Liu Yongkang Gai Lujie Yuan Sheng Wang Xiao Zhang Min Ye Yongxue Zhang Mingyuan Gao Yi Hou Xiaoli Lan Department of Nuclear Medicine Union HospitalTongji Medical CollegeHuazhong University of Science and TechnologyWuhan 430022People’s Republic of China Hubei Province Key Laboratory of Molecular Imaging Wuhan 430022People’s Republic of China School of Pharmacy Tongji Medical CollegeHuazhong University of Science and TechnologyWuhan 430030People’s Republic of China Center for Molecular Imaging and Nuclear Medicine State Key Laboratory of Radiation Medicine and ProtectionSchool for Radiological and Interdisciplinary Sciences(RAD-X)Soochow UniversitySuzhou 215123JiangsuPeople’s Republic of China Key Laboratory of Colloid Interface and Chemical ThermodynamicsInstitute of ChemistryChinese Academy of SciencesBeijing 100190People’s Republic of China

triple-negative breast cancer(TNBC)is a subtype of breast cancer in which the estrogen receptor and progesterone receptor are not expressed,and human epidermal growth factor receptor 2 is not amplified or overexpressed either,which make the clinical diagnosis and treatment very challenging.Molecular imaging can provide an effective way to diagnose TNBC.Upconversion nanoparticles(UCNPs),are a promising new generation of molecular imaging probes.However,UCNPs still need to be improved for tumor-targeting ability and biocompatibility.This study describes a novel probe based on cancer cell membrane-coated upconversion nanoparticles(CCm-UCNPs),owing to the low immunogenicity and homologous-targeting ability of cancer cell membranes,and modified multifunctional UCNPs.This probe exhibits excellent performance in breast cancer molecular classification and TNBC diagnosis through UCL/MRI/PET tri-modality imaging in vivo.By using this probe,MDA-MB-231 was successfully differentiated between MCF-7 tumor models in vivo.Based on the tumor imaging and molecular classification results,the probe is also expected to be modified for drug delivery in the future,contributing to the treatment of TNBC.The combination of nanoparticles with biomimetic cell membranes has the potential for multiple clinical applications.

关键词： triple-negative breast cancer Molecular classification Multimodality imaging Cancer cell membranes Upconversion

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Capecitabine maintenance therapy for XT chemotherapy-sensitive patients with metastatic triple-negative breast cancer

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Chinese Journal of Cancer Research 2014年第5期26卷 550-557页

作者： Xu Liang Lijun Di Guohong Song Ying Yan Chaoying Wang Hanfang Jiang Huiping Li Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education) Department of Breast OncologyPeking University Cancer Hospital & Institute

Objective： To investigate the efficacy and safety of capecitabine maintenance therapy（MT） after initial capecitabine plus docetaxel（XT） chemotherapy in patients with metastatic triple-negative breast cancer（m TNBC）.Methods： Fifty-five m TNBC patients treated with XT chemotherapy between May 2007 and June 2013 were retrospectively analyzed. When initial disease control was achieved by the combination chemotherapy, capecitabine was continued for 32 patients（MT）, while 23 patients remained without any treatment（nonMT）. We compared progression-free survival（PFS） and safety of both groups.Results： The median PFS of 55 patients was 8.1 months, overall median PFS time of 32 patients in the capecitabine MT group and 23 in the non-MT group was 10.1 vs. 6.7 months（P=0.032）, respectively. When compared PFS time of maintenance treatment, single-agent capecitabine prolonged PFS by 7.1 months, for non-MT patients, the PFS without any treatment was 3.1 months, and this between-group difference was statistically significant（P=0.003）. Adverse events, including of hematologic toxicity, gastrointestinal toxicities, hand-foot syndrome and abnormal liver function were not significantly different between two groups.Conclusions： After initial disease control was achieved with the XT combination chemotherapy, capecitabine MT can significantly prolong PFS time with a favorable safety profile in m TNBC patients.

关键词： Capecitabine maintenance therapy（MT） triple-negative metastatic breast cancer（MBC）

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Prognostic value of tumor-infiltrating lymphocyte subtypes in residual tumors of patients with triple-negative breast cancer after neoadjuvant chemotherapy

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Chinese Medical Journal 2020年第5期133卷 552-560页

作者： Yu-Ge Bai Guo-Xuan Gao Hong Zhang Shuang Zhang Yin-Hua Liu Xue-Ning Duan Ling Xu Breast Disease Center Peking University First HospitalBeijing 100034China Department of General Surgery Beijing Friendship HospitalCapital Medical UniversityBeijing 100050China Pathology Department Peking University First HospitalBeijing 100034China

Background:After neoadjuvant chemotherapy(NAC),non-pathological complete response of breast cancer patients can benefit from tailored adjuvant chemotherapy.However,it is difficult to select patients with poorer prognosis for additional adjuvant chemotherapy to maximize the benefits.Our study aimed to explore whether the subtypes of tumor-infiltrating lymphocytes(TILs)in residual tumors(RT)is related to the prognosis of triple-negative breast cancer(TNBC)after NAC.Methods:Data from patients with primary TNBC consecutively diagnosed at the Breast Disease Center of Peking University First Hospital from 2008 to 2014 were retrieved,and the cases with RT in the breast after NAC were enrolled.TILs subtypes in RT were observed by double-staining immunohistochemistry,and counted with the median TILs value per square millimeter as the cut-off to define high versus low TILs density in each subtype.The relationships between the TIL density of each subgroup and the clinicopathological characteristics of the RT after NAC patients were analyzed by Fisher exact test.Disease-free survival(DFS)and overall survival(OS)were analyzed by the Kaplan-Meier method and log-rank statistics.Results:A total of 37 eligible patients were included in this study,and the median follow-up period was 50 months(range 17–106 months).There was no significant correlation between the infiltrate density of CD4^+,CD8^+,CD20^+,and CD68^+lymphocytes and clinic-pathological characteristics.Significantly better prognosis was observed in patients with high CD4^+-TILs(DFS:P=0.005,OS:P=0.021)and high CD8^+-TILs(DFS:P=0.018)and low CD20^+-TILs(OS:P=0.042).Further analysis showed that patients with CD4^+/CD20^+ratio greater than 1(DFS:P=0.001,OS:P=0.002)or CD8^+/CD20^+ratio greater than 1(DFS:P=0.009,OS:P=0.022)had a better prognosis.Conclusions:Subtypes of TILs in RT is a potential predictive biomarker of survival in TNBC patients after NAC.

关键词： triple-negative breast cancer Neoadjuvant chemotherapy Residual tumors Tumor-infiltrating lymphocyte subtypes

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Cancer stem-like cells directly participate in vasculogenic mimicry channels in triple-negative breast cancer

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Cancer Biology & Medicine 2019年第2期16卷 299-311页

作者： Huizhi Sun Nan Yao Siqi Cheng Linqi Li Shiqi Liu Zhao Yang Guanjie Shang Danfang Zhang Zhi Yao Department of Pathology Tianjin Medical University Tianjin 300070 China Department of Pathology General Hospital of Tianjin Medical University Tianjin 300070 China Department of Immunology Tianjin Medical University Tianjin 300070 China

Objective: Vasculogenic mimicry(VM) channels that are lined by tumor cells are a functional blood supply in malignant tumors.However, the role of VM-initiating cells remains poorly understood. Cancer stem-like cells(CSCs) are positively correlated with VM. In this study, triple-negative breast cancer(TNBC) enriched with CSCs was used to investigate the relationship between VM and CSCs.Methods: The expression of several CSC markers was detected by immunohistochemistry in 100 human breast cancer samples.The clinical significance of CSC markers and the relationship between VM, CSCs, breast cancer subtypes, and VM-associated proteins were analyzed. CD133+ and ALDH+ human and mouse TNBC cells were isolated by FACS to examine the ability of VM formation and the spatial relationship between VM and CSCs.Results: CSCs were associated with TNBC subtype and VM in human invasive breast cancer. CSCs in TNBC MDA-MB-231 cells formed more VM channels and expressed more molecules promoting VM than the non-TNBC MCF-7 cells in vitro. MDA-MB-231 cells that encircled VM channels on Matrigel expressed CD133. Moreover, CSCs were located near VM channels in the 3D reconstructed blood supply system in human TNBC grafts. The CD133+ and ALDH+ cells isolated from TA2 mouse breast cancer formed more VM channels in vivo.Conclusions: CSCs line VM channels directly. Additionally, CSCs provide more VM-related molecules to synergize VM formation. The signaling pathways that control CSC differentiation may also be potential treatment targets for TNBC.

关键词： Vasculogenic mimicry triple-negative breast cancer cancer stem-like cells ALDH1 CD 133

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Adjuvant treatment for triple-negative breast cancer: a retrospective study of immunotherapy with autologous cytokine-induced killer cells in 294 patients

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Cancer Biology & Medicine 2019年第2期16卷 350-360页

作者： Yuhan Zhang Shuaibing Wang Beibei Yang Su Lu Yiyi Du Hong Liu The Second Department of Breast Cancer Tianjin Medical University Cancer Institute and Hospital/ National Clinical Research Center for Cancer/ Key Laboratory of Cancer Prevention and Therapy Tianjin/ Tianjin's Clinical Research Center for Cancer/ Key Laboratory of Breast Cancer Prevention and Therapy Tianjin Medical University Ministry of Education Tianjin 300060 China Oncology Department China National Petroleum Corporation Central Hospital Langfang 065000 China

Objective: To examine the efficacy and safety of a sequential combination of chemotherapy and autologous cytokine-induced killer(CIK) cell treatment in triple-negative breast cancer(TNBC) patients.Methods: A total of 294 post-surgery TNBC patients participated in the research from January 1, 2009 to January 1, 2015. After adjuvant chemotherapy, autologous CIK cells were introduced in 147 cases(CIK group), while adjuvant chemotherapy alone was used to treat the remaining 147 cases(control group). The major endpoints of the investigation were the disease-free survival(DFS) and overall survival(OS). Additionally, the side effects of the treatment were evaluated.Results: In the CIK group, the DFS and OS intervals of the patients were significantly longer than those of the control group(DFS:P = 0.047;OS: P = 0.007). The multivariate analysis demonstrated that the TNM(tumor-node-metastasis) stage and adjuvant CIK treatment were independent prognostic factors for both DFS [hazard ratio(HR)= 0.520, 95% confidence interval(CI):0.271-0.998, P = 0.049;HR = 1.449, 95% CI:1.118-1.877, P = 0.005, respectively] and OS(HR=0.414, 95% CI:0.190-0.903, P = 0.027;HR= 1.581, 95% CI:1.204-2.077, P = 0.001, respectively) in patients with TNBC. Additionally, longer DFS and OS intervals were associated with increased number of CIK treatment cycles(DFS: P = 0.020;OS: P = 0.040). The majority of the patients who benefitted from CIK cell therapy were relatively early-stage TNBC patients.Conclusion: Chemotherapy in combination with adjuvant CIK could be used to lower the relapse and metastasis rate, thus effectively extending the survival time of TNBC patients, especially those at early stages.

关键词： Immunotherapy triple-negative breast cancer cytokine-induced killer cell prognosis disease-free survival overall survival

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Tumor infiltrating lymphocytes in triple negative breast cancer receiving neoadjuvant chemotherapy

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World Journal of Clinical Oncology 2016年第5期7卷 387-394页

作者： Carlos A Castaneda Elizabeth Mittendorf Sandro Casavilca Yun Wu Miluska Castillo Patricia Arboleda Teresa Nunez Henry Guerra Carlos Barrionuevo Ketty Dolores-Cerna Carolina Belmar-Lopez Julio Abugattas Gabriela Calderon Miguel De La Cruz Manuel Cotrina Jorge Dunstan Henry L Gomez Tatiana Vidaurre Department of Research Instituto Nacional de Enfermedades Neoplasicas Department of Medical Oncology Instituto Nacional de Enfermedades Neoplasicas Department of Surgical Oncology the University of Texas MD Anderson Cancer Center Department of Pathology Instituto Nacional de Enfermedades Neoplasicas Department of Pathology Division of Pathology the University of Texas MD Anderson Cancer Center Department of Breast Cancer Surgery Instituto Nacional de Enfermedades Neoplasicas

AIM To determine influence of neoadjuvant-chemotherapy(NAC) over tumor-infiltrating-lymphocytes(TIL) intriple-negative-breast-cancer(TNBC).METHODS TILs were evaluated in 98 TNBC cases who came to Instituto Nacional de Enfermedades Neoplasicas from 2005 to 2010. Immunohistochemistry staining for CD3, CD4, CD8 and FOXP3 was performed in tissue microarrays(TMA) sections. Evaluation of H/E in full-face and immunohistochemistry in TMA sections was performed in pre and post-NAC samples. STATA software was used and P value < 0.05 was considered statistically significant. RESULTS Higher TIL evaluated in full-face sections from pre-NAC tumors was associated to pathologic-complete-response(pCR)(P = 0.0251) and outcome(P = 0.0334). TIL evaluated in TMA sections showed low level of agreement with full-face sections(ICC = 0.017-0.20) and was not associated to pCR or outcome. TIL in post-NAC samples were not associated to response or outcome. PostNAC lesions with pC R had similar TIL levels than those without pCR(P = 0.6331). NAC produced a TIL decrease in full-face sections(P < 0.0001). Percentage of TIL subpopulations was correlated with their absolute counts. Higher counts of CD3, CD4, CD8 and FOXP3 in pre-NAC samples had longer disease-free-survival(DFS). Higher counts of CD3 in pre-NAC samples had longer overallsurvival. Higher ratio of CD8/CD4 counts in pre-NAC was associated with pCR. Higher ratio of CD4/FOXP3 counts in pre-NAC was associated with longer DFS. Higher counts of CD4 in post-NAC samples were associated with pCR.CONCLUSION TIL in pre-NAC full-face sections in TNBC are correlated to longer survival. TIL in full-face differ from TMA sections, absolute count and percentage analysis of TIL subpopulation closely related.

关键词： triple-negative breast cancer Survival Tumor-infiltrating lymphocytes Neoadjuvant therapy

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Research progress of triple-negative breast cancer immunotherapy

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Tumor Microenvironment Research 2020年第2期2卷 60-65页

作者： Jin-Feng Liu Tianjin Medical University Cancer Institute and Hospital National Clinical Research Center for CancerKey Laboratory of Cancer Prevention and TherapyTianjin 300060China

Breast cancer is the most common type of female malignancy in the world.triple-negative breast cancer refers to breast cancer in which the expressions of estrogen receptor,progesterone receptor and human epidermal growth factor receptor 2 are all negative.It has the clinical characteristics of easy invasion,high recurrence rate and short survival time.At present,there is a lack of effective treatment in the clinic.Following surgical treatment,chemotherapy,endocrine therapy,and molecular targeted therapy,a new type of treatment,immunotherapy,is of great significance for the treatment of triple-negative breast cancer.

关键词： triple-negative breast cancer Immunotherapy Active immunotherapy Passive immunotherapy Tumor vaccine

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Meclizine Chloridrate and Methyl-β-Cyclodextrin Associated with Monophosphoester Synthetic Phosphoethanolamine Modulating Proliferative Potential in triple-negative Breast Cancer Cells

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Journal of Pharmacy and Pharmacology 2019年第7期7卷 408-420页

作者： Manuela Garcia Laveli da Silva Luciana Bastianelli Knop Durvanei Augusto Maria Molecular Biology Laboratory Butantan InstituteSao PauloSPBrazil

Synthetic phosphoethanolamine(Pho-s)is a monophosphoester ester with anti-inflammatory and pro-apoptotic properties.Meclizine chloridrate(MC)is a histamine H1 receptor blocker that is also able to inhibit cellular respiration.However,MC does not inhibit cellular respiration in isolated mitochondria such as antimycin and rotenone.Methyl-β-cyclodextrin(MβCD)belongs to theβ-cyclodextrin family,which is capable of removing cholesterol from the plasma membrane.The aim of this study was to evaluate the proliferative effects of meclizine chloridrate and methyl-β-cyclodextrin compounds associated with synthetic phosphoethanolamine in a triple-negative human breast tumor line,MDA-MB-231 Cell viability of the tumor line and normal cells FN1 was evaluated by MTT colorimetric test;the production of free radicals was determined by lipoperoxidation(LPO)test;and the percentage of cell cycle phases and proliferative index was evaluated by flow cytometry.Cell viability demonstrated a significant decrease with the treatments of MβCD,MC and Pho-s associated with MC.The production of free radicals decreases significantly in all treatments.In addition,a significant increase of DNA fragment and decrease in G0/G1 cell cycle phase were observed in cellular percentage with concentrations of 20 and 30 mM of Pho-s in association with MC and MβCD,respectively.

关键词： Human triple-negative breast cancer MDA-MB-231 synthetic phosphoethanolamine meclizine chloridrate methyl-β-cyclodextrin cell cycle

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Clinicopathological Characteristics of Basal Type Breast Cancer in triple-negative Breast Cancer

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Journal of Cancer Therapy 2012年第5期3卷 836-840页

作者： Goro Kutomi Tousei Ohmura Yasuyo Suzuki Hidekazu Kameshima Hiroaki Shima Tomoko Takamaru Fukino Satomi Seiko Otokozawa Mitsuru Mori Koichi Hirata Department of Public Health Sapporo Medical University School of Medicine Sapporo Japan First Department of Surgery Sapporo Medical University School of Medicine Sapporo Japan

Background: triple-negative breast cancer (TNBC) is defined by the absence of estrogen receptor (ER), progesterone receptor (PgR) and human epidermal growth factor 2 (HER2) expression. Patients with TNBC derive no benefit from molecularly targeted treatments, such as endocrine therapy or trastuzumab, as they lack the appropriate targets for these drugs. TNBC is characterized by its biological aggressiveness and poor prognosis, and consists of two subtypes, basal and nonbasal. The purpose of our study is to differentiate the clinicopathological characteristics of the two subtypes. Methods: 367 patients with primary breast cancer were recruited from April 2004 to December 2010 at 1st Department of Surgery, Sapporo Medical University. ER, PgR, and HER2 status were evaluated in all cases. Moreover, we classified TNBC into basal, nonbasal subtypes on the basis of immunohistochemical staining of epidermal growth factor receptor (EGFR), cytokeratin (CK) 5/6. Basal type was defined as CK5/6-positive and/or EGFR-positive, and nonbasal type was defined as no expression of these two markers. Results: Breast cancer subtypes by molecular classification were Hormone receptor (HR)-positive/HER2-negative (61%), HR-positive/HER2-positive (10%), HR-negative/HER2-positive (14%), and HR-negative/HER2-negative (15%). There was no difference between the basal type and the nonbasal type in clinicopathological factors. But, the basal type was significantly associated with Ki67 labeling index (p=0.0002), p53 expression (p=0.047), and BRCA1 expression (p=0.03). Further, patients with the basal type TNBC showed a shorter overall survival (p=0.032) than did patients with the nonbasal type. Conclusion: Classification of TNBC subtypes by EGFR, CK5/6 is a very useful prognostic factor, and highlights the need for the development of an adequate new strategy for the basal type TNBC.

关键词： triple-negative Breast Cancer Basal Type EGFR CK5/6

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Individual with concurrent chest wall tuberculosis and triplenegative essential thrombocythemia:A case report

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World Journal of Clinical Cases 2023年第22期11卷 5365-5372页

作者： Xiao-Yan Xu Yong-Bin Yang Jun Yuan Xiao-Xia Zhang Lin Kang Xiang-Shu Ma Jie Yang Department of Haematology Hebei General HospitalShijiazhuang 050051Hebei ProvinceChina Graduate School Hebei North UniversityZhangjiakou 075000Hebei ProvinceChina Department of Vascular Surgery Hebei General HospitalShijiazhuang 050051Hebei ProvinceChina Department of Pathology Hebei General HospitalShijiazhuang 050051Hebei ProvinceChina Clinical Laboratory Hebei General HospitalShijiazhuang 050051Hebei ProvinceChina

BACKGROUND Chest wall tuberculosis(TB)and triple-negative essential thrombocythemia(TNET)are rare medical conditions,and their combination is extremely rare globally.Only one case of TB peritonitis with thrombocytosis has been reported,which was identified in 1974.CASE SUMMARY Herein,we report the case of a 23-year-old man with concurrent chest wall mass and TN-ET.The patient presented to a local hospital due to having a headache and low-grade fever for 2 d,with their bodily temperature fluctuating at around 36.8°C.Hematological analysis showed a high platelet count of 1503×109/L.Subsequently,the patient visited our hospital for further investigation.Computed tomography of the chest suggested a submural soft tissue density shadow in the left lower chest wall.After surgical resection,the pathological findings of the swelling were reported as TB with massive caseous necrosis.According to the World Health Organization diagnostic criteria,the patient was diagnosed with TN-ET,as they met the requirement of four main criteria or the first three main criteria and one secondary criterion.The patient was eventually diagnosed with chest wall TB with TN-ET,which is extremely rare.CONCLUSION Chest wall TB is rare.TN-ET diagnosis requires secondary factor exclusion and satisfaction of primary diagnostic criteria.miRNA,combined with the methylation process,could explain suppressor of cytokine signaling(SOCS)1 and SOCS3 downregulation in ET-JAK2V617F-negative patients.The miRNA could participate in JAK2 pathway activation.SOCS3 may be a novel MPN biomarker.

关键词： Platelet Thrombocythemia triple-negative Chest wall tuberculosis SOCS3 gene JAK-STAT pathway Case report

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