AIM: To compare 2-deoxy-2-(<sup>18</sup>F)fluoro-D-glucose(<sup>18</sup>F-FDG) and <sup>18</sup>F-sodium (<sup>18</sup>F-NaF) positron emission tomography/computed tomog...AIM: To compare 2-deoxy-2-(<sup>18</sup>F)fluoro-D-glucose(<sup>18</sup>F-FDG) and <sup>18</sup>F-sodium (<sup>18</sup>F-NaF) positron emission tomography/computed tomography (PET/CT) accuracy in breast cancer patients with clinically/radiologically suspected or known bone metastases.METHODS: A total of 45 consecutive patients with breast cancer and the presence or clinical/biochemical or radiological suspicion of bone metastatic disease underwent <sup>18</sup>F-FDG and <sup>18</sup>F-fluoride PET/CT. Imaging results were compared with histopathology when available, or clinical and radiological follow-up of at least 1 year. For each technique we calculated: Sensitivity (Se), specificity (Sp), overall accuracy, positive and negative predictive values, error rate, and Youden’s index. McNemar’s χ<sup>2</sup> test was used to test the difference in sensitivity and specificity between the two diagnostic methods. All analyses were computed on a patient basis, and then on a lesion basis, with consideration ofthe density of independent lesions on the co-registered CT (sclerotic, lytic, mixed, no-lesions) and the divergent site of disease (skull, spine, ribs, extremities, pelvis). The impact of adding <sup>18</sup>F-NaF PET/CT to the work-up of patients was also measured in terms of change in their management due to <sup>18</sup>F-NaF PET/CT findings.RESULTS: The two imaging methods of <sup>18</sup>F-FDG and <sup>18</sup>F-fluoride PET/CT were significantly different at the patient-based analysis: Accuracy was 86.7% and 84.4%, respectively (McNemar’s χ<sup>2</sup> = 6.23, df = 1, P = 0.01). Overall, 244 bone lesions were detected in our analysis. The overall accuracy of the two methods was significantly different at lesion-based analysis (McNemar’s χ<sup>2</sup> = 93.4, df = 1, P < 0.0001). In the lesion density-based and site-based analysis, <sup>18</sup>F-FDG PET/CT provided more accurate results in the detection of CT-negative metastasis (P < 0.002) and vertebral localizations (P < 0.002); <sup>18</sup>F-NaF PET/CT was more accurate in detecting sclerotic (P < 0.005) and rib lesions (P < 0.04). <sup>18</sup>F-NaF PET/CT led to a change of management in 3 of the 45 patients (6.6%) by revealing findings that were not detected at <sup>18</sup>F-FDG PET/CT.CONCLUSION: <sup>18</sup>F-FDG PET/CT is a reliable imaging tool in the detection of bone metastasis in most cases, with a diagnostic accuracy that is slightly, but significantly, superior to that of <sup>18</sup>F-NaF PET/CT in the general population of breast cancer patients. However, the extremely high sensitivity of <sup>18</sup>F-fluoride PET/CT can exploit its diagnostic potential in specific clinical settings (i.e., small CT-evident sclerotic lesions, high clinical suspicious of relapse, and negative <sup>18</sup>F-FDG PET and conventional imaging).展开更多
We studied tumour lymphangiogenesis and lymphatic invasion using D2-40 endothelial marker in 35 breast cancer patients treated by primary surgery and correlated it with various clinico-pathological prognostic paramete...We studied tumour lymphangiogenesis and lymphatic invasion using D2-40 endothelial marker in 35 breast cancer patients treated by primary surgery and correlated it with various clinico-pathological prognostic parameters. Lymphangiogenesis was quantified using lymphatic micro vessel density (LMVD) by counting the immunostained lymphatic microvessels at 200X. The mean age was 45.97±12.09 years (range 30-80 years). LMVD ranged from 5/hpf to 56/hpf with a mean score of 13.4±10.8 and median of 9. The median value of 9 was taken to classify patients into a low or high LMVD. LMVD correlated significantly with tumour size (p=0.003), histological grade (p=0.046), lymph node status (p=0.030). There was no significant correlation of LMVD with stage, estrogen receptor, progesterone receptor or HER2/neu immunoreactivity. Lymphovascular invasion on D2-40 staining [LVI-D40] was found in 13 (37.1%) cases compared to 6 cases (17.1%) on H & E staining showing a poor agreement (k=0.244). LVI correlated significantly with lymph node status (p=0.011). There was a strong association between tumour size (p=0.142), histological grade (p=0.066) though the correlation was not statistically significant. No correlation was found with stage, estrogen receptor, progesterone receptor or HER2/neu immunoreactivity. The mean LMVD in LVI positive patients was higher (22.85±13.29) as compared to LVI negative patients (7.95±2.05) and this was statistically significant (p=0.001). Increased D2-40 detected LMVD and LVI correlated with poor prognostic parameters.展开更多
目的对比分析三阴性乳腺癌(triple-negative breast cancer,TNBC)与人HER-2过表达乳腺癌的临床病理特征。方法回顾性分析2012年3月一2018年10月苏州大学附属第一医院收治的163例女性乳腺浸润性导管癌患者(其中TNBC84例,HER2过表达乳腺...目的对比分析三阴性乳腺癌(triple-negative breast cancer,TNBC)与人HER-2过表达乳腺癌的临床病理特征。方法回顾性分析2012年3月一2018年10月苏州大学附属第一医院收治的163例女性乳腺浸润性导管癌患者(其中TNBC84例,HER2过表达乳腺癌79例),分析两组患者的临床资料,并对其临床病理特征进行对比研究。结果TNBC组中肿瘤直径cm者占91.67%,组织学分级Ⅲ级者占72.62%,远处转移占14.29%;HER-2过表达乳腺癌组的肿瘤直径≥2cm者占79.75%,组织学分级Ⅲ级者占50.63%,远处转移占5.06%,两组差异均有统计学意义(P<0.05)。结论TNBC较HER.2过表达乳腺癌的肿瘤体积更大,组织学分级更高,更容易复发及远处转移,而两组患者的发病年龄、腋窝淋巴结转移及临床分期方面无明显差异。展开更多
Although progress in clinical and basic research has significantly increased our understanding of breast cancer, little is known about the molecular mechanism underlying breast cancer metastasis. Identification of eff...Although progress in clinical and basic research has significantly increased our understanding of breast cancer, little is known about the molecular mechanism underlying breast cancer metastasis. Identification of effective therapeutic targets to prevent breast cancer metastasis is urgently needed. The function of mi R-503-3p has been investigated in other cancers, but its role in breast cancer remains undefined.Here, we found that mi R-503-3p was overexpressed in breast cancer tissue and plasma compared with adjacent normal breast tissue and with plasma from healthy individuals. Moreover, we identified mi R-503-3p to be an oncogene of breast cancer cell proliferation, migration and invasion. Upregulation of mi R-503-3p in breast cancer cells inhibited expression of epithelialemesenchymal transition（EMT）-related protein SMAD2 and the epithelial marker protein E-cadherin by directly binding to their m RNA30 untranslated region, whereas increased expression of mesenchymal marker proteins, including vimentin and N-cadherin. Taken together, our findings support a critical role for mi R-503-3p in induction of breast cancer EMT and suggest that plasma mi R-503-3p may be a useful diagnostic biomarker for breast cancer.展开更多
Metastatic breast cancer is incurable and often due to breast cancer stem cell(CSC)-mediated self-renewal.We previously determined that the aryl hydrocarbon receptor(AhR)agonist aminoflavone(AF)inhibits the expression...Metastatic breast cancer is incurable and often due to breast cancer stem cell(CSC)-mediated self-renewal.We previously determined that the aryl hydrocarbon receptor(AhR)agonist aminoflavone(AF)inhibits the expression of the CSC biomarkerα6-integrin(ITGA6)to disrupt the formation of luminal(hormone receptor-positive)mammospheres(3D breast cancer spheroids).In this study,we performed miRNA-sequencing analysis of luminal A MCF-7 mammospheres treated with AF to gain further insight into the mechanism of AF-mediated anti-cancer and anti-breast CSC activity.AF significantly induced the expression of>70 microRNAs(miRNAs)including miR125b-2–3p,a predicted stemness gene regulator.AF-mediated miR125b-2–3p induction was validated in MCF-7 mammospheres and cells.miR125b-2–3p levels were low in breast cancer tissues irrespective of subtype compared to normal breast tissues.While miR125b-2–3p levels were low in MCF-7 cells,they were much lower in AHR100 cells(MCF-7 cells made unresponsive to AhR agonists).The miR125b-2–3p mimic decreased,while the antagomiR125b-2–3p increased the expression of stemness genes ITGA6 and SOX2 in MCF-7 cells.In MCF-7 mammospheres,the miR125b-2–3p mimic decreased only ITGA6 expression although the antagomiR125b-2–3p increased ITGA6,SOX2 and MYC expression.AntagomiR125b-2–3p reversed AF-mediated suppression of ITGA6.The miR125b-2–3p mimic decreased proliferation,migration,and mammosphere formation while the antagomiR125b-2–3p increased proliferation and mammosphere formation in MCF-7 cells.The miR125b-2–3p mimic also inhibited proliferation,mammosphere formation,and migration in AHR100 cells.AF induced AhR-and miR125b2-3p-dependent anti-proliferation,anti-migration,and mammosphere disruption in MCF-7 cells.Our findings suggest that miR125b-2–3p is a tumor suppressor and AF upregulates miR125b-2–3p to disrupt mammospheres via mechanisms that rely at least partially on AhR in luminal A breast cancer cells.展开更多
New targeted therapies have been developed to overcome resistance to endocrine therapy(ET)and improve the outcome of HR^(+)/HER2^(-)advanced breast cancer(ABC).We conducted a meta-analysis and systemic review on rando...New targeted therapies have been developed to overcome resistance to endocrine therapy(ET)and improve the outcome of HR^(+)/HER2^(-)advanced breast cancer(ABC).We conducted a meta-analysis and systemic review on randomized controlled trials evaluating various targeted therapies in combination with ET in HR^(+)/HER2^(-)ABC.PUBMED and EMBASE databases were searched for eligible trials.Hazard ratios(HRs)for progression-free survival(PFS),odds ratios(ORs)for objective response rate(ORR),clinical benefit rate(CBR),and toxicity were meta-analyzed.Twenty-six studies with data on 10347 patients were included and pooled.The addition of cyclin-dependent kinase 4/6 inhibitors to ET significantly improved median PFS(pooled HR=0.547,P<0.001),overall survival(pooled HR=0.755,P<0.001),and tumor response rates(ORR,pooled OR=1.478,P<0.001;CBR,pooled OR=1.201,P<0.001)with manageable toxicities(pooled OR=3.280,P<0.001).The mammalian targets of rapamycin inhibitors and exemestane were not clinically beneficial for this pooled population including ET-naïve and ET-resistant patients.Moderate improvement in PFS(pooled HR=0.686,P<0.001)yet pronounced toxicities(pooled OR=2.154,P<0.001)were noted in the combination of phosphatidylinositol-4,5-bisphosphate 3-kinase inhibitors with fulvestrant.Future studies are warranted to optimize the population and the dosing sequence of these available options.展开更多
文摘AIM: To compare 2-deoxy-2-(<sup>18</sup>F)fluoro-D-glucose(<sup>18</sup>F-FDG) and <sup>18</sup>F-sodium (<sup>18</sup>F-NaF) positron emission tomography/computed tomography (PET/CT) accuracy in breast cancer patients with clinically/radiologically suspected or known bone metastases.METHODS: A total of 45 consecutive patients with breast cancer and the presence or clinical/biochemical or radiological suspicion of bone metastatic disease underwent <sup>18</sup>F-FDG and <sup>18</sup>F-fluoride PET/CT. Imaging results were compared with histopathology when available, or clinical and radiological follow-up of at least 1 year. For each technique we calculated: Sensitivity (Se), specificity (Sp), overall accuracy, positive and negative predictive values, error rate, and Youden’s index. McNemar’s χ<sup>2</sup> test was used to test the difference in sensitivity and specificity between the two diagnostic methods. All analyses were computed on a patient basis, and then on a lesion basis, with consideration ofthe density of independent lesions on the co-registered CT (sclerotic, lytic, mixed, no-lesions) and the divergent site of disease (skull, spine, ribs, extremities, pelvis). The impact of adding <sup>18</sup>F-NaF PET/CT to the work-up of patients was also measured in terms of change in their management due to <sup>18</sup>F-NaF PET/CT findings.RESULTS: The two imaging methods of <sup>18</sup>F-FDG and <sup>18</sup>F-fluoride PET/CT were significantly different at the patient-based analysis: Accuracy was 86.7% and 84.4%, respectively (McNemar’s χ<sup>2</sup> = 6.23, df = 1, P = 0.01). Overall, 244 bone lesions were detected in our analysis. The overall accuracy of the two methods was significantly different at lesion-based analysis (McNemar’s χ<sup>2</sup> = 93.4, df = 1, P < 0.0001). In the lesion density-based and site-based analysis, <sup>18</sup>F-FDG PET/CT provided more accurate results in the detection of CT-negative metastasis (P < 0.002) and vertebral localizations (P < 0.002); <sup>18</sup>F-NaF PET/CT was more accurate in detecting sclerotic (P < 0.005) and rib lesions (P < 0.04). <sup>18</sup>F-NaF PET/CT led to a change of management in 3 of the 45 patients (6.6%) by revealing findings that were not detected at <sup>18</sup>F-FDG PET/CT.CONCLUSION: <sup>18</sup>F-FDG PET/CT is a reliable imaging tool in the detection of bone metastasis in most cases, with a diagnostic accuracy that is slightly, but significantly, superior to that of <sup>18</sup>F-NaF PET/CT in the general population of breast cancer patients. However, the extremely high sensitivity of <sup>18</sup>F-fluoride PET/CT can exploit its diagnostic potential in specific clinical settings (i.e., small CT-evident sclerotic lesions, high clinical suspicious of relapse, and negative <sup>18</sup>F-FDG PET and conventional imaging).
文摘We studied tumour lymphangiogenesis and lymphatic invasion using D2-40 endothelial marker in 35 breast cancer patients treated by primary surgery and correlated it with various clinico-pathological prognostic parameters. Lymphangiogenesis was quantified using lymphatic micro vessel density (LMVD) by counting the immunostained lymphatic microvessels at 200X. The mean age was 45.97±12.09 years (range 30-80 years). LMVD ranged from 5/hpf to 56/hpf with a mean score of 13.4±10.8 and median of 9. The median value of 9 was taken to classify patients into a low or high LMVD. LMVD correlated significantly with tumour size (p=0.003), histological grade (p=0.046), lymph node status (p=0.030). There was no significant correlation of LMVD with stage, estrogen receptor, progesterone receptor or HER2/neu immunoreactivity. Lymphovascular invasion on D2-40 staining [LVI-D40] was found in 13 (37.1%) cases compared to 6 cases (17.1%) on H & E staining showing a poor agreement (k=0.244). LVI correlated significantly with lymph node status (p=0.011). There was a strong association between tumour size (p=0.142), histological grade (p=0.066) though the correlation was not statistically significant. No correlation was found with stage, estrogen receptor, progesterone receptor or HER2/neu immunoreactivity. The mean LMVD in LVI positive patients was higher (22.85±13.29) as compared to LVI negative patients (7.95±2.05) and this was statistically significant (p=0.001). Increased D2-40 detected LMVD and LVI correlated with poor prognostic parameters.
文摘目的对比分析三阴性乳腺癌(triple-negative breast cancer,TNBC)与人HER-2过表达乳腺癌的临床病理特征。方法回顾性分析2012年3月一2018年10月苏州大学附属第一医院收治的163例女性乳腺浸润性导管癌患者(其中TNBC84例,HER2过表达乳腺癌79例),分析两组患者的临床资料,并对其临床病理特征进行对比研究。结果TNBC组中肿瘤直径cm者占91.67%,组织学分级Ⅲ级者占72.62%,远处转移占14.29%;HER-2过表达乳腺癌组的肿瘤直径≥2cm者占79.75%,组织学分级Ⅲ级者占50.63%,远处转移占5.06%,两组差异均有统计学意义(P<0.05)。结论TNBC较HER.2过表达乳腺癌的肿瘤体积更大,组织学分级更高,更容易复发及远处转移,而两组患者的发病年龄、腋窝淋巴结转移及临床分期方面无明显差异。
基金supported by funding from the National Key Basic Research Program of China(973 Program,No.2012CB967003)the National Natural Science Foundation of China(Nos.81472661,21335007,and 81402463)the National High Technology Research and Development Program of China(863 Program,No.2015AA020104)
文摘Although progress in clinical and basic research has significantly increased our understanding of breast cancer, little is known about the molecular mechanism underlying breast cancer metastasis. Identification of effective therapeutic targets to prevent breast cancer metastasis is urgently needed. The function of mi R-503-3p has been investigated in other cancers, but its role in breast cancer remains undefined.Here, we found that mi R-503-3p was overexpressed in breast cancer tissue and plasma compared with adjacent normal breast tissue and with plasma from healthy individuals. Moreover, we identified mi R-503-3p to be an oncogene of breast cancer cell proliferation, migration and invasion. Upregulation of mi R-503-3p in breast cancer cells inhibited expression of epithelialemesenchymal transition（EMT）-related protein SMAD2 and the epithelial marker protein E-cadherin by directly binding to their m RNA30 untranslated region, whereas increased expression of mesenchymal marker proteins, including vimentin and N-cadherin. Taken together, our findings support a critical role for mi R-503-3p in induction of breast cancer EMT and suggest that plasma mi R-503-3p may be a useful diagnostic biomarker for breast cancer.
基金supported in part by funds from the Department of Basic Sciences Loma Linda University Health(LLUH)School of Medicinethe Grants for Research and School Partnerships award(LLUH intramural grant)+2 种基金the Grants to Promote Collaborative and Translational Research Award(LLUH intramural grant)NIH/National Institute of General Medical Sciences grant(award number 2R25GM060507)the National Institutes of Health(NIH)(Grant No.S10OD019960)。
文摘Metastatic breast cancer is incurable and often due to breast cancer stem cell(CSC)-mediated self-renewal.We previously determined that the aryl hydrocarbon receptor(AhR)agonist aminoflavone(AF)inhibits the expression of the CSC biomarkerα6-integrin(ITGA6)to disrupt the formation of luminal(hormone receptor-positive)mammospheres(3D breast cancer spheroids).In this study,we performed miRNA-sequencing analysis of luminal A MCF-7 mammospheres treated with AF to gain further insight into the mechanism of AF-mediated anti-cancer and anti-breast CSC activity.AF significantly induced the expression of>70 microRNAs(miRNAs)including miR125b-2–3p,a predicted stemness gene regulator.AF-mediated miR125b-2–3p induction was validated in MCF-7 mammospheres and cells.miR125b-2–3p levels were low in breast cancer tissues irrespective of subtype compared to normal breast tissues.While miR125b-2–3p levels were low in MCF-7 cells,they were much lower in AHR100 cells(MCF-7 cells made unresponsive to AhR agonists).The miR125b-2–3p mimic decreased,while the antagomiR125b-2–3p increased the expression of stemness genes ITGA6 and SOX2 in MCF-7 cells.In MCF-7 mammospheres,the miR125b-2–3p mimic decreased only ITGA6 expression although the antagomiR125b-2–3p increased ITGA6,SOX2 and MYC expression.AntagomiR125b-2–3p reversed AF-mediated suppression of ITGA6.The miR125b-2–3p mimic decreased proliferation,migration,and mammosphere formation while the antagomiR125b-2–3p increased proliferation and mammosphere formation in MCF-7 cells.The miR125b-2–3p mimic also inhibited proliferation,mammosphere formation,and migration in AHR100 cells.AF induced AhR-and miR125b2-3p-dependent anti-proliferation,anti-migration,and mammosphere disruption in MCF-7 cells.Our findings suggest that miR125b-2–3p is a tumor suppressor and AF upregulates miR125b-2–3p to disrupt mammospheres via mechanisms that rely at least partially on AhR in luminal A breast cancer cells.
文摘New targeted therapies have been developed to overcome resistance to endocrine therapy(ET)and improve the outcome of HR^(+)/HER2^(-)advanced breast cancer(ABC).We conducted a meta-analysis and systemic review on randomized controlled trials evaluating various targeted therapies in combination with ET in HR^(+)/HER2^(-)ABC.PUBMED and EMBASE databases were searched for eligible trials.Hazard ratios(HRs)for progression-free survival(PFS),odds ratios(ORs)for objective response rate(ORR),clinical benefit rate(CBR),and toxicity were meta-analyzed.Twenty-six studies with data on 10347 patients were included and pooled.The addition of cyclin-dependent kinase 4/6 inhibitors to ET significantly improved median PFS(pooled HR=0.547,P<0.001),overall survival(pooled HR=0.755,P<0.001),and tumor response rates(ORR,pooled OR=1.478,P<0.001;CBR,pooled OR=1.201,P<0.001)with manageable toxicities(pooled OR=3.280,P<0.001).The mammalian targets of rapamycin inhibitors and exemestane were not clinically beneficial for this pooled population including ET-naïve and ET-resistant patients.Moderate improvement in PFS(pooled HR=0.686,P<0.001)yet pronounced toxicities(pooled OR=2.154,P<0.001)were noted in the combination of phosphatidylinositol-4,5-bisphosphate 3-kinase inhibitors with fulvestrant.Future studies are warranted to optimize the population and the dosing sequence of these available options.
