Dual‐frequency irradiation CEST‐MRI of endogenous bulk mobile proteins

A novel MRI contrast is proposed which enables the selective detection of endogenous bulk mobile proteins in vivo. Such a non‐invasive imaging technique may be of particular interest for many diseases associated with pathological alterations of protein expression, such as cancer and neurodegenerative disorders. Specificity to mobile proteins was achieved by the selective measurement of intramolecular spin diffusion and the removal of semi‐solid macromolecular signal components by a correction procedure. For this purpose, the approach of chemical exchange saturation transfer (CEST) was extended to a radiofrequency (RF) irradiation scheme at two different frequency offsets (dualCEST). Using protein model solutions, it was demonstrated that the dualCEST technique allows the calculation of an image contrast which is exclusively sensitive to changes in concentration, molecular size and the folding state of mobile proteins. With respect to application in humans, dualCEST overcomes the selectivity limitations at relatively low magnetic field strengths, and thus enables examinations on clinical MR scanners. The feasibility of dualCEST examinations in humans was verified by a proof‐of‐principle examination of a brain tumor patient at 3 T. With its specificity for the mobile fraction of the proteome, its comparable sensitivity to conventional water proton MRI and its applicability to clinical MR scanners, this technique represents a further step towards the non‐invasive imaging of proteomic changes in humans.     

动态增强MRI对乳腺癌新辅助化疗的疗效评价及预测

【摘要】目的:探讨动态增强MRI评价和预测乳腺癌新辅助化疗（NAC）疗效的价值。方法:回顾性分析45例经手术病理 证实为浸润性乳腺癌并行术前NAC的患者资料。依据化疗前后组织病理学改变进行的疗效评价,将病人分为病理完全 缓解组和病理非完全缓解组。对比分析化疗前后两组动态增强MRI检查参数数值变化的差异,以病理反应性标准分组 为金标准,对其中有统计学意义的参数进行ROC曲线分析,并计算ROC曲线下面积（AUC）,评价各参数对NAC疗效的 评价效能,最后根据分析结果建立乳腺癌NAC疗效预测模型Logist P。结果:病理完全缓解组有16例患者,而病理非完 全缓解组有29例患者。两组间肿瘤最大经线变化率、肿瘤体积变化率、早期强化程度变化、时间信号强度曲线最大线性 斜率变化率、时间信号强度曲线类型的变化差异均有统计学意义（P<0.05）。最大经线变化率、肿瘤体积变化率、早期强化 程度变化、时间信号强度曲线最大线性斜率变化率、时间信号强度曲线类型的变化的AUC分别为0.711、0.759、0.711、 0.795、0.692,灵敏度/特异度分别为0.38/0.97、0.81/0.66、0.56/0.83、0.75/0.76、0.69/0.62,联合肿瘤体积变化率和最大线性 斜率变化率的Logist P模型的AUC为0.793（95%CI 0.644~0.942）。结论:早期动态增强MRI参数能用于评价和预测乳腺 癌NAC疗效。     

The iron chelator deferasirox synergises with chemotherapy to treat triple‐negative breast cancers

To ensure their high proliferation rate, tumor cells have an iron metabolic disorder causing them to have increased iron needs, making them more susceptible to iron deprivation. This vulnerability could be a therapeutic target. In breast cancers, the development of new therapeutic approaches is urgently needed for patients with triple‐negative tumors, which frequently relapse after chemotherapy and suffer from a lack of targeted therapies. In this study, we demonstrated that deferasirox (DFX) synergises with standard chemotherapeutic agents such as doxorubicin, cisplatin and carboplatin to inhibit cell proliferation and induce apoptosis and autophagy in triple‐negative breast cancer (TNBC) cells. Moreover, the combination of DFX with doxorubicin and cyclophosphamide delayed recurrences in breast cancer patient‐derived xenografts without increasing the side‐effects of chemotherapies alone or altering the global iron storage of mice. Antitumor synergy of DFX and doxorubicin seems to involve downregulation of the phosphoinositide 3‐kinase and nuclear factor‐κB pathways. Iron deprivation in combination with chemotherapy could thus help to improve the effectiveness of chemotherapy in TNBC patients without increasing toxicity. Copyright © 2018 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.     

Dynamic contrast‐enhanced MRI texture analysis for pretreatment prediction of clinical and pathological response to neoadjuvant chemotherapy in patients with locally advanced breast cancer

The aim of this study was to investigate the potential of texture analysis, applied to dynamic contrast‐enhanced MRI (DCE‐MRI), to predict the clinical and pathological response to neoadjuvant chemotherapy (NAC) in patients with locally advanced breast cancer (LABC) before NAC is started. Fifty‐eight patients with LABC were classified on the basis of their clinical response according to the Response Evaluation Criteria in Solid Tumors (RECIST) guidelines after four cycles of NAC, and according to their pathological response after surgery. T₁‐weighted DCE‐MRI with a temporal resolution of 1 min was acquired on a 3‐T Siemens Trio scanner using a dedicated four‐channel breast coil before the onset of treatment. Each lesion was segmented semi‐automatically using the 2‐min post‐contrast subtracted image. Sixteen texture features were obtained at each non‐subtracted post‐contrast time point using a gray level co‐occurrence matrix. Appropriate statistical analyses were performed and false discovery rate‐based q values were reported to correct for multiple comparisons. Statistically significant results were found at 1–3 min post‐contrast for various texture features for the prediction of both the clinical and pathological response. In particular, eight texture features were found to be statistically significant at 2 min post‐contrast, the most significant feature yielding an area under the curve (AUC) of 0.77 for response prediction for stable disease versus complete responders after four cycles of NAC. In addition, four texture features were found to be significant at the same time point, with an AUC of 0.69 for response prediction using the most significant feature for classification based on the pathological response. Our results suggest that texture analysis could provide clinicians with additional information to increase the accuracy of prediction of an individual response before NAC is started. Copyright © 2014 John Wiley & Sons, Ltd.     

Noninvasive evaluation of renal pH homeostasis after ischemia reperfusion injury by CEST‐MRI

Acute kidney injury (AKI) in mice caused by sustained ischemia followed by reperfusion is associated with acute tubular necrosis and renal dysfunctional blood flow. Although the principal role of the kidney is the maintenance of acid–base balance, current imaging approaches are unable to assess this important parameter, and clinical biomarkers are not robust enough in evaluating the severity of kidney damage. Therefore, novel noninvasive imaging approaches are needed to assess the acid–base homeostasis in vivo. This study investigates the usefulness of MRI‐chemical exchange saturation transfer (CEST) pH imaging (through iopamidol injection) in characterizing moderate and severe AKI in mice following unilateral ischemia reperfusion injury. Moderate (20 min) and severe (40 min) ischemia were induced in Balb/C mice, which were imaged at several time points thereafter (Days 0, 1, 2, 7). A significant increase of renal pH values was observed as early as one day after the ischemia reperfusion damage for both moderate and severe ischemia. MRI‐CEST pH imaging distinguished the evolution of moderate from severe AKI. A recovery of normal renal pH values was observed for moderate AKI, whereas a persisting renal pH increase was observed for severe AKI on Day 7. Renal filtration fraction was significantly lower for clamped kidneys (0.54–0.57) in comparison to contralateral kidneys (0.84–0.86) following impairment of glomerular filtration. The severe AKI group showed a reduced filtration fraction even after 7 days (0.38 for the clamped kidneys). Notably, renal pH values were significantly correlated with the histopathological score. In conclusion, MRI‐CEST pH mapping is a valid tool for the noninvasive evaluation of both acid–base balance and renal filtration in patients with ischemia reperfusion injury.     

Prediction of pathologic response to neoadjuvant chemotherapy in patients with breast cancer using diffusion‐weighted imaging and MRS

The aim of this study was to determine whether tumor size, MRS parameters and apparent diffusion coefficient (ADC) measurements could be applied to predict pathologic complete response (pCR) after neoadjuvant chemotherapy (NAC). Ninety patients with breast cancer (median size, 4.5 cm; range, 1.6–9.5 cm) were evaluated with single‐voxel ¹H MRS and dynamic contrast‐enhanced MRI. Diffusion‐weighted imaging was performed in 41 of these patients using a 1.5‐T scanner before and after completion of NAC. Pre‐ and post‐treatment measurements and changes in tumor size, MRS parameters [absolute and normalized total choline‐containing compound (tCho) integral and tCho signal‐to‐noise ratio (SNR)] and ADCs in pCR versus non‐pCR were compared using the nonparametric Mann–Whitney test. Receiver operating characteristic (ROC) curve analysis was performed to assess the diagnostic performance of each parameter. After NAC, 30 patients (33%) showed pCR and 60 (67%) showed non‐pCR. At pretreatment, ADC was the only significant parameter in differentiating between pCR and non‐pCR [(0.83 ± 0.05) × 10^–3 versus (0.97 ± 0.14) × 10^–3 mm²/s] (p = 0.014). Post‐treatment measurements after completion of NAC and changes in tumor size (both p < 0.001), MRS parameters (p = 0.027 and p = 0.020 for absolute tCho integral, p = 0.036 and p = 0.023 for normalized tCho integral, and p = 0.032 and p = 0.061 for tCho SNR) and ADC (p = 0.003 and p < 0.001) were significantly different between the pCR and non‐pCR groups, except for changes in tCho SNR. In ROC analysis, the areas under the ROC curve (AUCs) of 0.63–0.73 were obtained for tumor size and MRS parameters. AUCs for pre‐ and post‐treatment ADC and changes in ADC were 0.75, 0.80 and 0.96, respectively. The optimal cut‐off of the percentage change in ADC for predicting pCR was 40.7%, yielding 100% sensitivity and 91% specificity. Patients with pCR showed significantly lower pretreatment ADCs than those with non‐pCR. The change in ADC after NAC was the most accurate predictor of pCR. Copyright © 2012 John Wiley & Sons, Ltd.     

Diffusion‐weighted MRI monitoring of pancreatic cancer response to radiofrequency heat‐enhanced intratumor chemotherapy

The aim of this study was to evaluate the feasibility of using diffusion‐weighted MRI to monitor the early response of pancreatic cancers to radiofrequency heat (RFH)‐enhanced chemotherapy. Human pancreatic carcinoma cells (PANC‐1) in different groups and 24 mice with pancreatic cancer xenografts in four groups were treated with phosphate‐buffered saline (PBS) as a control, RFH at 42 °C, gemcitabine and gemcitabine plus RFH at 42 °C. One day before and 1, 7 and 14 days after treatment, diffusion‐weighted MRI and T₂‐weighted imaging were applied to monitor the apparent diffusion coefficients (ADCs) of tumors and tumor growth. MRI findings were correlated with the results of tumor apoptosis analysis. In the in vitro experiments, the quantitative viability assay showed lower relative cell viabilities for treatment with gemcitabine plus RFH at 42 °C relative to treatment with RFH only and gemcitabine only (37 ± 5% versus 65 ± 4% and 58 ± 8%, respectively, p < 0.05). In the in vivo experiments, the combination therapy resulted in smaller relative tumor volumes than RFH only and chemotherapy only (0.82 ± 0.17 versus 2.23 ± 0.90 and 1.64 ± 0.44, respectively, p = 0.003). In vivo, 14‐T MRI demonstrated a remarkable decrease in ADCs at day 1 and increased ADCs at days 7 and 14 in the combination therapy group. The apoptosis index in the combination therapy group was significantly higher than those in the chemotherapy‐only, RFH‐only and PBS treatment groups (37 ± 6% versus 20 ± 5%, 8 ± 2% and 3 ± 1%, respectively, p < 0.05). This study confirms that it is feasible to use MRI to monitor RFH‐enhanced chemotherapy in pancreatic cancers, which may present new options for the efficient treatment of pancreatic malignancies using MRI/RFH‐integrated local chemotherapy. Copyright © 2013 John Wiley & Sons, Ltd.     

新辅助化疗对乳腺癌组织病理学及免疫组织化学的影响

目的:探讨新辅助化疗对乳腺癌组织病理学及免疫组织化学的影响.方法:观察术前经粗针吸活检(core needle biopsy,CNB)确诊的80例乳腺癌新辅助化疗后肿瘤标本的组织病理学改变,并分析其手术前后ER、PR、HER2等免疫表型的变化.结果:新辅助化疗对乳腺癌总显效率为67.5%,手术前后肿瘤组织的ER、PR、HER2总阳性表达率差异无显著性(P>0.05),但ER、PR、HER2均出现较高的不符合率,依次为45.0%、37.5%、12.5%.结论:新辅助化疗能有效地作用于肿瘤组织,并能帮助寻找术后有针对性的化疗方案;但对ER、PR、HER2等免疫标记有较大影响,可能会对术后选择内分泌治疗及靶向治疗造成不确定因素.     

Vascular adhesion protein‐1 as indicator of breast cancer tumor aggressiveness and invasiveness

Recent studies suggest that vascular adhesion protein‐1 (VAP‐1), a 180‐KDa homodimeric glycoprotein, may be associated with cancer‐related events including tumor cell migration, motility, invasion, or metastasis. Therefore, this study applies VAP‐1 immunohistochemical staining to demonstrate the invasiveness component of the breast cancer. The VAP‐1 staining results were compared in 148 breast cancer cases to identify possible correlations with clinical status, including age, tumor size, tumor grade, TNM stage, lymphatic invasion, metastasis, recurrence, and survival rate. Immunohistochemical staining results showed VAP‐1 negative or weak staining in normal ducts and ductal carcinoma in situ (DCIS), but these phenotypes were positively associated with a stiffened VAP‐1 that presented at the invasive front of the lesion. Our data demonstrated that VAP‐1 expression was positively associated with lymphatic invasion, distant metastasis, and patient survival in breast carcinoma. Notably, VAP‐1 expression was found to be significantly correlated with the overall survival (p < 0.0001). Multivariate Cox analysis indicated that VAP‐1 expression was a significant independent prognostic indicator of overall survival in breast carcinoma (p < 0.0001). In conclusion, this study suggests that VAP‐1 is linked to progression of tumor invasion and metastasis in breast carcinoma. VAP‐1 is shown to be a biomarker that can be predict invasive potential and clinical outcome in breast cancer.     

新辅助化疗对局部进展期乳腺癌患者T淋巴细胞亚群及NK细胞免疫功能的影响

目的:探讨局部进展期乳腺癌患者新辅助化疗前、后T淋巴细胞亚群及NK细胞免疫功能的变化。方法:采用流式细胞术检测54例局部进展期乳腺癌患者新辅助化疗前后的静脉血T淋巴细胞亚群及NK细胞免疫功能。美国癌症联合会(American Joint Commitree on Cancer,AJCC)肿瘤分期为Ⅱb期(仅T3N0M0)和Ⅲ期(不包括N3),静脉血于第1周期新辅助化疗治疗前及第3周期化疗后21日抽取,淋巴细胞亚群检测包括:T(CD3+,CD4+,CD8+),NK(CD56+,CD16+),经过3周期新辅助化疗CEF方案(表柔比星、环磷酰胺和5-氟尿嘧啶),根据新辅助化疗临床效果评价分为2组,化疗有效组38例(CR和PR),化疗无效组16例(SD和PD),并与正常体检健康者(40例)作比较。结果:乳腺癌患者治疗前CD4+、CD4+/CD8+明显低于对照组(P<0.01),NK细胞明显低于对照组(P<0.05),新辅助化疗后,有效组总CD3+、CD4+、CD4+/CD8+、NK细胞较治疗前均显著升高(P<0.05),CD8+降低(P<0.05);无效组CD3+、CD4+/CD8+及NK细胞较治疗前显著降低(P<0.05),而CD8+升高(P<0.05)。结论:局部进展期乳腺癌患者免疫功能低下,有效的辅助化疗能提高患者的免疫功能,定期监测免疫功能对指导临床治疗有意义。     

集束化护理干预在乳腺癌化疗相关性口腔黏膜炎中的应用

目的:探讨集束化护理干预对乳腺癌化疗相关性口腔黏膜炎的改善效果.方法:选择在延安市人民医院肿瘤血液科化疗且发生化疗相关性口腔黏膜炎的乳腺癌患者作为研究对象,采用随机数字表法分为观察组和对照组,对照组采用常规的口腔护理干预措施,观察组实施集束化护理干预措施,比较两组患者干预前(D0)及干预3(D3)、5(D5)、7(D7)d后的口腔黏膜损伤程度评分、口腔疼痛评分、7 d恢复效果及总愈合时间.结果:两组在D3～7的口腔疼痛程度评分和口腔黏膜损伤程度评分均明显低于D0,且观察组的评分明显低于对照组,差异具有统计学意义(P<0.05);在干预7 d后,观察组痊愈24例、显效17例、有效10例、无效2例,对照组痊愈11例、显效14例、有效17例、无效9例,差异具有统计学意义(P<0.05);观察组的口腔黏膜炎愈合时间为(6.63±1.82)d,明显少于对照组的(11.35±2.36)d,差异具有统计学意义(P<0.05).结论:集束化护理干预能有效促进乳腺癌化疗相关性口腔黏膜炎的创面愈合,减少口腔疼痛症状,促进疾病康复.     

超声显像技术对乳腺癌新辅助化疗后病理反应性的预测作用

探讨不同超声显像技术在预测乳腺癌新辅助化疗(neoadjuvant chemotherapy,NAC)病理反应性方面的研究进展。目前用于预测NAC病理反应性的超声技术有二维灰阶超声、多普勒超声、超声造影、弹性成像、近红外光谱及光散射成像。超声可通过上述不同的技术模式从肿物形态、血流、硬度、及氧含量等不同方面对乳腺癌的生物学特性进行评估,进而对NAC后病理反应性进行预测,其在该领域应用前景广阔。     

Dynamic susceptibility contrast MRI in advanced pancreatic cancer: semi‐automated analysis to predict response to chemotherapy

The purpose of this study was to assess whether dynamic susceptibility contrast magnetic resonance imaging (DSC‐MRI) can predict response to chemotherapy in advanced pancreatic cancer. DSC‐MRI was performed using gradient‐echo echo‐planar imaging after bolus injection of contrast material. Fifty‐four patients with advanced pancreatic cancer who were scheduled for chemotherapy were enrolled. ΔR2* was calculated using semi‐automated computer analysis capable of tracking moving lesions during DSC‐MRI. Pre‐treatment maximum ΔR2* and clinical factors including gender, age, tumor stage (UICC III/IV), initial tumor size, and chemotherapy regimen were compared between patients with progressive disease and patients with stable disease as was determined at 3‐month follow‐up, and between patients with progressive disease and patients with stable disease as was determined at 6‐month follow‐up. Receiver operating characteristic (ROC) analysis and the Kaplan–Meier method with log‐rank test were used to assess the relationship between the pre‐treatment maximum ΔR2* and early progression (i.e. at 3‐month follow‐up). The pre‐treatment maximum ΔR2* of patients with disease progression at 3‐month follow‐up (10.68 ± 3.88 s^?1) was significantly different (p < 0.01) from that of patients with stable disease at 3‐month follow‐up (6.94 ± 3.12 s^?1). Pre‐treatment maximum ΔR2* of patients with disease progression at 6‐month follow‐up was not significantly different from that of patients with stable disease at 6‐month follow‐up, although a trend was noted (p = 0.08). Pre‐treatment clinical factors were not significantly different between progressive and stable patients at 3‐ and 6‐month follow‐up. Tumor progression rate was significantly higher in patients with a higher pre‐treatment maximum ΔR2* than in those with a lower pre‐treatment maximum ΔR2* (median progression time, 38 vs 138 days, p < 0.01, using a cut‐off value of 8.13 s^?1 as determined by ROC analysis). In conclusion, DSC‐MRI may predict early progression in patients with advanced pancreatic cancer undergoing chemotherapy. Copyright © 2009 John Wiley & Sons, Ltd.     

化疗对乳腺癌患者甲状腺功能或结构的影响

目的探讨化疗对乳腺癌患者甲状腺功能或结构的近期影响。方法选取蚌埠医学院第一附属医院于2017年3月至2018年12月收治的40例女性初治原发性乳腺癌患者,检测并比较化疗后2和4疗程与化疗前的甲状腺功能5项(包括T3、T4、FT3、FT4和TSH)及其结构的变化。结果乳腺癌患者化疗2和4疗程后T4、FT4水平明显低于化疗前(P<0.05);患者化疗4疗程后甲状腺TI-RADS分级及其结构异常的发生率较化疗前均明显升高(P<0.05)。结论化疗后近期可引起或加重乳腺癌患者甲状腺功能或结构的异常,适时进行检查并干预可防止病情进一步发展,具有重要的临床意义。     

An associated classification of triple negative breast cancer: the risk of relapse and the response to chemotherapy

Background: Triple negative breast cancer (TNBC) is heterogeneous and considered as an aggressive tumor. This study was to evaluate the associated classification and its correlations with prognosis and the response to chemotherapy in Chinese women. Methods: Four hundred and twenty-eight cases of invasive TNBC were involved in this study. The expression of estrogen receptor (ER), progesterone receptor (PR), human epidermal growth factor receptor 2 (HER2), epidermal growth factor receptor (EGFR), and cytokeratin 5/6 (CK5/6), Ki67 and p53 were analyzed by immunohistochemistry and compared with patient outcome, and its implications and chemotherapy response were evaluated in four subgroups: typical medullary carcinoma (TMC), atypical medullary carcinoma (AMC), non-specific invasive ductal carcinoma (IDC) and other types. Results: The factors of tumor grade, tumor stage, lymph node status, EGFR/CK5/6 status and p53 labeling index were different among the groups. TMC tumors had the lowest rate of relapse (5.8%), while AMC, IDC and other types were associated with an increased risk of relapse (19.1%, 26.7% and 38.2% respectively). Many factors were risk predictors of relapse for TNBC and IDC, while only positive lymph node was for AMC. For MC tumors, adjunctive chemotherapy decreased the risk of relapse in lymph node positive subgroup (36.8% and 66.7%), while not significant in lymph node negative one (8.1% and 10.0%). Conclusion: The classification based on histologic and IHC findings may be a significant improvement in predicting outcome in TNBC. The different chemotherapy response in subgroups may contribute to guiding the treatment of TNBC.     

Stem cells and breast cancer

Proliferation in continuously renewing tissues, including the mammary gland, is hierarchically organized with a small number of slowly dividing stem cells and a greater number of more rapidly proliferating 'transit amplifying' cells. Mammary stem cells have been recently identified and purified based on their surface antigen expression. The recognition of mammary epithelial stem cells had led to the hypothesis that these may be at the root of breast cancer. In support of this, a highly tumorigenic subpopulation of cancer cells – cancer stem cells – has recently been identified in primary and metastatic breast cancer samples and in a number of established breast cancer cell lines. The existence of cancer stem cells would explain why only a small minority of cancer cells is capable of extensive proliferation and transferral of the tumour. In this article we aim to review the evidence in support of the existence of both normal mammary stem cells and breast cancer stem cells, and provide further insight into how taking this subpopulation of cells into account may affect the way we treat epithelial cancers in the future.