MRI reveals the in vivo cellular and vascular response to BEZ235 in ovarian cancer xenografts with different PI3-kinase pathway activity

Background:

The phosphoinositide-3 kinase (PI3K) pathway is an attractive therapeutic target. However, difficulty in predicting therapeutic response limits the clinical implementation of PI3K inhibitors. This study evaluates the utility of clinically relevant magnetic resonance imaging (MRI) biomarkers for noninvasively assessing the in vivo response to the dual PI3K/mTOR inhibitor BEZ235 in two ovarian cancer models with differential PI3K pathway activity.

Methods:

The PI3K signalling activity of TOV-21G and TOV-112D human ovarian cancer cells was investigated in vitro. Cellular and vascular response of the xenografts to BEZ235 treatment (65 mg kg⁻¹, 3 days) was assessed in vivo using diffusion-weighted (DW) and dynamic contrast-enhanced (DCE)-MRI. Micro-computed tomography was performed to investigate changes in vascular morphology.

Results:

The TOV-21G cells showed higher PI3K signalling activity than TOV-112D cells in vitro and in vivo. Treated TOV-21G xenografts decreased in volume and DW-MRI revealed an increased water diffusivity that was not found in TOV-112D xenografts. Treatment-induced improvement in vascular functionality was detected with DCE-MRI in both models. Changes in vascular morphology were not found.

Conclusions:

Our results suggest that DW- and DCE-MRI can detect cellular and vascular response to PI3K/mTOR inhibition in vivo. However, only DW-MRI could discriminate between a strong and weak response to BEZ235.     

Dynamic contrast-enhanced MRI in patients with luminal Crohn's disease

Objectives

To prospectively assess dynamic contrast-enhanced (DCE-)MRI as compared to conventional sequences in patients with luminal Crohn's disease.

Methods

Patients with Crohn's disease undergoing MRI and ileocolonoscopy within 1 month had DCE-MRI (3T) during intravenous contrast injection of gadobutrol, single shot fast spin echo sequence and 3D T1-weighted spoiled gradient echo sequence, a dynamic coronal 3D T1-weighted fast spoiled gradient were performed before and after gadobutrol. Maximum enhancement (ME) and initial slope of increase (ISI) were calculated for four colon segments (ascending colon + coecum, transverse colon, descending colon + sigmoid, rectum) and (neo)terminal ileum. C-reactive protein (CRP), Crohn's disease activity index (CDAI), per patient and per segment Crohn's disease endoscopic index of severity (CDEIS) and disease duration were determined. Mean values of the (DCE-)MRI parameters in each segment from each patient were compared between four disease activity groups (normal mucosa, non-ulcerative lesions, mild ulcerative and severe ulcerative disease) with Mann–Whitney test with Bonferroni adjustment. Spearman correlation coefficients were calculated for continuous variables.

Results

Thirty-three patients were included (mean age 37 years; 23 females, median CDEIS 4.4). ME and ISI correlated weakly with segmental CDEIS (r = 0.485 and r = 0.206) and ME per patient correlated moderately with CDEIS (r = 0.551). ME was significantly higher in segments with mild (0.378) or severe (0.388) ulcerative disease compared to normal mucosa (0.304) (p < 0.001). No ulcerations were identified at conventional sequences. ME correlated with disease duration in diseased segments (r = 0.492), not with CDAI and CRP.

Conclusions

DCE-MRI can be used as a method for detecting Crohn's disease ulcerative lesions.     

磁共振成像、弥散加权成像及动态增强成像诊断子宫内膜癌的临床研究

目的 探讨弥散加权成像(DWI)和动态增强成像(DCE-MRI)及磁共振成像(MRI)诊断子宫内膜癌的价值.方法 分析80例疑似子宫内膜癌病人的MRI和DWI及DCE-MRI影像的资料,以手术后病理诊断结果为标准,分析MRI、DWI及DCE-MRI诊断子宫内膜癌的价值,ROC分析定量参数Ktrans值、Kep值、Ve值...     

MRI动态增强定量分析技术在乳腺癌新辅助化疗疗效评价中的应用研究

目的:探讨MRI动态增强(DCE-MRI)定量分析技术在评价乳腺癌患者新辅助化疗中的应用可行性.方法:选取2013年1月至2015年1月我院收治的乳腺癌患者86例,作为研究对象.所有患者均经穿刺病理活检证实为乳腺浸润性导管癌,所有患者均接受4～6个疗程的新辅助化疗,并于治疗前后行DCE-MRI检查,并于治疗后再次行相同病灶穿刺活检观察有无再次浸润将患者分为无效组(n=32)与缓解组(n=54),比较两组患者治疗前后各项DCE-MRI相关指标.结果:两组患者化疗前DCE-MRI检查结果中细胞外血管外间隙容积比(Ve)、容量转移常数(Ktrans)、速率常数(Kep)指标比较差异无统计学意义,但治疗后缓解组患者Ktrans、Kep变化量高于无效组,并且Ve水平变化量无效组,P＜0.05,差异有统计学意义;DCE-MRI对缓解组治疗后疗效评估准确率为92.59％,对无效组治疗后疗效评估准确率为90.62％,差异无统计学意义,P＞0.05.结论:DCE-MRI定量分析技术可准确评估乳腺癌患者新辅助化疗的临床疗效,可通过相关增强指标定量评估癌灶浸润与转移,具有临床应用及推广价值.     

Multi-parameter MRI to investigate vasculature modulation and photo-thermal ablation combination therapy against cancer

Nanotransducer-mediated photothermal therapy (PTT) has emerged as an attractive therapy modality against cancer, but its efficacy is often limited by the amount of nanoparticles delivered to tumors. Previous studies showed a vasculature modulation treatment, which dilates or prunes tumor blood vessels, may enhance tumor uptake of nanoparticles. However, exploiting these approaches for improved PTT has seldom been studied. In this study, we investigated the impact of mild hyperthermia or anti-angiogenesis therapy on PTT. Briefly, we gave tumor-bearing balb/c mice low doses of sunitinib or submerged tumors in a 42?°C water bath. Next, we injected PEGylated reduced graphene oxide (RGO-PEG) and irradiated the tumors to induce PTT. We then followed up the treatment with multi-parameter MRI. Contrary to expectation, both vessel modulation strategies led to diminished PTT efficacy. Our results show that vessel modulation does not warrant improved PTT, and should be carefully gauged when used in combination with PTT.     

DWI及DCE-MRI在鼻咽癌侵犯斜坡诊断中的应用价值

目的：分析和研究针对鼻咽癌患者给予DWI及DCE-MRI在其侵犯斜坡诊断过程中的作用价值。方法方便选取2009年3月—2015年12月来该院治疗的鼻咽癌患者75例和同期来该院体检中心健康的受检者15名作为此次研究的试验对象。根据90例受检者的斜坡MRI图像随机数表分为斜坡健康组、斜坡侵犯组、治疗后斜坡改善组。分别检测和统计3组的磁共振扩散加权像的弥散系数和动态增强磁共振成像的强化百分数、强化峰值、达峰时间等。分析弥散系数和动态增强指标在确诊侵犯斜坡过程中的价值。结果结果显示,DWI指标比较发现：斜坡健康组、斜坡侵犯组、治疗后斜坡改善组弥散系数分别为：（0.03±0.0110)-3mm2/s、（1.06±0.4910)-3mm2/s、（0.27±0.1810)-3mm2/s,可知,斜坡侵犯组测量的数据明显高于斜坡健康组和斜坡改善组。差异有统计学意义,P﹤0.05。3组受检者的动态增强磁共振成像的各指标,斜坡侵犯组的强化百分数和峰值均高于斜坡健康组和斜坡改善组。差异有统计学意义,P﹤0.05。斜坡改善组的达峰时间明显优于斜坡健康组和斜坡侵犯组。差异有统计学意义,P﹤0.05。结论磁共振扩散加权像和动态增强磁共振成像在检测患者存在斜坡侵犯过程中具有良好的精准性和灵敏性。临床检查过程中应结合两种技术,效果更佳。     

DCE-MRI using small-molecular and albumin-binding contrast agents in experimental carcinomas with different stromal content

Objectives

To compare DCE-MRI experiments performed using a standard small-molecular (Gd-DTPA) and an albumin-binding (MS-325) contrast agent in two carcinoma models with different stromal content.

Materials and methods

DU-145 or BXPC-3 cancer cells were subcutaneously injected into nude mice. DCE-MRI was performed by a bolus injection of Gd-DTPA or MS-325 about 2 weeks after inoculation. For quantitative analysis a volume of interest was manually drawn over each tumor. To address the heterogeneous enhancement, each tumor volume was then divided into the 20% most-enhancing and the remaining 80% least-enhancing fractions. Mean tumor enhancement was calculated over these selected tumor volumes and compared between tumor groups and contrast agents. Maps of differential enhancement, peak enhancement and time-to-peak were used for visual evaluation. CD31 and VEGF immunohistochemistry were performed in excised tumors.

Results

In the 80% least-enhancing volume, at late time points of the dynamic scan, the mean enhancement elicited by MS-325 was higher in BXPC-3 than in DU-145 tumors. In the 20% most-enhancing volume, using either contrast agents, significant difference between the two tumors types were observed only early, while at later time points of the dynamic scan the difference were obscured by the faster washout observed in the BXPC-3 tumors. Enhancement maps confirmed that BXPC-3 tumors were characterized by marked washout rate using either contrast agent, particularly in the higher enhancing peripheral rim. With MS-325 this washout pattern appeared to be specific to the BXPC-3 carcinomas, since it was not observed in the DU-145 tumors. Finally, in both tumor types, MS-325 produced significantly higher enhancement than Gd-DTPA in the late phase of the dynamic scan. Ex vivo analysis confirmed the marked presence of aberrant infiltrative stroma in BXPC-3 tumors, in which tumor vessels were embedded. In all tumors the central portion was less viable and less infiltrated by stromal tissue then the peripheral areas.

Conclusions

Contrast distribution proved to be related to stromal content, which presumably produced the higher enhancement and faster washout observed in the BXPC-3 tumors. In particular, ‘early’ contrast-enhanced MRI, appeared as the most sensitive technique to detect the tumor portions characterized by a high stromal content, i.e. the peripheral rim of the BXPC-3 tumors. Since the same tumor models were recently investigated using FDG-PET imaging, showing inverse relationship between FDG uptake and stromal content, contrast-enhanced MRI and FDG-PET could provide complementary and comprehensive sensitivity in the assessment of carcinomas.     

A computerized global MR image feature analysis scheme to assist diagnosis of breast cancer: a preliminary assessment

Objectives

To develop a new computer-aided detection scheme to compute a global kinetic image feature from the dynamic contrast enhanced breast magnetic resonance imaging (DCE-MRI) and test the feasibility of using the computerized results for assisting classification between the DCE-MRI examinations associated with malignant and benign tumors.

Materials and Methods

The scheme registers sequential images acquired from each DCE-MRI examination, segments breast areas on all images, searches for a fraction of voxels that have higher contrast enhancement values and computes an average contrast enhancement value of selected voxels. Combination of the maximum contrast enhancement values computed from two post-contrast series in one of two breasts is applied to predict the likelihood of the examination being positive for breast cancer. The scheme performance was evaluated when applying to a retrospectively collected database including 80 malignant and 50 benign cases.

Results

In each of 91% of malignant cases and 66% of benign cases, the average contrast enhancement value computed from the top 0.43% of voxels is higher in the breast depicted suspicious lesions as compared to another negative (lesion-free) breast. In classifying between malignant and benign cases, using the computed image feature achieved an area under a receiver operating characteristic curve of 0.839 with 95% confidence interval of [0.762, 0.898].

Conclusions

We demonstrated that the global contrast enhancement feature of DCE-MRI can be relatively easily and robustly computed without accurate breast tumor detection and segmentation. This global feature provides supplementary information and a higher discriminatory power in assisting diagnosis of breast cancer.     

Simultaneous whole-body 18F-FDG PET-MRI in primary staging of breast cancer: A pilot study

PurposeAccurate initial staging in breast carcinoma is important for treatment planning and for establishing the likely prognosis. The purpose of this study was to assess the utility of whole body simultaneous ¹⁸F-FDG PET-MRI in initial staging of breast carcinoma.Methods36 patients with histologically confirmed invasive ductal carcinoma underwent simultaneous whole body ¹⁸F-FDG PET-MRI on integrated 3 T PET-MR scanner (Siemens Biograph mMR) for primary staging. Primary lesion, nodes and metastases were evaluated on PET, MRI and PET-MRI for lesion count and diagnostic confidence (DC). Kappa co relation analysis was done to assess agreement between the satellite, nodal and metastatic lesions detected by PET and MRI. Histopathology, clinical/imaging follow-up served as the reference standard.Results36 patients with 37 histopathologically proven index breast cancer were retrospectively studied. Of 36 patients, 25 patients underwent surgery and 11 patients received systemic therapy. All index cancers were seen on PET and MR. Fused PET-MRI showed highest diagnostic confidence score of 5 as compared to PET (median 4; range 3–5) and MRI (median 4; range 4–5) alone. 2/36 (5.5%) patients were detected to have unsuspected contralateral synchronous cancer. 47 satellite lesions were detected on DCE MRI of which 23 were FDG avid with multifocality and multicentricity in 21 (58%) patients. Kappa co relation analysis revealed fair agreement for satellite lesion detection by the two modalities (κ = 0.303; P = 0.003).The study showed a sensitivity of 60% and 93.3% on PET and MRI respectively for detection of axillary lymph nodes with a specificity of 91% for both and a false negative rate of 6.7% on MRI and 40% on PET. Kappa co relation analysis between PET and MRI for all the lymph nodes detected revealed fair agreement by the two modalities (κ = 0.337; P = 0.000). Combined PET-MRI increased diagnostic confidence for nodal involvement (median DC 5, range 4–5; P < 0.05).Distant metastases were found in 8/36 (22%) patients at the time of diagnosis with a total of 91 metastatic lesions on PET (DC ≥ 4) and 105 on MRI (DC ≥ 4), the difference being statistically significant (P = 0.001) while Kappa co relation analysis showed significant agreement between the two modalities (κ = 0.667; P = 0.000). Overall PET-MRI led to a change in management in 12 (33.3%) patients.ConclusionIn this pilot study, simultaneous ¹⁸F-FDG PET-MR, has been found to be useful in whole-body initial staging of breast cancer patients.     

Diffusion and perfusion of the kidney

MRI of the kidney currently makes the transition from depiction of morphology to assessment of function. Functional renal imaging methods provide information on diffusion and perfusion on a microstructural level. This review article presents the current status of functional renal imaging with focus on DWI (diffusion-weighted imaging) and DCE-MRI (dynamic contrast-enhanced MRI), as well as BOLD (blood-oxygenation level dependent) MRI, DTI (diffusion tensor imaging) and arterial spin labeling (ASL). Technical background of these techniques is explained and clinical assessment of renal function, parenchymal disease, transplant function and solid masses is discussed.