Targeted positron emission tomography imaging of CXCR4 expression in patients with acute myeloid leukemia.

Acute myeloid leukemia originates from leukemia-initiating cells that reside in the protective bone marrow niche. CXCR4/CXCL12 interaction is crucially involved in recruitment and retention of leukemia-initiating cells within this niche. Various drugs targeting this pathway have entered clinical trials. To evaluate CXCR4 imaging in acute myeloid leukemia, we first tested CXCR4 expression in patient-derived primary blasts. Flow cytometry revealed that high blast counts in patients with acute myeloid leukemia correlate with high CXCR4 expression. The wide range of CXCR4 surface expression in patients was reflected in cell lines of acute myeloid leukemia. Next, we evaluated the CXCR4-specific peptide Pentixafor by positron emission tomography imaging in mice harboring CXCR4 positive and CXCR4 negative leukemia xenografts, and in 10 patients with active disease. [(68)Ga]Pentixafor-positron emission tomography showed specific measurable disease in murine CXCR4 positive xenografts, but not when CXCR4 was knocked out with CRISPR/Cas9 gene editing. Five of 10 patients showed tracer uptake correlating well with leukemia infiltration assessed by magnetic resonance imaging. The mean maximal standard uptake value was significantly higher in visually CXCR4 positive patients compared to CXCR4 negative patients. In summary, in vivo molecular CXCR4 imaging by means of positron emission tomography is feasible in acute myeloid leukemia. These data provide a framework for future diagnostic and theranostic approaches targeting the CXCR4/CXCL12-defined leukemia-initiating cell niche.

[Combined PET-MRI of the abdomen]. / Kombinierte PET-MRT des Abdomens.

The first fully integrated combined positron emission tomography-magnetic resonance imaging (PET-MRI) scanners have been clinically available since 2010. Large prospective studies regarding indications and diagnostic accuracy of this new modality are not yet available; however, preliminary studies have shown a higher diagnostic accuracy and confidence compared to PET-computed tomography (PET-CT) in regions where MRI is known to be superior to CT, such as the liver. The benefit of MRI in accurate lesion characterization and the additional value of diffusion-weighted imaging (DWI) as a complementary functional modality by means of the apparent diffusion coefficient (ADC) is apparent in entities with low tracer uptake (e.g. due to small size) and a decreased or absent accumulation pattern on PET.

Preoperative lymph node staging in patients with primary prostate cancer: comparison and correlation of quantitative imaging parameters in diffusion-weighted imaging and 11C-choline PET/CT.

PURPOSE: To compare the diagnostic performance of DWI and 11C-choline PET/CT in the assessment of preoperative lymph node status in patients with primary prostate cancer. MATERIAL AND METHODS: Thirty-three patients underwent DWI and 11C-choline PET/CT prior to prostatectomy and extended pelvic lymph node dissection. Mean standardised uptake value (SUV(mean)) and mean apparent diffusion coefficient (ADC) of 76 identified lymph nodes (LN) were measured and correlated with histopathology. ADC values and SUVs were compared using linear regression analysis. RESULTS: A significant difference between benign and malignant LN was observed for ADC values (1.17 vs. 0.96 × 10(-3) mm(2)/s; P < 0.001) and SUV(mean) (1.61 vs. 3.20; P < 0.001). ROC analysis revealed an optimal ADC threshold of 1.01 × 10(-3) mm(2)/s for differentiating benign from malignant LN with corresponding sensitivity/specificity of 69.70%/78.57% and an area under the curve (AUC) of 0.785. The optimal threshold for SUV(mean) was 2.5 with corresponding sensitivity/specificity of 69.72%/90.48% and with an AUC of 0.832. ADC values and SUV(mean) showed a moderate significant inverse correlation (r = -0.63). CONCLUSION: Both modalities reveal similar moderate diagnostic performance for preoperative lymph node staging of prostate cancer, not justifying their application in routine clinical practice at this time. The only moderate inverse correlation between ADC values and SUV(mean) suggests that both imaging parameters might provide complementary information on tumour biology. KEY POINTS: • Conventional imaging shows low performance for lymph node staging in prostate cancer. • DWI and 11C-choline PET/CT both provide additional functional information • Both functional modalities reveal only moderate diagnostic performance.

Association between survival in patients with primary invasive breast cancer and computer aided MRI.

PURPOSE: To identify the potential of semi-quantitative enhancement-analysis in breast MRI to predict disease-related death in primary breast cancer patients. MATERIALS AND METHODS: The present study was planned and conducted according to international recommendations. All patients referred for pretherapeutic staging of primary breast cancer during 24 consecutive months were included into the study collective. They were followed-up by our multidisciplinary breast center. For semi-quantitative MRI-analysis dedicated CAD-software (computer assisted diagnosis) was used. Association between enhancement parameters and disease-related survival was investigated using Cox proportional-hazards -regression (CR). RESULTS: A total of 115 patients were eligible for CR analysis. Median follow-up time was 52 months. In 15 patients, disease-related death occurred. CR analysis identified four enhancement parameters as independent and significant (P < 0.001) predictors of the endpoint. Coefficients were "Initial enhancement" (B = 0.0166), "Time to peak-enhancement" (B = 1.0573), "Tumor volume" (B = 0.0175), and proportion of "tumor volume" showing "slow initial enhancement" followed by a "persistent" curve-type (B = -0.0586). CONCLUSION: This study demonstrates the significant relationship between semi-quantitative enhancement analysis in breast MRI and disease-related death of breast cancer patients. As results were extracted from a routine staging examination, MRI noninvasively provides not only diagnostic information but also outcome data at one step. Future studies should address the impact of these findings on patient management and therapeutic approach.

Kinetic analysis of lesions without mass effect on breast MRI using manual and computer-assisted methods.

OBJECTIVE: To analyse the kinetic characteristics of lesions without mass effect in dynamic breast MRI using manual and computer assisted methods. METHODS: The enhancement pattern of 82 histopathologically verified lesions without mass effect (36 malignant, 46 benign) was evaluated on breast MRI using manual placement of a region of interest. Commercially available computer analysis software automatically assessed volume enhancement characteristics of a lesion voxelwise. Kinetic features evaluated included classification of the signal-intensity time curve as washout, plateau or persistent enhancement. RESULTS: Unlike manual ROI placement, computer-aided analysis demonstrated a significant difference in enhancement pattern between benign (washout: 32.6%, plateau: 32.6%, persistent: 34.8%) and malignant lesions without mass effect (77.1%, 8.6%, 14.3% respectively, P < 0.01, two-sided Chi-squared test) following initial rapid signal increase. Mean percentage of washout voxel volumes within a lesion was significantly higher in malignant lesions than in benign lesions (11.9% +/-12.7 (SD) vs. 6.9% +/-11.3 (SD), P < 0.01, Mann-Whitney U Test). Conversely, the mean percentage of persistent voxel volumes was significantly lower in malignant lesions than in benign lesions (60.1% +/-21.1 (SD) vs. 79% +/-23 (SD), P < 0.01, Mann-Whitney U Test). CONCLUSION: Computer-assisted enhancement pattern analysis might have diagnostic benefit in the evaluation of lesions without mass effect.

Noninvasive measurement of liver iron concentration at MRI in children with acute leukemia: initial results.

BACKGROUND: Routine assessment of body iron load in patients with acute leukemia is usually done by serum ferritin (SF) assay; however, its sensitivity is impaired by different conditions including inflammation and malignancy. OBJECTIVE: To estimate, using MRI, the extent of liver iron overload in children with acute leukemia and receiving blood transfusions, and to examine the association between the degree of hepatic iron overload and clinical parameters including SF and the transfusion iron load (TIL). MATERIAL AND METHODS: A total of 25 MRI measurements of the liver were performed in 15 children with acute leukemia (mean age 9.75 years) using gradient-echo sequences. Signal intensity ratios between the liver and the vertebral muscle (L/M ratio) were calculated and compared with SF-levels. TIL was estimated from the cumulative blood volume received, assuming an amount of 200 mg iron per transfused red blood cell unit. RESULTS: Statistical analysis revealed good correlation between the L/M SI ratio and TIL (r = -0.67, P = 0.002, 95% confidence interval CI = -0.83 to -0.34) in patients with acute leukemia as well as between L/M SI ratio and SF (r = -0.76, P = 0.0003, 95% CI = -0.89 to -0.52). CONCLUSION: SF may reliably reflect liver iron stores as a routine marker in patients suffering from acute leukemia.

Cost-effectiveness of MR-mammography vs. conventional mammography in screening patients at intermediate risk of breast cancer - A model-based economic evaluation.

PURPOSE: The aim of this study was to analyze the cost-effectiveness of screening patients of intermediate risk of breast cancer with MR-Mammography (MRM) versus conventional mammography (XM). METHOD: A decision model for both diagnostic modalities and a subsequent markov model for the simulation of follow-up costs and outcomes was developed. Input parameters were acquired from published literature for this markov modelling study. The expected cumulative costs and outcomes were calculated for both modalities in a 30-year timeframe in US-dollar ($) and quality-adjusted life years (QALYs). A deterministic sensitivity analysis and a probabilistic sensitivity analysis incorporating 30,000 Monte Carlo iterations were performed to investigate the model stability. RESULTS: In total, XM with its consecutive treatments resulted in total costs of $ 5,492.68 and an average cumulative quality of life of 18.87 QALYs, compared to MRM with costs of $ 5,878.66 and 18.92 QALYs. The corresponding incremental cost-effectiveness ratio (ICER) for MRM was $ 8,797.60 per QALY - distinctly below international willingness-to-pay thresholds for cost-effectiveness. The results were confirmed within the limits of the sensitivity analyses. CONCLUSIONS: In patients with intermediate risk for breast cancer due to their dense breast tissue, two-yearly screening with MRM may be considered as cost-effective.

Impact of specificity on cost-effectiveness of screening women at high risk of breast cancer with magnetic resonance imaging, mammography and ultrasound.

PURPOSE: Aim of this study was to analyze the comparative cost-effectiveness of MR-mammography vs conventional imaging in a screening setting for women with high risk of breast cancer, with particular focus on the impact of specificity of MRM. METHOD: Decision analytic modelling and Markov Modelling were applied to evaluate cumulative costs of each screening modality and their subsequent treatments as well as cumulative outcomes in quality adjusted life years (QALYs). For the selected time horizon of 30 years, false positive and false negative results were included. Model input parameters for women with high risk of breast cancer were estimated based on published data from a US healthcare system perspective. Major influence factors were identified and evaluated in a deterministic sensitivity analysis. Based on current recommendations for economic evaluations, a probabilistic sensitivity analysis was conducted to test the model stability. RESULTS: In a base-case analysis, screening with XM vs. MRM and treatment resulted in overall costs of $36,201.57 vs. $39,050.97 and a cumulative effectiveness of 19.53 QALYs vs. 19.59 QALYs. This led to an incremental cost-effectiveness ratio (ICER) of $ 45,373.94 per QALY for MRM. US and XM + US resulted in ICER values higher than the willingness to pay (WTP). In the sensitivity analyses, MRM remained a cost-effective strategy for screening high-risk patients as long as the specificity of MRM did not drop below 86.7 %. CONCLUSION: In high-risk breast cancer patients, MRM can be regarded as a cost-effective alternative to XM in a yearly screening setting. Specificity may be an important cost driver in settings with yearly screening intervals.

[68Ga-PSMA-11 PET/mpMRI for local detection of primary prostate cancer in men with a negative prior biopsy]. / 68Ga-PSMA-11 PET/mpMRT zur Lokaldetektion des primären Prostatakarzinom bei Männern mit negativer Vorbiopsie.

INTRODUCTION AND OBJECTIVE: Multiparametric MRI (mpMRI) represents the current gold standard for the detection of primary prostate cancer (PC) after a negative biopsy. PSMA PET imaging has been introduced in the diagnostic work-up of PC with high accuracy, but is currently mainly utilised in the setting of biochemical recurrence. This study aimed to determine the efficacy of combined 68Ga-PSMA-11 PET/mpMRI imaging to detect PC in patients with previously negative prostate biopsies. METHODS: A total of 57 patients who had undergone at least one prior negative prostate biopsy were included in this retrospective analysis. All patients underwent 68Ga-PSMA-11 PET/mpMRI imaging of the prostate. mpMRI was evaluated according to the PIRADS classification system and 68Ga-PSMA-11 PET was rated on a 5-point Likert scale (1: PC highly unlikely; 2: PC unlikely; 3: presence of PC is equivocal; 4: PC likely; 5: PC highly likely). All patients received a systematic random biopsy as well as a targeted transrectal biopsy of lesions suspicious on imaging. Imaging and histological biopsy outcomes were compared on a per-patient basis. RESULTS: In the histological analysis, 35/57 (61.4 %) patients harboured PC lesions. In patients with biopsy-proven PC, 21/35 (60.0 %) had a PI-RADS 4 or 5 lesion on mpMRI and 28 /35 (80.0 %) had a PET rating of 4 or 5. Combined 68Ga-PSMA-11 PET/mpMRI missed only one patient with a Gleason score (GS) 7a tumour (rating of 1 or 2 in both PET and mpMRI). Limitations include the retrospective analysis as well as possible false negative biopsy results even in a fusion biopsy setting. CONCLUSION: In this initial analysis, the combined 68Ga-PSMA-11 PET/mpMRI proved to be a valuable imaging tool to guide prostate biopsies for the detection of PC in patients with a negative prior biopsy. In this approach, 68Ga-PSMA-11 PET and mpMRI show partially complementary findings that enhance the detection of PC lesions.

The contralateral synchronous breast carcinoma: a comparison of histology, localization, and magnetic resonance imaging characteristics with the primary index cancer.

Women with unilateral breast carcinoma reveal an increased risk of suffering from malignancies in the contralateral breast. There is a controversy about the existence of bilateral phenotypic similarities. The aim of this investigation was to compare histologic findings, magnetic resonance imaging (MRI) parameters, and tumor localizations of synchronous bilateral carcinomas. MRI revealed in 42 of 875 women (4.8%) with primary index carcinomas a contralateral malignancy. Twenty-two of the 42 contralateral carcinomas could only be detected by MRI, not by clinical examination, X-ray mammography, or ultrasonography. In 875 patients, MRI therefore identified 22 (2.5%) otherwise occult contralateral cancers. To evaluate bilateral MRI similarities, multiple dynamic and morphologic parameters were evaluated. Of 42 bilateral cancer pairs, histologic tumor type was identical in 54.8% (correlation analysis, P < 0.05). Estrogen receptor status was simultaneously positive or negative in 86.2% (P < 0.01), progesterone receptor status in 79.3% (P < 0.05), expression of human epidermal growth factor receptor 2 in 76.2% (P < 0.05). In 75.8%, initial signal increase, and in 63.6%, postinitial curve types were bilaterally congruent on MRI (P < 0.05). Detected masses showed bilaterally similar T2-signal intensity in 81.8% (P < 0.001). Similar shape and margin of tumor masses and occurrence of non-mass-like enhancement were also frequently observed in both breasts (P < 0.05). The main tumor quadrant was the same in 61.9%, the main localization (retromamillar, central, or dorsal) in 66.7% (P < 0.01). Contralateral carcinomas frequently present similar histologic findings, tumor localizations and MRI characteristics reflecting analogies of tumor neoangiogenesis, histopathologic components, and infiltration in the surrounding stroma. Bilateral synchronous carcinomas may represent on each site distinct, but similar biologic entities, due to analogous influences of tumor developments.

Computer-aided interpretation of dynamic magnetic resonance imaging reflects histopathology of invasive breast cancer.

OBJECTIVE: To perform a semiautomated software-based comparison of invasive breast carcinoma dynamic enhancement patterns in MR mammography with histological prognostic factors considering whole lesion volumes. MATERIAL AND METHODS: A total of 128 patients with 145 invasive breast carcinomas underwent dynamic MR mammography. Kinetic features from the invasive breast lesions were obtained using commercially available software to automatically assess volume enhancement characteristics of a manually chosen lesion. Findings were compared with histological factors determining tumour aggressiveness (lymph node status, LN; oestrogen/progesterone receptor (ER/PR) status; HER-2/neu status; tumour grade) by using nonparametric rank tests and binary logistic regression analysis (BLRA). RESULTS: Volume enhancement characteristics were significantly influenced by LN, ER/PR and HER-2/neu status (P < 0.05). BLRA implied that total lesion and plateau voxel volume were independent predictors of ER/PR and HER-2/neu status. Strongest initial enhancement predicted negative ER/PR, and time to peak of the most suspect curve was inversely correlated with positive LN status. On the other hand, no statistical significance could be observed between histological tumour grading and kinetic features. CONCLUSION: Histopathological criteria associated with poor prognosis lead to significantly more aggressive dynamic enhancement patterns in MR mammography. In this study, higher lesion volumes as well as higher and earlier initial enhancement were independent covariates predicting higher tumour aggressiveness.

Magnetic resonance mammography of invasive lobular versus ductal carcinoma: systematic comparison of 811 patients reveals high diagnostic accuracy irrespective of typing.

OBJECTIVE: Invasive lobular (ILC) and ductal carcinomas (IDC) are the most frequent subtypes of breast cancer. Diagnosis of ILC is often challenging. This study was conducted to (1) evaluate dynamic and morphologic profiles and to (2) compare the diagnostic accuracy of IDC and ILC in magnetic resonance mammography (MRM). METHODS: Our database consisted of all consecutive MRMs over a 12-year period (standardized protocol: T1-weighted fast low-angle shot; 0.1-mmol gadolinium-diethylenetriaminepentaacetate per kilogram of body weight; T2-weighted turbo spin-echo, 1.5 T; histological verification after MRM), which were evaluated by experienced (>500 MRMs) radiologists in consensus, applying 17 predefined descriptors. All the patients gave written consent; this study was approved by the local institutional review board. Extracting all the ILCs (n = 108), IDCs (n = 347), and benign lesions (n = 436) from the database, the data set of the study was created.In ILC and IDC diagnostic accuracy of single descriptors was calculated and compared separately (chi test). Using all the descriptors, a combined binary logistic regression analysis was applied to calculate the overall diagnostic accuracy for ILC and IDC. The corresponding areas under the curve were compared. RESULTS: ILC and IDC, showed wash-in and an irregular shape without difference (P = 1.0 and P = 0.4). Wash-out was more typical of IDC (72.6%; ILC, 57.4%; P = 0.007). Perifocal edema was diagnosed more frequently in IDC (45.5%; P = 0.05). For overall accuracy, the areas under the curve were 0.929 for ILC and 0.939 for IDC (P = 0.5). CONCLUSIONS: The dynamic and morphologic profiles of ILC and IDC were overlapping, and minor differences between both subgroups could be identified. Accordingly, the overall diagnostic accuracy of MRM was high and without difference between both subtypes of breast cancer.

Differential diagnosis of breast lesions 5 mm or less: is there a role for magnetic resonance imaging?

OBJECTIVES: According to magnetic resonance (MR) imaging Breast Imaging Reporting and Data System, foci are small enhanced lesions 5 mm or less in diameter. This study was conducted to (a) assess morphological and dynamic profiles in malignant versus benign foci in breast MR imaging (MRM) and to (b) identify overall diagnostic accuracy of MRM for differential diagnosis of foci. METHODS: This study was approved by the local institutional review board; all patients gave written consent. All MRM (T1w-FLASH; 0.1 mmol/kg body weight gadolinium-diethylenetriamine penta-acetic acid; T2w-TSE; consecutive 12-year period; with histological verification after MRM were evaluated by 2 experienced (>500 MRM) radiologists in consensus using 16 predefined descriptors and were included into a database. A data set was created by extracting all lesions 5 mm or less (benign, 27; malignant, 61). Accuracy of individual descriptors was assessed (Crosstabs, chi2-test; positive/negative likelihood ratios (LR+/-); diagnostic odds ratio [DOR]). Binary logistic regression analysis was applied to identify overall diagnostic accuracy using all descriptors combined (area under the receiver operating characteristic curve,). RESULTS: Washout was typically associated with malignancy (P < 0.05; DOR, 3.5). Irregular shape was feasible for differential diagnosis of foci (DOR, 7.3), yet majority of malignancies demonstrated a round shape (55.6%). Additional descriptors such as blooming (DOR, 4.0, LR+, 2.8), adjacent vessel (DOR, 4.8; LR+, 4.5), and root sign (DOR, 5.6; LR+, 4.1) showed a high accuracy. Overall accuracy for differentiation of benign versus malignant foci showed an area under the curve of 0.887 (P = 0.0001). CONCLUSIONS: Assessment of dynamic and morphological profiles in foci 5 mm or less was feasible. Using all descriptors combined, a high potential for differential diagnosis of foci in magnetic resonance-mammography could be identified.

Sensitivity and specificity of unilateral edema on T2w-TSE sequences in MR-Mammography considering 974 histologically verified lesions.

The objective of this investigation was to determine the diagnostic value of unilateral edema in differentiating benign from malignant breast disease on T2w-TSE images in MR-Mammography (MRM). All patients from a 10-year period undergoing surgery in the same institution after having received MRM in our department were included in this prospective analysis of previous acquired examinations. To eliminate bias caused by prior procedures, all patients having had biopsy, operation, radiation therapy, or chemotherapy before MRM were excluded. T2w-TSE images were acquired after a dynamic contrast-enhanced series of T1-weighted images in a standardized examination protocol (1.5 T). Edema was defined as a high-signal intensity on T2w-TSE images and it was categorized as absent, perifocal, or diffuse. Examinations were rated by two experienced observers blinded to all procedures and results following MRM. In cases of disconcordance, the opinion of a third radiologist decided. Statistical testing included Pearson's Chi-squared test and Fisher's exact testing. A total of 1,010 patients with a mean age of 55 years (SD: 11.6 years, range: 16-87 years) with 1,129 histologically verified lesions were included in this investigation. After removing all patients with prior procedures from the patient collective, 974 lesions were left for statistical analysis. Perifocal edema was highly significantly (p < 0.001) associated with malignant disease, leading to a sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of 33.5%, 93.9%, 89.6, and 57.1%, respectively. Unilateral edema in general showed the following diagnostic parameters: sensitivity 53.0%, specificity 80.5%, PPV 80.9%, and NPV 52.3%. Edema seems to be associated with malignancy in the majority of cases. Especially, specificity and PPV were found to be high. These findings may be helpful in diagnostic decisions on otherwise equivocal cases.