Tibor Vag

First Experience with Chemokine Receptor CXCR4–Targeted PET Imaging of Patients with Solid Cancers

CXCR4 is a chemokine receptor that is overexpressed in various human cancers and is involved in tumor metastasis. The aim of this proof-of-concept study was to evaluate a novel CXCR4-targeted PET probe in patients with solid cancers with reported in vitro evidence of CXCR4 overexpression and to estimate its potential diagnostic value. Methods: Twenty-one patients with histologically proven pancreatic cancer, laryngeal cancer, non–small cell lung cancer, prostate cancer, melanoma, breast cancer, hepatocellular carcinoma, glioblastoma, sarcoma, or cancer of unknown primary underwent PET imaging using the novel CXCR4 nuclear probe 68Ga-pentixafor. The SUVmax of the liver, spleen, and bone marrow was measured to determine physiologic tracer distribution. For evaluation of tracer accumulation in solid cancers, SUVmax and tumor-to-background (T/B) ratios were determined in a total of 43 malignant lesions, including 8 primary tumors, 3 locally recurrent tumors, and 32 metastases. When available, the SUVmax of malignant lesions was compared with the corresponding SUVmax measured in routine 18F-FDG PET. Results: Moderate tracer accumulation was detectable in the liver, bone marrow, and spleen, with a mean SUVmax of 3.1, 3.7, and 5.6, respectively. By visual interpretation criteria, 9 of 11 primary and locally recurrent tumors were detectable, exhibiting a mean SUVmax of 4.7 (range, 2.1–10.9) and a mean T/B ratio of 2.9. Twenty of 32 evaluated metastases were visually detectable (mean SUVmax, 4.5 [range, 3.2–13.8]; mean T/B ratio, 2.8). The highest signal was detected in a patient with non–small cell lung cancer (SUVmax, 10.9; T/B ratio, 8.4) and a patient with cancer of unknown primary (SUVmax, 13.8; T/B ratio, 8.1). Compared with 18F-FDG PET, which was additionally performed in 10 patients, 68Ga-pentixafor PET had a lower SUVmax in all measured malignant lesions. Conclusion: On the basis of these first observations in a small and heterogeneous patient cohort, the in vitro CXCR4 expression profile of solid cancers and metastases described in the previous literature does not seem to sufficiently depict the in vivo distribution revealed by CXCR4-targeted PET. Moreover, the detectability of solid cancers seems to be generally lower for 68Ga-pentixafor than for 18F-FDG PET.

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

To identify the potential of semi‐quantitative enhancement‐analysis in breast MRI to predict disease‐related death in primary breast cancer patients.

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

ObjectiveTo analyse the kinetic characteristics of lesions without mass effect in dynamic breast MRI using manual and computer assisted methods.MethodsThe 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.ResultsUnlike 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).ConclusionComputer-assisted enhancement pattern analysis might have diagnostic benefit in the evaluation of lesions without mass effect.

Intrapatient Comparison of 111In-PSMA I&T SPECT/CT and Hybrid 68Ga-HBED-CC PSMA PET in Patients With Early Recurrent Prostate Cancer.

Purpose The aim of this study was to evaluate the detection efficiency of 111In-PSMA-I&T SPECT/CT in comparison to hybrid 68Ga-PSMA HBED-CC PET in patients with early recurrent prostate cancer. Methods Twenty-two patients (mean age, 68.2 ± 6.8 years; range, 52–76 years) with rising prostate-specific antigen (PSA; median, 1.03 ng/mL; range, 0.2–7.2ng/mL) and known positive lesions in hybrid 68Ga-PSMA HBED-CC PET scheduled for salvage surgery were included. Whole-body scintigraphy and SPECT/CT were performed 4 hours after application of 147.0 ± 24.8 MBq (range, 90–183 MBq) 111In-PSMA I&T. Images were evaluated for suspected lesions, and conspicuity of all lesions was rated using a 4-point-scale (0 = not seen, 1 = retrospectively seen in knowledge of 68Ga-PSMA HBED-CC PET, 2 = low signal, 3 = high signal). Tumor-to-background ratios were determined for SPECT and PET and compared. Tumor-to-background ratio of SPECT was correlated with lesion size as well as patients’ Gleason score and PSA level. Results 111In-PSMA I&T SPECT/CT detected 14 of 29 PET-positive lesions (48.3%) with no additional lesions identified with 111In-PSMA I&T SPECT/CT. There was a significant weak to moderate correlation of PSA level with tumor-to-background ratio of 111In-PSMA I&T SPECT/CT (correlation coefficient r = 0.6406; 95% confidence interval, 0.1667–0.8741; P = 0.0136). There was no significant difference (P > 0.05), but a weak trend toward a higher detectability in 111In-PSMA I&T SPECT/CT regarding lesion size and initial PSA level. Conclusions In a preselected collective of recurrent prostate cancer patients with low PSA values, 111In-PSMA I&T SPECT/CT showed lower detection rates than hybrid 68Ga-HBED-CC PSMA PET. However, 111In-PSMA I&T SPECT/CT showed a patient based detection rate of 59%, making it a potentially valuable imaging tool where PET is not available apart from its proven value as a PSMA-targeted probe for radioguided surgery.

Computerized analysis of enhancement kinetics for preoperative lymph node staging in rectal cancer using dynamic contrast-enhanced magnetic resonance imaging

For this feasibility study, dynamic contrast-enhanced magnetic resonance imaging (dceMRI) was performed preoperatively in 9 patients with histologically proven rectal carcinoma. A total of 41 lymph nodes detected were matched to histopathology. Their contrast enhancement patterns were evaluated using computer-aided analysis and categorized in persistent, plateau, and washout curve type. Highest diagnostic accuracy for detecting malignancy was observed, when less than 31.8% of the voxels within a lymph node demonstrated a washout curve (sensitivity/specificity of 81.8%/89.7%; area under the curve, AUC=0.87). In comparison, conventional size measurements revealed lower AUC of 0.81 (sensitivity/specificity of 75%/72.4%). We conclude that dceMRI might be of diagnostic value for preoperative lymph node staging.

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. [68Ga]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.

Response assessment with the CXCR4-directed positron emission tomography tracer [68Ga]Pentixafor in a patient with extranodal marginal zone lymphoma of the orbital cavities

CXCR4 belongs to the family of chemokine receptors. Together with its sole known ligand CXCL12 (SDF-1alpha), it has a pivotal role during organogenesis and for homing of hematopoietic stem cells. CXCR4 is overexpressed in various malignancies, and this is often associated with poor prognosis. Therefore, molecular imaging of CXCR4 bears a great potential for diagnostics and selecting patients for CXCR4-directed therapies. The CXCR4-directed positron emission tomography (PET) tracer [68Ga]Pentixafor has been shown to visualize CXCR4 expression in various malignancies in vivo. Whereas this tracer has limitations compared to 18F-Fluorodeoxyglucose ([18F]FDG) in diagnostic PET imaging in peripheral tumour lesions, it might add valuable information in routine diagnostics and response assessment of tumours in close proximity to the central nervous system (CNS) and malignancies within this organ. As a proof-of-concept, we performed [68Ga]Pentixafor PET imaging in a patient with extranodal marginal zone lymphoma (MZL) of the orbital cavities at diagnosis and for post-therapy response assessment. Compared to routinely conducted [18F]FDG PET, the lymphoma lesions determined by magnetic resonance imaging (MRI) showed high tracer accumulation at diagnosis, which decreased upon treatment. We therefore propose that imaging of CXCR4 with [68Ga]Pentixafor is a potential diagnostic tool for tumours close to or within the CNS and suggest this being studied in clinical trials.

Random forest learning of ultrasonic statistical physics and object spaces for lesion detection in 2D sonomammography

Breast cancer is the most common form of cancer in women. Early diagnosis can significantly improve lifeexpectancy and allow different treatment options. Clinicians favor 2D ultrasonography for breast tissue abnormality screening due to high sensitivity and specificity compared to competing technologies. However, inter- and intra-observer variability in visual assessment and reporting of lesions often handicaps its performance. Existing Computer Assisted Diagnosis (CAD) systems though being able to detect solid lesions are often restricted in performance. These restrictions are inability to (1) detect lesion of multiple sizes and shapes, and (2) differentiate between hypo-echoic lesions from their posterior acoustic shadowing. In this work we present a completely automatic system for detection and segmentation of breast lesions in 2D ultrasound images. We employ random forests for learning of tissue specific primal to discriminate breast lesions from surrounding normal tissues. This enables it to detect lesions of multiple shapes and sizes, as well as discriminate between hypo-echoic lesion from associated posterior acoustic shadowing. The primal comprises of (i) multiscale estimated ultrasonic statistical physics and (ii) scale-space characteristics. The random forest learns lesion vs. background primal from a database of 2D ultrasound images with labeled lesions. For segmentation, the posterior probabilities of lesion pixels estimated by the learnt random forest are hard thresholded to provide a random walks segmentation stage with starting seeds. Our method achieves detection with 99.19% accuracy and segmentation with mean contour-to-contour error < 3 pixels on a set of 40 images with 49 lesions.

S2k Guidelines - Cutaneous Lymphomas Update 2016 - Part 2: Treatment and Follow-up (ICD10 C82 - C86): German guidelines for cutaneous lymphomas

Coordination: Prof. Dr. Edgar Dippel, Ludwigshafen am Rhein, Germany Edgar Dippel 1 , Chalid Assaf 2 , Jürgen C. Becker 3 , Michael von Bergwelt-Baildon 4 , Marc Beyer 5 , Antonio Cozzio 6 , Hans Theodor Eich 7 , Markus Follmann 8 , Stephan Grabbe 9 , Uwe Hillen 10 , Wolfram Klapper 11 , Claus-Detlev Klemke 12 , Cristina Lamos 1 , Carmen Loquai 9 , Frank Meiß 13 , Dominik Mestel 14 , Dorothee Nashan 15 , Jan P. Nicolay 16 , Ilske Oschlies 11 , Max Schlaak 17 , Christoph Stoll 18 , Tibor Vag 19 , Michael Weichenthal 20 , Marion Wobser 21 , Rudolf Stadler 22

S2k Guidelines - Cutaneous Lymphomas Update 2016 - Part 1: Classification and Diagnosis (ICD10 C82 - C86): German guidelines for cutaneous lymphomas

Edgar Dippel 1 , Chalid Assaf 2 , Jürgen C. Becker 3 , Michael von Bergwelt-Baildon 4 , Marc Beyer 5 , Antonio Cozzio 6 , Hans Theodor Eich 7 , Markus Follmann 8 , Stephan Grabbe 9 , Uwe Hillen 10 , Wolfram Klapper 11 , Claus-Detlev Klemke 12 , Cristina Lamos 1 , Carmen Loquai 9 , Frank Meiß 13 , Dominik Mestel 14 , Dorothee Nashan 15 , Jan P. Nicolay 16 , Ilske Oschlies 11 , Max Schlaak 17 , Christoph Stoll 18 , Tibor Vag 19 , Michael Weichenthal 20 , Marion Wobser 21 , Rudolf Stadler 22