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.

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.

CXCR4-Targeted PET Imaging of Central Nervous System B-Cell Lymphoma.

C-X-C chemokine receptor 4 (CXCR4) is a transmembrane chemokine receptor involved in growth, survival, and dissemination of cancer, including aggressive B-cell lymphoma. MRI is the standard imaging technology for central nervous system (CNS) involvement of B-cell lymphoma and provides high sensitivity but moderate specificity. Therefore, novel molecular and functional imaging strategies are urgently required. Methods: In this proof-of-concept study, 11 patients with lymphoma of the CNS (8 primary and 3 secondary involvement) were imaged with the CXCR4-directed PET tracer 68Ga-pentixafor. To evaluate the predictive value of this imaging modality, treatment response, as determined by MRI, was correlated with quantification of CXCR4 expression by 68Ga-pentixafor PET in vivo before initiation of treatment in 7 of 11 patients. Results:68Ga-pentixafor PET showed excellent contrast with the surrounding brain parenchyma in all patients with active disease. Furthermore, initial CXCR4 uptake determined by PET correlated with subsequent treatment response as assessed by MRI. Conclusion:68Ga-pentixafor PET represents a novel diagnostic tool for CNS lymphoma with potential implications for theranostic approaches as well as response and risk assessment.

FDG/PET-CT-Based Lymph Node Atlas in Breast Cancer Patients.

PURPOSE: The aim of this study was to localize locoregional lymph node metastases using positron emission tomography with fluorine 18-fluorodeoxyglucose positron emission tomography/computed tomography (FDG-PET/CT) data sets in a large cohort of patients and to evaluate the existing Radiation Therapy Oncology Group (RTOG) clinical target volume (CTV) and the European Society for Radiation Therapy & Oncology (ESTRO) CTV contouring guidelines. METHODS AND MATERIALS: A total of 235 patients with 580 FDG/PET-CT positive locoregional lymph node metastases were included in our analysis. The patients were divided into 4 groups according to their course of disease (primary vs recurrent breast cancer) and the presence or absence of distant metastasis at the time of the FDG-PET/CT staging (distant metastasis vs no distant metastasis). All imaging data were imported into the planning system, and each lymph node was manually contoured. A patient with "standard anatomy" was chosen as a template, and all contoured structures were registered rigidly and nonrigidly to this patient. A comprehensive 3-dimensional atlas was created, including all identified lymph node metastases. The incidences of lymph node metastases were analyzed and are presented with color coding in the atlas. Lymph node levels (axillary, internal mammary, supraclavicular) were contoured according to RTOG and ESTRO guidelines and evaluated. RESULTS: The mean volume of the lymph nodes was 1.7 ± 2.6 cm3 with an average diameter of 1.3 ± 0.7 cm. Most lymph nodes were in level I (n = 316; 54.5%) followed by the supraclavicular region (n = 80; 13.8%), level II (n = 57; 9.8%), level III (n = 58; 10.0%), and the internal mammary region (n = 55; 9.5%). The covered lymph node volume was 69.8% ± 35.5% (69.1% ± 36.3%) for primary breast cancer and 57.6% ± 38.9% (51.1% ± 39.1%) for recurrent breast cancer using the RTOG (ESTRO) guidelines. The internal mammary region and supraclavicular region were affected more often in recurrent breast cancer compared with primary breast cancer. The occurrence of lymph node metastases outside the RTOG and ESTRO margins in patients with and without distant metastases was similar. The largest geometric deviations between RTOG/ESTRO CTV contours and lymph node occurrence were measured in the supraclavicular region, the internal mammary region, and level II. CONCLUSIONS: The provided lymph node atlas illustrates where lymph node metastases occur in different clinical situations and presents areas at high risk (ie "hot spots" of lymph node metastases).

PET imaging of chemokine receptor CXCR4 in patients with primary and recurrent breast carcinoma.

BACKGROUND: CXCR4 is a chemokine receptor frequently overexpressed in invasive breast cancer that has been shown to play a major role in signaling pathways involved in metastasis. The aim of this retrospective analysis was to assess the diagnostic performance of CXCR4-directed PET imaging in patients with breast cancer using the recently introduced CXCR4-targeted PET probe 68Ga-Pentixafor. RESULTS: Thirteen patients with first diagnosis of breast cancer, four patients with recurrent disease after primary breast cancer, and one patient with axillary lymph node metastasis of unknown primary underwent CXCR4-targeted PET imaging using 68Ga-Pentixafor. Maximum standardized uptake values (SUVmax) and tumor-to-background (T/B) ratios of tumor lesions were measured and compared with pathological prognostic factors and molecular subtypes. 18F-FDG PET/CT images were available in 8/18 cases and were compared semi-quantitatively. Comparison with CXCR4 expression determined by immunohistochemistry was performed in 7/18 patients. Nine of 13 primary breast cancers were visually detectable on 68Ga-Pentixafor PET images (mean SUVmax of 3.0). The visually undetectable lesions included both cases of invasive lobular carcinoma (ILC) and two cases of invasive carcinoma of no special type (NST) without any hormone receptor and HER2 expression (triple negative). Metastases of recurrent breast cancer and unknown primary cancer were visually detectable in all five cases, exhibiting a mean SUVmax of 3.5. 18F-FDG PET demonstrated higher SUVmax in all patients compared to 68Ga-Pentixafor PET. A correlation between SUVmax obtained from 68Ga-Pentixafor PET and prognostic factors including estrogen receptor (ER), progesterone receptor (PR), human epidermal growth factor receptor 2 (HER2) status, proliferation index, tumor grade, or molecular subtypes was not observed. CONCLUSIONS: CXCR4-directed PET imaging in patients with primary and recurrent breast cancer is feasible; however, tumor detectability is significantly lower compared to 18F-FDG PET. Moreover, we did not find any correlation between aforementioned prognostic factors of breast cancer and CXCR4-targeted tracer accumulation. Based on these results in a small patient cohort, CXCR4-targeted PET imaging does not seem to be suitable as a general diagnostic tool for imaging of breast cancer. Future CXCR4 imaging studies should investigate whether this modality might be useful in more specific applications, e.g., in therapeutic approaches especially under the view of current developments in targeted immune cell and immune checkpoint inhibitory therapy.

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.

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 In-PSMA-I&T SPECT/CT in comparison to hybrid Ga-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 Ga-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) In-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 Ga-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: In-PSMA I&T SPECT/CT detected 14 of 29 PET-positive lesions (48.3%) with no additional lesions identified with In-PSMA I&T SPECT/CT. There was a significant weak to moderate correlation of PSA level with tumor-to-background ratio of In-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 In-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, In-PSMA I&T SPECT/CT showed lower detection rates than hybrid Ga-HBED-CC PSMA PET. However, In-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.

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.

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

UNLABELLED: 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 (68)Ga-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 (18)F-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 (18)F-FDG PET, which was additionally performed in 10 patients, (68)Ga-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 (68)Ga-pentixafor than for (18)F-FDG PET.

[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.

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.

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.