A decade of multi-modality PET and MR imaging in abdominal oncology.

OBJECTIVES: To investigate trends observed in a decade of published research on multimodality PET(/CT)+MR imaging in abdominal oncology, and to explore how these trends are reflected by the use of multimodality imaging performed at our institution. METHODS: First, we performed a literature search (2009-2018) including all papers published on the multimodality combination of PET(/CT) and MRI in abdominal oncology. Retrieved papers were categorized according to a structured labelling system, including study design and outcome, cancer and lesion type under investigation and PET-tracer type. Results were analysed using descriptive statistics and evolutions over time were plotted graphically. Second, we performed a descriptive analysis of the numbers of MRI, PET/CT and multimodality PET/CT+MRI combinations (performed within a ≤14 days interval) performed during a similar time span at our institution. RESULTS: Published research papers involving multimodality PET(/CT)+MRI combinations showed an impressive increase in numbers, both for retrospective combinations of PET/CT and MRI, as well as hybrid PET/MRI. Main areas of research included new PET-tracers, visual PET(/CT)+MRI assessment for staging, and (semi-)quantitative analysis of PET-parameters compared to or combined with MRI-parameters as predictive biomarkers. In line with literature, we also observed a vast increase in numbers of multimodality PET/CT+MRI imaging in our institutional data. CONCLUSIONS: The tremendous increase in published literature on multimodality imaging, reflected by our institutional data, shows the continuously growing interest in comprehensive multivariable imaging evaluations to guide oncological practice. ADVANCES IN KNOWLEDGE: The role of multimodality imaging in oncology is rapidly evolving. This paper summarizes the main applications and recent developments in multimodality imaging, with a specific focus on the combination of PET+MRI in abdominal oncology.

Studying local tumour heterogeneity on MRI and FDG-PET/CT to predict response to neoadjuvant chemoradiotherapy in rectal cancer.

OBJECTIVE: To investigate whether quantifying local tumour heterogeneity has added benefit compared to global tumour features to predict response to chemoradiotherapy using pre-treatment multiparametric PET and MRI data. METHODS: Sixty-one locally advanced rectal cancer patients treated with chemoradiotherapy and staged at baseline with MRI and FDG-PET/CT were retrospectively analyzed. Whole-tumour volumes were segmented on the MRI and PET/CT scans from which global tumour features (T2Wvolume/T2Wentropy/ADCmean/SUVmean/TLG/CTmean-HU) and local texture features (histogram features derived from local entropy/mean/standard deviation maps) were calculated. These respective feature sets were combined with clinical baseline parameters (e.g. age/gender/TN-stage) to build multivariable prediction models to predict a good (Mandard TRG1-2) versus poor (Mandard TRG3-5) response to chemoradiotherapy. Leave-one-out cross-validation (LOOCV) with bootstrapping was performed to estimate performance in an 'independent' dataset. RESULTS: When using only imaging features, local texture features showed an AUC = 0.81 versus AUC = 0.74 for global tumour features. After internal cross-validation (LOOCV), AUC to predict a good response was the highest for the combination of clinical baseline variables + global tumour features (AUC = 0.83), compared to AUC = 0.79 for baseline + local texture and AUC = 0.76 for all combined (baseline + global + local texture). CONCLUSION: In imaging-based prediction models, local texture analysis has potential added value compared to global tumour features to predict response. However, when combined with clinical baseline parameters such as cTN-stage, the added value of local texture analysis appears to be limited. The overall performance to predict response when combining baseline variables with quantitative imaging parameters is promising and warrants further research. KEY POINTS: • Quantification of local tumour texture on pre-therapy FDG-PET/CT and MRI has potential added value compared to global tumour features to predict response to chemoradiotherapy in rectal cancer. • However, when combined with clinical baseline parameters such as cTN-stage, the added value of local texture over global tumour features is limited. • Predictive performance of our optimal model-combining clinical baseline variables with global quantitative tumour features-was encouraging (AUC 0.83), warranting further research in this direction on a larger scale.

Pre-treatment prediction of early response to chemoradiotherapy by quantitative analysis of baseline staging FDG-PET/CT and MRI in locally advanced cervical cancer.

BACKGROUND: Early prediction of response to concurrent chemoradiotherapy (cCRT) could aid to further optimize treatment regimens for locally advanced cervical cancer (LACC) in the future. PURPOSE: To explore whether quantitative parameters from baseline (pre-therapy) magnetic resonance imaging (MRI) and FDG-PET/computed tomography (CT) have potential as predictors of early response to cCRT. MATERIAL AND METHODS: Forty-six patients with LACC undergoing cCRT after staging with FDG-PET/CT and MRI were retrospectively analyzed. Primary tumor volumes were delineated on FDG-PET/CT, T2-weighted (T2W)-MRI and diffusion-weighted MRI (DWI) to extract the following quantitative parameters: T2W volume; T2W signalmean; DWI volume; ADCmean; ADCSD; MTV42%; and SUVmax. Outcome was the early treatment response, defined as the residual tumor volume on MRI 3-4 weeks after start of external beam radiotherapy with chemotherapy (before the start of brachytherapy): patients with a residual tumor volume <10 cm3 were classified as early responders. Imaging parameters were analyzed together with FIGO stage to assess their performance to predict early response, using multivariable logistic regression analysis with bi-directional variable selection. Leave-one-out cross-validation with bootstrapping was used to simulate performance in a new, independent dataset. RESULTS: T2W volume (OR 0.94, P = 0.003) and SUVmax (OR 1.15, P = 0.18) were identified as independent predictors in multivariable analysis, rendering a model with an AUC of 0.82 in the original dataset, and AUC of 0.68 (95% CI 0.41-0.81) from cross-validation. CONCLUSION: Although the predictive performance achieved in this small exploratory dataset was limited, these preliminary data suggest that parameters from baseline MRI and FDG-PET/CT (in particular pre-therapy tumor volume) may contribute to prediction of early response to cCRT in cervical cancer.

Gross tumour volume delineation in anal cancer on T2-weighted and diffusion-weighted MRI - Reproducibility between radiologists and radiation oncologists and impact of reader experience level and DWI image quality.

PURPOSE: To assess how gross tumour volume (GTV) delineation in anal cancer is affected by interobserver variations between radiologists and radiation oncologists, expertise level, and use of T2-weighted MRI (T2W-MRI) vs. diffusion-weighted imaging (DWI), and to explore effects of DWI quality. METHODS AND MATERIALS: We retrospectively analyzed the MRIs (T2W-MRI and b800-DWI) of 25 anal cancer patients. Four readers (Senior and Junior Radiologist; Senior and Junior Radiation Oncologist) independently delineated GTVs, first on T2W-MRI only and then on DWI (with reference to T2W-MRI). Maximum Tumour Diameter (MTD) was calculated from each GTV. Mean GTVs/MTDs were compared between readers and between T2W-MRI vs. DWI. Interobserver agreement was calculated as Intraclass Correlation Coefficient (ICC), Dice Similarity Coefficient (DSC) and Hausdorff Distance (HD). DWI image quality was assessed using a 5-point artefact scale. RESULTS: Interobserver agreement between radiologists vs. radiation oncologists and between junior vs. senior readers was good-excellent, with similar agreement for T2W-MRI and DWI (e.g. ICCs 0.72-0.94 for T2W-MRI and 0.68-0.89 for DWI). There was a trend towards smaller GTVs on DWI, but only for the radiologists (P = 0.03-0.07). Moderate-severe DWI-artefacts were observed in 11/25 (44%) cases. Agreement tended to be lower in these cases. CONCLUSION: Overall interobserver agreement for anal cancer GTV delineation on MRI is good for both radiologists and radiation oncologists, regardless of experience level. Use of DWI did not improve agreement. DWI artefacts affecting GTV delineation occurred in almost half of the patients, which may severely limit the use of DWI for radiotherapy planning if no steps are undertaken to avoid them.

Value of combined multiparametric MRI and FDG-PET/CT to identify well-responding rectal cancer patients before the start of neoadjuvant chemoradiation.

OBJECTIVES: To explore the value of multiparametric MRI combined with FDG-PET/CT to identify well-responding rectal cancer patients before the start of neoadjuvant chemoradiation. METHODS: Sixty-one locally advanced rectal cancer patients who underwent a baseline FDG-PET/CT and MRI (T2W + DWI) and received long-course neoadjuvant chemoradiotherapy were retrospectively analysed. Tumours were delineated on MRI and PET/CT from which the following quantitative parameters were calculated: T2W volume and entropy, ADC mean and entropy, CT density (mean-HU), SUV maximum and mean, metabolic tumour volume (MTV42%) and total lesion glycolysis (TLG). These features, together with sex, age, mrTN-stage ("baseline parameters") and the CRT-surgery interval were analysed using multivariable stepwise logistic regression. Outcome was a good (TRG 1-2) versus poor histopathological response. Performance (AUC) to predict response was compared for different combinations of baseline ± quantitative imaging parameters and performance in an 'independent' dataset was estimated using bootstrapped leave-one-out cross-validation (LOOCV). RESULTS: The optimal multivariable prediction model consisted of a combination of baseline + quantitative imaging parameters and included mrT-stage (OR 0.004, p < 0.001), T2W-signal entropy (OR 7.81, p = 0.0079) and T2W volume (OR 1.028, p = 0.0389) as the selected predictors. AUC in the study dataset was 0.88 and 0.83 after LOOCV. No PET/CT features were selected as predictors. CONCLUSIONS: A multivariable model incorporating mrT-stage and quantitative parameters from baseline MRI can aid in identifying well-responding patients before the start of treatment. Addition of FDG-PET/CT is not beneficial. KEY POINTS: • A multivariable model incorporating the mrT-stage and quantitative features derived from baseline MRI can aid in identifying well-responding patients before the start of neoadjuvant chemoradiotherapy. • mrT-stage was the strongest predictor in the model and was complemented by the tumour volume and signal entropy calculated from T2W-MRI. • Adding quantitative features derived from pre-treatment PET/CT or DWI did not contribute to the model's predictive performance.

Integrated versus separate reading of F-18 FDG-PET/CT and MRI for abdominal malignancies - effect on staging outcomes and diagnostic confidence.

OBJECTIVE: Abdominal cancer patients increasingly undergo multimodality imaging. This study evaluates effects of integrated reading of PET/CT and abdominal MRI on staging outcomes and diagnostic confidence compared to "routine" separate reading. METHODS: In total, N = 201 patients who underwent abdominal MRI and whole-body F-18 FDG-PET/CT within 14 days were retrospectively analyzed. Original MRI and PET/CT reports were retrieved and reported findings translated into a 5-point confidence score (1 = definitely benign to 5 = definitely malignant) for 7 standardized regions (primary tumor/regional lymph nodes/distant lymph nodes/liver/lung/bone/peritoneum) per patient. Two-reader teams (radiologist + nuclear medicine physician) then performed integrated reading of the images using the same scoring system. RESULTS: Integrated reading led to discrepant findings in 59 of 201 (29%) of patients, with potential clinical impact in 25 of 201 (12%). Equivocal scores decreased from 5.7% (PET/CT) and 5.4% (MRI) to 3.2% (p = 0.05 and p = 0.14). Compared to the original PET/CT reports, integrated reading led to increased diagnostic confidence in 8.9% versus decreased confidence in 6.6% (p = 0.26). Compared with the original MRI reports, an increase in confidence occurred in 9.6% versus a decrease in 6.9% (p = 0.18). The effect on diagnostic confidence was most pronounced in lymph nodes (p = 0.08 vs. MRI), cervical cancer (p = 0.03 vs. MRI), and recurrent disease staging (p = 0.06 vs. PET/CT). CONCLUSIONS: Integrated PET/CT+MRI reading alters staging outcomes in a substantial proportion of cases with potential clinical impact in ± 1 out of 9 patients. It can also have a small positive effect on diagnostic confidence, particularly in lymph nodes and cervical cancer, and in post-treatment settings. These findings support further collaboration between radiology and nuclear medicine disciplines. KEY POINTS: • Increasing numbers of patients undergo multimodality imaging consisting of both MRI and PET/CT for staging of abdominal malignancies. • Integrated reading of FDG-PET/CT and abdominal MR images by a team, consisting of a radiologist and a nuclear medicine physician, can alter staging outcomes compared to separate reporting of the exams in a substantial proportion of cases and with potential clinical impact in ± 1 out of 9 patients. • Integrated PET/CT+MRI reading can have a small positive effect on diagnostic confidence.

Normal hematopoietic stem cells within the AML bone marrow have a distinct and higher ALDH activity level than co-existing leukemic stem cells.

Persistence of leukemic stem cells (LSC) after chemotherapy is thought to be responsible for relapse and prevents the curative treatment of acute myeloid leukemia (AML) patients. LSC and normal hematopoietic stem cells (HSC) share many characteristics and co-exist in the bone marrow of AML patients. For the development of successful LSC-targeted therapy, enabling eradication of LSC while sparing HSC, the identification of differences between LSC and HSC residing within the AML bone marrow is crucial. For identification of these LSC targets, as well as for AML LSC characterization, discrimination between LSC and HSC within the AML bone marrow is imperative. Here we show that normal CD34+CD38- HSC present in AML bone marrow, identified by their lack of aberrant immunophenotypic and molecular marker expression and low scatter properties, are a distinct sub-population of cells with high ALDH activity (ALDH(bright)). The ALDH(bright) compartment contains, besides normal HSC, more differentiated, normal CD34+CD38+ progenitors. Furthermore, we show that in CD34-negative AML, containing solely normal CD34+ cells, LSC are CD34- and ALDH(low). In CD34-positive AML, LSC are also ALDH(low) but can be either CD34+ or CD34-. In conclusion, although malignant AML blasts have varying ALDH activity, a common feature of all AML cases is that LSC have lower ALDH activity than the CD34+CD38- HSC that co-exist with these LSC in the AML bone marrow. Our findings form the basis for combined functionally and immunophenotypically based identification and purification of LSC and HSC within the AML bone marrow, aiming at development of highly specific anti-LSC therapy.