Faculty Bibliography

BACKGROUND:[18F]-FDG-PET/MR carries a high diagnostic value in whole-body oncologic imaging and allows simultaneous quantitative measurements of glucose metabolism (SUV) and cell density (ADC). PURPOSE:To determine the relationship between SUV and ADC values extracted from simultaneously acquired [18F]-FDG-PET/MR data of patients with FDG-avid lymphomas at staging. STUDY TYPE:Prospective. POPULATION:Patients with histologically proven lymphoma referred for staging. FIELD STRENGTH/SEQUENCES:-weighted half-Fourier acquisition single-shot turbo spin-echo. Single-shot, echo-planar imaging-based, spectral adiabatic inversion recovery diffusion-weighted imaging. ASSESSMENT:Staging was performed according to the modified Ann Arbor system by a board-certified radiologist and a board-certified nuclear medicine physician, blinded to the clinical and histological information, in consensus. SUVs and ADCs values were collected, for each positive nodal and extranodal region, from the lesion demonstrating the largest diameter. STATISTICAL TESTS:Descriptive data included absolute frequencies and percentages for categorical data, and arithmetic means and 95% confidence intervals for scale-type data. The Pearson correlation coefficient was used to assess the relationship between SUVs and ADCs (P ≤ 0.05). Additional separate analyses were performed according to histological lymphoma subtype, for nodal and extranodal lesions and excluding bone lesions. RESULTS:Overall, 100 patients were examined (55 males, 45 females; age ± SD in years, 51.6 ± 19.5). Histology revealed Hodgkin-lymphoma and non-Hodgkin-lymphoma in 26 and 74 patients, respectively. Twenty patients were stage I, 21 stage II, 24 stage III, and 31 stage IV on [18F]-FDG-PET/MR (ie, four patients negative at imaging). Based on 391 lesions (ie, 367 excluding bone lesions) no significant correlations between SUVmax and ADCmin, or between SUVmean and ADCmean, emerged (respectively, r = 0.091, P = 0.073, 95% CI [-0.01, 0.19] and r = -0.032, P = 0.527, 95% CI [-0.13, 0.07] including bone lesions; r = 0.06, P = 0.21, 95% CI [-0.04, 0.17] and r = -0.05, P = 0.32, 95% CI [-0.15, 0.05] excluding bone lesions). A significant correlation was observed only between ADCmean and SUVmean for follicular lymphoma (r = -0.33, P = 0.001). DATA CONCLUSION:SUVs and ADCs were demonstrated to be independent biomarkers in lymphomas. A moderate correlation between SUVs and ADCs likely is present in follicular lymphoma. LEVEL OF EVIDENCE:1 Technical Efficacy: Stage 3 J. Magn. Reson. Imaging 2018;47:1217-1226.

RATIONALE AND OBJECTIVES:This study aimed to determine the diagnostic utility of standardized uptake values (SUV) and apparent diffusion coefficients (ADC) for assessment of focal and diffuse bone marrow involvement in patients with malignant lymphoma. MATERIALS AND METHODS:/s) on whole-body-DWI, were extracted from focal lesions, or, in their absence, from the thoracic (Th8) and lumbar vertebral bodies (L4), the sacral bone (S1), and the iliac crest. Lesion-to-liver-ratios (SUVmax-ratio) were calculated. Pearson correlation coefficients were used to assess the correlation between SUVmax-ratios and ADCmean values. RESULTS:Bone marrow involvement was observed in 16 of 60 patients (8 of 16 with diffuse infiltration). The SUVmax-ratio cutoff value was 95.25% for focal and 70.2% for diffuse bone marrow involvement (sensitivity/specificity of 87.5%/86.4% and 100%/43.2%, respectively). The ADCmean cutoff value was 0.498 for focal and 0.401 for diffuse bone marrow involvement (sensitivity/specificity of 100%/90.9% and 87.5%/56.8%, respectively). No significant correlations were found between SUVmax-ratios and ADCmean values in the different groups. CONCLUSION:With the liver as reference tissue, quantitative [F18]-FDG-PET/CT may be useful to differentiate bone marrow involvement from normal bone marrow in patients with lymphoma, even though the specificity for diffuse marrow involvement is rather low. Quantitative DWI can be used only to distinguish focal bone marrow lesions from normal bone marrow.

Lenalidomide is an active agent for the treatment of MALT lymphoma. Recently, high expression levels of cereblon (CRBN) and MUM1 have been associated with better response rates in multiple myeloma treated with lenalidomide. However, there are no data on CRBN and MUM1 expression in MALT lymphoma. In the current study, we have systematically investigated a potential correlation of CRBN/MUM1 immunohistochemical expression and response to lenalidomide-based therapy in a series of 46 patients with MALT lymphoma treated at the Medical University Vienna 2009 to 2014. In total, 28% (13/46) of biopsy specimens derived from gastric tissues, while 72% (33/46) originated from extragastric MALT lymphoma. In terms of CRBN, 54% showed high expression (CRBN+, ≥50% positive cells); the remaining 46% were classified as low expression (CRBN-). In contrast to other reports, there was a non-significant trend towards worse response rates in CRBN+ (68% versus 86%, P = 0.161). Relapse rates (P = 0.592) and PFS (P = 0.306) did not differ between CRBN+/CRBN-, but all 3 patients progressing on lenalidomide were CRBN+ and both patients completely lacking CRBN expression responded to treatment. Concerning MUM1, 62% were MUM1-negative (MUM1-) and 38% positive (MUM1+). There was no difference in response to lenalidomide by MUM1-status (MUM1+ 71% versus MUM1- 79%, P = 0.546) and also relapse rates (P = 0.828) and PFS (P = 0.681) did not differ. Interestingly, a subgroup analysis of gastric lymphoma revealed a significantly better PFS for CRBN- and MUM1- patients, respectively (both P < 0.05). To conclude, there was no significant difference in response to lenalidomide between patients with low or high expression of CRBN/MUM1 in a general population of MALT lymphoma, and immunohistochemical CRBN/MUM1 assessment cannot be recommended in the clinical routine.

These are the final results of the Ofatumumab in MALT lymphoma study (O-MA 1), a pilot phase II trial evaluating the capacity and safety of ofatumumab to induce objective responses in patients with Helicobacter pylori eradication refractory or extragastric MALT lymphoma. Ofatumumab was given at 4 weekly doses (1000 mg) followed by 4 doses at 2-month intervals starting at week 8. According to protocol, a total of 16 patients were recruited (median age 69 years; range 38-85). Thirty one percent (5/16) of patients had primary gastric MALT lymphoma while the remaining 69% (11/16) presented with extragastric manifestations. Seventy-five percent (12/16) had localized lymphoma and 4 patients disseminated disease. The overall response rate to treatment with ofatumumab was 81% (13/16), with the median time to best response being 5.5 months. In detail, 50% (8/16) achieved complete remission; 31% (5/16), partial remission; and 19% (3/16), disease stabilization as best response. However, 1 patient with gastric lymphoma and complete remission at second restaging had a relapse at final assessment but ongoing complete remission during further follow-up. Tolerability was excellent accept low-grade infusion reactions occurring in 86% (14/16). At a median follow-up time of 25 months only 1 patient has relapsed suggesting durable responses in the majority of patients. This pilot trial shows clearly that ofatumumab is active and safe for the treatment of MALT lymphoma.

Primary follicular lymphoma of the duodenum (FL-D) constitutes a rare subtype of extranodal follicular lymphoma with a usually indolent course. To date, no distinct treatment recommendations have been defined for those patients. We report the case of a 58-year-old male patient presenting with endoscopically assessed, symptomatic FL-D who was treated with clarithromycin monotherapy in analogy to recent data for mucosa-associated lymphoid tissue lymphoma. Each treatment cycle consisted of clarithromycin 500 mg twice daily for 3 weeks followed by a 2-week break. After four cycles of treatment, the patient showed a very good response with normal macroscopic findings confirmed by endosonographic examination and only focal minimal residual disease of lymphoma persisting in the histological assessment. The patient is currently asymptomatic and without treatment for 24+ months. As clarithromycin combines antimicrobial and direct antiproliferative effects mediated through a variety of pleiotropic mechanisms, this appears to be an interesting treatment approach for indolent lymphoma, particularly in those where a chronic infectious background cannot be completely ruled out, i.e., gastrointestinal manifestations. We suggest further investigation of this treatment approach.

T-cell prolymphocytic leukemia (T-PLL) is a rare and aggressive T-lymphoid malignancy usually refractory to current treatment strategies and associated with short overall survival. By applying next-generation functional testing of primary patient-derived lymphoma cells using a library of 106 US Food and Drug Administration (FDA)-approved anticancer drugs or compounds currently in clinical development, we set out to identify novel effective treatments for T-PLL patients. We found that the B-cell lymphoma 2 (BCL-2) inhibitor venetoclax (ABT-199) demonstrated the strongest T-PLL-specific response when comparing individual ex vivo drug response in 86 patients with refractory hematologic malignancies. Mechanistically, responses to venetoclax correlated with protein expression of BCL-2 but not with expression of the BCL-2 family members myeloid cell leukemia 1 (MCL-1) and BCL-XL in lymphoma cells. BCL-2 expression was inversely correlated with the expression of MCL-1. Based on the ex vivo responses, venetoclax treatment was commenced in 2 late-stage refractory T-PLL patients resulting in clinical responses. Our findings demonstrate first evidence of single-agent activity of venetoclax both ex vivo and in humans, offering a novel agent in T-PLL.

BACKGROUND:Patients with refractory or relapsed haematological malignancies have few treatment options and short survival times. Identification of effective therapies with genomic-based precision medicine is hampered by intratumour heterogeneity and incomplete understanding of the contribution of various mutations within specific cancer phenotypes. Ex-vivo drug-response profiling in patient biopsies might aid effective treatment identification; however, proof of its clinical utility is limited. METHODS:We investigated the feasibility and clinical impact of multiparametric, single-cell, drug-response profiling in patient biopsies by immunofluorescence, automated microscopy, and image analysis, an approach we call pharmacoscopy. First, the ability of pharmacoscopy to separate responders from non-responders was evaluated retrospectively for a cohort of 20 newly diagnosed and previously untreated patients with acute myeloid leukaemia. Next, 48 patients with aggressive haematological malignancies were prospectively evaluated for pharmacoscopy-guided treatment, of whom 17 could receive the treatment. The primary endpoint was progression-free survival in pharmacoscopy-treated patients, as compared with their own progression-free survival for the most recent regimen on which they had progressive disease. This trial is ongoing and registered with ClinicalTrials.gov, number NCT03096821. FINDINGS/RESULTS:Pharmacoscopy retrospectively predicted the clinical response of 20 acute myeloid leukaemia patients to initial therapy with 88·1% accuracy. In this interim analysis, 15 (88%) of 17 patients receiving pharmacoscopy-guided treatment had an overall response compared with four (24%) of 17 patients with their most recent regimen (odds ratio 24·38 [95% CI 3·99-125·4], p=0·0013). 12 (71%) of 17 patients had a progression-free survival ratio of 1·3 or higher, and median progression-free survival increased by four times, from 5·7 (95% CI 4·1-12·1) weeks to 22·6 (7·4-34·0) weeks (hazard ratio 3·14 [95% CI 1·37-7·22], p=0·0075). INTERPRETATION/CONCLUSIONS:Routine clinical integration of pharmacoscopy for treatment selection is technically feasible, and led to improved treatment of patients with aggressive refractory haematological malignancies in an initial patient cohort, warranting further investigation. FUNDING/BACKGROUND:Austrian Academy of Sciences; European Research Council; Austrian Science Fund; Austrian Federal Ministry of Science, Research and Economy; National Foundation for Research, Technology and Development; Anniversary Fund of the Austrian National Bank; MPN Research Foundation; European Molecular Biology Organization; and Swiss National Science Foundation.

PURPOSE/OBJECTIVE:The aim of this study was to assess the diagnostic performance of simultaneous whole-body Ga-DOTANOC PET/MRI compared with Ga-DOTANOC PET/CT for detection of distant metastatic disease in patients with well-differentiated neuroendocrine tumors (NETs). METHODS:Patients with histologically proven, well-differentiated NET (G1 or G2) were included in this prospective, institutional review board-approved study. Patients underwent Ga-DOTANOC PET/CT and subsequent Ga-DOTANOC PET/MRI after a single tracer injection on the same day for staging or restaging purposes. Images were evaluated for the presence of NET lesions by 2 rater teams, each consisting of a nuclear medicine physician and a radiologist, in an observer-blinded fashion. Overall agreement, accuracy, sensitivity, and specificity, relative to a composite reference standard (consensus review including follow-up data), were calculated. RESULTS:Between July 2014 and June 2016, 28 patients were enrolled. Overall agreement and accuracy between the 2 rater teams were 91.7% (95% confidence interval [CI], 87.5%-95.9%) and 97% (95% CI, 94.4%-99.6%) for PET/MRI and 92.3% (95% CI, 88.3%-96.3%) and 94.6% (95% CI, 91.2%-98.1%) for PET/CT, respectively (P = 1.00).Overall, PET/MRI reached 89.8% sensitivity (95% CI, 77.8%-96.6%) and 100% specificity (95% CI, 97%-100%); PET/CT showed 81.6% sensitivity (95% CI, 68%-91.2%) and 100% specificity (95% CI, 97%-100%) for the detection of metastatic disease in NETs. CONCLUSIONS:Whole-body Ga-DOTANOC PET/MRI appears to be comparable to Ga-DOTANOC PET/CT for lesion detection in patients with well-differentiated NETs.

The aim of this study was to compare attenuation-correction (AC) approaches for PET/MRI in clinical neurooncology. Methods: Forty-nine PET/MRI brain scans were included: brain tumor studies using ¹⁸F-fluoro-ethyl-tyrosine (¹⁸F-FET) (n = 31) and ⁶⁸Ga-DOTANOC (n = 7) and studies of healthy subjects using ¹⁸F-FDG (n = 11). For each subject, MR-based AC maps (MR-AC) were acquired using the standard DIXON- and ultrashort echo time (UTE)-based approaches. A third MR-AC was calculated using a model-based, postprocessing approach to account for bone attenuation values (BD, noncommercial prototype software by Siemens Healthcare). As a reference, AC maps were derived from patient-specific CT images (CTref). PET data were reconstructed using standard settings after AC with all 4 AC methods. We report changes in diagnosis for all brain tumor patients and the following relative differences values (RDs [%]), with regards to AC-CTref: for ¹⁸F-FET (A)-SUVs as well as volumes of interest (VOIs) defined by a 70% threshold of all segmented lesions and lesion-to-background ratios; for ⁶⁸Ga-DOTANOC (B)-SUVs as well as VOIs defined by a 50% threshold for all lesions and the pituitary gland; and for ¹⁸F-FDG (C)-RD of SUVs of the whole brain and 10 anatomic regions segmented on MR images. Results: For brain tumor imaging (A and B), the standard PET-based diagnosis was not affected by any of the 3 MR-AC methods. For A, the average RDs of SUV_mean were -10%, -4%, and -3% and of the VOIs 1%, 2%, and 7% for DIXON, UTE, and BD, respectively. Lesion-to-background ratios for all MR-AC methods were similar to that of CTref. For B, average RDs of SUV_mean were -11%, -11%, and -3% and of the VOIs 1%, -4%, and -3%, respectively. In the case of ¹⁸F-FDG PET/MRI (C), RDs for the whole brain were -11%, -8%, and -5% for DIXON, UTE, and BD, respectively. Conclusion: The diagnostic reading of PET/MR patients with brain tumors did not change with the chosen AC method. Quantitative accuracy of SUVs was clinically acceptable for UTE- and BD-AC for group A, whereas for group B BD was in accordance with CTref. Nevertheless, for the quantification of individual lesions large deviations to CTref can be observed independent of the MR-AC method used.