Faculty Bibliography

UNLABELLED:MALT lymphomas express the chemokine receptor CXCR4 on a regular basis, and [68Ga]Ga-Pentixafor-PET has been shown to quantify CXCR4 expression non-invasively. We, therefore, aimed to evaluate [68Ga]Ga-Pentixafor-PET/MRI for the non-invasive assessment of MALT lymphomas. METHODS:We included 36 MALT lymphoma patients, who had not undergone previous systemic or radiation therapy, in our prospective, IRB-approved, proof-of-concept study. Involved anatomic regions were the orbit (n=14), stomach (n=10), lungs (n=5), and other sites (soft-tissues n=3; adrenal gland, tonsils, parotid gland, and urinary bladder n=1, respectively). MRI sequences included an axial 2-point Dixon T1 VIBE SPAIR 3D sequence for PET attenuation correction; a coronal T2 HASTE sequence; and an axial echo-planar imaging SPAIR-based diffusion-weighted sequence (DWI) obtained during free-breathing (b-values, 50 and 800), with corresponding ADC (apparent diffusion coefficient) maps. RESULTS:In 33/36 patients, there were MALT lymphomas with an increased uptake of [68Ga]Ga-Pentixafor; all current lymphoma manifestations showed an increased uptake and, accordingly, were positive on the PET/MRI. The remaining three patients had undergone surgery for their orbital MALT lymphomas prior to PET/MRI. Mean SUVmax was 8.6 ± 4.7, mean SUVmean was 4.7 ± 1.8, and mean SUVpeak was 8.0 ± 4.2. The mean SUVmax of the liver was 1.8, and the mean tumor-to-liver ratio was 2.9 ± 2.0. There were no significant differences in SUVmax (P=0.22), SUVmean (P=0.53), SUVpeak (P=0.29), or SUVt/l (P=0.92) between the four anatomic regions (orbit, stomach, lungs, other). The mean tumor volume was 146 ± 499. CONCLUSIONS:Our results thus indicate that [68Ga]Ga-Pentixafor-PET is feasible for the assessment of MALT lymphomas, with a good tumor-to-background ratio in terms of radiotracer uptake.

PURPOSE:Aim of present study was to determine whether the currently recommended 13-cm cranio-caudal diameter cut-off on CT for assessment of splenic involvement in lymphoma offers adequate sensitivity and specificity. MATERIALS AND METHODS:Patients with histologically proven lymphoma who had undergone [18F]FDG-PET/CT before therapy were included. Cranio-caudal diameters of the spleen were measured on the CT component of PET/CT, and ROC analyses with calculation of respective areas under the curve (AUC) were used to determine cut-off values of cranio-caudal measurements with their respective sensitivities and specificities, using [18F]FDG-PET as the reference standard. RESULTS:In 93 patients, we found a sensitivity of 74.1% and a specificity of 47% for the 13-cm splenic diameter cut-off. CONCLUSIONS:Our results show reasonable, though far from perfect sensitivities and specificities for the currently recommend 13-cm splenic diameter cut-off.

PURPOSE:F]DOPA PET/ceCT to stage MTC in patients with suspicious thyroid nodules and pathologically elevated serum calcitonin (Ctn) levels prior to total thyroidectomy and lymph node (LN) dissection. METHODS:A group of 32 patients with sonographically suspicious thyroid nodules and pathologically elevated basal Ctn (bCtn) and stimulated Ctn (sCtn) levels underwent DOPA PET/ceCT prior to surgery. Postoperative histology served as the standard of reference for ultrasonography and DOPA PET/ceCT region-based LN staging. Univariate and multivariate regression analyses as well as receiver operating characteristic analysis were used to evaluate the correlations between preoperative and histological parameters and postoperative tumour persistence or relapse. RESULTS:Primary MTC was histologically verified in all patients. Of the 32 patients, 28 showed increased DOPA decarboxylase activity in the primary tumour (sensitivity 88%, mean SUVmax 10.5). Undetected tumours were exclusively staged pT1a. The sensitivities of DOPA PET in the detection of central and lateral metastatic neck LN were 53% and 73%, in contrast to 20% and 39%, respectively, for neck ultrasonography. Preoperative bCtn and carcinoembryonic antigen levels as well as cN1b status and the number of involved neck regions on DOPA PET/ceCT were predictive of postoperative tumour persistence/relapse in the univariate regression analysis (P < 0.05). Only DOPA PET/ceCT cN1b status remained significant in the multivariate analysis (P = 0.016, relative risk 4.02). CONCLUSION:This study revealed that DOPA PET/ceCT has high sensitivity in the detection of primary MTC and superior sensitivity in the detection of LN metastases compared to ultrasonography. DOPA PET/ceCT identification of N1b status predicts postoperative tumour persistence. Thus, implementation of a DOPA-guided LN dissection might improve surgical success.

OBJECTIVE:F) FDG-PET/CT] compared to diffusion-weighted imaging (DWI)-MRI of lesion detection in patients with non-FDG avid gastric mucosa-associated lymphoid tissue (MALT) lymphoma. METHODS:F]-FDG-PET/CT and consecutive MRI/DWI. Images were evaluated for the presence of gastric lesions in two anatomically defined groups (region 1: cardia, body, fundus; region 2: antrum, pyloric region) by two senior board-certified radiologists, in an observer-blinded manner. Overall accuracy relative to the reference standard (histology obtained by biopsy) was calculated for each reader and a consensus rating. RESULTS:We found a statistically significant higher accuracy of lesion detection for lesions in region 1 (p = 0.030) and 2 (p = 0.070) for DWI-MRI (100%/78.9%) than for CT (68.4%/42.1%). CONCLUSION/CONCLUSIONS:DWI-MRI seems to be superior accurate to CT for lesion detection in non-FDG avid gastric MALT lymphoma. Advances in knowledge: DWI-MRI seems to be an alternative reliable imaging method for locoregional disease evaluation of non-FDG avid gastric MALT lymphoma.

OBJECTIVES:This prospective proof-of-principle study aimed to determine whether [Ga]Ga-Pentixafor uptake, which reflects CXCR4 expression, is higher in the bone marrow of chronic lymphocytic leukemia (CLL) than in other oncological diseases without bone marrow infiltration and can therefore be used for CLL imaging. MATERIALS AND METHODS:Thirteen CLL patients and 20 controls (10 with pancreatic adenocarcinoma and 10 with mucosa-associated lymphoid tissue lymphoma) with histologically proven cancer underwent [Ga]Ga-Pentixafor positron emission tomography/magnetic resonance imaging. Standardized [Ga]Ga-Pentixafor uptake values (SUVmax, SUVmean) were measured in the bone marrow of the pelvis, the lumbar vertebra L4, and the bony structure with the visually highest tracer uptake ("hottest lesion"). Mean apparent diffusion coefficient values were also measured in the pelvis. Serum leukocyte count (gram per liter), lymphocyte percentage (percent), lactate dehydrogenase (unit per liter), β2-microglobulin (milligram per deciliter), and C-reactive protein (milligram per deciliter) were measured. Statistical analyses comprised analysis of variance with Games-Howell post hoc tests and Spearman correlation coefficients. RESULTS:SUVmax and SUVmean differed significantly between CLL and pancreatic adenocarcinoma in the pelvis (P = 0.032 and P = 0.008) and lumbar vertebra L4 (both P < 0.001). SUVmean also differed in the pelvis (P = 0.020) and L4 (P = 0.041), and SUVmax in L4 (P = 0.019), between CLL and mucosa-associated lymphoid tissue lymphoma. Receiver operating characteristic-based areas under the curve for separation of CLL from the control groups were greatest for the SUVmax of the bony structure with the strongest [Ga]Ga-Pentixafor uptake (0.94) and the SUVmax of L4 (0.92). There was no significant correlation between [Ga]Ga-Pentixafor uptake and pelvic apparent diffusion coefficients or serum parameters. CONCLUSIONS:[Ga]Ga-Pentixafor positron emission tomography/magnetic resonance imaging may possibly be useful for CXCR4-based CLL imaging.

PURPOSE:F]FDG PET/MR can capture treatment effects within the first week after treatment initiation, and whether changes in glucose metabolism and cell density occur simultaneously. METHODS:F]FDG uptake values (SUVmax, SUVmean) and apparent diffusion coefficients (ADCmin, ADCmean) based on diffusion-weighted MRI, and metabolic and morphological tumour volumes (MTV, VOL) were assessed at each time-point. Multilevel analyses with an unstructured covariance matrix, and pair-wise post-hoc tests were used to test for significant changes in SUVs, ADCs, MTVs and VOLs between the three time-points. RESULTS:A total of 58 patients (11 with HL and 47 with NHL) with 166 lesions were analysed. Lesion-based mean rates of change in SUVmax, SUVmean, ADCmin, ADCmean, MTV and VOL between baseline and FU-1 were -46.8%, -33.3%, +20.3%, +14%, -46% and -12.8%, respectively, and between baseline and FU-2 were -65.1%, -49%, +50.7%, +32.4%, -61.1% and -24.2%, respectively. These changes were statistically significant (P < 0.01) except for the change in VOL between baseline and FU-1 (P = 0.079). CONCLUSION:F]FDG PET/MR can capture treatment-induced changes in glucose metabolism and cell density as early as 48-72 h after treatment initiation.

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.