Comparison of diagnostic quality of 3D ultrashort-echo-time techniques for pulmonary magnetic resonance imaging in free-breathing.

BACKGROUND: Ultrashort-echo-time (UTE) sequences have been developed to overcome technical limitations of pulmonary magnetic resonance imaging (MRI). Recently, it has been shown that UTE sequences with breath-hold allow rapid image acquisition with sufficient image quality. However, patients with impaired respiration require alternative acquisition strategies while breathing freely. PURPOSE: To compare the diagnostic performance of free-breathing three-dimensional (3D)-UTE sequences with different trajectories based on pulmonary imaging of immunocompromised patients. MATERIAL AND METHODS: In a prospective study setting, two 3D-UTE sequences performed in free-breathing and exploiting non-Cartesian trajectories-one using a stack-of-spirals and the other exploiting a radial trajectory-were acquired at 3 T in patients undergoing hematopoietic stem cell transplantation. Two radiologists assessed the images regarding presence of pleural effusions and pulmonary infiltrations. Computed tomography (CT) was used as reference. RESULTS: A total of 28 datasets, each consisting of free-breathing 3D-UTE MRI with the two sequence techniques and a reference CT scan, were acquired in 20 patients. Interrater agreement was substantial for pulmonary infiltrations using both sequence techniques (κ = 0.77 - 0.78). Regarding pleural effusions, agreement was almost perfect in the stack-of-spirals (κ = 0.81) and moderate in the radial sequence (κ = 0.59). No significant differences in detectability of the assessed pulmonary pathologies were observed between both 3D-UTE sequence techniques (P > 0.05), and their level of agreement was substantial throughout (κ = 0.62-0.81). Both techniques provided high sensitivities and specificities (79%-100%) for the detection of pulmonary infiltrations and pleural effusions compared to reference CT. CONCLUSION: The diagnostic performance of the assessed 3D-UTE MRI sequences was similar. Both sequences enable the detection of typical inflammatory lung pathologies.

Minimal residual disease and imaging-guided consolidation strategies in newly diagnosed and relapsed refractory multiple myeloma.

Measurement of minimal residual disease (MRD) by next-generation flow cytometry (NGF) is an important tool to define deep responses in multiple myeloma (MM). However, little is known about the value of combining NGF with functional imaging and its role for MRD-based consolidation strategies in clinical routine. In the present study, we report our experience investigating these issues with 102 patients with newly diagnosed (n = 57) and relapsed/refractory MM (n = 45). Imaging was performed using either positron emission tomography or diffusion-weighted magnetic resonance imaging. In all, 45% of patients achieved MRD-negativity on both NGF and imaging (double-negativity), and 8% and 40% of patients were negative on either NGF or imaging respectively. Thus, in a minority of patients imaging was the only technique to detect residual disease. Imaging-positivity despite negativity on NGF was more common in heavily pretreated disease (four or more previous lines) compared to newly diagnosed MM (p < 0.01). Among the 29 patients undergoing MRD-triggered consolidation, 51% responded with MRD conversion and 21% with improved serological response. MRD-triggered consolidation led to superior progression-free survival (PFS) when compared to standard treatment (p = 0.04). In conclusion, we show that combining NGF with imaging is helpful particularly in patients with heavily pretreated MM, and that MRD-based consolidation could lead to improved PFS.

Transient regulatory T-cell targeting triggers immune control of multiple myeloma and prevents disease progression.

Multiple myeloma remains a largely incurable disease of clonally expanding malignant plasma cells. The bone marrow microenvironment harbors treatment-resistant myeloma cells, which eventually lead to disease relapse in patients. In the bone marrow, CD4+FoxP3+ regulatory T cells (Tregs) are highly abundant amongst CD4+ T cells providing an immune protective niche for different long-living cell populations, e.g., hematopoietic stem cells. Here, we addressed the functional role of Tregs in multiple myeloma dissemination to bone marrow compartments and disease progression. To investigate the immune regulation of multiple myeloma, we utilized syngeneic immunocompetent murine multiple myeloma models in two different genetic backgrounds. Analyzing the spatial immune architecture of multiple myeloma revealed that the bone marrow Tregs accumulated in the vicinity of malignant plasma cells and displayed an activated phenotype. In vivo Treg depletion prevented multiple myeloma dissemination in both models. Importantly, short-term in vivo depletion of Tregs in mice with established multiple myeloma evoked a potent CD8 T cell- and NK cell-mediated immune response resulting in complete and stable remission. Conclusively, this preclinical in-vivo study suggests that Tregs are an attractive target for the treatment of multiple myeloma.

Pulmonary Imaging of Immunocompromised Patients during Hematopoietic Stem Cell Transplantation using Non-Contrast-Enhanced Three-Dimensional Ultrashort Echo Time (3D-UTE) MRI.

PURPOSE: To evaluate the feasibility of non-contrast-enhanced three-dimensional ultrashort echo time (3D-UTE) MRI for pulmonary imaging in immunocompromised patients during hematopoietic stem cell transplantation (HSCT). METHODS: MRI was performed using a stack-of-spirals 3D-UTE sequence (slice thickness: 2.34mm; matrix: 256 × 256; acquisition time: 12.7-17.6 seconds) enabling imaging of the entire thorax within single breath-holds. Patients underwent MRI before HSCT initiation, in the case of periprocedural pneumonia, before discharge, and in the case of re-hospitalization. Two readers separately assessed the images regarding presence of pleural effusions, ground glass opacities (GGO), and consolidations on a per lung basis. A T2-weighted (T2w) multi-shot Turbo Spin Echo sequence (BLADE) was acquired in coronal orientation during breath-hold (slice thickness: 6.00mm; matrix: 320 × 320; acquisition time: 3.1-5.5 min) and read on a per lesion basis. Low-dose CT scans in inspiration were used as reference and were read on a per lung basis. Only scans performed within a maximum of three days were included in the inter-method analyses. Interrater agreement, sensitivity, specificity, positive and negative predictive values, and diagnostic accuracy of 3D-UTE MRI were calculated. RESULTS: 67 MRI scans of 28 patients were acquired. A reference CT examination was available for 33 scans of 23 patients. 3D-UTE MRI showed high sensitivity and specificity regarding pleural effusions (n = 6; sensitivity, 92 %; specificity, 100 %) and consolidations (n = 22; sensitivity 98 %, specificity, 86 %). Diagnostic performance was lower for GGO (n = 9; sensitivity, 63 %; specificity, 84 %). Accuracy rates were high (pleural effusions, 98 %; GGO, 79 %; consolidations 94 %). Interrater agreement was substantial for consolidations and pleural effusions (κ = 0.69-0.82) and moderate for GGO (κ = 0.54). Compared to T2w imaging, 3D-UTE MRI depicted the assessed pathologies with at least equivalent quality and was rated superior regarding consolidations and GGO in ~50 %. CONCLUSION: Non-contrast 3D-UTE MRI enables radiation-free assessment of typical pulmonary complications during HSCT procedure within a single breath-hold. Yet, CT was found to be superior regarding the identification of pure GGO changes. KEY POINTS: · 3D-UTE MRI of the thorax can be acquired within a single breath-hold.. · 3D-UTE MRI provides diagnostic imaging of pulmonary consolidations and pleural effusions.. · 3D-UTE sequences improve detection rates of ground glass opacities on pulmonary MRI.. · 3D-UTE MRI depicts pulmonary pathologies at least equivalent to T2-weighted Blade sequence.. CITATION FORMAT: · Metz C, Böckle D, Heidenreich JF et al. Pulmonary Imaging of Immunocompromised Patients during Hematopoietic Stem Cell Transplantation using Non-Contrast-Enhanced Three-Dimensional Ultrashort Echo Time (3D-UTE) MRI. Fortschr Röntgenstr 2022; 194: 39 - 48.

Salvage therapy with "Dara-KDT-P(A)CE" in heavily pretreated, high-risk, proliferative, relapsed/refractory multiple myeloma.

The multi-agent therapy "VDT-PACE" represents an established regimen in relapsed/refractory multiple myeloma (RRMM). Here, we report on our experience with a "modified VDT-PACE" incorporating new generation anti-MM agents daratumumab and carfilzomib ("Dara-KDT-P(A)CE"). We retrospectively analyzed 38 patients with RRMM treated with "Dara-KDT-P(A)CE". The median age was 62 (range 45-82) years, and the patients were heavily pretreated with a median of 5 (range 2-12) prior lines of therapy. Twenty-one (55%) patients suffered from penta-refractory MM. High-risk cytogenetics was present in 31 (81%) patients. The patients received a median of 2 (range 1-10) cycles of this therapy, and the overall response rate (ORR) was 70%. Patients with penta-refractory MM and high-risk cytogenetics showed similar ORR of 65% and 79%, respectively. The median progression-free survival (PFS) and overall survival were 4.1 (95% CI 2.7-5.4) and 8.4 (95% CI 6.7-10.0) months, respectively. Patients with lactate dehydrogenase >250 IU/L showed significantly shorter PFS in comparison with others patients (p = 0.006). We used this regimen as bridging therapy prior to chimeric antigen receptor T-cell infusion in four patients. In conclusion, "Dara-KDT-P(A)CE" is an effective salvage therapy for patients with heavily pretreated, multi-refractory, high-risk RRMM lacking alternative options.

Sequential CD38 monoclonal antibody retreatment leads to deep remission in a patient with relapsed/refractory multiple myeloma.

We report on a currently 76-year-old female patient with relapsed/refractory (RR) multiple myeloma (MM) treated at our institution. This patient had received six lines of therapy including tandem autologous stem cell transplant, proteasome inhibitor, immunomodulatory drugs and CD38 antibody MOR202. At the last relapse, she progressed during treatment with pomalidomide and MOR202. In an individualized therapy concept, we started a multi-agent salvage therapy with pomalidomide, bortezomib, doxorubicin, dexamethasone, and CD38 antibody daratumumab ("Pom-PAD-Dara"), which resulted in a stringent complete remission with minimal residual disease (MRD) negativity after nine cycles. So far, our patient shows a progression free survival of more than 12 months. Our case demonstrates the feasibility of successful CD38 antibody retreatment in a patient with heavily pretreated CD38 antibody resistant MM.

18F-FDG, 11C-Methionine, and 68Ga-Pentixafor PET/CT in Patients with Smoldering Multiple Myeloma: Imaging Pattern and Clinical Features.

This study aimed to explore the correlation between imaging patterns and clinical features in patients with smoldering multiple myeloma (SMM) who simultaneously underwent 18F-FDG, 11C-Methionine, and 68Ga-Pentixafor positron emission tomography/computed tomography (PET/CT). We retrieved and analyzed clinical characteristics and PET imaging data of 10 patients with SMM. We found a significant correlation between bone marrow (BM) plasma cell (PC) infiltration and mean standardized uptake values (SUVmean) of lumbar vertebrae L2-L4 on 11C-Methionine PET/CT scans (r = 0.676, p = 0.031) and 68Ga-Pentixafor PET/CT scans (r = 0.839, p = 0.002). However, there was no significant correlation between BM involvement and SUVmean of lumbar vertebrae L2-L4 on 18F-FDG PET/CT scans (r = 0.558, p = 0.093). Similarly, mean target-to-background ratios (TBRmean) of lumbar vertebrae L2-L4 also correlated with bone marrow plasma cell (BMPC) infiltration in 11C-Methionine PET/CT (r = 0.789, p = 0.007) and 68Ga-Pentixafor PET/CT (r = 0.724, p = 0.018) PET/CT. In contrast, we did not observe a significant correlation between BMPC infiltration rate and TBRmean in 18F-FDG PET/CT (r = 0.355, p = 0.313). Additionally, on 11C-Methionine PET/CT scans, we found a significant correlation between BMPC infiltration and TBRmax of lumbar vertebrae L2-L4 (r = 0.642, p = 0.045). In conclusion, 11C-Methionine and 68Ga-Pentixafor PET/CT demonstrate higher sensitivity than 18F-FDG PET/CT in detecting BM involvement in SMM.

The Link between Cytogenetics/Genomics and Imaging Patterns of Relapse and Progression in Patients with Relapsed/Refractory Multiple Myeloma: A Pilot Study Utilizing 18F-FDG PET/CT.

Utilizing 18F-fluorodeoxyglucose (18F-FDG) positron emission tomography (PET)/computed tomography (CT), we performed this pilot study to evaluate the link between cytogenetic/genomic markers and imaging patterns in relapsed/refractory (RR) multiple myeloma (MM). We retrospectively analyzed data of 24 patients with RRMM who were treated at our institution between November 2018 and February 2020. At the last relapse/progression, patients had been treated with a median of three (range 1-10) lines of therapy. Six (25%) patients showed FDG avid extramedullary disease without adjacency to bone. We observed significantly higher maximum standardized uptake values (SUVmax) in patients harboring del(17p) compared with those without del(17p) (p = 0.025). Moreover, a high SUVmax of >15 indicated significantly shortened progression-free survival (PFS) (p = 0.01) and overall survival (OS) (p = 0.0002). One female patient exhibited biallelic TP53 alteration, i.e., deletion and mutation, in whom an extremely high SUVmax of 37.88 was observed. In summary, this pilot study suggested a link between del(17p)/TP53 alteration and high SUVmax on 18F-FDG PET/CT in RRMM patients. Further investigations are highly warranted at this point.

Carfilzomib Based Treatment Strategies in the Management of Relapsed/Refractory Multiple Myeloma with Extramedullary Disease.

Published experience with carfilzomib in patients with relapsed/refractory multiple myeloma (RRMM) and extramedullary disease (EMD) is still limited. The current study aimed to assess the efficacy and safety of carfilzomib containing therapy regimens in EMD. We retrospectively analyzed 45 patients with extramedullary RRMM treated with carfilzomib from June 2013 to September 2019. The median age at the start of carfilzomib was 64 (range 40-80) years. Twenty (44%) and 25 (56%) patients had paraosseous manifestation and EMD without adjacency to bone, respectively. The serological overall response rate (ORR) was 59%. Extramedullary response was evaluable in 33 patients, nine (27%) of them achieved partial remission (PR) (ORR = 27%). In 15 (33%) patients, we observed no extramedullary response despite serological response. The median progression-free survival (PFS) and overall survival (OS) were five (95% CI, 3.5-6.5) and ten (95% CI, 7.5-12.5) months, respectively. EMD without adjacency to bone was associated with a significantly inferior PFS (p = 0.004) and OS (p = 0.04) compared to paraosseous lesions. Carfilzomib based treatment strategies showed some efficacy in heavily pretreated patients with extramedullary RRMM but could not overcome the negative prognostic value of EMD. Due to the discrepancy between serological and extramedullary response, evaluation of extramedullary response using imaging is mandatory in these patients.

Clinical outcome of elderly patients (≥ 70 years) with esophageal cancer undergoing definitive or neoadjuvant radio(chemo)therapy: a retrospective single center analysis.

BACKGROUND: To analyse the outcome of elderly patients (≥70 years) with esophageal cancer treated with curative intent radio(chemo)therapy. METHODS: Fifty five patients (median 75 years) receiving curative intent radio(chemo)therapy for esophageal cancer from 1999 to 2015 were retrospectively analyzed. Most patients showed locally advanced disease (T3/4:78%, N+:58%) with squamous cell histology (74%). Charlson comorbidity score was > 1 in 27%. 48 patients (87%) received definitive treatment while 7 patients were treated neoadjuvantly. RT was carried out as 3D-conformal treatment or IMRT. Concurrent chemotherapy was applied in 85%, mainly cisplatin/5-FU or mitomycin/5-FU. 18FDG-PET/CT staging was used in 65%. RESULTS: Median follow-up was 11 months (1-68) and 21 months in survivors. 1- and 2-year rates of LRC, DC, FFTF and OS were 60%/45, 81%/72, 55%/41 and 46%/26% for the entire cohort. In univariate analysis, addition of surgery was associated with improved LRC and FFTF, nodal involvement with improved DC and lower T stage, lower Charlson score and use of PET-CT with improved OS. In multivariate analysis, lower T stage and lower Charlson score remained significant for OS. Patients treated after 2008 showed a significantly improved FFTF (1-year FFTF 64% vs 35%) and OS (1-year OS 66% vs 24%). Maximum (chemo)radiation related grade3+ toxicity was observed in 80% including 7 deaths (13%). Grade5 toxicity was significantly associated with Charlson score (CS > 1:33% vs CS ≤ 1:5%) and treatment period (24% before vs 3% after 2008). The patients treated after 2008 included significantly more SCCs, less T4 stages, had a higher percentage of PET-CT staging and were treated with smaller field lengths. Trends were also observed for lower Charlson scores and increased use of IMRT. CONCLUSION: Curative intent (chemo)radiation of elderly patients with esophageal cancer may result in considerable toxicity and unfavorable outcome. However, a clear improvement over time was observed in our cohort, probably based on improved patient selection. In patients with less advanced stages and lower comorbidity similar results as in younger cohorts seem achievable with modern staging and treatment approaches. Age per se should not be a decisive factor, but careful attention should be paid regarding patient selection including a structured and tight follow-up strategy.