First in-human evaluation of [1-13C]pyruvate in D2O for hyperpolarized MRI of the brain: A safety and feasibility study.

PURPOSE: To investigate the safety and value of hyperpolarized (HP) MRI of [1-13C]pyruvate in healthy volunteers using deuterium oxide (D2O) as a solvent. METHODS: Healthy volunteers (n = 5), were injected with HP [1-13C]pyruvate dissolved in D2O and imaged with a metabolite-specific 3D dual-echo dynamic EPI sequence at 3T at one site (Site 1). Volunteers were monitored following the procedure to assess safety. Image characteristics, including SNR, were compared to data acquired in a separate cohort using water as a solvent (n = 5) at another site (Site 2). The apparent spin-lattice relaxation time (T1) of [1-13C]pyruvate was determined both in vitro and in vivo from a mono-exponential fit to the image intensity at each time point of our dynamic data. RESULTS: All volunteers completed the study safely and reported no adverse effects. The use of D2O increased the T1 of [1-13C]pyruvate from 66.5 ± 1.6 s to 92.1 ± 5.1 s in vitro, which resulted in an increase in signal by a factor of 1.46 ± 0.03 at the time of injection (90 s after dissolution). The use of D2O also increased the apparent relaxation time of [1-13C]pyruvate by a factor of 1.4 ± 0.2 in vivo. After adjusting for inter-site SNR differences, the use of D2O was shown to increase image SNR by a factor of 2.6 ± 0.2 in humans. CONCLUSIONS: HP [1-13C]pyruvate in D2O is safe for human imaging and provides an increase in T1 and SNR that may improve image quality.

CXCR4 PET/MRI for follow-up of gastric mucosa-associated lymphoid tissue lymphoma after first-line Helicobacter pylori eradication.

Posttreatment evaluation of gastric mucosa-associated lymphoid tissue (MALT) lymphoma currently relies on esophagogastroduodenoscopy with histological assessment of biopsies. Overexpression of the G protein-coupled C-X-C chemokine receptor type 4 (CXCR4) has been previously observed in MALT lymphoma. The aim of this prospective study was to evaluate positron emission tomography (PET) with the novel CXCR4 tracer [68Ga]Pentixafor as a potential alternative to follow up biopsies for assessment of residual disease (noncomplete remission [CR]) after first-line Helicobacter pylori eradication. Forty-six post-H pylori eradication [68Ga]Pentixafor-PET/magnetic resonance imaging (MRI) examinations of 26 gastric MALT lymphoma patients, and 20 [68Ga]Pentixafor-PET/MRI examinations of 20 control group patients without lymphoma, were analyzed. In the MALT lymphoma group, time-matched gastric biopsies were used as reference standard and showed CR in 6 cases. Pooled examination-based accuracy, sensitivity, specificity, and positive and negative predictive values of [68Ga]Pentixafor-PET for detection of residual gastric MALT lymphoma at follow-up were 97.0%, 95.0%, 100.0%, 100.0%, and 92.9%, respectively. Maximum and mean PET standardized uptake values showed moderate correlation with immunohistochemistry-based CXCR4+ cell counts, with correlation coefficients of r = 0.51 and r = 0.52 (P = .008 and P = .006). In summary, CXCR4 imaging with [68Ga]Pentixafor-PET may represent a promising test for assessment of residual gastric MALT lymphomas after H pylori eradication.

Perceptions of radiologists on structured reporting for cancer imaging-a survey by the European Society of Oncologic Imaging (ESOI).

OBJECTIVES: To assess radiologists' current use of, and opinions on, structured reporting (SR) in oncologic imaging, and to provide recommendations for a structured report template. MATERIALS AND METHODS: An online survey with 28 questions was sent to European Society of Oncologic Imaging (ESOI) members. The questionnaire had four main parts: (1) participant information, e.g., country, workplace, experience, and current SR use; (2) SR design, e.g., numbers of sections and fields, and template use; (3) clinical impact of SR, e.g., on report quality and length, workload, and communication with clinicians; and (4) preferences for an oncology-focused structured CT report. Data analysis comprised descriptive statistics, chi-square tests, and Spearman correlation coefficients. RESULTS: A total of 200 radiologists from 51 countries completed the survey: 57.0% currently utilized SR (57%), with a lower proportion within than outside of Europe (51.0 vs. 72.7%; p = 0.006). Among SR users, the majority observed markedly increased report quality (62.3%) and easier comparison to previous exams (53.5%), a slightly lower error rate (50.9%), and fewer calls/emails by clinicians (78.9%) due to SR. The perceived impact of SR on communication with clinicians (i.e., frequency of calls/emails) differed with radiologists' experience (p < 0.001), and experience also showed low but significant correlations with communication with clinicians (r = - 0.27, p = 0.003), report quality (r = 0.19, p = 0.043), and error rate (r = - 0.22, p = 0.016). Template use also affected the perceived impact of SR on report quality (p = 0.036). CONCLUSION: Radiologists regard SR in oncologic imaging favorably, with perceived positive effects on report quality, error rate, comparison of serial exams, and communication with clinicians. CLINICAL RELEVANCE STATEMENT: Radiologists believe that structured reporting in oncologic imaging improves report quality, decreases the error rate, and enables better communication with clinicians. Implementation of structured reporting in Europe is currently below the international level and needs society endorsement. KEY POINTS: • The majority of oncologic imaging specialists (57% overall; 51% in Europe) use structured reporting in clinical practice. • The vast majority of oncologic imaging specialists use templates (92.1%), which are typically cancer-specific (76.2%). • Structured reporting is perceived to markedly improve report quality, communication with clinicians, and comparison to prior scans.

Attitudes and perceptions of radiologists towards online (virtual) oncologic multidisciplinary team meetings during the COVID-19 pandemic-a survey of the European Society of Oncologic Imaging (ESOI).

OBJECTIVES: To explore radiologists' opinions regarding the shift from in-person oncologic multidisciplinary team meetings (MDTMs) to online MDTMs. To assess the perceived impact of online MDTMs, and to evaluate clinical and technical aspects of online meetings. METHODS: An online questionnaire including 24 questions was e-mailed to all European Society of Oncologic Imaging (ESOI) members. Questions targeted the structure and efficacy of online MDTMs, including benefits and limitations. RESULTS: A total of 204 radiologists responded to the survey. Responses were evaluated using descriptive statistical analysis. The majority (157/204; 77%) reported a shift to online MDTMs at the start of the pandemic. For the most part, this transition had a positive effect on maintaining and improving attendance. The majority of participants reported that online MDTMs provide the same clinical standard as in-person meetings, and that interdisciplinary discussion and review of imaging data were not hindered. Seventy three of 204 (35.8%) participants favour reverting to in-person MDTs, once safe to do so, while 7/204 (3.4%) prefer a continuation of online MDTMs. The majority (124/204, 60.8%) prefer a combination of physical and online MDTMs. CONCLUSIONS: Online MDTMs are a viable alternative to in-person meetings enabling continued timely high-quality provision of care with maintained coordination between specialties. They were accepted by the majority of surveyed radiologists who also favoured their continuation after the pandemic, preferably in combination with in-person meetings. An awareness of communication issues particular to online meetings is important. Training, improved software, and availability of support are essential to overcome technical and IT difficulties reported by participants. KEY POINTS: • Majority of surveyed radiologists reported shift from in-person to online oncologic MDT meetings during the COVID-19 pandemic. • The shift to online MDTMs was feasible and generally accepted by the radiologists surveyed with the majority reporting that online MDTMs provide the same clinical standard as in-person meetings. • Most would favour the return to in-person MDTMs but would also accept the continued use of online MDTMs following the end of the current pandemic.

Added value of quantitative, multiparametric 18F-FDG PET/MRI in the locoregional staging of rectal cancer.

PURPOSE: The purpose of this study was to determine whether multiparametric positron emission tomography/magnetic resonance imaging (mpPET/MRI) can improve locoregional staging of rectal cancer (RC) and to assess its prognostic value after resection. METHODS: In this retrospective study, 46 patients with primary RC, who underwent multiparametric 18F-fluorodeoxyglucose (FDG) PET/MRI, followed by surgical resection without chemoradiotherapy, were included. Two readers reviewed T- and N- stage, mesorectal involvement, sphincter infiltration, tumor length, and distance from anal verge. In addition, diffusion-weighted imaging (DWI) and PET parameters were extracted from the multiparametric protocol and were compared to radiological staging as well as to the histopathological reference standard. Clinical and imaging follow-up was systematically assessed for tumor recurrence and death. RESULTS: Locally advanced rectal cancers (LARC) exhibited significantly higher metabolic tumor volume (MTV, AUC 0.74 [95% CI 0.59-0.89], p = 0.004) and total lesion glycolysis (TLG, AUC 0.70 [95% CI 0.53-0.87], p = 0.022) compared to early tumors. T-stage was associated with MTV (AUC 0.70 [95% CI 0.54-0.85], p = 0.021), while N-stage was better assessed using anatomical MRI sequences (AUC 0.72 [95% CI 0.539-0.894], p = 0.032). In the multivariate regression analysis, depending on the model, both anatomical MRI sequences and MTV/TLG were capable of detecting LARC. Combining anatomical MRI stage and MTV/TLG led to a superior diagnostic performance for detecting LARC (AUC 0.81, [95% CI 0.68-0.94], p < 0.001). In the survival analysis, MTV was independently associated with overall survival (HR 1.05 [95% CI 1.01-1.10], p = 0.044). CONCLUSION: Multiparametric PET-MRI can improve identification of locally advanced tumors and, hence, help in treatment stratification. It provides additional information on RC tumor biology and may have prognostic value.

Accuracy of PET quantification in [68Ga]Ga-pentixafor PET/MR imaging of carotid plaques.

AIM: The aim of this study was to evaluate and correct for partial-volume-effects (PVE) on [68Ga]Ga-Pentixafor uptake in atherosclerotic plaques of the carotid arteries, and the impact of ignoring bone in MR-based attenuation correction (MR-AC). METHODS: Twenty [68Ga]Ga-pentixafor PET/MR examinations including a high-resolution T2-TSE MR of the neck were included in this study. Carotid plaques located at the carotid bifurcation were delineated and the anatomical information was used for partial-volume-correction (PVC). Mean and max tissue-to-background ratios (TBR) of the [68Ga]Ga-Pentixafor uptake were compared for standard and PVC-PET images. A potential influence of ignoring bone in MR-AC was assessed in a subset of the data reconstructed after incorporating bone into MR-AC and a subsequent comparison of standardized-uptake values (SUV). RESULTS: In total, 34 atherosclerotic plaques were identified. Following PVC, mean and max TBR increased by 77 and 95%, respectively, when averaged across lesions. When accounting for bone in the MR-AC, SUV of plaque changed by 0.5%. CONCLUSION: Quantitative readings of [68Ga]Ga-pentixafor uptake in plaques are strongly affected by PVE, which can be reduced by PVC. Including bone information into the MR-AC yielded no clinically relevant effect on tracer quantification.

Functional imaging using radiomic features in assessment of lymphoma.

Lymphomas are typically large, well-defined, and relatively homogeneous tumors, and therefore represent ideal targets for the use of radiomics. Of the available functional imaging tests, [18F]FDG-PET for body lymphoma and diffusion-weighted MRI (DWI) for central nervous system (CNS) lymphoma are of particular interest. The current literature suggests that two main applications for radiomics in lymphoma show promise: differentiation of lymphomas from other tumors, and lymphoma treatment response and outcome prognostication. In particular, encouraging results reported in the limited number of presently available studies that utilize functional imaging suggest that (1) MRI-based radiomics enables differentiation of CNS lymphoma from glioblastoma, and (2) baseline [18F]FDG-PET radiomics could be useful for survival prognostication, adding to or even replacing commonly used metrics such as standardized uptake values and metabolic tumor volume. However, due to differences in biological and clinical characteristics of different lymphoma subtypes and an increasing number of treatment options, more data are required to support these findings. Furthermore, a consensus on several critical steps in the radiomics workflow -most importantly, image reconstruction and post processing, lesion segmentation, and choice of classification algorithm- is desirable to ensure comparability of results between research institutions.

Multidisciplinary Recommendations Regarding Post-Vaccine Adenopathy and Radiologic Imaging: Radiology Scientific Expert Panel.

Vaccination-associated adenopathy is a frequent imaging finding after administration of COVID-19 vaccines that may lead to a diagnostic conundrum in patients with manifest or suspected cancer, in whom it may be indistinguishable from malignant nodal involvement. To help the medical community address this concern in the absence of studies and evidence-based guidelines, this special report offers recommendations developed by a multidisciplinary panel of experts from three of the leading tertiary care cancer centers in the United States. According to these recommendations, some routine imaging examinations, such as those for screening, should be scheduled before or at least 6 weeks after the final vaccination dose to allow for any reactive adenopathy to resolve. However, there should be no delay of other clinically indicated imaging (eg, for acute symptoms, short-interval treatment monitoring, urgent treatment planning or complications) due to prior vaccination. The vaccine should be administered on the side contralateral to the primary or suspected cancer, and both doses should be administered in the same arm. Vaccination information-date(s) administered, injection site(s), laterality, and type of vaccine-should be included in every preimaging patient questionnaire, and this information should be made readily available to interpreting radiologists. Clear and effective communication between patients, radiologists, referring physician teams, and the general public should be considered of the highest priority when managing adenopathy in the setting of COVID-19 vaccination.

Consensus criteria for diagnosis, staging, and treatment response assessment of T-cell prolymphocytic leukemia.

T-cell prolymphocytic leukemia (T-PLL) is a rare, mature T-cell neoplasm with a heterogeneous clinical course. With the advent of novel treatment options that will potentially change the management of patients with T-PLL, it has become necessary to produce consensus guidelines for the design and conduct of clinical trials. The T-PLL International Study group (TPLL-ISG) set out to define standardized criteria for diagnosis, treatment indication, and evaluation of response. These criteria will facilitate comparison of results from clinical trials in T-PLL, and will thus support clinical decision making, as well as the approval of new therapeutics by healthcare authorities.

18F FDG PET/MRI with hepatocyte-specific contrast agent for M staging of rectal cancer: a primary economic evaluation.

PURPOSE: Rectal cancer is one of the most frequent causes of cancer-related morbidity and mortality in the world. Correct identification of the TNM state in primary staging of rectal cancer has critical implications on patient management. Initial evaluations revealed a high sensitivity and specificity for whole-body PET/MRI in the detection of metastases allowing for metastasis-directed therapy regimens. Nevertheless, its cost-effectiveness compared with that of standard-of-care imaging (SCI) using pelvic MRI + chest and abdominopelvic CT is yet to be investigated. Therefore, the aim of this study was to analyze the cost-effectiveness of whole-body 18F FDG PET/MRI as an alternative imaging method to standard diagnostic workup for initial staging of rectal cancer. METHODS: For estimation of quality-adjusted life years (QALYs) and lifetime costs of diagnostic modalities, a decision model including whole-body 18F FDG PET/MRI with a hepatocyte-specific contrast agent and pelvic MRI + chest and abdominopelvic CT was created based on Markov simulations. For obtaining model input parameters, review of recent literature was performed. Willingness to pay (WTP) was set to $100,000/QALY. Deterministic sensitivity analysis of diagnostic parameters and costs was applied, and probabilistic sensitivity was determined using Monte Carlo modeling. RESULTS: In the base-case scenario, the strategy whole-body 18F FDG PET/MRI resulted in total costs of $52,186 whereas total costs of SCI were at $51,672. Whole-body 18F FDG PET/MRI resulted in an expected effectiveness of 3.542 QALYs versus 3.535 QALYs for SCI. This resulted in an incremental cost-effectiveness ratio of $70,291 per QALY for PET/MRI. Thus, from an economic point of view, whole-body 18F FDG PET/MRI was identified as an adequate diagnostic alternative to SCI with high robustness of results to variation of input parameters. CONCLUSION: Based on the results of the analysis, use of whole-body 18F FDG PET/MRI was identified as a feasible diagnostic strategy for initial staging of rectal cancer from a cost-effectiveness perspective.

An international expert opinion statement on the utility of PET/MR for imaging of skeletal metastases.

BACKGROUND: MR is an important imaging modality for evaluating musculoskeletal malignancies owing to its high soft tissue contrast and its ability to acquire multiparametric information. PET provides quantitative molecular and physiologic information and is a critical tool in the diagnosis and staging of several malignancies. PET/MR, which can take advantage of its constituent modalities, is uniquely suited for evaluating skeletal metastases. We reviewed the current evidence of PET/MR in assessing for skeletal metastases and provided recommendations for its use. METHODS: We searched for the peer reviewed literature related to the usage of PET/MR in the settings of osseous metastases. In addition, expert opinions, practices, and protocols of major research institutions performing research on PET/MR of skeletal metastases were considered. RESULTS: Peer-reviewed published literature was included. Nuclear medicine and radiology experts, including those from 13 major PET/MR centers, shared the gained expertise on PET/MR use for evaluating skeletal metastases and contributed to a consensus expert opinion statement. [18F]-FDG and non [18F]-FDG PET/MR may provide key advantages over PET/CT in the evaluation for osseous metastases in several primary malignancies. CONCLUSION: PET/MR should be considered for staging of malignancies where there is a high likelihood of osseous metastatic disease based on the characteristics of the primary malignancy, hight clinical suspicious and in case, where the presence of osseous metastases will have an impact on patient management. Appropriate choice of tumor-specific radiopharmaceuticals, as well as stringent adherence to PET and MR protocols, should be employed.

Radiomics of high-resolution computed tomography for the differentiation between cholesteatoma and middle ear inflammation: effects of post-reconstruction methods in a dual-center study.

OBJECTIVES: To evaluate the performance of radiomic features extracted from high-resolution computed tomography (HRCT) for the differentiation between cholesteatoma and middle ear inflammation (MEI), and to investigate the impact of post-reconstruction harmonization and data resampling. METHODS: One hundred patients were included in this retrospective dual-center study: 48 with histology-proven cholesteatoma (center A: 23; center B: 25) and 52 with MEI (A: 27; B: 25). Radiomic features (co-occurrence and run-length matrix, absolute gradient, autoregressive model, Haar wavelet transform) were extracted from manually defined 2D-ROIs. The ten best features for lesion differentiation were selected using probability of error and average correlation coefficients. A multi-layer perceptron feed-forward artificial neural network (MLP-ANN) was used for radiomics-based classification, with histopathology serving as the reference standard (70% of cases for training, 30% for validation). The analysis was performed five times each on (a) unmodified data and on data that were (b) resampled to the same matrix size, and (c) corrected for acquisition protocol differences using ComBat harmonization. RESULTS: Using unmodified data, the MLP-ANN classification yielded an overall median area under the receiver operating characteristic curve (AUC) of 0.78 (0.72-0.84). Using original data from center A and resampled data from center B, an overall median AUC of 0.88 (0.82-0.99) was yielded, while using ComBat harmonized data, an overall median AUC of 0.89 (0.79-0.92) was revealed. CONCLUSION: Radiomic features extracted from HRCT differentiate between cholesteatoma and MEI. When using multi-centric data obtained with differences in CT acquisition parameters, data resampling and ComBat post-reconstruction harmonization clearly improve radiomics-based lesion classification. KEY POINTS: • Unenhanced high-resolution CT coupled with radiomics analysis may be useful for the differentiation between cholesteatoma and middle ear inflammation. • Pooling of data extracted from inhomogeneous CT datasets does not appear meaningful without further post-processing. • When using multi-centric CT data obtained with differences in acquisition parameters, post-reconstruction harmonization and data resampling clearly improve radiomics-based soft-tissue differentiation.

Incorporating radiomics into clinical trials: expert consensus endorsed by the European Society of Radiology on considerations for data-driven compared to biologically driven quantitative biomarkers.

Existing quantitative imaging biomarkers (QIBs) are associated with known biological tissue characteristics and follow a well-understood path of technical, biological and clinical validation before incorporation into clinical trials. In radiomics, novel data-driven processes extract numerous visually imperceptible statistical features from the imaging data with no a priori assumptions on their correlation with biological processes. The selection of relevant features (radiomic signature) and incorporation into clinical trials therefore requires additional considerations to ensure meaningful imaging endpoints. Also, the number of radiomic features tested means that power calculations would result in sample sizes impossible to achieve within clinical trials. This article examines how the process of standardising and validating data-driven imaging biomarkers differs from those based on biological associations. Radiomic signatures are best developed initially on datasets that represent diversity of acquisition protocols as well as diversity of disease and of normal findings, rather than within clinical trials with standardised and optimised protocols as this would risk the selection of radiomic features being linked to the imaging process rather than the pathology. Normalisation through discretisation and feature harmonisation are essential pre-processing steps. Biological correlation may be performed after the technical and clinical validity of a radiomic signature is established, but is not mandatory. Feature selection may be part of discovery within a radiomics-specific trial or represent exploratory endpoints within an established trial; a previously validated radiomic signature may even be used as a primary/secondary endpoint, particularly if associations are demonstrated with specific biological processes and pathways being targeted within clinical trials. KEY POINTS: • Data-driven processes like radiomics risk false discoveries due to high-dimensionality of the dataset compared to sample size, making adequate diversity of the data, cross-validation and external validation essential to mitigate the risks of spurious associations and overfitting. • Use of radiomic signatures within clinical trials requires multistep standardisation of image acquisition, image analysis and data mining processes. • Biological correlation may be established after clinical validation but is not mandatory.

PET/MRI versus PET/CT in oncology: a prospective single-center study of 330 examinations focusing on implications for patient management and cost considerations.

PURPOSE: PET/MRI has recently been introduced into clinical practice. We prospectively investigated the clinical impact of PET/MRI compared with PET/CT, in a mixed population of cancer patients, and performed an economic evaluation of PET/MRI. METHODS: Cancer patients referred for routine staging or follow-up by PET/CT underwent consecutive PET/CT and PET/MRI, using single applications of [18F]FDG, [68Ga]Ga-DOTANOC, or [18F]FDOPA, depending on tumor histology. PET/MRI and PET/CT were rated separately, and lesions were assessed per anatomic region; based on regions, per-examination and per-patient accuracies were determined. A simulated, multidisciplinary team meeting served as reference standard and determined whether differences between PET/CT and PET/MRI affected patient management. The McNemar tests were used to compare accuracies, and incremental cost-effectiveness ratios (ICERs) for PET/MRI were calculated. RESULTS: Two hundred sixty-three patients (330 same-day PET/CT and PET/MRI examinations) were included. PET/MRI was accurate in 319/330 examinations and PET/CT in 277/330 examinations; the respective accuracies of 97.3% and 83.9% differed significantly (P < 0.001). The additional findings on PET/MRI-mainly liver and brain metastases-had implications for patient management in 21/263 patients (8.0%). The per-examination cost was 596.97 EUR for PET/MRI and 405.95 EUR for PET/CT. ICERs for PET/MRI were 14.26 EUR per percent of diagnostic accuracy and 23.88 EUR per percent of correctly managed patients. CONCLUSIONS: PET/MRI enables more appropriate management than PET/CT in a nonnegligible fraction of cancer patients. Since the per-examination cost is about 50% higher for PET/MRI than for PET/CT, a histology-based triage of patients to either PET/MRI or PET/CT may be meaningful.

MRI and PET/MRI in hematologic malignancies.

The role of MRI differs considerably between the three main groups of hematological malignancies: lymphoma, leukemia, and myeloma. In myeloma, whole-body MRI (WB-MRI) is recognized as a highly sensitive test for the assessment of myeloma, and is also endorsed by clinical guidelines, especially for detection and staging. In lymphoma, WB-MRI is presently not recommended, and merely serves as an alternative technique to the current standard imaging test, [18 F]FDG-PET/CT, especially in pediatric patients. Even for lymphomas with variable FDG avidity, such as extranodal mucosa-associated lymphoid tissue lymphoma (MALT), contrast-enhanced computed tomography (CT), but not WB-MRI, is presently recommended, despite the high sensitivity of diffusion-weighted MRI and its ability to capture treatment response that has been reported in the literature. In leukemia, neither MRI nor any other cross-sectional imaging test (including positron emission tomography [PET]) is currently recommended outside of clinical trials. This review article discusses current clinical applications as well as the main research topics for MRI, as well as PET/MRI, in the field of hematological malignancies, with a focus on functional MRI techniques such as diffusion-weighted imaging and dynamic contrast-enhanced MRI, on the one hand, and novel, non-FDG PET imaging probes such as the CXCR4 radiotracer [68 Ga]Ga-Pentixafor and the amino acid radiotracer [11 C]methionine, on the other hand. Level of Evidence: 5 Technical Efficacy Stage: 3 J. Magn. Reson. Imaging 2020;51:1325-1335.

Transformed mucosa-associated lymphoid tissue lymphomas: A single institution retrospective study including polymerase chain reaction-based clonality analysis.

Given the lack of consistent data regarding the clinico-pathological features and clonal lymphomagenesis of patients with mucosa-associated lymphoid tissue (MALT) lymphoma and histological transformation (HT), we have systematically analysed 379 patients (32% gastric, 68% extra-gastric; median follow-up 52 months) diagnosed with HT at the Medical University Vienna 1999-2017, and reassessed tissues of identified patients by polymerase chain reaction (PCR)-based clonality analysis. HT was documented in 12/379 patients (3·2%) and occurred at a median time of 22 months (range; 6-202 months) after diagnosis of MALT lymphoma. By PCR-based clonality analysis, we detected a clear-cut clonal relationship of MALT lymphoma and diffuse large B-cell lymphoma (DLBCL) in 8 of 11 analysed cases proving that the large majority of DLBCL following MALT lymphoma are clonally-related and constitute a real transformation. Interestingly, HT occurred within the first 2·5 years after diagnosis in patients with clonal relationship, whereas time to aggressive lymphoma was longer in patients identified as clonally-unrelated (most likely secondary) lymphoma (82-202 months), suggesting that HT is an early event in this disease. Survival of patients with HT was poor with 6/12 dying at 1·5-33 months after HT, however, patients with localized gastric transformation had a superior outcome with only 1/6 dying due to progression of lymphoma.

First-in-human response of BCL-2 inhibitor venetoclax in T-cell prolymphocytic leukemia.

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.

Radiomic features of glucose metabolism enable prediction of outcome in mantle cell lymphoma.

PURPOSE: To determine whether [18F]FDG PET/CT-derived radiomic features alone or in combination with clinical, laboratory and biological parameters are predictive of 2-year progression-free survival (PFS) in patients with mantle cell lymphoma (MCL), and whether they enable outcome prognostication. METHODS: Included in this retrospective study were 107 treatment-naive MCL patients scheduled to receive CD20 antibody-based immuno(chemo)therapy. Standardized uptake values (SUV), total lesion glycolysis, and 16 co-occurrence matrix radiomic features were extracted from metabolic tumour volumes on pretherapy [18F]FDG PET/CT scans. A multilayer perceptron neural network in combination with logistic regression analyses for feature selection was used for prediction of 2-year PFS. International prognostic indices for MCL (MIPI and MIPI-b) were calculated and combined with the radiomic data. Kaplan-Meier estimates with log-rank tests were used for PFS prognostication. RESULTS: SUVmean (OR 1.272, P = 0.013) and Entropy (heterogeneity of glucose metabolism; OR 1.131, P = 0.027) were significantly predictive of 2-year PFS: median areas under the curve were 0.72 based on the two radiomic features alone, and 0.82 with the addition of clinical/laboratory/biological data. Higher SUVmean in combination with higher Entropy (SUVmean >3.55 and entropy >3.5), reflecting high "metabolic risk", was associated with a poorer prognosis (median PFS 20.3 vs. 39.4 months, HR 2.285, P = 0.005). The best PFS prognostication was achieved using the MIPI-bm (MIPI-b and metabolic risk combined): median PFS 43.2, 38.2 and 20.3 months in the low-risk, intermediate-risk and high-risk groups respectively (P = 0.005). CONCLUSION: In MCL, the [18F]FDG PET/CT-derived radiomic features SUVmean and Entropy may improve prediction of 2-year PFS and PFS prognostication. The best results may be achieved using a combination of metabolic, clinical, laboratory and biological parameters.

Prolonged follow-up on lenalidomide-based treatment for mucosa-associated lymphoid tissue lymphoma (MALT lymphoma)-Real-world data from the Medical University of Vienna.

Based on results of two pilot trials, lenalidomide (LEN) was found to be active and safe as monotherapy and showed an increased response rate of 80% in combination with rituximab (R) for patients with mucosa-associated lymphoid tissue (MALT) lymphoma. While initial results were promising, there are currently no data on long-term outcome, and larger international phase II/III trials on LEN for indolent lymphoma lack specific subgroup analyses. Thus, we have systematically analyzed 50 patients treated with LEN-based therapy (LEN-monotherapy n = 16, R-LEN n = 34) at the Medical University of Vienna 2009 to 2019 and investigated long-term outcome and relapse patterns. At a follow-up of more than 5 years (median 68 months), 54% of patients are free of relapse, and estimated median progression-free survival (PFS) was 72 months (95%CI 49-96). There was no difference in PFS according to stage of disease, i.e. localized versus disseminated disease (P = .67) and previous systemic treatment (P = .16). Interestingly, but with the caveat of the limited number of patients included in this series, primary extragastric disease had a superior PFS compared with gastric lymphoma (P = .04) and also depth of response, i.e. complete or partial response versus stable disease was associated with significantly prolonged PFS (P = .01). We documented four patients (8%) with pronounced improvement of response during follow-up including three patients initially rated as partial remission and finally achieving complete remission at 12 to 32 months. This highlights the potential of delayed responses to LEN treatment. Estimated overall survival at 5 years was excellent at 92%. These "real-world" data confirm long-term activity of LEN in MALT lymphoma.

Treatment of mucosa associated lymphoid tissue lymphoma with a long-term once-weekly regimen of oral azithromycin: Results from the phase II MALT-A trial.

The macrolide clarithromycin has been reported as active for therapy of mucosa associated lymphoid tissue (MALT) lymphoma. Pharmacokinetic properties, however, require continuous daily intake over a prolonged period of time. As the macrolide azithromycin is characterized by a long half-life as well as potential antineoplastic activity in vitro, we have performed a phase II trial of long-term once-weekly oral azithromycin for treatment of MALT lymphoma. In a 2-stage-design, 16 patients (10 f/6 m) with histologically verified and measurable MALT lymphoma were included in the first phase of the trial, which could be expanded to a maximum of 46 patients depending on remissions in the first phase. Patients were given oral azithromycin 1500 mg once-weekly 4 times a month, and restaging was performed after 3 and 6 months. Two patients had gastric and 14 extragastric MALT lymphoma; 12/16 patients were treatment-naive and received azithromycin as first line treatment. Tolerance of this regimen was excellent, and 14/16 patients received 6 months of treatment as scheduled, while 1 patient each discontinued after 4 (progressive disease) and 1 cycle (personal reasons), respectively. The most commonly observed side effects were mild nausea (n = 8) and diarrhea (n = 4). Efficacy, however, was low as only 4/16 patients (25%) responded, with 2 complete and 2 partial remissions, 9 patients (56%) had stable disease, and 3 patients 19%) were rated as progressive disease. As the predefined activity of more than 7/16 patients responding was not reached, the study was stopped after 16 patients. Although long-term once-weekly oral azithromycin showed some antilymphoma activity, the response rate was below the predefined threshold of interest. However, based on our data, one cannot rule out suboptimal dosing in our study; attempts to study azithromycin at a different mode of application might be warranted in the future.