Diffuse Bone Marrow Infiltration Research Articles

Value of third-generation of VNCa dual-energy CT for differentiating diffuse marrow infiltration of multiple myeloma from red bone marrow.

This study aims to investigate the ability of bone marrow imaging using third-generation dual-energy computed tomography (CT) virtual noncalcium (VNCa) to differentiate between multiple myeloma (MM) with diffuse bone marrow infiltration and red bone marrow (RBM). Bone marrow aspiration or follow-up results were used as reference. We retrospectively reviewed 188 regions of interests (ROIs) from 21 patients with confirmed MM and diffuse bone marrow infiltrations who underwent VNCa bone marrow imaging between May 2019 and September 2022. At the same time, we obtained 98 ROIs from 11 subjects with RBM for comparative study, and 189 ROIs from 20 subjects with normal yellow bone marrow for the control group. The ROIs were delineated by 2 radiologists independently, the interobservers reproducibility was evaluated by interclass correlation coefficients. The correlation with MRI grade results was analyzed by Spearman correlation coefficient. Receiver operating characteristic (ROC) curve analysis was used to determine the optimal threshold for differentiating between these groups and to assess diagnostic performance. There were statistically significant differences in VNCa CT values of bone marrow among the MM, RBM, and control groups (all P < .001), with values decreasing sequentially. A strong positive rank correlation was observed between normal bone marrow, subgroup MM with moderately and severe bone marrow infiltration divided by MRI and their corresponding CT values (ρ = 0.897, 95%CI: 0.822 to 0.942, P < .001). When the CT value of VNCa bone marrow was 7.15 HU, the area under the curve (AUC) value for differentiating RBM and MM was 0.723, with a sensitivity of 50.5% and a specificity of 89.8%. When distinguishing severe bone marrow infiltration of MM from RBM, the AUC value was 0.80 with a sensitivity 70.9% and a specificity 78.9%. The AUC values for MM, RBM, and the combined group compared to the control group were all >0.99, with all diagnostic sensitivity and specificity exceeding 95%. VNCa bone marrow imaging using third-generation dual-energy CT accurately differentiates MM lesions from normal bone marrow or RBM. It demonstrates superior diagnostic performance in distinguishing RBM from MM with diffuse bone marrow infiltration.

The advantage of PET/CT in detecting bone metastases: a case report

Introduction: When detecting bone metastases bone scintigraphy has been long used as the most sensitive radiological modality, especially in lytic metastases, to assess the spread of disease in skeletal structures. Currently bone scintigraphy and CT remain the gold standard for bone metastasis detection in oncological patients in our nation. Method: We describe the case of a 45-year-old man who was diagnosed with large B-cell lymphoma and was having a whole-body PET/CT scan for staging purposes. The overall report identified the pathological lymph nodes, in more than one region of lymph node stations. These nodes had increased in size compared to the previous study of the patient. Diffuse skeletal pathological uptake of the radiotracer indicated diffuse bone marrow infiltration, while the CT images alone showed no evidence of typical lytic bone lesions. Other findings included splenomegaly and secondary splenic infiltration. Discussion: One of the primary diagnoses for which PET/CT is particularly effective is lymphoma, when it comes to identifying intra and extraosseous recurrence. This is particularly true when it comes to identifying marrow infiltration. Few centers in Kosovo and Albania have used the combined PET/CT modality in the last two years, besides the importance of including it as part of the imaging protocol in the follow-up of the patients with lymphoma, or oncologic patients in general. Keywords: Case report, PET/CT, scintigraphy, metabolically active, bone lesions, lymphoma.

MEDB-34. A very rare case: medulloblastoma relapse with bone marrow infiltration in a toddler

We report about a female toddler congenitally deaf and diagnosed with a non-metastatic desmoplastic medulloblastoma (SHH activated, TP53-wt, variant in LDB1 gene). No tumor predisposition syndrome was found. After complete tumor resection the patient was treated according to I-HIT-MED-Guidance protocol. Five months later an asymptomatic localised relapse (same histology, PTEN frameshift deletion, TERT mutation, LDB1 mutation) detected by routine MRI was treated by complete resection, craniospinal irradiation and an antiangiogenic regimen adapted from the MEMMAT scheme including fenofibrate, thalidomide, celecoxib, topotecan, temozolomide, bevacizumab and intraventricular cytarabine. Before start of systemic treatment blood cell counts were normal. In the second cycle we had to interrupt chemotherapy due to a leukopenia while continuing the antiangiogenic treatment. In order to avoid relevant bone marrow toxicity chemotherapy doses were reduced. Nevertheless we had to stop the fourth cycle because of a severe pancytopenia. Same time the girl presented with fever, neck and leg pain. A full blood count showed: hemoglobin 6.92 g/dl, leukocytes 640/µl, platelets 8,000/µl. Suspecting an infection supported by the presence of a high CrP value of 230 mg/l the patient was treated with i.v. antibiotics. MRI showed an unspecific retropharyngeal soft tissue augmentation, a pleural effusion and high T2 signals in multiple vertebral bodies but no central tumor relapse. The bone marrow diagnostics revealed a diffuse medulloblastoma cell infiltration with the known PTEN frameshift deletion and LDB1 mutation. The liquor was tumor-cell free. We report on an extremely rare case of an early local relapse of desmoplastic medulloblastoma progressing to a diffuse bone marrow infiltration in a toddler. The girl died due to therapy resistance 9 weeks after bone marrow relapse. It remains unclear whether the fatal course was related to the hereditary deafness syndrome and the molecular alterations of the tumor.

Amino Acid and Proliferation PET/CT for the Diagnosis of Multiple Myeloma

Multiple myeloma (MM) is a hematologic malignancy characterized by infiltration of monoclonal plasma cells in the bone marrow (BM). The standard examination performed for the assessment of bone lesions has progressed from radiographic skeletal survey to the more advanced imaging modalities of computed tomography (CT), magnetic resonance imaging (MRI), and positron emission tomography/computed tomography (PET/CT). The Durie–Salmon PLUS staging system (upgraded from the Durie–Salmon staging system) applies 2-[18F]-fluoro-2-deoxy-glucose (18F-FDG) PET/CT, and MRI findings to the staging of MM, and18F-FDG PET/CT has been incorporated into the International Myeloma Working Group (IMWG) guidelines for the diagnosis and staging of MM. However,18F-FDG PET/CT has significant limitations in the assessment of diffuse BM infiltration and in the differentiation of MM lesions from inflammatory or infectious lesions. The potential of several new PET tracers that exploit the underlying disease mechanism of MM has been evaluated in terms of improving the diagnosis. L-type amino acid transporter 1 (LAT1), a membrane protein that transports neutral amino acids, is associated with cell proliferation and has strong ability to represent the status of MM. This review evaluates the potential of amino acid and proliferation PET tracers for diagnosis and compares the characteristics and accuracy of non-FDG tracers in the management of patients with MM.

Skeletal changes in plasma cell dyscrasias

Plasma cell dyscrasias are aspectrum of diseases characterized by clonal plasma cell proliferation. Important entities within this group are monoclonal gammopathy of unknown significance, smoldering multiple myeloma, and symptomatic multiple myeloma. The goal of this review is to illustrate plasma cell dyscrasia imaging findings of bone and bone marrow as seen on whole-body computed tomography (CT) and magnetic resonance imaging (MRI) and to discuss the relevance of imaging for management of patients with plasma cell dyscrasias. Selective literature search with analysis of dedicated original research articles and reviews and discussion of clinical guidelines. Diagnostic classification of plasma cell dyscrasias is based on the SLiM-CRAB criteria. CT primarily represents imaging of mineralized bone to show osseous end organ damage by detecting osteodestruction. MRI is primarily used for bone marrow imaging to detect diffuse or focal bone marrow infiltration, even in the absence of bone destruction. Different patterns of bone marrow infiltration can be distinguished. Treatment response is associated with characteristic imaging signs of lesion regression. Imaging plays aprominent role in treatment stratification of patients with plasma cell dyscrasia at first diagnosis and during follow-up.

Prophylactic Peripheral Blood Stem Cell Collection in Patients with Extensive Bone-Marrow Infiltration of Neuroendocrine Tumours Prior to Peptide Receptor Radionuclide Therapy with 177Lu-DOTATATE.

Peptide receptor radionuclide therapy (PRRT) of metastatic neuroendocrine tumors (NET) can be successfully repeated but may eventually be dose-limited. Since 177Lu-DOTATATE dose limitation may come from hematological rather than renal function, hematological peripheral blood stem cell backup might be desirable. Here, we report our initial experience of peripheral blood stem-cell collection (PBSC) in patients with treatment-related cytopenia and therefore high risk of bone-marrow failure. Five patients with diffuse bone-marrow infiltration of NET and relevant myelosuppression (≥grade 2) received PBSC before one PRRT cycle with 177Lu-DOTATATE (7.6 ± 0.8 GBq/cycle). Standard stem-cell mobilization with Granulocyte-colony stimulating factor (G-CSF) was applied, and successful PBSC was defined as a collection of >2 × 106/kg CD34+ cells. In case of initial failure, Plerixafor was administered in addition to G-CSF prior to apheresis. PBSC was successfully performed in all patients with no adverse events. Median cumulative activity was 44.8 GBq (range, 21.3–62.4). Three patients had been previously treated with PRRT, two of which needed the addition of Plerixafor for stem-cell mobilization. Only one of five patients required autologous peripheral blood stem-cell transplantation during the median follow up time of 28 months. PBSC collection seems to be feasible in NET with bone-marrow involvement and might be worth considering as a backup strategy prior to PRRT, in order to overcome dose-limiting bone-marrow toxicity.

Review of diffusion-weighted imaging and dynamic contrast-enhanced MRI for multiple myeloma and its precursors (monoclonal gammopathy of undetermined significance and smouldering myeloma).

The last decades, increasing research has been conducted on dynamic contrast-enhanced and diffusion-weighted MRI techniques in multiple myeloma and its precursors. Apart from anatomical sequences which are prone to interpretation errors due to anatomical variants, other pathologies and subjective evaluation of signal intensities, dynamic contrast-enhanced and diffusion-weighted MRI provide additional information on microenvironmental changes in bone marrow and are helpful in the diagnosis, staging and follow-up of plasma cell dyscrasias. Diffusion-weighted imaging provides information on diffusion (restriction) of water molecules in bone marrow and in malignant infiltration. Qualitative evaluation by visually assessing images with different diffusion sensitising gradients and quantitative evaluation of the apparent diffusion coefficient are studied extensively. Dynamic contrast-enhanced imaging provides information on bone marrow vascularisation, perfusion, capillary resistance, vascular permeability and interstitial space, which are systematically altered in different disease stages and can be evaluated in a qualitative and a (semi-)quantitative manner. Both diffusion restriction and abnormal dynamic contrast-enhanced MRI parameters are early biomarkers of malignancy or disease progression in focal lesions or in regions with diffuse abnormal signal intensities. The added value for both techniques lies in better detection and/or characterisation of abnormal bone marrow otherwise missed or misdiagnosed on anatomical MRI sequences. Increased detection rates of focal lesions or diffuse bone marrow infiltration upstage patients to higher disease stages, provide earlier access to therapy and slower disease progression and allow closer monitoring of high-risk patients. Despite promising results, variations in imaging protocols, scanner types and post-processing methods are large, thus hampering universal applicability and reproducibility of quantitative imaging parameters. The myeloma response assessment and diagnosis system and the international myeloma working group provide a systematic multicentre approach on imaging and propose which parameters to use in multiple myeloma and its precursors in an attempt to overcome the pitfalls of dynamic contrast-enhanced and diffusion-weighted imaging.Single sentence summary statementDiffusion-weighted imaging and dynamic contrast-enhanced MRI provide important additional information to standard anatomical MRI techniques for diagnosis, staging and follow-up of patients with plasma cell dyscrasias, although some precautions should be taken on standardisation of imaging protocols to improve reproducibility and application in multiple centres.

18f-Fluorocholine Versus 18f-Fluorodeoxyglucose for PET/CT Imaging in Staging, Follow up or Suspected Relapse of Multiple Myeloma

Introduction: Hybrid positron emission tomography/computed tomography (PET/CT) has now become available, as well as whole body, low dose multi-detector row computed tomography (MDCT) or magnetic resonance imaging (MRI). The usefulness of 18F-fluorodeoxyglucose (FDG) PET/CT in evaluating multiple myeloma (MM) has been proven for several years but its sensitivity is imperfect. In a pilot study, we showed that 18F-fluorocholine (FCH) could have some advantages compared to FDG in suspected relapsing or progressive MM, since it is able to pinpoint lesions with a less intense metabolism and/or located in the skull, which are not revealed by FDG. The aim of the present study was to compare the diagnostic performance of PET/CT using FCH and FDG, in various settings of MM: staging, follow-up or suspected relapse.Methods: FDG and FCH PET/CTs were both performed within few days (less than 30 and without specific treatment in the meanwhile) in 77 consecutive patients with MM referred between November 2015 and June 2017. For each patient and each tracer, two blind readers determined the number of foci (intraosseous and extraosseous), measured their intensity of uptake by their SUVmax and by the corresponding target/non-target ratio (T/NT). A consensus reading was made between the two masked readers. Bone spread was divided into three patterns: innumerable foci (more than 10), countable bone foci (less or equal to 10) or diffuse bone marrow infiltration.Results: The 77 patients (average age = 67.3 year old) underwent 95 couples of FDG and FCH PET/CTs, all within 30 days: 17 for staging, 45 for follow-up (some patients had iterative PET/CTs) and 33 for suspected relapse. Among the 45 follow-up PET/CTs, 13 were intended purely to monitor treatment. No foci were found in 41 PET/CTs (6 for staging, 22 for follow-up and 13 for suspected relapse). Uncountable foci were observed in 10 cases with both tracers, but mismatched FDG/FCH foci in 1 case. Concerning countable foci, in 5 staging PET/CTs FDG showed 21 foci vs. 22 FCH foci, in 18 follow-up PET/CTs 32 FDG foci vs. 41 FCH foci, in 14 cases of suspected relapse 26 FDG foci vs. 55 FCH foci (+53%). Median SUVmax and T/NT was overall greater for FCH than for FDG, significantly in case of suspected relapse. There was no significant difference for median SUVmax and T/NT between FDG and FCH PET/CTs performed for staging. Of the 7 cases of diffuse bone marrow infiltration, 2 were better detected with FDG and 5 with FCH. Extramedullary spread was detected in 2 patients, foci of similar intensity being visible with both tracers. In all PET/CTs monitoring treatment for efficacy evaluation, FCH showed as reliable results as did FDG . FCH had better specificity than FDG, without some misleading foci of FDG in cases of inflammation (two cases), brown fat (one case) or post-traumatic fracture (one case). In 3 patients, the management decided on basis of FDG PET/CT was changed in view of FCH PET/CT.Conclusions: These findings suggest that FCH PET/CT could have a role in all settings of MM, in particular in case of suspected relapse or progression, because it would reveal more lesions than FDG and avoid some pitfalls. Further investigations are needed to determine significance of mismatched FDG and FCH foci, and in which patients it is worthwhile to complete the exploration with FCH, or whether using FCH instead of FDG would lead to detrimental decisions in some patients. [Display omitted] DisclosuresGarderet:Amgen: Honoraria; Takeda: Honoraria.

Improved 18-FDG PET/CT diagnosis of multiple myeloma diffuse disease by radiomics analysis.

In multiple myeloma, the diagnosis of diffuse bone marrow infiltration on 18-FDG PET/CT can be challenging. We aimed to develop a PET/CT radiomics-based model that could improve the diagnosis of multiple myeloma diffuse disease on 18-FDG PET/CT. We prospectively performed PET/CT and whole-body diffusion-weighted MRI in 30 newly diagnosed multiple myeloma. MRI was the reference standard for diffuse disease assessment. Twenty patients were randomly assigned to a training set and 10 to an independent test set. Visual analysis of PET/CT was performed by two nuclear medicine physicians. Spine volumes were automatically segmented, and a total of 174 Imaging Biomarker Standardisation Initiative-compliant radiomics features were extracted from PET and CT. Selection of best features was performed with random forest features importance and correlation analysis. Machine-learning algorithms were trained on the selected features with cross-validation and evaluated on the independent test set. Out of the 30 patients, 18 had established diffuse disease on MRI. The sensitivity, specificity and accuracy of visual analysis were 67, 75 and 70%, respectively, with a moderate kappa coefficient of agreement of 0.6. Five radiomics features were selected. On the training set, random forest classifier reached a sensitivity, specificity and accuracy of 93, 86 and 91%, respectively, with an area under the curve of 0.90 (95% confidence interval, 0.89-0.91). On the independent test set, the model achieved an accuracy of 80%. Radiomics analysis of 18-FDG PET/CT images with machine-learning overcame the limitations of visual analysis, providing a highly accurate and more reliable diagnosis of diffuse bone marrow infiltration in multiple myeloma patients.

The Role of PET-MRI in Multiple Myeloma Patients

Introduction Low-dose CT scans and magnetic resonance imaging (MRI) using T2- and T1-weighted contrasted enhanced images are the standard methods of bone staging for newly diagnosed and relapsed multiple myeloma (MM) patients. Fluoro-desoxy-glucose positron emission tomography (18F-FDG PET) is also a validated procedure for the imaging of MM bone lesions and the evaluation of extramedullary plasmacytoma. Furthermore, PET CT is useful to determine the prognosis and to assess the minimal residual disease. A new hybrid technology combining PET and MRI provides metabolic and anatomic information simultaneously. We evaluated the results obtained using this new examination. Materials and Methods Thirty-nine MM patients were prospectively included in this single center observational study. Fifty-one PET-MRI scans were performed in 4 patient populations: 1/ newly diagnosed smoldering MM (NDSMM, n =10); 2/ newly diagnosed symptomatic MM (NDMM, n=18); 3/ MM patients with long term follow-up (FU, n=17); 4/ MM patients with biochemical relapse (Rel, n=6). The imaging protocol consisted of T1-weighted, DIXON and diffusion-weighted (b=50 and b=800) axial sequences from the head to the knees simultaneously acquired by PET, followed by coronal and sagittal T1-weighted and T2-weighted sequences centered on the full spine and basin. MRI was considered to be positive in the case of diffuse bone marrow infiltration (DI), diffuse patchy bone marrow infiltration (DPI), focal bone marrow lesions (FL) or extra-medullary disease (EMD). PET was considered to be positive when FDG-avid focal bone lesions, a diffuse medullary area and/or FDG-avid EMD were observed. Medullary compression was also evaluated using MRI. Results The characteristics of the patients are summarized in Table 1. They were classified according to the ISS scale (I, n=18; II, n=7; III, n=3; missing, n=11) and none had high-risk cytogenetics or extra-medullary disease. The hybrid PET-MRI technique provided good image quality in all cases with no artefacts. No medullary compression was detected by MRI. Among the overall 51 PET-MRI examinations, 38 (74%) were positive for MRI and 27 (53%) for PET. Table 2 summarizes the bone marrow results obtained using MRI and PET in the four groups of patients. EMD was not detected by either MRI or PET. In NDSMM patients, MRI was positive and PET was negative in 30%, while none were positive only for PET. In NDMM, MRI was positive and PET was negative in 22% of cases, while 5% were positive only for PET (Figure 1 shows a negative PET and a positive MRI scan in the same patient). In FU patients, 35% of MRI scans remained positive with PET negative, while 6% were PET-positive and MRI-negative. In the case of relapsed patients, MRI and PET scans were in 100% agreement. Conclusions Using PET-MRI, in addition to a search for medullary compression, MRI can provide additional bone marrow information with respect to PET in about 22 to 30% of cases, particularly in NDSMM and NDMM. In a single examination, PET-MRI can detect bone, as well as potential extra-medullary lesions and medullary compression, without irradiation. The baseline PET examination is useful to evaluate the prognosis. Legend to Figure 1: PET and MRI scans in an asymptomatic myeloma patient. PET is negative but MRI reveals a bone lesion in the left iliac crest (arrow). Disclosures Leblond: Janssen: Honoraria; Lilly: Honoraria; Astra Zeneca: Honoraria; Roche: Honoraria; Amgen: Honoraria; Gilead: Honoraria; Beigene: Honoraria; Beigene: Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees; AbbVie: Membership on an entity's Board of Directors or advisory committees; Astra Zeneca: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; AbbVie: Honoraria.

Focal, Symptomatic Bone Marrow Lesions in Waldenström Macroglobulinaemia Characterised By Dense Infiltration with Lymphoplasmacytic Lymphoma: A Newly Defined Indication for Systemic Treatment

BACKGROUND Waldenström Macroglobulinaemia (WM) is an indolent, IgM-producing lymphoplasmacytic lymphoma (LPL) that infiltrates bone marrow (BM) and other tissues. Only symptomatic patients (with IgM-related complications, cytopenias, constitutional symptoms, bulky extramedullary disease) require treatment. Symptomatic BM lesions are not a recognised manifestation of WM and, if present, may raise the possibility of high-grade transformation. AIMS To characterise the clinical, radiological and histological features of focal bone marrow lesions (FBML) identified in WM patients with unrelenting pain in bones and/or joints, and outline implications for treatment. METHODS This study retrospectively reviewed investigations performed at the time of FBMLpresentation, including MRI of the site of pain, total body FDG-PET/CT, review of histology from BM trephine biopsy of the posterior superior iliac spine (PSIS) and CT-guided core biopsy of the identified FBML, and routine blood panels. RESULTS The 6 patients identified (Table 1) presented with localised skeletal pain at different stages of their WM disease course: 1 at initial WM diagnosis, 1 after 10 years of observation, 3 in remission following R-chemotherapy, and 1 during active treatment with R-chemotherapy. Median age at diagnosis of WM was 57 years (41-64 years). Median time from diagnosis to presentation with FBML was 28 months (0-120 months). MRI demonstrated well-defined areas of abnormal signal within the medullae of symptomatic bones and no evidence of cortical or trabecular bone involvement (Fig. 1A), with T1 hypointensity, diffusion restriction and mild STIR hyperintensity in excess of background BM changes. The FBML showed a predilection for the lower limbs (knees, ankles and/or feet involvement in 3 patients, 50%) and periarticular spaces (5 patients, 83%). They were CT-occult and only mildly FDG-avid. In all cases, core biopsies of the FBML showed heavy BM infiltration with diffuse interstitial infiltrate of small, mature lymphocytes (Fig. 1B, 1C) expressing CD20, CD79a and IgM; CD138 staining highlighted scattered interstitial plasma cells (&amp;lt;10%). There was no evidence of infarct or high-grade transformation. When compared to contemporaneous PSIS biopsies (Fig. 1D, 1E), all FBML demonstrated significantly higher proportions of lymphoid infiltration into the haematopoietic space (80-100% vs 0-80%, p=0.03), confirming FBML represent heavier disease infiltrationthan the background BM disease burden. On blood panels, LDH, ALP and platelet count were normal and Hb was &amp;gt;100g/L in all but the 1 patient with active WM (who had Hb 79g/L and ALP 149IU/L). There was no corresponding rise in paraprotein at the time of FBML presentation. In all cases, the detection of FBML prompted initiation/escalation of systemic treatment despite no evidence of progression using conventional criteria; this resulted in resolution of pain and disappearance of the T1 hypointense lesions on MRI in all cases. CONCLUSION Painful, LPL-dense, infiltrative lesions confined to the BM of affected appendicular bones are an unreported manifestation in WM. They are clinicopathologically different from the osteolytic lesions seen in myeloma and the painless, diffuse BM infiltration seen in low-grade lymphomas and can induce unrelenting focal skeletal pain. Based on our findings, such cases should be evaluated for focal bone marrow lesions; MRI is the preferred modality as lesions are CT-occult. They do not necessarily represent high-grade transformation. This small yet comprehensive series suggests they constitute a hitherto undescribed novel indication for systemic therapy irrespective of the general disease status. Disclosures D'Sa: Janssen:Honoraria, Research Funding;BeiGene:Honoraria, Research Funding;Sanofi:Honoraria.

Quantitative bone marrow magnetic resonance imaging through apparent diffusion coefficient and fat fraction in multiple myeloma patients.

Quantitative bone marrow (BM) MR sequences, as DWI and CSI, were used to evaluate BM water-fat composition. The aim of the study was to assess the potential usefulness of fat fraction (FF) and ADC, calculated by CSI or DWI, in diagnosing and classifying myeloma (MM) patients according to their different BM infiltration patterns. The study group included 43 MM patients (19F; 24M; mean age 64years), 15 asymptomatic, 15 symptomatic with diffuse BM infiltration and 13 symptomatic with focal lesions (FLs). The control group was made up of 15 healthy subjects (7F; 8M; mean age 64years). MRI examinations consisted of sagittal T1w TSE on the spinal column, axial DWI (b 50-400-800mm2/s) and coronal T2 Dixon, on the whole body. Mean ADC and FF were calculated placing 1 ROI on 6 vertebras and 2 ROIs on either the pelvis or FL. ANOVA with Bonferroni's correction showed a significant difference in ADC values among the different groups of MM patients (P < 0.05), while FF was only significantly different between patients with diffuse infiltration and patients with FL (P = 0.002). ADC allowed distinguishing MM patients from normal BM patients with diffuse BM infiltration (cutoff value: 0.491 × 10-3mm2/s; sensitivity 73%, specificity 80%). FF helped better discriminate healthy controls from normal BM patients (cutoff = 0.33, sensitivity 73%, specificity 92%) and patients with diffuse BM infiltration from those with FL (cutoff = 0.16, sensitivity 82%, specificity 92%). ADC and FF are potentially useful parameter for the quantitative evaluation of BM infiltration in MM patients.

The role of CT in PET/CT for assessing diffuse infiltration of bone marrow in multiple myeloma using the Durie-Salmon PLUS staging system.

PET/CT has been identified as one of the routine methods for the assessment of multiple myeloma (MM) bone marrow infiltration. In the routine method of performing PET/CT, the 18F-Fludeoxyglucose (18F-FDG) uptake in this disease is often used in the assessment of this condition, however CT diagnosis is not currently commonly used. The aim of the present study was to investigate the importance of CT in PET/CT for assessing diffuse infiltration (DI) of bone marrow in MM. MRI was used as a control in the present study, which is the gold standard for assessing DI of bone marrow and is divided into 3 levels: Mild, moderate and severe DI. Subsequently, a total of four combinations of PET and CT results were listed using the enumeration method for the evaluation of DI in the bone marrow. These combinations were respectively compared with the three levels of MR imaging to screen the most consistent method. The concordances of the new method and routine 18F-FDG PET/CT for the assessment of DI with MR imaging were compared using the McNemar test, respectively. The results of the DI assessment from the two methods were verified by performing Durie-Salmon (D-S) PLUS staging. Compared with MR imaging, the results were as follows: PET and CT exhibited negative results, suggesting mild DI; one of them was positive, suggesting moderate DI; and two were positive, suggesting severe DI. The results of concordance between two methods (new and routine) and MR imaging are indicated as follows: For the new method, McNemar test, P=0.513 and Kappa=0.745; for the routine 18F-FDG PET/CT method, McNemar test, P=0.03 and Kappa=0.547. Re-performance of D-S PLUS staging presented the following results: New method, McNemar test, P=0.317 and Kappa=0.93; for the routine method, McNemar test, P=0.223 and Kappa=0.811. These findings indicated that the CT component of PET/CT could improve the concordance with MRI results in the assessment of DI, and the same results were obtained when D-S PLUS staging was performed. The CT in PET/CT can enhance diagnostic accuracy in the assessment of DI by reducing the false negatives when compared with the routine 18F-FDG method.

State-of-the-art imaging for diagnosis of metastatic bone disease.

Metastatic bone disease (MBD) is common—it is detected in up to 65–75% of patients with breast or prostate cancer, in over 35% of patients with lung cancer; and almost all patients with symptomatic multiple myeloma have focal lesions or a diffuse bone marrow infiltration. Metastatic bone disease can cause a variety of symptoms and is often associated with a poorer prognosis, with high social and health-care costs. Population-based cohort studies confirm significantly increased health-care utilization costs in patients presenting with cancer with MBD compared with those without MBD. The prolonged survival of patients with bone metastasis thanks to advances in therapy presents an opportunity for better treatments for this patient cohort. Early and accurate diagnosis of bone metastases is therefore crucial. The patterns and presentation of MBD are quite heterogeneous and necessitate good knowledge of the possibilities and limitations of each imaging modality. Here, we review the state-of-the-art imaging techniques, assess the need for evidence-based and cost-effective patient care pathways, and advocate multidisciplinary management based on collaborations between orthopedic surgeons, pathologists, oncologists, radiotherapists, and radiologists aimed at improving patient outcomes. Radiologists play a key role in this multidisciplinary approach to decision-making through correlating the tumor entity, the tumor biology, the impact on the surrounding tissues and progression, as well as the overall condition of the patient. This approach helps to choose the best patient-tailored imaging plan advocating a “choose wisely” strategy throughout the initial diagnosis, minimally invasive treatment procedures, as well as follow-up care plans.

Positron Emission Tomography (PET) Radiopharmaceuticals in Multiple Myeloma.

Multiple myeloma (MM) is a plasma cell disorder, characterized by clonal proliferation of malignant plasma cells in the bone marrow. Bone disease is the most frequent feature and an end-organ defining indicator of MM. In this context, imaging plays a pivotal role in the management of the malignancy. For several decades whole-body X-ray survey (WBXR) has been applied for the diagnosis and staging of bone disease in MM. However, the serious drawbacks of WBXR have led to its gradual replacement from novel imaging modalities, such as computed tomography (CT), magnetic resonance imaging (MRI) and positron emission tomography/computed tomography (PET/CT). PET/CT, with the tracer 18F-fluorodeoxyglucose (18F-FDG), is now considered a powerful diagnostic tool for the detection of medullary and extramedullary disease at the time of diagnosis, a reliable predictor of survival as well as the most robust modality for treatment response evaluation in MM. On the other hand, 18F-FDG carries its own limitations as a radiopharmaceutical, including a rather poor sensitivity for the detection of diffuse bone marrow infiltration, a relatively low specificity, and the lack of widely applied, established criteria for image interpretation. This has led to the development of several alternative PET tracers, some of which with promising results regarding MM detection. The aim of this review article is to outline the major applications of PET/CT with different radiopharmaceuticals in the clinical practice of MM.

Adult Case Series of Extramedullary Relapsing Acute Myeloid Leukemia (AML) after Allogeneic Stem Cell Transplantation in Whom a Rapid Response and a Reasonably Long Remission Could be Achieved with Gemtuzumab Ozogamycin (GO)

Gemtuzumab Ozogamycin (GO) is a drug conjugated monoclonal antibody which targets CD33 an antigen highly expressed on the surface of AML blasts. GO is approved for the treatment of both newly-diagnosed and relapsed AML. Despite growing evidence regarding its efficacy and safety among AML patients there is limited data about the use of GO in isolated extra-medullary relapsed AML. Extramedullary AML remains as an unmet clinical need regarding the poor prognosis and lack of a standard therapeutic approach. Our cases demonstrated a rapid and long lasting response with a favorable toxicity profile, in patients who were treated with GO as a single agent after an isolated extramedullary relapsing disease. Our first case was a 40-years-old woman admitted to our outpatient clinic with pain in her joints and redness in her back and stomach. She was diagnosed with CD33-positive Acute Myeloid Leukemia according to the immunophenotyping of bone marrow blasts. Idarubicin and ARA-C (7+3) combination initiated as a frontline induction therapy and morphological remission was achieved after the first cycle of induction. After the first cycle of consolidation chemotherapy with high dose ARA-C she has relapsed with skin myeloid sarcomas and diffuse bone marrow infiltration. Soon after the relapsing disease she was put on to ida-flag salvage chemotherapy and she responded well with the disappearance of skin lesions and morphological complete remission of bone marrow. After achieving response, an allogeneic stem cell transplantation (HSCT) was applied from her sibling donor with a myeloablative conditioning. Unfortunately patient had a relapsing extramedullary disease with reappearance of skin lesions even with an ongoing acute skin gvhd (Figure) soon after allogeneic HSCT. Bone marrow biopsy revealed no increase in blast count. We have decided to initiate a novel targetted therapy to control the extramedullary disease. As her blasts infiltrating the skin were universally CD 33 positive we considered to put her on GO therapy with the approval obtained from health authority. GO was applied according to the dosage approved by FDA for relapsing disease. After the first cycle of GO she had a rapid disappearance of all skin lesions just complicated with a febrile neutropenic episode and re-activation of CMV infection which was controlled with Gancyclovir. She has retained a complete remission regarding extramedullary disease throughout the repeated courses of GO for 3 times, and she is still in remission for 4 months after the first appearance of skin lesions (Figure). Our second case was a 24-years-old boy who admitted to our outpatient clinic with a worsening fatigue and shortness of breath. He was also diagnosed with CD33-positive Acute Myeloid Leukemia according to the immunophenotyping of bone marrow blasts and was able to achieve a morphological CR after frontline induction therapy with 7+3 protocol. After two cycles of high dose ARA-C consolidation he was transplanted from a matched unrelated donor because of an intermediate cytogenetic risk profile. At the 14th month of allogeneic transplantation he had relapsed with a bone marrow blast count of 90% and harboring a monosomy on the 10th chromosome. After the first salvage chemotherapy with IDA-FLAG protocol he has achieved a morphological CR and we have decided to proceed with an alternative donor transplantation. But unfortunately soon after discharge, he has admitted to the emergency clinic with a new onset headache and nausea and vomiting. A cranial CT revealed multiple foci of solid masses with peripheral edema. We have performed a lumbar puncture and CSF fluid revealed a high number of CD33 positive blastic cells (over 100 cells per HPF). At the time of central nervous system (CNS) relapse his bone marrow was free of blastic infiltration. We decided to initiate GO treatment with the diagnosis of isolated central nervous system relapse of AML, accompanying intra-thecal chemotherapy via an Omaya Reservoir. He has received two cycles of GO which was complicated with neutropenic fever and grade 4 leukopenia and thrombocytopenia, and his CNS lesions also responded well and clinically he had no CNS related signs or symptoms. The patient received additional GO with continued response but unfortunately after a severe pneumonia he passed away at intensive care unit. Our case series documented a clinically relevant therapeutic field for GO in isolated extramedullary relapse of AML. Disclosures No relevant conflicts of interest to declare.

Evaluation of the Prognostic Value of Positron Emission Tomography-Computed Tomography (PET-CT) at Diagnosis and Follow-up in Transplant-Eligible Newly Diagnosed Multiple Myeloma (TE NDMM) Patients Treated in the Phase 3 Cassiopeia Study: Results of the Cassiopet Companion Study

Evaluation of the Prognostic Value of Positron Emission Tomography-Computed Tomography (PET-CT) at Diagnosis and Follow-up in Transplant-Eligible Newly Diagnosed Multiple Myeloma (TE NDMM) Patients Treated in the Phase 3 Cassiopeia Study: Results of the Cassiopet Companion Study

Whole Body Diffusion Weighted MRI (WB DWI) for the Management of Multiple Myeloma: High Concordance between MRI Diffuse Pattern and BONE Marrow Plasma CELL Infiltration RATE

Background: Diffusion-weighted whole body MRI (WB-DWI) is a new functional imaging technique comprising anatomical and functional sequences with an emerging role in the management of multiple myeloma (MM) patients (pts) since it allows highly sensitive detection of diffuse bone marrow (BM) infiltration pattern and focal lesions, avoiding intravenous injections and radiation exposure. The aims of our study were 1) to test the correlation between plasma cells infiltration (BMPC) rate at BM biopsy and the presence of diffuse infiltration pattern at WB-DWI. 2) to compare response according to IMWG criteria and WB-DWI response and to establish the rate of discordancy (WB-DWI progression with increased focal lesions and at least a partial response according to IMWG criteria) Methods: We reviewed data regarding 45 MM patients (pts) observed in our Centre between September 2018 and July 2019 for whom quantification of serum and urine monoclonal component (MC), free light chains value (FLC), BM biopsy, whole body CT scan and WB-DWI data were available at the same time point. Sequential assessment of WB-DWI and laboratory data was available in 20 pts. Patients performed a WB-DWI (Magnetom Area, 1.5T, Siemens Enlarged Germany) for head to knee. The protocol included anatomical sequences T1 and T2 weighted with fat suppression on the sagittal plane specifically for the spine. Coronal T2 weighted fat suppression sequences are performed for the study of femural bone. Axial Dixon T1 weighted sequences of the whole scan region, in breath-old. The functional part is formed by diffusion weighted sequences in the axial plane. MM diagnosis and response were assessed by IMWG criteria. Response were categorized as follows: responsive patients if ≥PR, progressive disease if &lt;PR. BM infiltration rate was used as a continuous variable. WB-DWI findings at first evaluation were categorized as follows: presence/absence of focal lesions, presence/absence of diffuse pattern of BM infiltration. Radiological re-assessment of both focal lesions and diffuse pattern was categorized as follows: reduced/stable/increased. Discordant pattern of progression was defined as: ≥PR + diffuse pattern stable/reduced + focal lesions increased. Association between two categorical variables was evaluated by Fisher's exact test. Mann-Whitney test was used to compare a quantitative variable among two independent groups of patients. P-values&lt;0.05 were considered significant. Results: Table 1 summarizes the clinical and radiological data of the population on study. Median age was 64 years (range 38-86), median number of previous lines of therapy at time of evaluation was 0 (range 0-)2; 47% pts were at the onset, 31% were in follow-up after treatment completion, 22% had progressive disease. WB-DWI showed a diffuse pattern in 22 pts (49%); in 23 patients without a diffuse pattern, 7 (30%) had PBMC &gt;10%; BMPC infiltration rate was significantly higher in pts with presence of diffuse pattern at WB-DWI (p&lt;0.001; Figure 1). WB-DWI showed focal lesions in 35 pts (78%): 19 of them were at onset of disease. Most of the patients performing sequential assessment of WB-DWI were responsive according to IMWG criteria at time of WB-DWI re-evaluation (17 pts with ≥PR, 85%). Table 2 shows radiological findings according to IMWG response. Focusing on patients with ≥PR, WB-DWI diffuse pattern was reduced in 13 pts (76.5%) and stable in 4 pts (23.5%) with complete concordance between hematological and radiological findings (increased diffuse pattern in no pt with ≥PR); focal lesions were reduced in 76.5% and increased in 23.5%; a discordant pattern of progression was found in 4 patients (20%). Conclusions: Our study findsa significant correlation between presence of WB-DWI diffuse infiltration patter and BMPC rate, highlighting the possible future use of this radiological technique for monitoring BM residual disease. In addition, this study shows the possible not negligible emergence of discordant pattern of progression, probably deriving from the spatial heterogeneity of MM clones and their different sensitivity to therapy. Disclosures Mangiacavalli: celgene: Consultancy; Janssen cilag: Consultancy; Amgen: Consultancy. Varettoni:Gilead: Other: travel expenses; ABBVIE: Other: travel expenses; Roche: Consultancy; Janssen: Consultancy. Arcaini:Celgene: Speakers Bureau; Celgene, Roche, Janssen-Cilag, Gilead: Other: Travel expenses; Gilead Sciences: Research Funding; Bayer, Celgene, Gilead Sciences, Roche, Sandoz, Janssen-Cilag, VERASTEM: Consultancy.

Pattern of bone marrow involvement in non Hodgkin's lymphoma classified according to WHO classification: Report of a developing country Pakistan.

BACKGROUND:Limited information is available from developing countries in patients of non-Hodgkin's lymphoma (NHL). Hence, we reviewed the demographical profile along with bone marrow infiltration pattern in patients with NHL presented at Liaquat National Hospital and Medical College.MATERIALS AND METHODS:In this descriptive study, adult patients with NHL were enrolled from January 2011 to December 2015.RESULTS:One hundred and Eighty-four histopathologically confirmed cases of NHL were identified. There were 139 males and 45 females, with a male-to-female ratio of 3:1. The mean age was 48.5 ± 16.0 years with the median age of 50 years. B-symptoms were present in 80.4% of patients. Lymph node enlargement was present in 71.1% of the cases. One hundred and sixty-eight patients had B-cell lymphoma (91.3%) and 16 patients had T-cell lymphoma (8.6%). Overall 158 (85.8%) patients had aggressive lymphoma. The frequency of bone marrow infiltration in our NHL patients was found to be 31.5%. Pattern of infiltrate was diffuse (14.6%) predominantly followed by interstitial (6.5%) and paratrabecular (5.4%) types of infiltration. The least common was nodular infiltrate accounted in 9 (4.8%) patients.CONCLUSIONS:B-cell lymphoma is more frequent than T-cell lymphoma. Younger age, aggressive lymphoma, and predominance of B-symptoms are more frequently seen. Diffuse bone marrow infiltration is more common in our set up probably because of a relatively late presentation in our patients.

Donor T-cell responses and disease progression patterns of multiple myeloma

Donor T-cells transferred after allogeneic stem cell transplantation (alloSCT) can result in long-term disease control in myeloma by the graft-versus-myeloma (GvM) effect. However, T-cell therapy may show differential effectiveness against bone marrow (BM) infiltration and focal myeloma lesions resulting in different control and progression patterns. Outcomes of 43 myeloma patients who underwent T-cell-depleted alloSCT with scheduled donor lymphocyte infusion (DLI) were analyzed with respect to diffuse BM infiltration and focal progression. For comparison, 12 patients for whom a donor search was started but no alloSCT was performed, were analyzed. After DLI, complete disappearance of myeloma cells in BM occurred in 86% of evaluable patients. The probabilities of BM progression-free survival (PFS) at 2 years after start of donor search, alloSCT and DLI, were 17% (95% confidence interval 0-38%), 51% (36-66%), and 62% (44-80%) respectively. In contrast, the probabilities of focal PFS at 2 years after start of donor search, alloSCT and DLI, were 17% (0-38%), 30% (17-44%) and 28% (11-44%), respectively. Donor-derived T-cell responses effectively reduce BM infiltration, but not focal progression in myeloma, illustrating potent immunological responses in BM with only limited effect of T-cells on focal lesions.