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Multiple myeloma (MM) patients frequently present with extensive osteolytic bone lesions. However, the impact of myeloma treatment on focal lytic lesion remineralization has not been extensively studied. In this study, the effect of anti-myeloma treatment on the extent of bone remineralization was examined and potential mediators identified. Newly diagnosed MM patients enrolled in the Total Therapy 4 and 5 (TT4; n = 231, TT5; n = 64) protocols were longitudinally evaluated for changes in radiological parameters for a median of 6.1 years. Bone remineralization was defined as a sclerotic CT change within the lytic lesion and quantified as a percentage of remineralization, using the initial lesion size as a reference. Such changes were correlated to clinical and biochemical parameters, and the gene expression profile of bone marrow biopsy. Overall, remineralization occurred in 72% of patients (213/295). Of those patients that experienced remineralization, 36% (107/295) achieved at least 25% of bone remineralization. Patients with high-risk disease defined by gene expression profile signature (GEP70 ≥ 0.66) experienced significant remineralization compared to low-risk MM. Female patients were also more likely to experience bone remineralization and in a shorter median time (2.0 vs. 3.3 y). Factors such as serum alkaline phosphatase along with high levels of RUNX2 and SOX4 gene expression correlated with increasing extent of bone remineralization. This analysis demonstrated significant remineralization of lytic lesions in MM patients treated on TT clinical trials. While the underlying mechanism remains elusive these findings support the hypothesis that patient baseline bone-related factors play a fundamental role in the skeletal repair of bone lesions in MM that provide new opportunities for improving patient outcomes., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Due to the low frequency of abnormalities affecting the spleen, this organ is often overlooked during radiological examinations. Here, we report on the unexpected finding, that the spleen signal on diffusion-weighted MRI (DW-MRI) is associated with clinical parameters in patients with plasma cell dyscrasias. Methods : We investigated the spleen signal on DW-MRI together with clinical and molecular parameters in 295 transplant-eligible newly diagnosed Multiple Myeloma (NDMM) patients and in 72 cases with monoclonal gammopathy of undetermined significance (MGUS). Results : Usually, the spleen is the abdominal organ with the highest intensities on DW-MRI. Yet, significant signal loss on DW-MRI images was seen in 71 of 295 (24%) NDMM patients. This phenomenon was associated with the level of bone marrow plasmacytosis ( P =1x10 -10 ) and International Staging System 3 ( P =0.0001) but not with gain(1q), and del(17p) or plasma cell gene signatures. The signal was preserved in 72 individuals with monoclonal gammopathy of undetermined significance and generally re-appeared in MM patients responding to treatment, suggesting that lack of signal reflects increased tumor burden. While absence of spleen signal in MM patients with high risk disease defined a subgroup with very poor outcome, re-appearance of the spleen signal after autologous stem cell transplantation was seen in patients with improved outcome. Our preliminary observation suggests that extramedullary hematopoiesis in the spleen is a factor that modifies the DW-MRI signal of this organ. Conclusions : The DW-MRI spleen signal is a promising marker for tumor load and provides prognostic information in MM., Competing Interests: Competing Interests: Bart Barlogie is a co-inventor on patents and patent applications related to use of GEP in cancer medicine that have been licensed to Signal Genetics Inc. The remaining authors declare no conflict of interest.

The iliac crest is the sampling site for minimal residual disease (MRD) monitoring in multiple myeloma (MM). However, the disease distribution is often heterogeneous, and imaging can be used to complement MRD detection at a single site. We have investigated patients in complete remission (CR) during first-line or salvage therapy for whom MRD flow cytometry and the two imaging modalities positron emission tomography (PET) and diffusion-weighted magnetic resonance imaging (DW-MRI) were performed at the onset of CR. Residual focal lesions (FLs), detectable in 24% of first-line patients, were associated with short progression-free survival (PFS), with DW-MRI detecting disease in more patients. In some patients, FLs were only PET positive, indicating that the two approaches are complementary. Combining MRD and imaging improved prediction of outcome, with double-negative and double-positive features defining groups with excellent and dismal PFS, respectively. FLs were a rare event (12%) in first-line MRD-negative CR patients. In contrast, patients achieving an MRD-negative CR during salvage therapy frequently had FLs (50%). Multi-region sequencing and imaging in an MRD-negative patient showed persistence of spatially separated clones. In conclusion, we show that DW-MRI is a promising tool for monitoring residual disease that complements PET and should be combined with MRD.

Spatial intratumor heterogeneity is frequently seen in multiple myeloma (MM) and poses a significant challenge for risk classifiers, which rely on tumor samples from the iliac crest. Because biopsy-based assessment of multiple skeletal sites is difficult, alternative strategies for risk stratification are required. Recently, the size of focal lesions (FLs) was shown to be a surrogate marker for spatial heterogeneity, suggesting that data from medical imaging could be used to improve risk stratification approaches. Here, we investigated the prognostic value of FL size in 404 transplant-eligible, newly diagnosed MM patients. Using diffusion-weighted magnetic resonance imaging with background suppression, we identified the presence of multiple large FLs as a strong prognostic factor. Patients with at least 3 large FLs with a product of the perpendicular diameters >5 cm 2 were associated with poor progression-free survival (PFS) and overall survival (OS; median, 2.3 and 3.6 years, respectively). This pattern, seen in 13.8% of patients, was independent of the Revised International Staging System (RISS), gene expression profiling (GEP)-based risk score, gain(1q), or extramedullary disease (hazard ratio, 2.7 and 2.2 for PFS and OS in multivariate analysis, respectively). The number of FLs lost its negative impact on outcome after adjusting for FL size. In conclusion, the presence of at least 3 large FL is a feature of high risk, which can be used to refine the diagnosis of this type of disease behavior and as an entry criterion for risk-stratified trials., (© 2018 by The American Society of Hematology.)

Objective: We aimed to evaluate the use of 4-dimensional computed tomography (4DCT) for characterization of thyroid nodules., Methods: Our study drew from 100 consecutive patients with primary hyperparathyroidism who underwent 4D parathyroid CT imaging for adenoma localization. Included subjects had tissue sampling of a thyroid nodule within 3 months of 4DCT., Results: Twenty subjects (18 women and 2 men) had thyroid nodules that were pathologically confirmed. Precontrast nodule attenuation was significantly lower in malignant nodules when compared with benign nodules (36 vs 61 HU, P = 0.05). Arterial phase and delayed phase nodule attenuations were not significantly different in malignant and benign nodules (128 vs 144 HU, P = 0.7; 74 vs 98 HU, P = 0.3)., Conclusions: Our initial experience with a small group of patients was unable to support the use of 4DCT for characterizing thyroid nodules; however, precontrast nodule attenuation was significantly lower in malignant nodules when compared with benign nodules.

Posterior reversible encephalopathy syndrome (PRES) is a neurotoxic process that typically occurs in the setting of immune dysregulation. In contrast to the characteristic pattern involving parieto-occipital and posterior frontal regions, predominant involvement of the infratentorial brain occurs in a minority of PRES patients. We examined six patients with infratentorial predominant posterior reversible encephalopathy syndrome (IPPRES) relative to those with typical PRES in terms of clinical factors of toxicity and outcomes. We review the current understanding of PRES pathophysiology. An institutional database of PRES patients was created through an IRB-approved search of the electronic record from 2007 to 2012. MR images were reviewed and classified by two neuro radiologists. Clinical data including laboratory data, blood pressure, and discharge outcome were collected through review of existing electronic medical records. Characteristics of the two groups were compared. Six cases among 80 PRES patients displayed an atypical distribution of signal abnormality predominantly involving the infratentorial brain. In IPPRES patients, signal abnormalities within the supratentorial brain, when present, showed a predominantly central distribution rather than the typical peripheral distribution. IPPRES patients showed higher rates of extreme hypertension, renal dysfunction, abnormal serum calcium, and abnormal serum magnesium relative to typical PRES patients. Outcomes were similar between the two groups. In our small series, IPPRES differs from typical PRES patients not only in the distribution of imaging abnormalities but also in rates of extreme hypertension and several laboratory indices. Despite these differences, clinical outcome in the IPPRES group was similar to that of typical PRES.

We report two cases of posterior reversible encephalopathy syndrome (PRES) occurring in association with supra-therapeutic serum lithium levels. Although the neurologic manifestations of lithium toxicity are well known, this is, to our knowledge, the first report describing a link between lithium toxicity and PRES. We discuss the current understanding of the pathogenesis of PRES and suggest mechanisms by which lithium may play a role in its development., (Copyright © 2014 by the American Society of Neuroimaging.)

The pathophysiology of posterior reversible encephalopathy syndrome (PRES) is incompletely understood; however, an underlying state of immune dysregulation and endothelial dysfunction has been proposed. We examined alterations of serum lactate dehydrogenase (LDH), a marker of endothelial dysfunction, relative to the development of PRES in patients receiving chemotherapy. A retrospective Institutional Review Board approved database of 88 PRES patients was examined. PRES diagnosis was confirmed by congruent clinical diagnosis and MRI. Clinical features at presentation were recorded. Serum LDH values were collected at three time points: prior to, at the time of, and following PRES diagnosis. Student's t-test was employed. LDH values were available during the course of treatment in 12 patients (nine women; mean age 57.8 years [range 33-75 years]). Chemotherapy-associated PRES patients were more likely to be normotensive (25%) versus the non-chemotherapy group (9%). LDH levels at the time of PRES diagnosis were higher than those before and after (p=0.0263), with a mean difference of 114.8 international units/L. Mean time intervals between LDH measurement prior to and following PRES diagnosis were 44.8 days and 51.4 days, respectively. Mean elapsed time between last chemotherapy administration and PRES onset was 11.1days. In conclusion, serum LDH, a marker of endothelial dysfunction, shows statistically significant elevation at the onset of PRES toxicity in cancer patients receiving chemotherapy. Our findings support a systemic process characterized by endothelial injury/dysfunction as a factor, if not the prime event, in the pathophysiology of PRES., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Multiple myeloma causes major morbidity resulting from osteolytic lesions that can be detected by metastatic bone surveys. Magnetic resonance imaging and positron emission tomography can detect bone marrow focal lesions long before development of osteolytic lesions. Using data from patients enrolled in Total Therapy 3 for newly diagnosed myeloma (n=303), we analyzed associations of these imaging techniques with baseline standard laboratory variables assessed before initiating treatment. Of 270 patients with complete imaging data, 245 also had gene expression profiling data. Osteolytic lesions detected on metastatic bone surveys correlated with focal lesions detected by magnetic resonance imaging and positron emission tomography, although, in two-way comparisons, focal lesion counts based on both magnetic resonance imaging and positron emission tomography tended to be greater than those based on metastatic bone survey. Higher numbers of focal lesions detected by magnetic resonance imaging and positron emission tomography were positively linked to high serum concentrations of C-reactive protein, gene-expression-profiling-defined high risk, and the proliferation molecular subgroup. Positron emission tomography focal lesion maximum standardized unit values were significantly correlated with gene-expression-profiling-defined high risk and higher numbers of focal lesions detected by positron emission tomography. Interestingly, four genes associated with high-risk disease (related to cell cycle and metabolism) were linked to counts of focal lesions detected by magnetic resonance imaging and positron emission tomography. Collectively, our results demonstrate significant associations of all three imaging techniques with tumor burden and, especially, disease aggressiveness captured by gene-expression-profiling-risk designation. (Clinicaltrials.gov identifier: NCT00081939).

Purpose: Magnetic resonance imaging (MRI) permits the detection of diffuse and focal bone marrow infiltration in the absence of osteopenia or focal osteolysis on standard metastatic bone surveys (MBSs)., Patients and Methods: Both baseline MBS and MRI were available in 611 of 668 myeloma patients who were treated uniformly with a tandem autologous transplantation-based protocol and were evaluated to determine their respective merits for disease staging, response assessment, and outcome prediction., Results: MRI detected focal lesions (FLs) in 74% and MBS in 56% of imaged anatomic sites; 52% of 267 patients with normal MBS results and 20% of 160 with normal MRI results had FL on MRI and MBS, respectively. MRI- but not MBS-defined FL independently affected survival. Cytogenetic abnormalities (CAs) and more than seven FLs on MRI (MRI-FLs) distinguished three risk groups: 5-year survival was 76% in the absence of both more than seven MRI-FLs and CA (n = 276), 61% in the presence of one MRI-FL (n = 262), and 37% in the presence of both unfavorable parameters (n = 67). MRI-FL correlated with low albumin and elevated levels of C-reactive protein, lactate dehydrogenase, and creatinine, but did not correlate with age, beta-2-microglobulin, and CA. Resolution of MRI-FL, occurring in 60% of cases and not seen with MBS-defined FL, conferred superior survival., Conclusion: MRI is a more powerful tool for detection of FLs than is MBS. MRI-FL number had independent prognostic implications; additionally, MRI-FL resolution identified a subgroup with superior survival. We therefore recommend that, in addition to MBS, MRI be used routinely for staging, prognosis, and response assessment in myeloma.

Involvement of the central nervous system (CNS) by multiple myeloma, defined by the detection of malignant plasma cells in the cerebrospinal fluid in the presence of suggestive symptoms, is considered extremely rare. We present the characteristics of 25 such patients (18 previously reported) intended to receive high-dose treatment at the University of Arkansas over the last 12 years; an extensive review of the published literature since 1968, including 71 patients, is also presented. In both patient groups, high tumor burden was overwhelmingly present while circulating plasma cells were detected in a significant proportion of cases. We also observed a strong association of CNS involvement with unfavorable cytogenetic abnormalities (especially translocations and deletion of the chromosome 13), plasmablastic morphology and additional extramedullary myeloma manifestations. The presence of these features should alert clinicians to the possibility of CNS involvement. The prognosis of such patients is poor despite aggressive systemic and local treatment and reflects the underlying disease biology. Application of allogeneic transplantation and administration of prophylactic CNS treatment are also discussed. Further elucidation of the factors predisposing patients with high-risk disease features to CNS myeloma involvement is needed.

Intracranial chordoma is a locally aggressive and relatively rare tumor of the skull base that is thought to originate from embryonic remnants of the primitive notochord. Both computed tomography (CT) and magnetic resonance (MR) imaging are usually required for evaluation of intracranial chordomas due to bone involvement and the proximity of these tumors to many critical soft-tissue structures. At CT, intracranial chordoma typically appears as a centrally located, well-circumscribed, expansile soft-tissue mass that arises from the clivus with associated extensive lytic bone destruction. However, MR imaging is the single best imaging modality for both pre- and posttreatment evaluation of intracranial chordoma. On T1-weighted MR images, intracranial chordomas demonstrate intermediate to low signal intensity and are easily recognized within the high-signal-intensity fat of the clivus. On T2-weighted MR images, they characteristically demonstrate very high signal intensity, a finding that likely reflects the high fluid content of vacuolated cellular components. Moderate to marked enhancement is common and often heterogeneous on contrast material-enhanced images. Combination treatment with radical surgical resection and proton beam radiation therapy achieves the best results., (Copyright RSNA, 2003)

Magnetic resonance angiography (MRA) and venography (MRV) are useful tools in the diagnosis and analysis of both intracranial and head and neck tumors. These procedures illuminate the three-dimensional relationships of the tumors and the adjacent cerebral vasculature. Contrast administration allows further analysis of these lesions. Research continues to improve the spatial resolution that may preclude conventional angiography. For the first time, MRA allows non-invasive diagnosis of neurovascular conditions such as trigeminal neuralgia and pulsatile tinnitus. This accurate diagnosis revolutionizes therapy. Although MRA has certain limitations, its role continues to expand. The value of MRA for diagnosis and treatment planning is paramount.