Erdheim-Chester disease with Rosai-Dorfman-like lesions: treatment with methotrexate, anakinra and upadacitinib.

Erdheim-Chester disease (ECD) is a non-Langerhans cell histiocytosis characterised by clonal expansion of histiocytes in various organs. These induce an inflammatory environment, which leads to damage of the affected areas. Recently, a new disease entity was proposed encompassing key features of ECD but also of Rosai-Dorfman-Destombes disease, another histiocytosis. Mitogen-activated protein kinase kinase 1 (MAP2K1) mutations seem to present a specific genetic lesion for this subtype.Here, we describe a case of this new disease entity with clinical, radiological and genetic findings compatible with ECD but histological findings compatible with Rosai-Dorfman-Destombes disease. In particular, there were intraabdominal and retroperitoneal lesions, which tested positive for a (c.167A>C; p.Q56P) mutation of the MAP2K1 gene. On histological examination, S100-positive, giant histiocytes with focal emperipolesis of haematological cells in addition to infiltration by lymphocytes and granulocytes were seen.As described for this rare variant of ECD, there was also bilateral testicular infiltration. We also describe a manifestation of oligoarthritis in this patient with ECD.The patient was treated with methotrexate and prednisolone. While radiological response to this regime was excellent, arthritis persisted. We added anakinra, which induced a response of the arthritis for more than a year. Due to treatment failure therapy was switched to upadacitinib, which induced a remission of the arthritis as well.This case adds a rare phenotype to an already rare presentation of ECD. The patient responded to immunosuppressive therapy.

Multi-parametric whole-body MRI evaluation discerns vital from non-vital multiple myeloma lesions as validated by 18F-FDG and 11C-methionine PET/CT.

PURPOSE: We tested a novel multi-parametric (mp) whole body (WB)-MRI evaluation algorithm for medullary lesions in comparison to positron emission tomography (PET) radiotracers 18F-fluorodeoxyglucose (18F-FDG) and 11C-methionine (11C-MET). METHODS AND MATERIALS: This retrospective single-center study included 44 MM patients, who received both 18F-FDG-PET and WB-MRI within ten days. MRI classified focal lesions as vital when showing 1) significant diffusion-restriction, 2) a fat fraction (FF) less than 20 % and 3) homogenous hypointensity on T2-weighted images. On a lesion-by-lesion level the findings were compared to 18F-FDG PET by using a 5-point scoring system (analogous to the Deauville score [DS]). In 24/44 (55 %) patients additional comparison to 11C-MET PET was available. RESULTS: Among two radiologists, an excellent inter-observer reliability for mpWB-MRI in a total of 84 medullary lesions was observed (ICC = 1, k = 1, p <.01). 16/17 (94.1 %) MRI-classified vital lesions had a DS of 4 or 5 on either 18F-FDG-PET or 11C-MET-PET. MRI-rated non-vital lesions correlated with PET-based DS ≤ 3. When results of mpWB-MRI were compared to 18F-FDG, a fair inter-observer agreement was recorded (ICC = 0.52, k = 0.53, p <.01), while for 11C-MET, an excellent concordance rate was achieved (ICC = 0.81, k = 0.79, p <.01). CONCLUSION: The proposed mpWB-MRI interpretation algorithm allowed to assess tumor activity of myeloma lesions with high inter-observer reproducibility. We observed a substantial concordance between the mpWB-MRI classification of lesions and PET assessment based on a semi-automatically calculated 5-point scoring system analogous to the Deauville scores.

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

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

Whole-Body MRI with an Ultrahigh b-Value of 2000 s/mm2 Improves the Specificity of Diffusion-Weighted Imaging in Patients with Plasma Cell Dyscrasias.

RATIONALE AND OBJECTIVES: Our study compared sensitivity, specificity, and accuracy of whole-body diffusion-weighted imaging (WB-DWI) using a b-value of 2000 s/mm2 with that of the commonly used b-value of 800 s/mm2 for depiction of active tumor sites in patients with plasma cell diseases. We introduced an ultrahigh b-value to reduce interfering signals from benign and post-therapeutic inactive lesions by suppressing T2-shine-through effects. MATERIALS AND METHODS: The prospective single-center study included patients when they went through a whole-body MRI (WB-MRI) staging or response evaluation procedure. The apparent diffusion coefficient (ADC) and morphologic appearance served as reference for classifying focal lesions on WB-DWI as vital or post-therapeutic. Additionally, we compared our classification with patients' serological markers of disease activity. RESULTS: One hundred participants (65 ± 10 years, 58 men) underwent WB-DWI between June and October 2019. The detection rate of vital focal lesions was similar for both b-values with a sensitivity of 0.99 using b = 800 s/mm2 and 0.98 using b = 2000 s/mm2. By contrast, specificity and accuracy were 0.09 and 0.71 when using a b-value of 800 s/mm2, and 0.96 and 0.98 when using a b-value of 2000 s/mm2, respectively. The difference in specificity and accuracy was statistically significant (p < 0.001). CONCLUSION: Using a b-value of 2000 s/mm2 significantly improved the specificity of lesion detection with WB-DWI as compared to the commonly used b-value of 800 s/mm2. The high b-value significantly reduced signal intensities of post-therapeutic or benign lesions and provided a significantly more accurate representation of active tumor load.

R-CHOP intensification with mid-cycle methotrexate and consolidating AraC/TT with BCNU/aHSCT in primary aggressive lymphoma with CNS involvement.

PURPOSE: Patients suffering from aggressive systemic peripheral lymphoma with primary central nervous system involvement (PCL) are a rare and sparsely investigated population. Recommended treatment regimens include a combination of intrathecal and systemic chemotherapy as well as whole brain radiotherapy while offering relatively poor survival. METHODS: We conducted a single-center retrospective study that analyzed safety and outcome of 4 + 4 cycles Rituximab (R)-CHOP and R-high-dose Methotrexate (HD-MTX) for newly diagnosed, transplant-eligible patients ("Ping-Pong"), followed by Cytarabine (AraC)/Thiotepa (TT), BCNU/TT, and autologous hematologic stem cell transplantation (aHSCT). We retrospectively analyzed a set of 16 patients with high-intermediate or high-risk IPI status. RESULTS: Overall response rate to Ping-Pong was 100% measured by CT/MRI, including 93.75% complete remissions after BCNU/TT followed by PBSCT. One patient failed to qualify for high-dose chemotherapy due to progression when receiving Cytarabine/TT. All patients experienced grade III adverse events, 3 of them a grade IV adverse event. Estimated progression-free survival is 93.75% after a 4.8-year follow-up currently. CONCLUSION: Our study suggests high effectivity of R-CHOP with mid-cycle MTX with aHSCT consolidation towards acceptable OS results in this challenging patient population.

Efficacy of Zoledronic Acid in the Treatment of Nonmalignant Painful Bone Marrow Lesions: A Triple-Blind, Randomized, Placebo-Controlled Phase III Clinical Trial (ZoMARS).

Bone marrow lesions (BML) represent areas of deteriorated bone structure and metabolism characterized by pronounced water-equivalent signaling within the trabecular bone on magnetic resonance imaging (MRI). BML are associated with repair mechanisms subsequent to various clinical conditions associated with inflammatory and non-inflammatory injury to the bone. There is no approved treatment for this condition. Bisphosphonates are known to improve bone stability in osteoporosis and other bone disorders and have been used off-label to treat BML. A randomized, triple-blind, placebo-controlled phase III trial was conducted to assess efficacy and safety of single-dose zoledronic acid (ZOL) 5 mg iv with vitamin D 1000 IU/d as opposed to placebo with vitamin D 1000 IU/d in 48 patients (randomized 2:1) with BML. Primary efficacy endpoint was reduction of edema volume 6 weeks after treatment as assessed by MRI. After treatment, mean BML volume decreased by 64.53% (±41.92%) in patients receiving zoledronic acid and increased by 14.43% (±150.46%) in the placebo group (p = 0.007). A decrease in BML volume was observed in 76.5% of patients receiving ZOL and in 50% of the patients receiving placebo. Pain level (visual analogue scale [VAS]) and all categories of the pain disability index (PDI) improved with ZOL versus placebo after 6 weeks but reconciled after 6 additional weeks of follow-up. Six serious adverse events occurred in 5 patients, none of which were classified as related to the study drug. No cases of osteonecrosis or fractures occurred. Therefore, single-dose zoledronic acid 5 mg iv together with vitamin D may enhance resolution of bone marrow lesions over 6 weeks along with reduction of pain compared with vitamin D supplementation only. © 2021 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).

Homozygous BCMA gene deletion in response to anti-BCMA CAR T cells in a patient with multiple myeloma.

B cell maturation antigen (BCMA) is a target for various immunotherapies and a biomarker for tumor load in multiple myeloma (MM). We report a case of irreversible BCMA loss in a patient with MM who was enrolled in the KarMMa trial ( NCT03361748 ) and progressed after anti-BCMA CAR T cell therapy. We identified selection of a clone with homozygous deletion of TNFRSF17 (BCMA) as the underlying mechanism of immune escape. Furthermore, we found heterozygous TNFRSF17 loss or monosomy 16 in 37 out of 168 patients with MM, including 28 out of 33 patients with hyperhaploid MM who had not been previously treated with BCMA-targeting therapies, suggesting that heterozygous TNFRSF17 deletion at baseline could theoretically be a risk factor for BCMA loss after immunotherapy.

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

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

Lack of Spleen Signal on Diffusion Weighted MRI is associated with High Tumor Burden and Poor Prognosis in Multiple Myeloma: A Link to Extramedullary Hematopoiesis?

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.

Treatment of Refractory Adrenocortical Carcinoma with Thalidomide: Analysis of 27 Patients from the European Network for the Study of Adrenal Tumours Registry.

OBJECTIVE: Adrenocortical carcinoma (ACC) is a rare malignancy with a dismal prognosis. In advanced stages, tumour control by mitotane and cytotoxic chemotherapy is often temporary and salvage treatments are warranted. METHODS: Retrospective cohort study of participants in the prospective European Networks for the Study of Adrenal Tumours (ENSAT) registry. Main outcome measures were best response during treatment, progression-free survival (PFS), both measured according to RECIST 1.1 by two blinded radiologists, and overall survival (OS). RESULTS: Twenty-seven patients (13 males; median age 44.1 years) progressing after mitotane and a median of 4 further systemic treatments were included. Thalidomide was administered as tolerated with a starting dose of 50 mg and target dose of 200 mg /d. The median interval between treatment initiation and first imaging was 10.5 (4.4-17.5) weeks. The best response to treatment was stable disease (SD, n=2) and progressive disease (n=25), with a median PFS of 11.2 weeks and a median OS of 36.4 weeks. The first patient with SD discontinued treatment due to mild epistaxis and diarrhea after 22.3 weeks. The second patient had SD at the second treatment evaluation after 25.2 weeks and continued thalidomide but then had clinical progression and deceased after 54.3 weeks. In general, thalidomide induced only mild or moderate adverse effects (mainly fatigue and gastrointestinal complaints). CONCLUSION: Thalidomide was overall well tolerated but resulted in disease control in only 2/27 (7.4%) patients. In the absence of predictive response markers, thalidomide should only be considered in exceptional cases as a salvage therapy in ACC.

Multiple Myeloma and Dual-Energy CT: Diagnostic Accuracy of Virtual Noncalcium Technique for Detection of Bone Marrow Infiltration of the Spine and Pelvis.

Purpose To determine the diagnostic performance of dual-energy computed tomography (CT) for detection of bone marrow (BM) infiltration in patients with multiple myeloma by using a virtual noncalcium (VNCa) technique. Materials and Methods In this prospective study, 34 consecutive patients with multiple myeloma or monoclonal gammopathy of unknown significance sequentially underwent dual-energy CT and magnetic resonance (MR) imaging of the axial skeleton. Two independent readers visually evaluated standard CT and color-coded VNCa images for the presence of BM involvement. MR imaging served as the reference standard. Analysis on the basis of the region of interest (ROI) of VNCa CT numbers of infiltrated (n = 75) and normal (n = 170) BM was performed and CT numbers were subjected to receiver operating characteristic analysis to calculate cutoff values. Results In the visual analysis, VNCa images had an overall sensitivity of 91.3% (21 of 23), specificity of 90.9% (10 of 11), accuracy of 91.2% (31 of 34), positive predictive value of 95.5% (21 of 22), and a negative predictive value of 83.3% (10 of 12). ROI-based analysis of VNCa CT numbers showed a significant difference between infiltrated and normal BM (P < .001). Receiver operating characteristic analysis revealed an area under the curve of 0.978. A cutoff of -44.9 HU provided a sensitivity of 93.3% (70 of 75), specificity of 92.4% (157 of 170), accuracy of 92.7% (227 of 245), positive predictive value of 84.3% (70 of 83), and negative predictive value of 96.9% (157 of 162) for the detection of BM infiltration. Conclusion Visual and ROI-based analyses of dual-energy VNCa images had excellent diagnostic performance for assessing BM infiltration in patients with multiple myeloma with precision comparable to that of MR imaging. © RSNA, 2017 Online supplemental material is available for this article.

Quantification of fat fraction in lumbar vertebrae: correlation with age and implications for bone marrow dosimetry in molecular radiotherapy.

Absorbed dose to active bone marrow is a predictor of hematological toxicity in molecular radiotherapy. Due to the complex composition of bone marrow tissue, the necessity to improve the personalized dosimetry has led to the application of non-conventional imaging methods in nuclear medicine. The aim of this study is to apply magnetic resonance imaging (MRI) for quantification of the fat fraction in lumbar vertebrae and to analyze its implications for bone marrow dosimetry. First, a highly accelerated two-point Dixon MRI sequence for fat-water separation was validated in a 3T system against the magnetic resonance spectroscopy (MRS) gold standard. The validation was performed in a fat-water phantom composed of 11 vials with different fat fractions between 0% and 100%, and subsequently repeated in the lumbar vertebrae of three healthy volunteers. Finally, a retrospective study was performed by analyzing the fat fraction in five lumbar vertebrae of 44 patients scanned with the two-point Dixon sequence. The two-point Dixon phantom acquisition showed a good agreement (maximum difference = 2.9%) between the nominal fat fraction and MRS. In the volunteers, a statistical analysis showed a non-significant difference (p = 0.19) between MRI and MRS. In the patients, gender-specific linear fits for female and male data indicated that the age-dependent marrow conversion (red → yellow marrow) is slower in males (0.3% per year) than in females (0.5% per year). Lastly, the fat fraction values showed a considerable variability in patients of similar ages and the same gender. Two-point Dixon MRI enables a non-invasive and spatially resolved quantification of the fat fraction in bone marrow. Our study provides important evidence on the differences in marrow conversion between females and males. In addition, differences were observed in the cellularity values of the International Commission on Radiological Protection (ICRP) reference man (0.7) and the median values obtained in our patient group. These observations lead to the conclusion that the fat fraction in bone marrow should be considered as a patient-specific variable in clinical dosimetry procedures.

Case report: subacute tetraplegia in an immunocompromised patient.

BACKGROUND: Clinical reasoning in Neurology is based on general associations which help to deduce the site of the lesion. However, even "golden principles" may occasionally be deceptive. Here, we describe the case of subacute flaccid tetraparesis due to motor cortical lesions. To our knowledge, this is the first report to include an impressive illustration of nearly symmetric motor cortical involvement of encephalitis on brain MRI. CASE PRESENTATION: A 51 year old immunocompromized man developed a high-grade pure motor flaccid tetraparesis over few days. Based on clinical presentation, critical illness polyneuromyopathy was suspected. However, brain MRI revealed symmetrical hyperintensities strictly limited to the subcortical precentral gyrus. An encephalitis, possibly due to CMV infection, turned out to be the most likely cause. CONCLUSION: While recognition of basic clinical patterns is indispensable in neurological reasoning, awareness of central conditions mimicking peripheral nervous disease may be crucial to detect unsuspected, potentially treatable conditions.

Vertebral Compression Fractures: Third-Generation Dual-Energy CT for Detection of Bone Marrow Edema at Visual and Quantitative Analyses.

Purpose To assess the diagnostic performance of a third-generation dual-energy computed tomographic (CT) virtual noncalcium (VNCa) technique for detection of traumatic bone marrow edema in patients with vertebral compression fractures. Materials and Methods This prospective study was approved by the institutional review board. Informed consent was obtained from all participants. Twenty-two consecutive patients with 37 morphologic vertebral fractures were studied between October 2015 and May 2016. All patients underwent dual-energy CT (90 kV and 150 kV with a tin filter) and 3-T magnetic resonance (MR) imaging. Two independent readers visually evaluated all vertebral bodies (n = 163) for the presence of abnormal bone marrow attenuation on VNCa images by using color-coded maps and performed a quantitative analysis of CT numbers on VNCa images. MR images served as the reference standard. CT numbers were subjected to receiver operating characteristic analysis to calculate cutoff values. Results In the visual analysis, VNCa images had an overall sensitivity of 64.0%, specificity of 99.3%, accuracy of 93.9%, positive predictive value of 94.1%, and negative predictive value of 93.8%. The interobserver agreement was excellent (κ = 0.85). CT numbers obtained from VNCa images were significantly different in vertebral bodies with and without edema (P < .001). Receiver operating characteristic analysis revealed an area under the curve of 0.922. A cutoff value of -47 provided sensitivity of 92.0%, specificity of 82.6%, accuracy of 84.0%, positive predictive value of 48.9%, and negative predictive value of 98.3% for the differentiation of edematous vertebral bodies. Conclusion Visual and quantitative analyses of dual-energy VNCa images showed excellent diagnostic performance for assessing traumatic bone marrow edema in vertebral compression fractures. © RSNA, 2017 Online supplemental material is available for this article.

Salvage Treatment of Adrenocortical Carcinoma with Trofosfamide.

Adrenocortical carcinoma (ACC) has a dismal prognosis in advanced stages. Despite treatment with the adrenal toxicant mitotane and/or aggressive chemotherapy, tumor control is often short-lived. Here, we examine trofosfamide as a salvage treatment of ACC in an observational cohort study within the German ACC registry. Response defined as progression-free survival (PFS) at first tumor evaluation was assessed by RECIST 1.1 or clinically, and PFS and overall survival (OS) were estimated by the Kaplan-Meier method. Twenty-seven patients (11 males; median age 46.9 years) progressing after mitotane and three (median, range 0-5) other systemic treatments were evaluated for safety. Trofosfamide (150 mg/day) was administered as monotherapy (n = 13) or in combination with mitotane (n = 14). Overall tolerability was good with only mild adverse events. Six patients did not meet criteria for response assessment. Of the 21 patients, 8 patients had clinically progressive disease (3 deaths from ACC); among the 13 patients evaluable by RECIST 1.1, best response to treatment was stable disease (SD, n = 3) or progressive disease (n = 10). Hence, predefined response criteria were met in 3/21 patients (14 %). Median PFS was 84 days (95 % confidence interval 74-95) and median OS survival 198 days (95 % CI 89-307). One prolonged disease stabilization (best response by RECIST 1.1 -26 %) was observed for 479 days. In conclusion, trofosfamide is overall well tolerated but disease stabilization is rather rare. Accordingly, it may be used in selected cases of ACC not amenable to other treatment options such as clinical trials.

The role of surgery in the management of recurrent adrenocortical carcinoma.

CONTEXT: Surgery is the standard of care for localized adrenocortical carcinomas, but its role for recurrent disease is not well defined. OBJECTIVE: Our objective was to evaluate clinical outcome after surgery for recurrence. DESIGN: We conducted a retrospective analysis in 154 patients with first recurrence after initial radical resection from the German Adrenocortical Carcinoma Registry. MAIN OUTCOME MEASURES: We evaluated progression-free survival (PFS) and overall survival (OS) by Kaplan-Meier method and identified prognostic factors by Cox regression analysis. RESULT: A total of 101 patients underwent repeated surgery (radical resection, n = 78), and 99 received (additional) nonsurgical therapy. After a median of 6 (1-221) months, 144 patients (94%) experienced progression. Multivariate analysis adjusted for age, sex, tumor burden, time to first recurrence (TTFR), surgery for recurrence (including resection status), and additional therapy indicated that only two factors were significantly associated with shorter PFS [hazard ratio for progression: for TTFR ≤ 12 months, 1.8 (95% confidence interval = 1.3-2.6) vs. TTFR > 12 months; for macroscopically incomplete resection, 3.4 (1.5-7.9), and for no surgery, 3.4 (1.6-7.0) vs. microscopically complete (R0)-resection and OS [hazard ratio for death: for TTFR > 12 months, 3.1 (2.0-4.7) vs. TTFR ≤ 12 months; for macroscopically incomplete resection, 2.7 (1.1-6.9), and no surgery, 4.2 (1.8-9.6) vs. R0-resection]. Patients who had both TTFR over 12 months and R0-resection of recurrent tumors (n = 22) had the best prognosis (median PFS, 24 months; median OS, >60 months). CONCLUSIONS: The best predictors of prolonged survival after first recurrence are TTFR over 12 months and R0-resection. Our data suggest that patients with longer TTFR and tumors amenable to radical resection should be operated, whereas individualized treatment decisions are needed for patients with short TTFR or with not completely resectable tumors.