Tobin, W Oliver

Abstract Background: Erdheim-Chester disease (ECD) is characterized by multi-organ infiltration of clonal histiocytes bearing activating mutations predominantly in the MAPK pathway. The diagnosis of ECD is clinico-pathologic; histopathologic findings alone are often non-specific. Characteristic pathognomonic finding of ECD is the symmetric osteosclerosis of the distal femur and proximal tibia/fibula, seen in >90% of cases, and referred to herein as classic ECD (C-ECD). There is a paucity of data on the phenotypic and mutational differences between C-ECD and non-classic ECD (NC-ECD). Determining phenotypic patterns may allow for earlier suspicion and diagnosis. Methods: Patients who met the revised ECD criteria proposed by Haroche J et al (Blood 2020;135:1311-1318) and had full body imaging that included the lower legs (18-FDG-PET/CT or CT/bone scan) were included. ECD diagnosis was made when >1 major criteria plus >1 minor criteria were present. Major criteria: 1) symmetric meta-diaphyseal osteosclerosis in legs; 2) "hairy kidneys"; "coated aorta", right atrial pseudotumor, xanthelasma, exophthalmos; or osteosclerosis of paranasal sinuses. Minor criteria: 1) histologic finding of typical foamy histiocytes (CD68+/CD163+/CD1a-) associated with fibrosis; 2) mutation/gene fusion of BRAF, CSF1R, or MAPK/PI3K pathways. We compared the organ involvement and BRAF V600Emutational status between C-ECD and NC-ECD. Results: A total of 105 patients were included. The median age at diagnosis was 57 years (range, 38-81) and most were males (62%). Majority had 18-FDG-PET/CT (83%) and BRAF V600E testing (65%). The main organ systems involved were skeletal (83%), renal (64%), adrenal (44%), and pulmonary (42%). Central diabetes insipidus (DI), "hairy kidneys", and "coated aorta" were present in 27 (26%), 54 (51%), and 44 (42%) patients, respectively. Among those tested, BRAF V600E mutation was found in 48/67 (72%) by immunohistochemistry. In our cohort, most patients (n=87. 83%) had C-ECD. NC-ECD had significantly lower number of organs/systems involved compared with C-ECD (median 3 vs 6, p=0.002). C-ECD had significantly higher rates of involvement of paranasal sinuses (51%/7%, p=0.002), DI (26%/0%, p=0.02), and similar rates of lung (44%/43%), cardiac (34%/14%), and skin (14%14%) involvement when compared to NC-ECD. BRAF V600E was significantly more common in C-ECD (88%/30%, p=0.004). Thirty-nine (37%) patients underwent next generation sequencing, of whom 33 (31%) had successful testing. In C-ECD, 3 patients had mutations other than BRAF V600E, these included: NRAS, MAP2K1, and MEF2C-FLT3 fusion. In NC-ECD, 5 patients had mutations other than BRAF V600E, these included: MAP2K1, KRAS, and NF1. Conclusions: Our study suggests distinct differences in clinical presentation and molecular findings exist between C-ECD and NC-ECD. C-ECD has a higher degree of organ involvement and harbor BRAF V600E more frequently than NC-ECD. Further analysis of histopathologic findings and outcomes in this cohort may provide insights into these ECD subsets that can optimize future management of this disease. Figure 1: Sites of involvement of classical Erdheim-Chester Disease (C-ECD) versus non-classical Erdheim-Chester Disease (NC-ECD) Figure 1 Figure 1. Disclosures Vassallo: Bristol-Myers-Squibb: Research Funding; Sun Pharma.: Research Funding; Pfizer: Research Funding. Tobin: Mayo Clinic Center for MS and Autoimmune Neurology: Research Funding; Mallinckrodt Pharmaceuticals: Research Funding; National Institutes of Health: Research Funding. Bennani: Verastem: Other: Advisory Board; Purdue Pharma: Other: Advisory Board; Vividion: Consultancy, Other: Advisory Board; Daichii Sankyo Inc: Other: Advisory Board; Kyowa Kirin: Other: Advisory Board.

Abstract INTRODUCTION Rosai-Dorfman disease (RDD) is a rare histiocytic disorder associated with histiocytes expressing high level of macrophage colony stimulating factor receptor (c-fms). Mutations in mitogen-activated protein kinase (MAPK) pathway have been reported in RDD, indicating an underlying clonal process in some patients. Aberrant activation of MAPK pathway can occur due to mutations or high c-fms expression. Data on the use of MAPK/extracellular-signal-related kinase (ERK)-inhibitor therapy in RDD are very limited. Cobimetinib is a MEK inhibitor, which is listed in the National Comprehensive Cancer Network Compendium ® for the treatment of RDD. We present our retrospective experience of cobimetinib treatment in a large series of patients with RDD. METHODS Following approval of the institutional reviewed board, patients (pts) with RDD who were consecutively seen at Mayo Clinic and treated with cobimetinib between 2013-2021 were included. Response was assessed as described by Goyal et al (Haematologica 2020;105:2). Cobimetinib was given 20-60 mg once a day by mouth for 21 days in a 28-day cycle. Adverse events (AEs) were graded using the National Cancer Institute Common Toxicity Criteria v5.0. Time-to-event analyses were calculated from the time of treatment initiation, while duration of response was calculated from the time of 1 st response. Tumor genomic profile was analyzed using Tempus-xT ® assay (Chicago, IL), which includes targeted DNA sequencing (648 oncogenes) and whole transcriptome sequencing. RESULTS Of the 54 pts with RDD, ten were treated with cobimetinib and included in this study. The median follow-up was 16 months (m) [95% confidence interval (CI): 13-not reached (NR)] and most (n=8; 80%) were females. The median age at the time of treatment was 63 years (range: 36-74). Cobimetinib was used as first line therapy in four pts. Overall response rate was 70%, with 30% and 40% achieving complete (CR) and partial (PR) responses, respectively. One had stable disease (SD) and two had progressive disease (PD) (Table 1). The median progression-free-survival was 6.4 m (95%CI: 4.9-NR) and at 6 and 12 m, 67% and 50% of pts remained free from disease progression or death, respectively (Figure 1). The median duration of response was 7.6 m (95%CI: 3.1-NR). At the time of last follow-up, nine (90%) pts were alive. One pt died due to myelodysplastic syndrome with excessive blasts. She had multiple chemotherapy treatments before initiation of cobimetinib. Cobimetinib was discontinued in this pt due to grade 3 anemia and skin toxicity after 6 m of therapy and had SD as the best response. Median duration of treatment for the entire cohort was 6 m (range: 2-14). In the seven pts who responded, the median duration of treatment was 7 m (range: 2-14). Cobimetinib was discontinued in seven pts: disease progression (n=3; one disease progression after achieving PR and two PD while on therapy), grade 3 left ventricular systolic dysfunction (n=1), grade 3 diarrhea (n=1), grade 3 anemia (n=1), and grade 2 creatinine elevation (n=1). Five (50%) pts were started at a reduced dose of cobimetinib at the discretion of treating physician [20 mg (n=4) and 40mg, (n=1)]. Two pts were started at 60 mg and dose reduced to 20 mg after one cycle of treatment due to grade 2 skin toxicity in one and grade 2 skin toxicity and diarrhea in the other. Both pts achieved a PR but progressed after four and six cycles, respectively. One pt started at 40 mg and reduced to 20 mg due to grade 2 skin toxicity after two cycles achieving a PR. The response was sustained in this pt for at least 9 months, until the time of last follow-up (Table 1). Tissue molecular testing showed five pts with MAPK pathway alterations and all of them responded to therapy (CR=3 and PR=2). Of the other five pts who either did not have a MAPK pathway alteration (n=4) or had test failure (n=1), responses were observed in two (40%) pts, both PR (Table 1). CONCLUSION Our study suggests that cobimetinib is an effective treatment in RDD, with responses observed in all pts having MAPK pathway alterations. Less than half of pts without a MAPK pathway alteration achieved a response. However, treatment discontinuations due to AEs were common despite dose reductions. Patients who were treated at low doses of cobimetinib also had remarkable clinical response. Further studies are needed in evaluating other MAPK pathway inhibitors with better toxicity profile to improve adherence and outcomes. Figure 1 Figure 1. Disclosures Tobin: National Institutes of Health: Research Funding; Mayo Clinic Center for MS and Autoimmune Neurology: Research Funding; Mallinckrodt Pharmaceuticals: Research Funding. Bennani: Vividion: Other: Advisory Board; Kyowa Kirin: Other: Advisory Board; Daichii Sankyo Inc: Other: Advisory Board; Verastem: Other: Advisory Board; Purdue Pharma: Other: Advisory Board; Kymera: Other: Advisory Board. Vassallo: Pfizer: Research Funding; Bristol-Myers-Squibb: Research Funding; Sun Pharma.: Research Funding.

AbstractBackground and purposeTumefactive demyelination (TD) presents with large inflammatory lesions mimicking tumors or other space‐occupying lesions. Limited epidemiological, clinical and radiological data exist for TD. We aimed to report the incidence rate, and clinical and radiological features of TD in Olmsted County, Minnesota.MethodsWe retrospectively reviewed patients with central nervous system inflammatory demyelination‐related diagnostic codes (January 1, 1998 to December 31, 2018) in the Rochester Epidemiology Project database, and adjusted incidence rates by age and sex to the 2010 US total population. We used the Expanded Disability Status Scale (EDSS) to assess outcomes (index attack and last follow‐up).ResultsOf 792 multiple sclerosis (MS) patients, 15 (eight males, seven females) had tumefactive MS, representing 1.9% of the MS population. The median (range) age at attack onset was 34.2 (2–61) years. Tumefactive lesion was the first clinical MS attack in 8/16 patients. Cerebrospinal fluid oligoclonal bands (OCBs) were present in 8/12 patients and 11/16 patients met the Barkhof criteria for dissemination in space. Most patients remained fully ambulatory (EDSS score ≤4 in 13/16 patients [81%]) after a median (range) follow‐up duration of 10.5 (1–20.5) years. Age‐adjusted annual incidence rates were 0.46/100,000 (95% confidence interval [CI] 0.12–0.81) for female patients, 0.66/100,000 (95% CI 0.23–1.02) for male patients, and 0.56/100,000 [95% CI 0.28–0.83] overall. When age‐ and sex‐adjusted to the 2010 US total population, the overall annual incidence rate was 0.57 (95% CI 0.28–0.84). Despite aggressive clinical presentation at disease onset, most patients remained fully ambulatory (EDSS score ≤4 in 13/16 patients) with a relapsing‐remitting course.ConclusionsAlthough incidence is rare, TD should be suspected in patients presenting with subacutely progressive neurological deficits associated with magnetic resonance imaging findings of ring enhancement, apparent diffusion coefficient restriction, and OCB on spinal fluid analysis.

AbstractLangerhans cell histiocytosis (LCH) is a histiocytic neoplasm that can involve the lungs as single system (LCH‐SSL) or multisystem disease (LCH‐MSL). The role of full‐body radiographic staging to determine whether patients have LCH‐SSL or LCH‐MSL is unclear. Long‐term outcomes of LCH‐SSL versus LCH‐MSL and multisystem without lung involvement (LCH‐MSNL) are unknown. A retrospective study of adult LCH patients seen at our center from January 2000 to 2020 was performed. In Part 1, we addressed utility of whole‐body staging imaging among those presenting with isolated pulmonary signs or symptoms. Staging was defined as fluorodeoxyglucose positron emission tomography‐computed tomography (CT) or whole‐body CT obtained within 3 months of diagnosis. In Part 2, we examined the frequency of developing extra‐pulmonary disease over time and mortality in patients with LCH‐SSL. In Part 3, we compared the overall survival of LCH‐SSL, LCH‐MSL, and LCH‐MSNL. Part 1: 240 patients with LCH were identified. A total of 112 (47%) had pulmonary signs or symptoms at presentation. Thirty‐four (30%) underwent radiographic staging and only one showed evidence of extra‐pulmonary disease. Part 2: 108 (45%) were LCH‐SSL. Median follow‐up duration of 4.5 years (95% confidence interval [CI]: 2.9–6.0). None developed extra‐pulmonary disease. Part 3: 5‐year survival: 94% (95% CI: 84%–98%) for LCH‐SSL, 78% (95% CI: 59%–90%) for LCH‐MSL, and 75% (95% CI: 53%–89%) for LCH‐MSNL. LCH patients presenting with isolated pulmonary signs or symptoms rarely have extra‐pulmonary involvement at the time of diagnosis and generally do not develop extra‐pulmonary progression. LCH‐SSL has the best overall survival, while LCH‐MSL and LCH‐MSNL have similar clinical outcomes.

Abstract Many neuro-oncology studies commonly assess the association between a prognostic factor (predictor) and disease or outcome, such as the association between age and glioma. Predictors can be continuous (eg, age) or categorical (eg, race/ethnicity). Effects of categorical predictors are frequently easier to visualize and interpret than effects of continuous variables. This makes it an attractive, and seemingly justifiable, option to subdivide the continuous predictors into categories (eg, age <50 years vs age ≥50 years). However, this approach results in loss of information (and power) compared to the continuous version. This review outlines the use cases for continuous and categorized predictors and provides tips and pitfalls for interpretation of these approaches.

ObjectiveHistology reveals that early active multiple sclerosis lesions can be classified into 3 main interindividually heterogeneous but intraindividually stable immunopathological patterns of active demyelination (patterns I–III). In patterns I and II, a T‐cell‐ and macrophage‐associated demyelination is suggested, with pattern II only showing signs of a humoral immune response. Pattern III is characterized by inflammatory lesions with an oligodendrocyte degeneration. Patterns suggest pathogenic heterogeneity, and we postulated that they have distinct magnetic resonance imaging (MRI) correlates that may serve as biomarkers.MethodsWe evaluated in an international collaborative retrospective cohort study the MRI lesion characteristics of 789 conventional prebiopsy and follow‐up MRIs in relation to their histopathologically classified immunopathological patterns (n = 161 subjects) and lesion edge features (n = 112).ResultsA strong association of a ringlike enhancement and a hypointense T2‐weighted (T2w) rim with patterns I and II, but not pattern III, was observed. Only a fraction of pattern III patients showed a ringlike enhancement, and this was always atypical. Ringlike enhancement and T2w rims colocalized, and ringlike enhancement showed a strong association with macrophage rims as shown by histology. A strong concordance of MRI lesion characteristics, meaning that different lesions showed the same features, was found when comparing biopsied and nonbiopsied lesions at a given time point, indicating lesion homogeneity within individual patients.InterpretationWe provide robust evidence that MRI characteristics reflect specific morphological features of multiple sclerosis immunopatterns and that ringlike enhancement and T2w hypointense rims might serve as a valuable noninvasive biomarker to differentiate pathological patterns of demyelination. ANN NEUROL 2021;90:440–454

Background: Limited studies have described long-term outcomes in pathology confirmed multiple sclerosis (MS). Objectives: To describe long-term clinical–radiographic–cognitive outcomes in a prospectively followed cohort of patients with pathologically confirmed CNS demyelinating disease, consistent with MS. Methods: Subjects underwent clinical assessment, standardized 3T-MRI brain, and cognitive battery. Results: Seventy-five patients were included. Biopsied lesion size was ⩾ 2 cm in 62/75. At follow-up, median duration since biopsy was 11 years. Median EDSS was 3 and lesion burden was large (median 10 cm 3 ). At follow-up, 57/75 met MS criteria, 17/75 had clinically isolated syndrome, and 1 radiographic changes only. Disability scores were comparable to a prevalence cohort in Olmsted County ( p < 0.001, n = 218). Cognitive outcomes below age-normed standards included psychomotor, attention, working memory, and executive function domains. Total lesion volume and index lesion-related severity correlated with EDSS and cognitive performance. Volumetric cortical/subcortical GM correlated less than lesion metrics to cognitive outcomes. Conclusion: Despite early aggressive course in pathologically confirmed MS, its long-term course was comparable to typical MS in our study. Cognitive impairment in this group seemed to correlate strongest to index lesion severity and total lesion volume. It remains to be established how the aggressive nature of the lesion, biopsy, and treatment affect clinical/cognitive outcomes.