Tobin, W. Oliver

Abstract Introduction: Langerhans Cell Histiocytosis (LCH) is a rare histiocytic neoplasm, with approximately 90% of patients exhibiting alterations in the MAPK pathway. BRAF and MEK inhibitors have shown promising results in treating MAPK pathway-altered LCH. However, treatment interruptions due to adverse effects are common, and limited access to targeted therapies complicates care globally. While chemotherapy remains a common treatment for LCH, the outcomes for patients with MAPK pathway-altered LCH specifically receiving chemotherapy are still unclear. Methods: This multi-institutional international retrospective cohort study analyzed adult patients with BRAF or MAP2K (gain-of-function, GOF) altered LCH that were consecutively seen at Mayo Clinic, MN, AZ, and FL, University of Alabama at Birmingham, and Peking Union Medical College Hospital in China between 2007 and 2024. All patients who were included in this study were treated with chemotherapy, and those who have received targeted therapies or other modalities of frontline treatment were excluded. All time-to-event analyses were performed from the frontline therapy initiation, using the Kaplan-Meier method. Progression-free survival (PFS) included death and progression as events and was measured from the time of treatment initiation. The response assessment was based on radiographic evaluation in accordance with the most recent Histiocyte Society consensus guideline. Risk organ involvement was defined as disease involving the liver, spleen, bone marrow or central nervous system. Results: A total of 63 patients with LCH were included. The median age of the population was 34 years (range: 27-43), and males were 59%. Risk organ involvement was seen in 44 (70%) of patients and multisystemic LCH was observed in 48 (76%) patients. Among the 63 patients, BRAF gain-of-function alterations were observed in 79%, MAP2K mutations in 19%, and BRAF fusions in 2%. Of the BRAF gain-of-function alterations, BRAFV600E mutation was seen in 64% patients and [p.N486_P490del] deletion in 36%. There was no significant difference in organ involvement (single-system versus multisystem) or risk organ involvement between patients with BRAF and MAP2K alterations. All 63 patients received systemic therapy with chemotherapy and the regimens included Cytarabine (n=43), Cladribine (n=5), Etoposide (n=1), Methotrexate (n=1), and combined Methotrexate and Cytarabine (n=13). The median follow-up for the entire cohort was 3.8 years (range 3.2–5.0 years), with similar durations observed in patients with single-system vs. multisystem involvement and those with risk-organ involvement vs. no risk-organ involvement. The overall response rate among patients who received chemotherapy was 89%, with complete responses in 15 patients (26%) and partial responses in 40 patients (64.5%). The median progression-free survival (PFS) for the entire cohort was 2.61 years (95% CI: 2.06–NA). The 3-year PFS did not significantly differ based on risk organ involvement: 50.6% (95% CI: 36–71) for patients with risk organ involvement versus 47.4% (95% CI: 28–81) for those without, p=0.52. Patients with single-system disease experienced longer PFS compared to those with multisystem disease; the 3-year PFS was 80.2% (95% CI: 58.7–100) versus 42.2% (95% CI: 29–61.5), respectively, p=0.04. Conclusions: Our results indicate that LCH patients with a GOF alteration in the MAPK pathway derive significant clinical benefit from chemotherapy, achieving deep and durable responses. Therefore, patients should not be excluded from treatment due to the absence of targeted therapies, as they can still attain substantial responses and clinical improvement with chemotherapy, even in the context of MAPK pathway-driven disease.

Abstract Background Adult xanthogranuloma (AXG) is a rare clonal histiocytic neoplasm (HN) with a poorly defined mutational landscape. Clinically and immunophenotypically, AXG can resemble other HNs such as Erdheim-Chester Disease (ECD) which frequently harbor MAPK pathway alterations and carry BRAF V600E mutations in close to 50% of cases. However, due to the rarity of AXG, the prevalence of the BRAF V600E mutation and the broader mutational landscape is not well known. In this study, we characterize the mutational profile of AXG. Methods We conducted a retrospective analysis of patients diagnosed with AXG at our institution between January 1, 2016, and July 15, 2025. The study was approved by the institutional review board. To ensure inclusion of true AXG cases, only patients with a confirmed histopathologic diagnosis and without multisystemic involvement or characteristic imaging findings of ECD, such as symmetric long bone osteosclerosis, were included. BRAF alterations were identified by immunohistochemistry (IHC) and/or next-generation sequencing (NGS). We also performed an extensive literature review of mutational studies in AXG and included cases that underwent comprehensive NGS. Results Seventeen patients with AXG were identified. The median age at diagnosis was 40 years (range: 18–75 years). Out of the 17 patients, 11 (65%) reported the face as the primary site of disease, and 11 (65%) had solitary lesions. Of the 17 patients, 13 (76%) underwent BRAF V600E IHC staining, and none tested positive. Twelve (71%) patients had tissue samples analyzed via NGS, and none exhibited the BRAF V600E mutation. Eight of the 12 (67%) patients with NGS testing harbored other alterations involving the MAPK pathway. These included BRAF fusions (n=3), KRAS mutations (n=2), and individual cases with TRAF7 mutation, ALK1 fusion and FGFR1 fusion. One patient was found to have a mutation in WRN, which is not previously reported in AXG. Three patients had no identifiable pathogenic alterations on NGS. Ten patients were monitored without treatment, 2 underwent surgical resections and 3 received chemotherapy (1 had a complete response [CR], 2 achieved a partial response). One patient with FGFR1 fusion was treated with pemigatinib and achieved a CR for over 3 years. One patient with TRAF mutation obtained a CR after treatment with rituximab. We also identified 51 cases of AXG with adequate mutational testing reported in the literature, which reported findings similar to ours. In a retrospective study from France involving 29 patients, MAPK alterations were observed in 55% of cases: however, only 10% harbored BRAF V600E mutations (1). Another analysis of 270 patients with various HN subtypes included 13 individuals with AXG, none had BRAF mutations. MAP2K1 mutations were seen in 31% of patients (2). Taken together, across a combined cohort of 68 AXG patients, the most common alterations were: KRAS mutations (16%), fusions (14%), MAP2K1 mutations (7%) and BRAF V600E (6%). Among fusions, the most involved gene was BRAF (50%), and GAB2 was the most common fusion partner (n=2). In total, 59% of patients had MAPK alterations. These findings collectively underscore the diverse mutational landscape of AXG and highlight the rarity of BRAF V600E mutations relative to closely related HNs. Conclusion We present a series of AXG cases with mutational profiling, from our institution and the published literature. We demonstrate that MAPK alterations are frequently observed in AXG and are driven by heterogeneous mutations. In contrast to other HNs where BRAF V600E mutations are common, we identified no such mutations in our cohort and found only rare cases in the literature. Our institutional data, along with findings from the existing literature, suggest that AXG may have a distinct molecular profile compared to other HNs. A deeper understanding of its mutational landscape may offer insights into disease biology and identify therapeutic targets. ReferencesAnnabi E, Mahévas T, Chasset et al. Clinical, Histopathologic, and Molecular Features and Treatment of Multiple Xanthogranuloma in Adults. JAMA Dermatol. 2025;161(7):765-768. doi:10.1001/jamadermatol.2025.0886.Durham BH, Lopez Rodrigo E, Picarsic J, et al. Activating mutations in CSF1R and additional receptor tyrosine kinases in histiocytic neoplasms. Nat Med. 2019;25(12):1839-1842. doi:10.1038/s41591-019-0653-6

Abstract Background:Erdheim-Chester Disease (ECD) is a rare, incurable histiocytic neoplasm. Since its recognition in 1930, our understanding of ECD's pathophysiology has evolved. The identification of its clonal nature after 2015 established ECD as a cancer, prompting increased disease awareness and treatment advances. Targeted therapies show promising responses, but changes in ECD mortality over time have not been extensively documented. Methods:A multi-institutional retrospective cohort study analyzed adults with ECD consecutively seen at Mayo Clinic MN, AZ, and FL and the University of Alabama at Birmingham between 2007 and 2024. Clinical and prognostic data were abstracted. Overall survival was estimated using the Kaplan-Meier method and compared to expected survival using U.S. Census data, based on age at diagnosis (by calendar year), date of diagnosis, and sex. Standardized mortality ratios (SMRs) were calculated by dividing the number of observed deaths in the study population by the expected number of deaths using U.S. population data. Risk of death was compared by date of diagnosis (pre- and post-2015) using Cox proportional hazards analysis. Statistical analysis was performed with R software. Results:A total of 159 ECD patients were included (median age 58 years [range 19-82], 65% male). Forty-nine patients were diagnosed between 1990-2014 and 110 between 2015-2024. Median follow-up for the entire cohort was 4.0 years (95% CI: 3.2-4.4). Median follow-up for those diagnosed between 1990-2014 was 10.4 years (CI: 3.2-16.8), compared to 3.5 years (CI: 3.0-4.2) for those diagnosed between 2015-2024. The 5-year overall survival rate was 80% (95% CI: 72-88). Patients with ECD had an increase in mortality over expected, with 28 deaths compared to an expected 11.2, an SMR of 2.5 (95% CI: 1.7-3.6, p<0.001). Of 17 patients with an identified cause of death, death was attributable to ECD in 11 (65%), secondary malignancy in 1 (7%), and unrelated causes in 5 (29%). Cause of death was unknown in 11 patients. Among deaths, 11 (39%) were treated with targeted therapy, 8 (29%) with chemotherapy, and 1 (4%) received both. One patient (4%) received steroids, 1 received immunomodulator and targeted therapy (4%), and 6 (21%) received no disease-directed therapy. Of the patients whose death was related to ECD, 10 (91%) had multisystem disease. For 49 patients diagnosed pre-2015, 14 deaths occurred during the follow-up, significantly higher than the expected 5.2 deaths based on U.S. population data (SMR of 2.7 [95% CI: 1.5-4.4, p=0.001]). Among those diagnosed between 2015 and 2024, 14 deaths occurred, compared to expected 6.1 (SMR of 2.3 [95% CI: 1.3-3.8, p=0.006]). In an age- and sex-adjusted Cox proportional hazards model, diagnosis after 2015 vs. diagnosis prior to 2015 yielded a hazard ratio of 0.59 (95% CI: 0.27-1.31, p=0.19). Conclusion:The mortality rate of ECD patients remains higher than the general population, despite advancements in disease recognition and development of targeted therapies. While our data suggest a possible trend toward improved survival among patients diagnosed after 2015, we did not find statistically significant evidence of decreased mortality compared to those diagnosed prior to 2015. Larger cohorts with longer follow-up periods are needed to draw definitive conclusions regarding mortality.

Abstract Glioblastoma, IDH-wildtype (GBM), and primary central nervous system lymphoma (PCNSL) are two aggressive brain tumors with distinct treatment strategies but overlapping imaging features on MRI. Accurate preoperative differentiation remains a clinical challenge, due to their overlapping imaging features, even when advanced MRI techniques are employed. This study explored deep learning approaches leveraging multi-sequence MRI to distinguish GBM from PCNSL. Models were developed utilizing 146 PCNSL cases, which were matched to146 GBM by age, sex and year of diagnosis. A 3D-DenseNet121 convolutional neural network was trained using two analytical strategies: (i) loss-based model selection and (ii) ensemble prediction using five-fold cross-validation. Model performance was evaluated on an independent validation set of 256 GBM and 37 PCNSL from the same institution as well as 36 PCNSL cases from an external institution. All MRIs were preprocessed using the FeTS pipeline. Using the independent validation cohort, area under the receiver operating characteristic curve (AUC) and 95% confidence intervals (CI) were computed overall and stratified by demographic characteristics. Using both T1 post-contrast (T1Gd) and T2-weighted images, the loss-based model achieved AUC=0.83 (95% CI: 0.77-0.88) and the ensemble model yielded an AUC=0.82 (95% CI: 0.76-0.89). Model performance was similar across males and females; however, model performance was better for subjects older than 50 years of age versus younger than 50. When using only T1Gd images, the loss-based model dropped to AUC=0.55 (95% CI: 0.48-0.63), whereas the ensemble model had AUC=0.79 (95% CI: 0.72-0.85). Models trained with only T2 images achieved AUCs of 0.67 (95% CI: 0.60-0.73) (loss-based) and 0.75 (95% CI: 0.69-0.82) (ensemble). These results highlight the added value of the multi-sequence input. Our results confirm the feasibility of using automated deep learning models to differentiate GBM from PCNSL. Notably, the model generalized well to external MRI data, emphasizing its potential utility as a diagnostic aid in real-world clinical workflows.

Abstract Glioblastoma (GBM) diagnosis integrates morphology and tumor molecular alterations. Patients with classic morphology are designated as histologic GBM (hGBM). Patients without classic morphology harboring TERT promoter mutation (TERTp), or epidermal growth factor receptor amplification (EGFRamp), or combined gain of chromosome 7 and loss of 10 (+7/-10) designate molecular GBM (mGBM). We compared radiographic features, genomic alterations, and clinical outcome between hGBM and mGBM. 109 mGBM Mayo Clinic cases diagnosed between 1993-2021 were matched to 101 cGBM by age, sex, year of diagnosis, and TERT promoter (TERTp) status. Clinical and radiographic data abstraction was blinded. Progression-free and overall survival were compared across groups in the subset of patients who received standard of care. Contrast enhancement was present on index MRI (MRI at diagnosis) for 98% (96/98) hGBM and 50% (54/107) mGBM (p<0.0001) patients. mGBM tumors harbored fewer total copy number alterations (median of 16.5 vs 20, p=0.029) and were less likely to have CDKN2A/B homozygous deletion (56% vs 77%, p=0.005). Among the 87 mGBM and 82 hGBM receiving standard of care, median overall survival was longer for mGBM versus hGBM (2.24 vs 1.62 years, p=0.016). mGBM patients with +7/-10 (HR=2.60, p=0.035) or CDKN2A/B (HR=3.61, p=0.002) had poorer overall survival compared to mGBM patients without the corresponding alteration. On index MRI mGBM patients without contrast enhancement had better overall survival compared to hGBM (HR=0.50; p=0.003) whereas there was no survival difference between mGBM with enhancement and hGBM. mGBM with enhancement on index MRI likely represent undersampled, or early / evolving hGBM. mGBM patients with non-enhancing MRI, younger than 60, with long symptom profile including seizures, and some combination of non-anaplastic morphology, TERTp only, no homozygous deletion of CDKN2A/B, and low copy number complexity may represent other IDHwt glioma entities. Caution is advised in counseling, management, discussing prognosis, and inclusion in clinical trials.

Abstract The 2021 WHO classification redefined glioblastoma IDH-wildtype (GBM), integrating histopathological and tumor molecular features. Diffuse astrocytic glioma lacking histologic features of necrosis and microvascular proliferation are classified as (molecular) GBM if the tumor is IDH- and H3-wildtype and has one or more additional tumor molecular alterations: TERT promoter mutation, EGFR amplification, or +7/-10. Due to the absence of histopathological features of classic GBM and presentation without enhancement on MRI in approximately 50% of cases, molecular GBM frequently resemble low-grade IDH-mutant gliomas. We hypothesized that MRI-based deep learning models could distinguish IDH-mutant glioma from molecular GBM. We retrospectively identified 97 individuals with molecular GBM, who were matched to 97 individuals with IDH-mutant glioma by age, sex, year of diagnosis, and enhancement on MRI. Of the 97 IDH-mutant gliomas, 51% were 1p/19q codeleted, 42% grade 2, 47% grade 3, and 10% grade 4. Preoperative postcontrast T1-weighted (T1C) and T2-weighted (T2) MRI sequences were used to train a 3D-DenseNet121 model. The model was validated on an independent prospective set of 150 IDH-mutant gliomas and 71 molecular GBM. The MRI-based deep learning model achieved an area under the receiver operator curve (AUC) of 0.75 (95% CI: 0.68-0.82) in the prospective validation set. Sex-stratified AUCs were 0.72 (95% CI: 0.59-0.85) for females and 0.76 (95% CI: 0.68-0.85) for males. Age stratified AUCs were 0.71 (95% CI: 0.60-0.83) for patients under 55 years of age and 0.64 (95% CI: 0.50-0.79) for patients older than 55. These results suggest that discriminative MRI features of IDH-mutant glioma and molecular GBM exist and can be identified from deep learning models. However, radiographic ambiguity exists and underscores the need for further optimization of the deep learning architecture or by integrating additional non-invasive modalities. For example, future work entails integrating germline variants into the model, including rs55705857, which is a causal variant for IDH-mutant glioma. With further validation and integration of multi-modal data, a noninvasive tool may support more personalized decision-making.

Abstract BACKGROUND Mixed histiocytic neoplasms with overlapping features of Erdheim-Chester Disease (ECD) and Rosai-Dorfman Disease (RDD) are extremely rare and diagnosis may be delayed due to lack of awareness and complex histology features. METHODS We report a case of mixed ECD/RDD misdiagnosed as IgG4-related disease and review the literature. RESULTS A 50-year-old man presented for evaluation of spastic paraparesis in the context of a thoracic dural lesion. Two years prior he developed an inflammatory monoarthritis concerning for rheumatoid arthritis unresponsive to methotrexate. Six months prior he developed leg spasms, gait spasticity, and urinary incontinence. MRI demonstrated a T2 hypointense enhancing epidural mass with spinal cord compression. Epidural biopsy showed fibrosis and non-specific inflammation. Given elevated serum IgG4 (170 mg/dL) and clinical findings, he was diagnosed with IgG4-related disease. He received high dose prednisone and etanercept without radiographic or clinical improvement. He then presented to our institution. Given high concern for RDD, he underwent FDG-PET CT which demonstrated an infiltrative process and FDG avid regions in the upper thoracic spinal cord, paranasal sinus, renal hilum, perivascular abdominal vessels, testicle, and multiple joint effusions. Biopsy of left testicle demonstrated CD163-positive histiocytes which coexpressed S100, cyclin D1, and OCT2, consistent with RDD. Biopsy of the left shoulder synovium demonstrated an atypical CD163-positive histiocytic infiltrate expressing Factor XIIIa, cyclin D1 and S100 (partial), and appeared negative for OCT2, consistent with ECD. The atypical histiocytes in both biopsies were negative for CD1a and BRAF V600E by immunohistochemistry. Genomic sequencing of the testicular tissue demonstrated a MAP2K1 (Q56P) alteration. He was treated with radiation therapy targeting the dural lesion with temporarily worsening symptoms improved with steroids and started on cobimetinib. DISCUSSION This case expands on the phenotypic description of mixed ECD/RDD. Histiocytic neoplasms should be considered in the differential diagnosis of dural based lesions.

Background: Tremor in multiple sclerosis (MS) is often refractory to medications. Deep brain stimulation (DBS) may help, but possible side effects and disease exacerbation limit its use. Objectives: Evaluate outcomes of DBS for MS-associated tremor. Methods: Retrospective review of 18 patients with MS-associated tremor who underwent DBS, analyzing Expanded Disability Status Scale (EDSS) and Fahn–Tolosa–Marin (FTM) tremor scores. Results: Median age at surgery was 49.5 years (range, 28–75), with postoperative follow-up 2.5 years (range, 0–22). No relapses (0/18) or new lesions (0/8) occurred postoperatively. All had ventral intermediate nucleus leads; other targets were not used in programming. EDSS remained stable (median 6 to 6.25; p = 0.2). FTM scores improved (median 14.5 to 10, p = 0.008). Patients with EDSS 3.5–6 had variable outcomes ( p = 0.02). Conclusions: DBS is a potential treatment for severe MS tremor and did not provoke relapse. Targeting VIM alone may optimize tremor control and maintain magnetic resonance imaging (MRI) access.

Background: Spasticity is common in spinal cord injury (SCI) and multiple sclerosis (MS), and it can manifest as repeated, rhythmic muscle contractions called clonus. The spontaneous nature of clonus can disrupt independent performance of activities of daily living and negatively impact overall health and quality of life. Objectives: To quantify biomarkers of clonus and explore management of clonus in individuals with SCI or progressive MS using epidural spinal cord stimulation (ES) or dorsal root stimulation (DRS). Methods: Four male participants were included in this case series study: 3 with SCI and 1 with MS. All participants underwent temporary percutaneous ES lead placement over the dorsolateral thoracolumbar region of the spinal cord. Participants with SCI were also implanted with DRS leads at the L4 dorsal root. Clonus was elicited mechanically at the ankle while recording electromyography of the soleus muscle synchronized to direct spinal cord field potential recordings from ES and DRS percutaneous leads. Results: Clonus was evident as a prominent band (5-8 Hz) in recordings from ES leads, DRS leads, soleus muscle, and accelerometry. In 4 participants, percutaneous spinal stimulation reduced median clonus duration and cycle count. Clonus was immediately suppressed upon activation of spinal cord stimulation, and the suppression persisted even when clonus was reinitiated after turning off the stimulation. Conclusion: The use of objective biomarkers, including spinal cord potentials, to quantify clonus in real time combined with the immediate and reversible effects of stimulation highlight the potential of neuromodulation as a therapeutic tool for managing clonus. These data demonstrate preliminary efficacy of ES and DRS for clonus monitoring and treatment in 4 participants.

Background: Tumefactive demyelination (TD) is a rare variant of multiple sclerosis (MS) characterized by tumor-like lesions that often require aggressive management. Genome-wide association studies (GWAS) identified variants associated with MS; similar analyses in TD are lacking. Objective: A GWAS was performed to identify variants associated with TD. Methods: The case–control study included 142 TD cases and 293 controls. TD patients were required to have a demyelinating event and magnetic resonance imaging (MRI) showing one or more lesions. Controls were patients without a neurologic or systemic inflammatory disease or cancer. Logistic regression was used to compare cases versus controls for each variant; age, sex, and principal components were included as covariates. A p -value threshold of 5 × 10 −8 was GWAS significant and 5 × 10 −6 nominally significant. A polygenic risk score (PRS) was compared across TD and controls. Results: Variants on chromosome 14 (rs117797734, p = 2.06 × 10 −11 , odds ratio (OR) = 13.14) and chromosome 6 (most significant rs6936540, p = 5.5 × 10 −7 , OR = 2.61) near DCBLD1 were significant. Seven non-MHC and two MHC variants associated with MS were associated with TD. The PRS was significantly higher in TD versus controls. Conclusion: We identified novel regions associated with TD, demonstrating the importance of performing GWAS in homogeneous subtypes of MS. Further validation and functional experiments are necessary.