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The BRAF V600E mutation and BRAF inhibitor responsiveness characterize ∼50% of patients with the non-Langerhans cell histiocytosis (non-LCH) Erdheim-Chester disease (ECD). We interrogated the non-LCH molecular landscape [ECD, n = 35; Rosai-Dorfman disease (RDD), n = 3; mixed ECD/RDD, n = 1] using BRAF V600E PCR and/or next-generation sequencing [tissue and cell-free DNA (cfDNA) of plasma and/or urine]. Of 34 evaluable patients, 17 (50%) had the BRAF V600E mutation. Of 31 patients evaluable for non-BRAF V600E alterations, 18 (58%) had ≥1 alteration and 12 putative non-BRAF V600E MAPK pathway alterations: atypical BRAF mutation; GNAS, MAP2K1, MAP2K2, NF1, and RAS mutations; RAF1 or ERBB2 amplifications; LMNA-NTRK1 (TRK inhibitor-sensitive) and CAPZA2-BRAF fusions. Four patients had JAK2, MPL ASXL1, U2AF1 alterations, which can correlate with myeloid neoplasms, a known ECD predisposition, and one developed myelofibrosis 13 months after cfDNA testing. Therefore, our multimodal comprehensive genomics reveals clinically relevant alterations and suggests that MAPK activation is a hallmark of non-LCH.

Background Patients with glioblastoma (GBM) often have inaccurate perceptions of prognosis. Strong religious beliefs have been associated with limited illness understanding (IU) in patients with advanced cancer, but IU and religiousness have not been investigated in patients with GBM. The aim of this study was to evaluate the association between religiousness and spirituality and IU in patients with GBM. Methods Patients enrolled in a prospective multicenter study of recurrent GBM (Coping with Glioblastoma, NCT02375841). Within one month of medical visits discussing MRI scans showing GBM progression, patients completed study surveys containing published measures of IU and religiousness. IU was compared between participants with moderate or high versus slight or no religiousness based on several patient-reported prompts using Fisher's exact tests. Results Twenty-four patients completed surveys of religiousness and IU. IU was partial within our cohort. Fifteen participants (62.5%) acknowledged that their illness was terminal. Only 6 (25%) correctly acknowledged their prognosis (months). Eleven patients (46%) were moderately or very religious, while 9 (38%) were either slightly religious or not at all religious. High religiousness and spirituality were each associated with partial IU (P  = .06 and P  = .01, respectively). A belief that God could perform a miracle to cure them of cancer and a belief in sanctity through suffering were also each associated with partial IU. Conclusions This prospective study that suggests religiousness, including the belief in miracles and a belief in sanctification through suffering, might influence patients' IU. Further research is warranted to study this association. [ABSTRACT FROM AUTHOR]

Background/aims Ocular manifestations of histiocytosis and their genetic underpinnings are poorly characterised. This study characterises ocular sites of histiocytosis, notate genetic alterations and correlates to histiocytosis clinical features including subtype and sites of disease. Methods Prospective registry-based study of predominantly adult histiocytosis patients at a single-institution tertiary referral centre. 180 eyes of 90 patients (46 males, 44 females) with histiocytosis (Erdheim-Chester disease 34, Rosai-Dorfman 20, xanthogranuloma 7, mixed histiocytosis 13, Langerhans cell histiocytosis (LCH) 15, ALK-positive histiocytosis 1). Ocular findings were categorised by the structure involved. Histiocytosis subtype, sites of disease and genetic status were correlated to ocular findings. Results Ocular disease was present in more than half the histiocytosis patient cohort and occurred with other disease sites. Ocular findings were statistically significantly different across histiocytic subtypes with LCH subtypes having the lowest proportion of ocular findings (7%) and all other subtypes having rates of ocular findings which were five times that of patients with LCH (p=0.0009). Of patients with ocular findings, 41% of patients reported ocular symptoms and were significantly more in the group with ocular disease present versus those patients without ocular involvement. The presence of ocular findings was not statistically different by BRAFV600E, MAP2K1 or RAS isoform mutational status. Conclusions Ocular disease is a common feature of histiocytosis with significant visual symptomatology and occurrence in tandem with multisystem sites. Ocular findings vary by histiocytic subtype. The mutational profile of the cohort reflects known mutations in this clinical population, with no specific driver mutation associated with ocular disease. [ABSTRACT FROM AUTHOR]

BackgroundErdheim-Chester disease (ECD) is a rare non-Langerhans histiocytosis characterized by systemic inflammation and granulomatous infiltration of multiple organs including the central nervous system (CNS), bones, and retroperitoneum. CNS infiltration occurs in one third of patients, but cognitive changes are common in patients without CNS disease. Here we investigate whether there is a neuroanatomic basis to observed cognitive deficits, even in absence of CNS disease.MethodsWe present a volumetric analysis of eleven ECD patients without CNS tumors or prior neurotoxic treatments.ResultsCompared to age-matched controls, ECD patients have diffuse, bihemispheric reduction in cortical thickness and subcortical gray matter.ConclusionsThese findings provide the first corroborating evidence for neurologic disease in ECD patients without direct CNS infiltration.

Langerhans cell histiocytosis (LCH) is a myeloid neoplastic disorder characterized by lesions with CD1a‐positive/Langerin (CD207)‐positive histiocytes and inflammatory infiltrate that can cause local tissue damage and systemic inflammation. Clinical presentations range from single lesions with minimal impact to life‐threatening disseminated disease. Therapy for systemic LCH has been established through serial trials empirically testing different chemotherapy agents and durations of therapy. However, fewer than 50% of patients who have disseminated disease are cured with the current standard‐of‐care vinblastine/prednisone/(mercaptopurine), and treatment failure is associated with long‐term morbidity, including the risk of LCH‐associated neurodegeneration. Historically, the nature of LCH—whether a reactive condition versus a neoplastic/malignant condition—was uncertain. Over the past 15 years, seminal discoveries have broadly defined LCH pathogenesis; specifically, activating mitogen‐activated protein kinase pathway mutations (most frequently, BRAFV600E) in myeloid precursors drive lesion formation. LCH therefore is a clonal neoplastic disorder, although secondary inflammatory features contribute to the disease. These paradigm‐changing insights offer a promise of rational cures for patients based on individual mutations, clonal reservoirs, and extent of disease. However, the pace of clinical trial development behind lags the kinetics of translational discovery. In this review, the authors discuss the current understanding of LCH biology, clinical characteristics, therapeutic strategies, and opportunities to improve outcomes for every patient through coordinated agent prioritization and clinical trial efforts. Langerhans cell histiocytosis is an inflammatory myeloid neoplastic disorder driven by activating somatic mutations in mitogen‐activated protein kinase pathway genes. Rapid advances in mechanistic understanding of Langerhans cell histiocytosis now offer opportunities to improve outcomes for patients. [ABSTRACT FROM AUTHOR]

Author(s): Eli L. Diamond [sup.1] [sup.2] , Benjamin H. Durham [sup.3] [sup.4] , Gary A. Ulaner [sup.2] [sup.5] , Esther Drill [sup.6] , Justin Buthorn [sup.1] , Michelle Ki [sup.4] [...], Histiocytic neoplasms are a heterogeneous group of clonal haematopoietic disorders that are marked by diverse mutations in the mitogen-activated protein kinase (MAPK) pathway.sup.1,2. For the 50% of patients with histiocytosis who have BRAF.sup.V600 mutations.sup.3-5, RAF inhibition is highly efficacious and has markedly altered the natural history of the disease.sup.6,7. However, no standard therapy exists for the remaining 50% of patients who lack BRAF.sup.V600 mutations. Although ERK dependence has been hypothesized to be a consistent feature across histiocytic neoplasms, this remains clinically unproven and many of the kinase mutations that are found in patients who lack BRAF.sup.V600 mutations have not previously been biologically characterized. Here we show ERK dependency in histiocytoses through a proof-of-concept clinical trial of cobimetinib, an oral inhibitor of MEK1 and MEK2, in patients with histiocytoses. Patients were enrolled regardless of their tumour genotype. In parallel, MAPK alterations that were identified in treated patients were characterized for their ability to activate ERK. In the 18 patients that we treated, the overall response rate was 89% (90% confidence interval of 73-100). Responses were durable, with no acquired resistance to date. At one year, 100% of responses were ongoing and 94% of patients remained progression-free. Cobimetinib treatment was efficacious regardless of genotype, and responses were observed in patients with ARAF, BRAF, RAF1, NRAS, KRAS, MEK1 (also known as MAP2K1) and MEK2 (also known as MAP2K2) mutations. Consistent with the observed responses, the characterization of the mutations that we identified in these patients confirmed that the MAPK-pathway mutations were activating. Collectively, these data demonstrate that histiocytic neoplasms are characterized by a notable dependence on MAPK signalling--and that they are consequently responsive to MEK inhibition. These results extend the benefits of molecularly targeted therapy to the entire spectrum of patients with histiocytosis. A proof-of-concept clinical trial of patients with histiocytoses with MAPK-pathway mutations showed durable responses to treatment with the MEK1 and MEK2 inhibitor cobimetinib, which indicates that histiocytic neoplasms are dependent on MAPK signalling.

Introduction Fusions involving neurotrophic receptor tyrosine kinases (NTRKs) were among the first gene translocations described in cancer (1, 2). NTRK1, NTRK2, and NTRK3 (encoding TrkA, TrkB, and TrkC, respectively; hereafter [...], Rearrangements involving the neurotrophic receptor kinase genes (NTRK1, NTRK2, and NTRK3; hereafter referred to as TRK) produce oncogenic fusions in a wide variety of cancers in adults and children. Although TRK fusions occur in fewer than 1% of all solid tumors, inhibition of TRK results in profound therapeutic responses, resulting in Breakthrough Therapy FDA approval of the TRK inhibitor larotrectinib for adult and pediatric patients with solid tumors, regardless of histology. In contrast to solid tumors, the frequency of TRK fusions and the clinical effects of targeting TRK in hematologic malignancies are unknown. Here, through an evaluation for TRK fusions across more than 7,000 patients with hematologic malignancies, we identified TRK fusions in acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), histiocytosis, multiple myeloma, and dendritic cell neoplasms. Although TRK fusions occurred in only 0.1% of patients (8 of 7,311 patients), they conferred responsiveness to TRK inhibition in vitro and in vivo in a patient-derived xenograft and a corresponding AML patient with ETV6-NTRK2 fusion. These data identify that despite their individual rarity, collectively, TRK fusions are present in a wide variety of hematologic malignancies and predict clinically significant therapeutic responses to TRK inhibition.