ABSTRACT
ABSTRACT: Radioembolization using 90 Y is a growing procedure in nuclear medicine for treating hepatocellular carcinoma. Current guidelines suggest postponing liver transplantation or surgical resection for a period of 14 to 30 d after radioembolization to minimize surgeons' exposure to ionizing radiation. In light of a radiation protection incident, we reevaluated the minimum delay required between radioembolization and subsequent liver transplantation. A patient with a hepatocellular carcinoma underwent a liver transplantation 44 h after undergoing radioembolization using 90 Y (860 MBq SIR-Spheres). No specific radioprotection measures were followed during surgery and pathological analysis. We subsequently (1) evaluated the healthcare professionals' exposure to ionizing radiation by conducting dose rate measurements from removed liver tissue and (2) extrapolated the recommended interval to be observed between radioembolization and surgery/transplantation to ensure compliance with the radiation dose limits for worker safety. The surgeons involved in the transplantation procedure experienced the highest radiation exposure, with whole-body doses of 2.4 mSv and extremity doses of 24 mSv. The recommended delay between radioembolization and liver transplantation was 8 d when using SIR-Spheres and 15 d when injecting TheraSphere. This delay can be reduced further when considering the specific 90 Y activity administered during radioembolization. This dosimetric study suggests the feasibility of shortening the delay for liver transplantation/surgery after radioembolization from the 8th or 15th day after using SIR-Spheres or TheraSphere, respectively. This delay can be decreased further when adjusted to the administrated activity while upholding radiation protection standards for healthcare professionals.
Subject(s)
Carcinoma, Hepatocellular , Feasibility Studies , Liver Neoplasms , Liver Transplantation , Occupational Exposure , Radiation Protection , Yttrium Radioisotopes , Humans , Yttrium Radioisotopes/therapeutic use , Radiation Protection/methods , Liver Neoplasms/radiotherapy , Carcinoma, Hepatocellular/radiotherapy , Occupational Exposure/prevention & control , Occupational Exposure/analysis , Embolization, Therapeutic/methods , Male , Middle AgedABSTRACT
OBJECTIVES: Sarcoidosis is a multisystemic granulomatosis diagnosed mainly in young adults.18F-fluorodeoxyglucose (18F-FDG) positron emission tomography-computed tomography (PET-CT) is useful in sarcoidosis cases to search for a biopsiable site or assess disease activity.18F-FDG PET-CT can reveal bone hypermetabolism in sarcoidosis patients, even in the absence of osteoarticular symptoms. The aim of this study was to describe metabolic bone involvement in sarcoidosis patients and to evaluate its prognostic impact. METHODS: This was an observational, comparative, retrospective, monocentric study. Inclusion criteria were a confirmed diagnosis of sarcoidosis according to the World Association of Sarcoidosis and Other Granulomatous Diseases (WASOG) criteria and at least one 18F-FDG PET-CT scan during follow-up. Metabolic bone involvement of sarcoidosis was defined as focal bone hypermetabolism with no argument for a differential diagnosis of bone 18F-FDG uptake. Patients with and without bone involvement were compared. RESULTS: Among the 175 included patients, 32 (18%) had metabolic bone involvement of sarcoidosis. The metabolic bone involvement was mainly axial and mostly without bone abnormalities on CT. Metabolic bone involvement was associated with intrathoracic and extrathoracic lymph node involvement and with a higher number of organs involved. Patients with metabolic bone involvement more frequently received corticosteroids, methotrexate and tumor necrosis factor (TNF)-α inhibitors and a higher number of treatments. Relapse of sarcoidosis occurred sooner in patients with metabolic bone involvement. CONCLUSION: These results suggest that metabolic bone involvement is associated with more diffuse and more severe sarcoidosis.
ABSTRACT
BACKGROUND: Integrating immunotherapy with locoregional therapies marks a significant milestone in the realm of hepatocellular carcinoma (HCC) treatment . This study aimed to assess the impact of addition of Atezolizumab-Bevacizumab (AtezoBev) on the outcome patients treated with SIRT. METHODS: We conducted a study that included all Child-Pugh A HCC treated with SIRT since 2017. We examined the effects of the addition of 3 infusions of AtezoBev before the SIRT procedure and after SIRT on patients outcome (AtezoBev-SIRT group). Time-to-event data were analyzed using Kaplan-Meier with the log-rank test. RESULTS: Thirty five HCC patients treated with SIRT were included, of whom 23 % also received AtezoBev infusions. The two groups were similar in terms of liver function and HCC parameters. The median OS was not reached for patients who received AtezoBev in combination with SIRT and 14 months for patients only treated by SIRT. The median PFS was higher in the group treated by SIRT and AtezoBev vs SIRT alone (11.3 months vs 5.8 months). In the global cohort, 8 patients presented a downstaging (23 %), 4 underwent liver surgery (1 in the AtezoBev-SIRT group) and 4 liver transplantation (1 in the AtezoBev-SIRT group) CONCLUSIONS: The administration of AtezoBev, both before and after SIRT, is associated with enhanced OS and PFS outcomes compared to SIRT alone for unresectable HCC.
Subject(s)
Antibodies, Monoclonal, Humanized , Carcinoma, Hepatocellular , Liver Neoplasms , Humans , Carcinoma, Hepatocellular/drug therapy , Carcinoma, Hepatocellular/pathology , Liver Neoplasms/drug therapy , Liver Neoplasms/pathology , Bevacizumab/therapeutic use , Treatment OutcomeABSTRACT
PURPOSE: Primary objective was to compare the per-patient detection rates (DR) of [18F]DCFPyL versus [18F]fluoromethylcholine positron emission tomography/computed tomography (PET/CT), in patients with first prostate cancer (PCa) biochemical recurrence (BCR). Secondary endpoints included safety and impact on patient management (PM). METHODS: This was a prospective, open label, cross-over, comparative study with randomized treatment administration of [18F]DCFPyL (investigational medicinal product) or [18F]fluoromethylcholine (comparator). Men with rising prostate-specific antigen (PSA) after initial curative therapy were enrolled. [18F]DCFPyL and [18F]fluoromethylcholine PET/CTs were performed within a maximum time interval of 12 days. DR was defined as the percentage of positive PET/CT scans identified by 3 central imaging readers. PM was assessed by comparing the proposed pre-PET/CT treatment with the local treatment", defined after considering both PET/CTs. RESULTS: A total of 205 patients with first BCR after radical prostatectomy (73%; median PSA = 0.46 ng/ml [CI 0.16;27.0]) or radiation therapy (27%; median PSA = 4.23 ng/ml [CI 1.4;98.6]) underwent [18F]DCFPyL- and/or [18F]fluoromethylcholine -PET/CTs, between July and December 2020, at 22 European sites. 201 patients completed the study. The per-patient DR was significantly higher for [18F]DCFPyL- compared to [18F]fluoromethylcholine -PET/CTs (58% (117/201 patients) vs. 40% (81/201 patients), p < 0.0001). DR increased with higher PSA values for both tracers (PSA ≤ 0.5 ng/ml: 26/74 (35%) vs. 22/74 (30%); PSA 0.5 to ≤ 1.0 ng/ml: 17/31 (55%) vs. 10/31 (32%); PSA 1.01 to < 2.0 ng/ml: 13/19 (68%) vs. 6/19 (32%);PSA > 2.0: 50/57 (88%) vs. 39/57 (68%) for [18F]DCFPyL- and [18F]fluoromethylcholine -PET/CT, respectively). [18F]DCFPyL PET/CT had an impact on PM in 44% (90/204) of patients versus 29% (58/202) for [18F]fluoromethylcholine. Overall, no drug-related nor serious adverse events were observed. CONCLUSIONS: The primary endpoint of this study was achieved, confirming a significantly higher detection rate for [18F]DCFPyL compared to [18F]fluoromethylcholine, in men with first BCR of PCa, across a wide PSA range. [18F]DCFPyL was safe and well tolerated.
Subject(s)
Boidae , Prostatic Neoplasms , Male , Animals , Humans , Positron Emission Tomography Computed Tomography/methods , Prostate-Specific Antigen , Prospective Studies , Prostatic Neoplasms/surgery , Neoplasm Recurrence, LocalABSTRACT
Immune thrombocytopenia (ITP) is a rare autoimmune-mediated condition characterized by isolated thrombocytopenia (<100 G/L) after exclusion of other causes. Mostly primary, it is associated with hematological malignancy, autoimmune disorders, or infection in 20% of patients. It is exceptionally described in patients with histiocytosis, mostly in children (seven patients in literature). We report a case of a 69-year-old man with ITP leading to the diagnosis of histiocytosis. At ITP's diagnosis, the patient had elevated gamma-globulins leading to computed tomography showing bilateral peri-renal infiltration. The biopsy showed enriched IgG-4 peri-renal Rosai Dorfman disease with MAP2K1 mutation, although peri-renal infiltration is highly suggestive of Erdheim-Chester disease. This overlapping association was described in men with mutation in MAP2K1 gene. Macrophages are implicated in the pathophysiology of ITP in multiple ways, notably by the phagocytosis of opsonized platelets and their function of antigen-presenting cells able to stimulate autoreactive T cells. Histiocytic cells derivate from monocyte-macrophage lineage. Activation of macrophages in active histiocytosis is responsible for consequential platelet destruction in ITP associated histiocytosis. Finally, this case highlights a rare presentation of ITP revealing histiocytosis, both being efficiently treated with rituximab.
ABSTRACT
Trained immunity (TI) is a proinflammatory program induced in monocyte/macrophages upon sensing of specific pathogens and is characterized by immunometabolic and epigenetic changes that enhance cytokine production. Maladaptive activation of TI (ie, in the absence of infection) may result in detrimental inflammation and development of disease; however, the exact role and extent of inappropriate activation of TI in the pathogenesis of human diseases is undetermined. In this study, we uncovered the oncogene-induced, maladaptive induction of TI in the pathogenesis of a human inflammatory myeloid neoplasm (Erdheim-Chester disease, [ECD]), characterized by the BRAFV600E oncogenic mutation in monocyte/macrophages and excess cytokine production. Mechanistically, myeloid cells expressing BRAFV600E exhibit all molecular features of TI: activation of the AKT/mammalian target of rapamycin signaling axis; increased glycolysis, glutaminolysis, and cholesterol synthesis; epigenetic changes on promoters of genes encoding cytokines; and enhanced cytokine production leading to hyperinflammatory responses. In patients with ECD, effective therapeutic strategies combat this maladaptive TI phenotype; in addition, pharmacologic inhibition of immunometabolic changes underlying TI (ie, glycolysis) effectively dampens cytokine production by myeloid cells. This study revealed the deleterious potential of inappropriate activation of TI in the pathogenesis of human inflammatory myeloid neoplasms and the opportunity for inhibition of TI in conditions characterized by maladaptive myeloid-driven inflammation.
Subject(s)
Erdheim-Chester Disease/genetics , Inflammation/genetics , Proto-Oncogene Proteins B-raf/genetics , Cells, Cultured , Epigenesis, Genetic , Erdheim-Chester Disease/immunology , Erdheim-Chester Disease/pathology , Humans , Immunity , Inflammation/immunology , Inflammation/pathology , Macrophages/immunology , Macrophages/metabolism , Macrophages/pathology , Oncogenes , Point Mutation , Proto-Oncogene Proteins B-raf/immunologyABSTRACT
OBJECTIVE: CNS involvement in Erdheim-Chester disease (ECD) leads to substantial morbidity and mortality. To assess CNS manifestations in a French cohort of 253 patients with ECD, we determined clinical characteristics and outcomes, including those under targeted therapies. METHODS: This was a retrospective longitudinal study. CNS manifestations were determined by clinical examination and brain or spine MRI. Targeted therapy efficacy was assessed using global assessment from a physician and a radiologist. The study was approved by the ethics committee Comité de Protection des Personnes Ile de France III. RESULTS: Ninety-seven of 253 patients (38%) with ECD had CNS involvement. CNS involvement was significantly associated with a younger age at diagnosis (mean 55.5 years) and at symptom onset (mean 50.5 years), as well as with the presence of the BRAF V600E mutation (in 77% of cases), xanthelasma (34%), and diabetes insipidus (36%). Median survival among patients with CNS involvement was significantly lower than that of patients with ECD without CNS involvement (124 months vs 146 months, p = 0.03). Seventy-four CNS MRIs were centrally reviewed, which showed 3 patterns: tumoral in 66%, pseudo-degenerative in 50%, and vascular in 18%. Targeted therapy (BRAF or MEK inhibitors) was associated with improved symptoms in 43% of patients and MRI improvement in 45%. CONCLUSIONS: CNS manifestations are typically associated with poor prognosis in patients with ECD. Three distinct patterns can be recognized: tumoral, pseudodegenerative, and vascular. CLASSIFICATION OF EVIDENCE: This study provides Class III evidence that targeted therapy leads to clinical or imaging improvement in almost 50% of patients.
Subject(s)
Brain Stem/pathology , Cerebral Cortex/pathology , Erdheim-Chester Disease/drug therapy , Erdheim-Chester Disease/pathology , Protein Kinase Inhibitors/pharmacology , Spinal Cord/pathology , Adult , Age Factors , Aged , Atrophy/pathology , Brain Stem/diagnostic imaging , Cerebellum/diagnostic imaging , Cerebellum/pathology , Cerebral Cortex/diagnostic imaging , Diabetes Insipidus/etiology , Erdheim-Chester Disease/complications , Erdheim-Chester Disease/genetics , Female , France , Humans , Longitudinal Studies , Magnetic Resonance Imaging , Male , Middle Aged , Prognosis , Proto-Oncogene Proteins B-raf/antagonists & inhibitors , Proto-Oncogene Proteins B-raf/genetics , Retrospective Studies , Spinal Cord/diagnostic imaging , Treatment OutcomeABSTRACT
BACKGROUND: Cardiac sarcoidosis (CS) is a challenging diagnosis. Patients may progress to end-stage congestive heart failure and require cardiac transplantation without ever having been diagnosed. Characteristics and outcomes of patients with granulomas in the explanted hearts are unknown. METHODS: All French heart transplantation centers were contacted to participate in the study. Each center searched through local databases for the cases of non-caseating granuloma in the explanted hearts between 2000 and 2017. Data before and after transplantation were recorded from medical charts. Survival of CS and all- cause heart transplantation patients were compared. RESULTS: Fifteen patients (10 men, 5 women) received a diagnosis of CS based on pathologic data of the explanted heart and were recruited for the study. All patients were diagnosed as non-ischemic dilated or hypertrophic cardiomyopathy and presented congestive heart failure. Eight patients (53%) had ventricular rhythm disturbances, and 3 (20%) a complete heart block. Ten out of 13 patients (77%) had extracardiac radiological signs compatible with sarcoidosis on chest computed tomography (CT) scans. One patient died 3 months after transplantation from infectious complications. The 14 remaining patients were still alive at the end of the study (median follow-up of 28.8 months). One patient had a second heart transplantation 5 years later because of chronic allograft vasculopathy. One patient presented a relapse of CS confirmed by myocardial biopsies 9 years after transplantation, requiring an escalation of immunosuppressive therapy. CONCLUSION: CS may be undiagnosed before heart transplantation. In 77% of cases, sarcoidosis could have been detected before transplantation with non-invasive imaging techniques.
Subject(s)
Cardiomyopathies , Heart Failure , Heart Transplantation , Sarcoidosis , Cardiomyopathies/complications , Cardiomyopathies/diagnosis , Cardiomyopathies/surgery , Female , Granuloma/complications , Granuloma/diagnosis , Granuloma/surgery , Heart Failure/diagnosis , Heart Failure/etiology , Heart Failure/surgery , Heart Transplantation/adverse effects , Humans , Male , Sarcoidosis/diagnosis , Sarcoidosis/epidemiology , Sarcoidosis/surgeryABSTRACT
BACKGROUND: Destombes-Rosai-Dorfman disease (RDD) is a rare multisystemic histiocytosis. Pulmonary involvement during RDD has been poorly described. The goal of this study was to examine the clinical presentations, radiological features, and outcomes of 15 patients with RDD and lung involvement. METHODS: The cases of RDD with lung involvement were extracted from the French National Histiocytosis registry. Efficacy of the MEK inhibitor cobimetinib in treating lung disease was evaluated with an 18fluorodeoxyglucose PET scanner and chest CT scans. RESULTS: Fifteen patients (six women; median age, 40 years at RDD diagnosis) were included. All patients had evidence of systemic disease with extrapulmonary localizations of the disease (lymphadenopathy [n = 12], skin [n = 9], bones [n = 6], retroperitoneal involvement [n = 3], sinuses [n = 3], parotid gland [n = 2], submandibular gland [n = 1], and breast [n = 1]). Presenting symptoms were dominated by dyspnea and dry cough in seven patients. Restrictive physiology was observed in two of five patients. BAL showed lymphocytosis in one of five cases. Eight patients received corticosteroids, all but one with variable immunosuppressive or immunomodulatory therapies. Two patients received cobimetinib for severe lung disease, with dramatic pulmonary metabolic and tumoral responses. Two patients died during follow-up: one of hemoptysis, and the other of an unrelated cerebral tumor. CONCLUSIONS: Pulmonary involvement in RDD is rare, proteiform, and sometimes severe. The MEK inhibitor cobimetinib can lead to dramatic responses.
Subject(s)
Histiocytosis, Sinus/physiopathology , Lung Diseases/physiopathology , Lung/diagnostic imaging , Adolescent , Adrenal Cortex Hormones/therapeutic use , Adult , Aged , Aged, 80 and over , Azetidines/therapeutic use , Bronchoalveolar Lavage Fluid/cytology , Cough/etiology , Dyspnea/etiology , Female , Fluorodeoxyglucose F18 , France , Histiocytosis, Sinus/complications , Histiocytosis, Sinus/diagnostic imaging , Histiocytosis, Sinus/drug therapy , Humans , Immunosuppressive Agents/therapeutic use , Lung Diseases/diagnostic imaging , Lung Diseases/drug therapy , Lung Diseases/etiology , Lymphocytosis/etiology , Male , Middle Aged , Piperidines/therapeutic use , Positron Emission Tomography Computed Tomography , Protein Kinase Inhibitors/therapeutic use , Radiopharmaceuticals , Registries , Retrospective Studies , Young AdultSubject(s)
Azetidines/therapeutic use , Erdheim-Chester Disease/drug therapy , Erdheim-Chester Disease/genetics , Piperidines/therapeutic use , Protein Kinase Inhibitors/therapeutic use , Proto-Oncogene Proteins B-raf/genetics , Adult , Aged , Azetidines/pharmacology , Erdheim-Chester Disease/diagnosis , Erdheim-Chester Disease/metabolism , Fluorodeoxyglucose F18 , Humans , MAP Kinase Signaling System/drug effects , Male , Middle Aged , Piperidines/pharmacology , Positron-Emission Tomography , Protein Kinase Inhibitors/pharmacology , Treatment OutcomeABSTRACT
CONTEXT: Chronic kidney disease is a frequent complication in persons living with HIV/AIDS. Although previous studies have suggested that the CKD-EPI formula is appropriate to estimate glomerular filtration rate (GFR) in HIV-positive adults with normal kidney function, the optimal way to estimate GFR in those with Stage 3 chronic kidney disease is not known. Moreover, the impact of muscle mass on creatinine level and GFR estimation is unknown. AIM AND METHODS: Our study aimed to evaluate the accuracy of different diagnostic tests available compared to the gold standard measurement of GFR. A group of 44 HIV-1 patients with an estimated GFR between 60 and 30 ml/min/1.73 m2 were included in a single-center cross-sectional study. Serum creatinine and cystatin C were measured. GFR was estimated using Cockcroft-Gault, MDRD, sMDRD, CKD-EPI, CKD-EPIcyst, and CKD-EPIcyst/creat formulae and was measured using isotopic Chrome51 EDTA clearance. Bone density and muscle mass were measured by DXA scan. RESULTS: Mean age was 62±10 years. Mean BMI was 23±4 kg/m2. Prevalence of diabetes was 30% and of hypertension was 47%. Viral load was <40 copies/ml for 90% of the patients, and mean CD4 count was 446±191 cells/mm3. Mean measured GFR was 63.4±16.5 ml/min/1.73 m2. All formulae under-estimated GFR. The best relative precision and accuracy were provided by the CKP-EPI formula. sMDRD, CKD-EPIcyst, and CKD-EPIcyst/creat performed worse than the CKD-EPI formula. Body composition did not significantly influence accuracy or precision of GFR estimation. CONCLUSION: In HIV-infected patients in stable immunovirologic conditions with CKD stage 3 and high prevalence of metabolic associated conditions, the CKD-EPI formula performed best, although all formulae under estimate GFR.
Subject(s)
Body Composition , Bone Density , Glomerular Filtration Rate , HIV Infections/physiopathology , Absorptiometry, Photon , Aged , Cross-Sectional Studies , Female , Humans , Male , Middle AgedABSTRACT
BACKGROUND AND OBJECTIVE: Tumor segmentation from hybrid PET/MRI scans may be highly beneficial in radiotherapy treatment planning. Indeed, it gives for both modalities the suitable information that could make the delineation of tumors more accurate than using each one apart. We aim in this work to propose a co-segmentation method that deals with several challenges, notably the lack of one-to-one correspondence between tumors of the two modalities and the boundaries' smoothing. METHODS: The proposed method is designed to surpass these limits, we propose a segmentation method based on the GCsummax technique. The method takes the advantage of Iterative Relative Fuzzy Connectedness (IRFC) on seeds initialization, and the standard min-cut/max-flow technique for the boundary smoothing. Seed initialization was accurately performed thanks to high uptake regions on PET. Besides, a visibility weighting scheme was adapted to achieve the task of co-segmentation using the IRFC algorithm. Then, given the co-segmented regions, we introduce a morphological-based technique that provides object seeds to standard Graph Cut (GC) allowing it to avoid the shrinking problem. Finally, for each modality, the segmentation task is formulated as an energy minimization problem which is resolved by a min-cut/max-flow technique. RESULTS: The overlap ratio (denoted DSC) between our segmentation results and the ground-truth for PET images is 92.63 ⯱⯠1.03, while the DSC for MRI images is 90.61 ⯱⯠3.70. CONCLUSIONS: The proposed method was tested on different types of diseases and it outperformed the state-of-the-art methods. We show its superiority in terms of assymetric relation between PET and MRI and tumors heterogeneity.
Subject(s)
Image Processing, Computer-Assisted , Magnetic Resonance Imaging , Neoplasms/diagnostic imaging , Positron-Emission Tomography , Algorithms , HumansSubject(s)
Azetidines/therapeutic use , Erdheim-Chester Disease/drug therapy , Imidazoles/therapeutic use , Indoles/therapeutic use , Molecular Targeted Therapy , Oximes/therapeutic use , Piperidines/therapeutic use , Protein Kinase Inhibitors/therapeutic use , Sulfonamides/therapeutic use , Azetidines/administration & dosage , Drug Administration Schedule , Erdheim-Chester Disease/diagnostic imaging , Erdheim-Chester Disease/genetics , Follow-Up Studies , France , Humans , Imidazoles/administration & dosage , Indoles/administration & dosage , Multicenter Studies as Topic , Oximes/administration & dosage , Piperidines/administration & dosage , Positron Emission Tomography Computed Tomography , Proto-Oncogene Proteins B-raf/antagonists & inhibitors , Proto-Oncogene Proteins B-raf/genetics , Registries , Retrospective Studies , Sulfonamides/administration & dosage , Treatment Outcome , VemurafenibABSTRACT
In a compatible clinico-radiological setting, the diagnosis of Erdheim-Chester disease (ECD) involves the analysis of histiocytes in tissue biopsies: they are typically foamy and CD68+ CD1a, whereas in Langerhans cell histiocytosis (LCH) they are CD68+ CD1a+. Overlap forms of histiocytoses are frequent. Technetium bone scintigraphy showing nearly constant tracer uptake by the long bones is highly suggestive of ECD and a 'hairy kidney' appearance on abdominal CT scan is observed in more than half ECD cases. CNS involvement is a strong prognostic factor and an independent predictor of death in cases of ECD. Optimal initial therapy for ECD appears to be administration of IFN-α (and/or pegylated IFN-α) and prolonged treatment significantly improves survival; however, tolerance may be poor. Best alternative therapies are anakinra, mainly effective for mild forms of the disease, infliximab, and sirolimus. Cases of ECD present with strong systemic immune activation, involving IFN-α, IL-1/IL1-RA, IL-6, IL-12, and MCP-1, consistent with the systemic immune Th-1-oriented disturbance associated with the disease. Between 57 and 75 % of ECD patients carry the BRAFV600E mutation, an activating mutation of the proto-oncogene BRAF. More than 50 cases harboring BRAF mutation and with severe multisystemic and refractory ECD (sometimes associated with LCH) have been treated worldwide with vemurafenib, a BRAF inhibitor that proved to be very beneficial. Other recurrent mutations of the MAPK (NRAS, MAP2K1) and PIK3 pathways (PIK3CA) have been found among ECD patients. As recurrent mutations in the MAPK pathway are found in ECD and LCH on a background of chronic inflammation, we believe that both conditions should be redefined as an inflammatory myeloid neoplasia.
Subject(s)
Erdheim-Chester Disease/drug therapy , Erdheim-Chester Disease/pathology , Leukemia, Myeloid/drug therapy , Leukemia, Myeloid/pathology , Diagnosis, Differential , Erdheim-Chester Disease/genetics , Humans , Inflammation/pathology , Interferon-alpha/therapeutic use , Interleukin 1 Receptor Antagonist Protein/therapeutic use , Leukemia, Myeloid/genetics , Protein Kinase Inhibitors/therapeutic use , Proto-Oncogene Mas , Proto-Oncogene Proteins B-raf/antagonists & inhibitors , Proto-Oncogene Proteins B-raf/geneticsSubject(s)
Erdheim-Chester Disease/drug therapy , Interleukin 1 Receptor Antagonist Protein/therapeutic use , Adult , Aged , Aged, 80 and over , Bone and Bones/diagnostic imaging , Bone and Bones/pathology , C-Reactive Protein/analysis , Central Nervous System/diagnostic imaging , Central Nervous System/pathology , Disease Progression , Drug Resistance , Erdheim-Chester Disease/diagnostic imaging , Erdheim-Chester Disease/pathology , Fatigue/chemically induced , Female , Heart/diagnostic imaging , Humans , Interferon-alpha/therapeutic use , Interleukin 1 Receptor Antagonist Protein/adverse effects , Male , Middle Aged , Myocardium/pathology , Organ Specificity , Pain/chemically induced , Positron-Emission Tomography , Treatment Outcome , Young AdultABSTRACT
Erdheim-Chester disease (ECD) is a rare, non-Langerhans histiocytosis, characterized by the infiltration of tissues by foamy CD68(+)CD1a(-) histiocytes. (99)Technetium bone scintigraphy revealing almost constant tracer uptake by the long bones is highly suggestive of ECD, and a 'hairy kidney' appearance on abdominal computed tomography scan is observed in about half of all ECD cases. CNS involvement is a strong prognostic factor and independent predictor of death. IFN-α seems to be the best initial treatment for ECD. More than half of all ECD patients carry the BRAF(V600E) mutation. More than 30 patients worldwide harboring this mutation and displaying multisystemic, refractory ECD have been treated with vemurafenib, a BRAF inhibitor, which has proven highly beneficial. Other recurrent mutations of the MAPK and PIK3 pathways (NRAS, PIK3CA) have recently been described. These mutations should lead to a new classification of histiocytic disorders such that Langerhans cell histiocytosis and ECD are classified as inflammatory myeloid neoplasms.
Subject(s)
Erdheim-Chester Disease/genetics , Mutation , Myeloid Cells/metabolism , Neoplasms/genetics , Proto-Oncogene Proteins B-raf/genetics , Erdheim-Chester Disease/diagnosis , Erdheim-Chester Disease/drug therapy , Humans , Indoles/therapeutic use , Interferon-alpha/therapeutic use , Myeloid Cells/drug effects , Myeloid Cells/pathology , Neoplasms/diagnosis , Neoplasms/drug therapy , Proto-Oncogene Proteins B-raf/antagonists & inhibitors , Sulfonamides/therapeutic use , Treatment Outcome , VemurafenibABSTRACT
PURPOSE: Histiocytoses are rare disorders with heterogeneous prognosis. BRAF(V600E) mutations have been observed in half of patients with Langerhans cell histiocytosis (LCH) and in 50% to 100% of patients with Erdheim-Chester disease (ECD) patients. We recently reported short-term efficacy of a BRAF inhibitor (vemurafenib) in three patients with multisystemic ECD. PATIENTS AND METHODS: Vemurafenib was given to eight patients with multisystemic ECD with CNS and/or cardiac involvement. All patients were refractory to first-line treatment and harbored a BRAF(V600E) mutation. Four patients also had LCH lesions. Positron emission tomography (PET) scan response at month 6 was used as the main evaluation criterion. Secondary evaluation criteria were comparison at baseline and at last visit of PET and of cardiovascular and cerebral infiltrations (computed tomography scan and magnetic resonance imaging [MRI]). RESULTS: All patients were partial metabolic responders at 6 months of vemurafenib, and the median reduction in maximum standardized uptake value was 63.5% (range, 41.3% to 86.9%). Evaluation of cardiac and aortic infiltrations showed that seven patients had a partial response and one patient had stable disease according to surface measurements derived from RECIST criteria. The four patients with infratentorial CNS infiltration had an objective decrease of the lesions on MRI. All patients had an improvement of general symptoms and a persistent response to vemurafenib, with a median follow-up time of 10.5 months (range, 6 to 16 months). Skin adverse effects were frequent and severe. CONCLUSION: Vemurafenib has an objective and sustained efficacy in BRAF(V600E)-mutated ECD as second-line therapy. In contrast to melanoma, no resistance has emerged to date after 6 to 16 months.