scholarly journals BRAF Mutation Correlates With High-Risk Langerhans Cell Histiocytosis and Increased Resistance to First-Line Therapy

2016 ◽  
Vol 34 (25) ◽  
pp. 3023-3030 ◽  
Author(s):  
Sébastien Héritier ◽  
Jean-François Emile ◽  
Mohamed-Aziz Barkaoui ◽  
Caroline Thomas ◽  
Sylvie Fraitag ◽  
...  
Keyword(s):  
High Risk ◽  
Langerhans Cell Histiocytosis ◽  
Clinical Manifestations ◽  
Langerhans Cell ◽  
Response To Therapy ◽  
Organ Involvement ◽  
Wild Type ◽  
Response To Chemotherapy ◽  
The Impact

Purpose Langerhans cell histiocytosis (LCH) is an inflammatory myeloid neoplasia with a broad spectrum of clinical manifestations and outcomes in children. The somatic BRAFV600E mutation occurs frequently, but clinical significance remains to be determined. Patients and Methods BRAFV600E mutation was investigated in a French LCH cohort. We analyzed associations between mutation status and clinical presentation, extent of disease, reactivation rate, response to therapy, and long-term permanent sequelae. Results Among 315 patients with successfully determined BRAF status, 173 (54.6%) carried a BRAFV600E mutation. Patients with BRAFV600E manifested more severe disease than did those with wild-type BRAF. Patients with BRAFV600E comprised 87.8% of patients (43 of 49) with multisystem LCH with risk organ involvement (liver, spleen, hematology), 68.6% of patients (35 of 51) with multisystem LCH without risk organ involvement, 43.9% of patients (86 of 196) with single-system LCH, and 42.1% of patients (8 of 19) with lung-involved LCH (P < .001). BRAFV600E mutation was also associated with organ involvement that could lead to permanent, irreversible damage, such as neurologic (75%) and pituitary (72.9%) injuries. Compared with patients with wild-type BRAF, patients with BRAFV600E more commonly displayed resistance to combined vinblastine and corticosteroid therapy (21.9% v 3.3%; P = .001), showed a higher reactivation rate (5-year reactivation rate, 42.8% v 28.1%; P = .006), and had more permanent, long-term consequences from disease or treatment (27.9% v 12.6%; P = .001). Conclusion In children with LCH, BRAFV600E mutation was associated with high-risk features, permanent injury, and poor short-term response to chemotherapy. Further population-based studies should be undertaken to confirm our observations and to assess the impact of BRAF inhibitors for this subgroup of patients who may benefit from targeted therapy.

scholarly journals Clinical characteristics and outcomes of Langerhans cell histiocytosis at a single institution in Thailand: a 20-year retrospective study

2021 ◽  
Vol 15 (4) ◽  
pp. 171-181
Author(s):  
Ponrachet Kitticharoenjit ◽  
Nucharin Supakul ◽  
Piya Rujkijyanont ◽  
Chanchai Traivaree ◽  
Apichat Photia ◽  
...  
Keyword(s):  
Prognostic Factors ◽  
Langerhans Cell Histiocytosis ◽  
Clinical Characteristics ◽  
Clinical Manifestations ◽  
Langerhans Cell ◽  
Organ Involvement ◽  
Bone Imaging ◽  
X Ray ◽  
Wide Range ◽  
Conjugated Hyperbilirubinemia

Abstract Background Langerhans cell histiocytosis (LCH) is a rare disease characterized by the various systems involved and clinical manifestations with a wide range of symptoms. Objectives To describe clinical characteristics, imaging, treatment, and outcomes of pediatric LCH at Phramongkutklao Hospital, Bangkok, Thailand. Methods We conducted a 20-year retrospective review of the medical records of patients diagnosed with LCH from birth to 21 years old from January 1, 1997, to December 31, 2016. Results In all, 14 patients with median age of 2.5 years were studied. Six (43%) patients had single-system (SS) LCH. Five patients (63%) with multisystem (MS) LCH (n = 8. 57%) had risk-organ involvement (RO+). All patients had plain X-ray imaging of their skull with 11 (79%) showing abnormal findings. Tc-99m bone imaging and fluorodeoxyglucose F18 (FDG) positron emission tomography (PET)-computed tomography (CT) demonstrated abnormal findings in 8 (89%) and 4 (29%) patients, respectively. The 5-year event-free survival (EFS) for patients with RO+ MS-LCH was less than that for those without risk-organ involvement (RO−) MS-LCH and SS-LCH (20% vs. 100%, P = 0.005). Hematological dysfunction, hypoalbuminemia, and conjugated hyperbilirubinemia may be worse prognostic factors for RO+ MS-LCH. Conclusion FDG-PET-CT might have a greater accuracy to detect LCH disease than conventional plain X-ray and Tc-99m bone imaging. RO+ MS-LCH has been encountered with relapse and poor outcomes. Hematopoietic involvement, hypoalbuminemia, and conjugated hyperbilirubinemia may be worse prognostic factors for RO+ MS-LCH.

Plasma Biomarker Profiling In Langerhans Cell Histiocytosis: Risk-Stratifying The Inflammatory Storm

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 2854-2854
Author(s):  
Miguel Dario Cantu ◽  
Tricia L Peters ◽  
Karen Phaik-Har Lim ◽  
Albert Shih ◽  
Rikhia Chakraborty ◽  
...  
Keyword(s):  
High Risk ◽  
Risk Stratification ◽  
Langerhans Cell Histiocytosis ◽  
Risk Groups ◽  
Langerhans Cell ◽  
Response To Therapy ◽  
Low Risk ◽  
Clinical Risk ◽  
Clinical Risk Groups ◽  
Single Lesion

Abstract Introduction Despite indistinguishable histology and the common feature of Birbeck granules in lesion biopsies, clinical presentation of patients with Langerhans Cell Histiocytosis (LCH) is highly variable, from single lesion cured by curretage, to multi-system disease requiring aggressive chemotherapy or stem cell transplant. Risk stratification for Langerhans Cell Histiocytosis has historically assigned clinical risk groups based on anatomic location and extent of LCH lesions, which is the basis for dose and duration of chemotherpy on recent Histiocyte Society trials. In this study, we test the hypothesis that distinct subgroups of patients with LCH may be identified by relative levels of circulating biomarkers. Methods Pre-therapy plasma was collected on 97 patients with LCH (82 Pediatric: 17 High-Risk, 23 Multisystem/Multifocal “Non-risk”, 42 Single Lesion “Non-risk”; 15 Adult: 5 High-Risk, 5 Multisystem/Multifocal “Non-risk”, 5 Single Lesion “Non-risk”) and 49 control subjects (32 Pediatric, 17 Adult). Quantitative levels of plasma proteins (158 analytes) was determined by multiplex analysis with Millipore MagPix kits and the Luminex plate reader. Data were analyzed with both unsupervised and supervised methodologies. Results Consensus clustering with non-negative matrix factorization (NMF) clusters identified three groups which were analyzed along with clinical categories. Significant clinical variables included age (adult samples clustered in NMF group 1) and LCH risk category (High-Risk LCH samples clustered in NMF group 3). Samples from patients with the BRAF-V600Emutation or relapse within 1 year did not cluster into any NMF group with signifiance. Additionally, supervised analysis identified specific molecules that were significantly differentially expressed between different clinical categories after multiple testing correction (FDR<0.10): Pediatric LCH vs Adult LCH (72 molecules significant, largest differences in MMP-3, MMP-2 and osteopontin); Pediatric Control vs Pediatric LCH (66 molecules significant, largest differences in SDF-1a, IL-20, MIP-1d, FGF-2 and sIL-4R); Pediatric Low-Risk vs Pediatric High-Risk (47 molecules significant, largest differences in sTNF-R11, sTNF-RI, I-309, sIL2Ra and osteopontin). While previous studies have analyzed expression differences of cytokines in LCH lesions and plasma, in this study the most striking differences are between control vs LCH samples are chemokine molecules. The largest differences between Low-Risk and High-Risk LCH patients include inflammatory cytokines and receptors. Conclusions Despite mounting evidence supporting pathogenesis of LCH as a myeloid neoplasia arising from immature dendritic cell precursors, these results are consistent with exuberant chemokine and cytokine expression in patients with active LCH, supporting a potential role for inflammation in pathogenesis. This study demonstrates the feasibility of identifying novel LCH sub-groups according to plasma protein profiles with unsupervised analysis, and significant differences can be detected in protein levels between clinical risk groups. Future studies will validate the clinical utility of plasma biomarkers in diagnosis, risk-stratification and determining response to therapy. Finally, feasibility of collecting plasma compared to viable lesions makes plasma studies ideal for prospective collection and analysis in cooperative group studies. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Paediatric Langerhans Cell Histiocytosis Disease: Long-Term Sequelae in the Hypothalamic Endocrine System

2021 ◽  
pp. 1-9
Author(s):  
Elisa Vaiani ◽  
Guido Felizzia ◽  
Fabiana Lubieniecki ◽  
Jorge Braier ◽  
Alicia Belgorosky
Keyword(s):  
Anterior Pituitary ◽  
Langerhans Cell Histiocytosis ◽  
Endocrine System ◽  
Langerhans Cell ◽  
Hormone Deficiency ◽  
Bone Lesions ◽  
Pituitary Hormone ◽  
Multisystem Disease ◽  
Anterior Pituitary Hormone

Langerhans cell histiocytosis (LCH) is a disorder of the mononuclear phagocyte system that can affect almost any organ and system. The most common central nervous system (CNS) manifestation in LCH is the infiltration of the hypothalamic-pituitary region leading to destruction and neurodegeneration of CNS tissue. The latter causes the most frequent endocrinological manifestation, that is, central diabetes insipidus (CDI), and less often anterior pituitary hormone deficiency (APD). The reported incidence of CDI is estimated between 11.5 and 24% and is considered a risk factor for neurodegenerative disease and APD. Three risk factors for development of CDI are recognized in the majority of the studies: (1) multisystem disease, (2) the occurrence of reactivations or active disease for a prolonged period, and (3) the presence of craniofacial bone lesions. Since CDI may occur as the first manifestation of LCH, differential diagnosis of malignant diseases like germ cell tumours must be made. APD is almost always associated with CDI and can appear several years after the diagnosis of CDI. Growth hormone is the most commonly affected anterior pituitary hormone. Despite significant advances in the knowledge of LCH in recent years, little progress has been made in preventing long-term sequelae such as those affecting the hypothalamic-pituitary system.

Influence of Obesity on Clinical Manifestations and Response to Therapy in Cutaneous Leishmaniasis caused by Leishmania braziliensis

2021 ◽  
Author(s):  
Tainã Lago ◽  
Lucas Carvalho ◽  
Mauricio Nascimento ◽  
Luiz H Guimarães ◽  
Jamile Lago ◽  
...  
Keyword(s):  
Cutaneous Leishmaniasis ◽  
Clinical Presentation ◽  
Clinical Manifestations ◽  
Healing Time ◽  
Response To Therapy ◽  
Leishmania Braziliensis ◽  
Cutaneous Lesions ◽  
Cytokine Levels ◽  
Cure Rates ◽  
The Impact

Abstract Background Cutaneous leishmaniasis (CL) caused by L. braziliensis is characterized by a single ulcer or multiple cutaneous lesions with raised borders. Cure rates below 60% are observed in response to meglumine antimoniate therapy. We investigated the impact of obesity on CL clinical presentation and therapeutic response. Methods A total of 90 age-matched CL patients were included (30 obese, 30 overweight and 30 with normal BMI). CL was diagnosed through documentation of L. braziliensis DNA by PCR or identification of amastigotes in biopsied skin lesion samples. Serum cytokine levels were determined by chemiluminescence. Antimony therapy with Glucantime (20mg/kg/day) was administered for 20 days. Results Obese CL patients may present hypertrophic ulcers rather than typical oval, ulcerated lesions. A direct correlation between BMI and healing time was noted. After one course of Antimony, cure was achieved in 73% of patients with normal BMI, 37% of overweight subjects, yet just 18% of obese CL patients (p&lt;0.01). Obese CL cases additionally presented higher leptin levels than overweight patients or those with normal BMI (p&lt;0.05). Conclusions Obesity modifies the clinical presentation of CL and host immune response, and is associated with greater failure to therapy.

scholarly journals The impact of pathologic staging on the long-term oncologic outcomes of patients with clinically high-risk prostate cancer

Cancer ◽  
2014 ◽  
Vol 120 (11) ◽  
pp. 1656-1662 ◽  
Author(s):  
Michael R. Abern ◽  
Martha K. Terris ◽  
William J. Aronson ◽  
Christopher J. Kane ◽  
Christopher L. Amling ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
High Risk ◽  
Oncologic Outcomes ◽  
High Risk Prostate Cancer ◽  
Pathologic Staging ◽  
Risk Prostate Cancer ◽  
The Impact

Abstract 2143: Improved Long-Term Survival in a High Risk Population Following Drug Eluting Stent Availability

Circulation ◽  
2007 ◽  
Vol 116 (suppl_16) ◽  
Author(s):  
Maheer Gandhavadi ◽  
Kendrick A Shunk ◽  
Edward J McNulty
Keyword(s):  
High Risk ◽  
Independent Predictor ◽  
Drug Eluting Stent ◽  
High Risk Population ◽  
Term Survival ◽  
Risk Population ◽  
Long Term Survival ◽  
Drug Eluting ◽  
The Impact

Background Data regarding the impact of drug eluting stent (DES) use on long-term outcomes outside trial populations are limited. Methods 1,547 consecutive patients underwent stent implantation from January 2000 until December 2006 at the San Francisco Veterans Affairs Medical Center. To assess the impact of DES availability on mortality, that population was partitioned into a pre-DES cohort (N=591) and a post-DES availability cohort (N=956). Kaplan-Meier survival curves for the two cohorts were compared. Results The entire population was relatively high risk: 37% had diabetes, 38% a reduced ejection fraction, and 53% a prior MI or elevated troponin prior to the procedure. Median follow up was 4.7 years for the pre-DES cohort and 1.8 years for the post-DES cohort. DES were used in 83% of procedures in the post-DES cohort. Survival improved significantly in the post-DES cohort (P = .04, Log Rank)(see Figure ). Baseline characteristics, procedural variables and discharge medications were analyzed in a Cox proportional hazards model (see Table ). DES use was an independent predictor of improved survival (Hazard Ratio for death 0.52, 95% CI .28–.95). Conclusions In an unselected, high risk population, long-term survival improved following the availability of drug eluting stents. After adjusting for potential confounding factors, DES use was an independent predictor of improved survival. Independent Predictors of Death in all 1,547 Patients

Adult-onset Neurological Langerhans Cell histiocytosis and Response to Treatment

2021 ◽  
Vol 8 (1) ◽  
Author(s):  
Al-Hader R ◽  
◽  
Suneja A ◽  
Memon AB ◽  
Mukherje A ◽  
...  
Keyword(s):  
Langerhans Cell Histiocytosis ◽  
Brain Magnetic Resonance Imaging ◽  
Langerhans Cell ◽  
Response To Therapy ◽  
Response To Treatment ◽  
Adult Onset ◽  
Multisystem Disease ◽  
Clonal Proliferation ◽  
Magnetic Resonance Imaging Mri ◽  
Mass Lesions

Introduction: Langerhans Cell Histiocytosis (LCH) is a rare form of cancer that mostly affects children and rarely adults. LCH involves an abnormal clonal proliferation of Langerhans cells in the bone marrow. These cells are capable of migrating from the skin to lymph nodes. Therefore, it is characterized as a multisystem disease. Neurological manifestations are not common, and often patients’ present with endocrine dysfunction with neuroimaging findings of hypothalamic and pituitary masses can mimic pituitary adenoma. Here, we discuss two instances of unusual adult-onset, primary neurological LCH in patients with a positive response to therapy-these two patients presented with mass lesion and neurodegenerative form of LCH, respectively. LCH can manifest features of mass lesions or neurodegeneration on brain Magnetic Resonance Imaging (MRI). Since it is rare in adults, it is crucial to identify this condition as timely treatment can have a better prognosis.

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