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1.
Hematol Oncol ; 2019 Aug 13.
Artigo em Inglês | MEDLINE | ID: mdl-31408541

RESUMO

In absence of red blood cells disease or immune defect, parvovirus B19 (PVB-19) is usually considered as a benign condition. Here, we report the case of a 10-year-old boy, previously healthy, presenting with a PVB-19 infection revealed by a bicytopenia and a voluminous axillary adenopathy. Pathophysiology examination showed reactional lymphoid population. Nine months later and in the absence of remission, a new biopsy of the same adenopathy revealed a Hodgkin lymphoma with area of T-cell rich aggressive large B-cell lymphoma. This case suggests PVB-19 as potential trigger of this malignant childhood hemopathy. Although no definitive conclusion can be drawn, our clinical case questions the role of PVB-19 in lymphomagenesis.

2.
Artigo em Inglês | MEDLINE | ID: mdl-31358461

RESUMO

BACKGROUND: Aneurysmal bone cyst (ABC) is a benign tumour whose progression involves the RANK/RANKL signalling pathway. Surgery is the reference standard treatment but carries risks that vary with the site of the tumour. Denosumab is a human monoclonal IgG2 antibody that targets the RANK/RANKL pathway and may therefore hold promise for inhibiting ABC progression. The objective of this study was to evaluate denosumab use in paediatric patients (younger than 18 years) with ABC and to describe the clinical and radiological outcomes, as well as the side effect profile. HYPOTHESIS: Denosumab is a viable option in children with ABC refractory to standard treatments. MATERIAL AND METHODS: We retrospectively reviewed the medical files of paediatric patients given denosumab to treat ABC in any of 32 centres affiliated with the French Paediatric Cancer Society (Société Française du Cancer de l'Enfant, SFCE) and French Sarcoma Group (Groupe Sarcome Français, GSF-GETO). We identified 5 patients treated between March 2015 and June 2018. Median age was 8 years (range, 7-17 years). Pain was a symptom in all 5 patients and neurological deficits were present in 3 patients. Surgery was performed in 4 patients, either before (n=3) or after (n=1) denosumab therapy; the remaining patient had no surgery. Denosumab was given as monthly injections in a dosage of 70mg/m2 for a median of 12 months (range, 4-23 months). The clinical outcomes and changes in computed tomography and/or magnetic resonance imaging findings were evaluated. RESULTS: Abnormalities in calcium and phosphate levels secondary to the ABC occurred in 2 patients. At median of 24 months (range, 0-28 months) after denosumab initiation, all 5 patients were free of pain, and the neurological deficits in 3 patients had improved. Central remineralisation and cortical reconstitution were demonstrated consistently by the imaging studies. DISCUSSION: Denosumab is a viable treatment option in selected paediatric patients with inoperable ABC. The immediate adverse effect profile is acceptable. A larger study with a longer follow-up would be welcome to further assess the contribution of denosumab to the treatment of ABC. LEVEL OF EVIDENCE: IV.

4.
Bull Cancer ; 106(5): 461-467, 2019 May.
Artigo em Francês | MEDLINE | ID: mdl-30910228

RESUMO

Atypical genital development (AGD), also called disorders of sex development are a set of miscellaneous pathologies who have in common a morphological and/or functional abnormality of the internal and/or external genital organs. The Chicago classification identifies 3 major groups based on karyotype, hormone balance and genetic studies. Some AGD predispose to the occurrence of tumors, mainly malignant germ cell tumors. The tumor risk depends on many factors: the type of AGD, the position of the gonad, the age of the patient, the phenotype, the function of the gonad and the presence of germ cells in the gonad. AGD with the highest tumor risk are those with gonadal dysgenesis, implying an incomplete differentiation of the bipotential gonad (dysplasia). Monitoring of patients with AGD and indication of prophylactic gonadectomies should be individualized according to tumor risk.


Assuntos
Disgenesia Gonadal/complicações , Neoplasias Ovarianas/etiologia , Neoplasias Testiculares/etiologia , Feminino , Disgenesia Gonadal/classificação , Humanos , Masculino , Neoplasias Ovarianas/epidemiologia , Fatores de Risco , Neoplasias Testiculares/epidemiologia
5.
Mod Pathol ; 2018 Nov 06.
Artigo em Inglês | MEDLINE | ID: mdl-30401946

RESUMO

The prognosis of malignant pediatric adrenocortical tumors is closely related to disease stage, which is used to guide perioperative treatment recommendations. However, current scoring systems are inadequate to distinguish between benign and malignant adrenocortical tumors. Robust microscopic prognostic features that could help determine perioperative therapy are also lacking. The aim of this national study was to review the prognostic value of the Wieneke scoring criteria and Ki67 labeling index in unselected pediatric adrenocortical tumors. Using strict definitions previously defined by expert pathologists, a Wieneke score was re-attributed to each tumor after an independent and centralized review. In addition, Ki67 proliferation index was performed and reviewed for each case. A total of 95 cases were selected; all were treated between 2000 and 2018 and had histopathologic material and sufficient outcome-related information available. Localized disease was found in 88% of patients. Among those with advanced disease, 6% had tumor extension into adjacent organs and 5% had metastases at diagnosis. Median follow-up was 5 years and 3 months. The 5-year PFS was 82%, 95% CI [73%-91%]. Tumor stage significantly correlated with PFS (p < 0.0001). Tumor weight up to 200 g, extra-adrenal extension and initial non-complete surgical resection were statistically associated with worse outcomes. No recurrences nor metastases occurred when the Ki67 index was < 15%. Up to two of the following five factors including tumor necrosis, adrenal capsular invasion, venous invasion, mitotic count > 15/20 high-power fields, and Ki67 index > 15%, significantly correlated with worse outcomes. We propose a pathological scoring system incorporating the Ki67 index as part of a two-step approach after disease staging to guide adjuvant treatment in pediatric adrenocortical tumors, especially after incomplete resection. These results should be validated in an independent cohort.

6.
Pediatr Nephrol ; 33(7): 1263-1267, 2018 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-29594503

RESUMO

BACKGROUND: Hyperphosphatemic familial tumoral calcinosis (HFTC) is a rare autosomal recessive disease caused by mutations in genes encoding FGF23 or its regulators, and leading to functional deficiency or resistance to fibroblast growth factor 23 (FGF23). Subsequent biochemical features include hyperphosphatemia due to increased renal phosphate reabsorption, and increased or inappropriately normal 1,25-dihydroxyvitamin D (1,25-D) levels. CASE-DIAGNOSIS/TREATMENT: A 15-year-old girl was referred for a 1.2-kg-calcified mass of the thigh, with hyperphosphatemia (2.8 mmol/L); vascular impairment and soft tissue calcifications were already present. DNA sequencing identified compound heterozygous mutations in the FGF23 gene. Management with phosphate dietary restriction, phosphate binders (sevelamer, aluminum, nicotinamide), and acetazolamide moderately decreased serum phosphate levels; oral ketoconazole was secondary administered, leading to significantly decreased 1,25-D levels albeit only moderate additionally decreased phosphate levels. However, therapeutic compliance was questionable. Serum phosphate levels always remained far above the upper normal limit for age. The patient presented with two relapses of the thigh mass, requiring further surgery. CONCLUSIONS: We suggest that control of phosphate metabolism is crucial to prevent recurrences and vascular complications in HFTC; however, the medical management remains challenging.

7.
Pediatr Blood Cancer ; 65(6): e27005, 2018 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-29469200

RESUMO

Germline DICER1 pathogenic variants predispose to numerous benign and malignant tumors. In this report, we describe DICER1 gene analysis in an adolescent diagnosed with multinodular goiter, ovarian Sertoli-Leydig cell tumor, and lung cyst. DICER1 mutational screening at the DNA level failed to detect any pathogenic variant. Subsequent messenger RNA (mRNA) analysis revealed a 132 nucleotide intronic sequence exonization. This truncating event was caused by a deep intronic mutation generating a de novo acceptor splice site. This study demonstrates that some undetected DICER1 mutations should be investigated at the mRNA level.

8.
Nephrol Ther ; 14(2): 105-108, 2018 Apr.
Artigo em Francês | MEDLINE | ID: mdl-29290619

RESUMO

Goodpasture's syndrome is a triad of anti-glomerular basement membrane (anti-GBM) circulating antibodies, glomerulonephritis and pulmonary hemorrhage. We reported a 65-year-old woman with headaches, asthenia and weight loss. Giant cell arteritis was confirmed by temporal artery biopsy. The patient had associated renal condition with moderate acute renal failure, proteinuria and haematuria. Renal biopsy showed extracapillary glomerulonephritis and linear staining of immunoglobulins G along glomerular basement membrane. There was no clinical pulmonary involvement. Anti-MBG antibody was positive and allowed Goodpasture's syndrome diagnosis. The patient was treated with corticoids and cyclophosphamide. Patient's condition and renal function improved quickly and anti-MBG antibodies became negative. Goodpasture's syndrome may be characterized by isolated renal expression without pulmonary involvement. We described for the first time association of Goodpasture's syndrome with giant cell arteritis.


Assuntos
Doença Antimembrana Basal Glomerular/diagnóstico , Arterite de Células Gigantes/complicações , Idoso , Doença Antimembrana Basal Glomerular/complicações , Doença Antimembrana Basal Glomerular/tratamento farmacológico , Autoanticorpos/metabolismo , Ciclofosfamida/uso terapêutico , Feminino , Glucocorticoides/uso terapêutico , Humanos , Imunossupressores/uso terapêutico , Rim/patologia
10.
J Immunother Cancer ; 5(1): 57, 2017 07 18.
Artigo em Inglês | MEDLINE | ID: mdl-28716106

RESUMO

BACKGROUND: The anti-Programmed Death receptor 1 (anti-PD-1) antibodies nivolumab and pembrolizumab are new treatments in metastatic melanoma. Immunotherapies are best known to be responsible for thrombotic microangiopathy. However, immune interstitial nephritis has been described in a patient treated by nivolumab and ipilimumab concomitantly, and three cases of granulomatous interstitial nephritis have been reported with ipilimumab monotherapy. We report herein a case of acute interstitial immune nephritis in a patient treated with nivolumab after ipilimumab for pulmonary metastatic melanoma. CASE PRESENTATION: Interstitial nephritis was diagnosed after acute kidney injury following three cycles and was confirmed by kidney biopsy. Kidney injury responded rapidly to prednisolone, which was then gradually reduced. As a follow-up computed tomography scan indicated mixed response, with minimal size progression of a pulmonary nodule, but a significant reduction in the size of the other nodules, nivolumab was reintroduced after renal function improvement. Low-dose corticosteroids were first maintained during nivolumab treatment and subsequently discontinued. Only one month after prednisolone discontinuation, creatinine levels increased. A second kidney biopsy confirmed relapse of acute interstitial nephritis. CONCLUSIONS: To our knowledge, this is the first case of nivolumab-induced acute interstitial immune nephritis. This case highlights that anti-PD-1 immunotherapy may be continued when renal function is adequate, and this requires close interaction between dermatologists and nephrologists. This adverse effect should be made known to prescribers as nivolumab is associated with significant improvement of survival in metastatic melanoma and may be used in many different types of cancer.


Assuntos
Anticorpos Monoclonais/efeitos adversos , Antineoplásicos Imunológicos/efeitos adversos , Neoplasias do Ânus/tratamento farmacológico , Ipilimumab/efeitos adversos , Melanoma/tratamento farmacológico , Nefrite Intersticial/induzido quimicamente , Doença Aguda , Lesão Renal Aguda/induzido quimicamente , Idoso , Anticorpos Monoclonais/administração & dosagem , Antineoplásicos Imunológicos/administração & dosagem , Substituição de Medicamentos , Feminino , Humanos , Infusões Intravenosas , Ipilimumab/administração & dosagem , Neoplasias Pulmonares/secundário , Melanoma/secundário , Nódulos Pulmonares Múltiplos/secundário , Recidiva Local de Neoplasia/etiologia , Nivolumabe , Recidiva
11.
J Pediatr Hematol Oncol ; 39(5): 388-394, 2017 07.
Artigo em Inglês | MEDLINE | ID: mdl-28375941

RESUMO

BACKGROUND: Germ cell tumors with somatic malignant transformation (GCT with SMT) are rare in children and poorly described. Data are missing to determine if therapies should target the GCT, the SMT compound, or both simultaneously. PATIENTS AND METHODS: A retrospective national study was conducted in the Société Française des cancers de l'Enfant (SFCE) Centers. Medical records from patients aged 0 to 18 years diagnosed with GCT with SMT between 2000 and 2015 were analyzed. Any stages and primary sites were considered as well as synchronous and metachronous cases. RESULTS: Fifteen patients were identified. Thirteen patients had synchronous GCT with SMT. In the latter cases, primaries were ovary (5), mediastinum (3), pineal gland (3), sacrococcyx (1), and parametrium (1). SMT histologies were central primitive neuroectodermal tumor (5), embryonal rhabdomyosarcomas (3) or thyroid papillary adenocarcinoma, leukemia, poorly differentiated carcinoma, mixed sarcomas, and miscellaneous histology (1 case each). Chemotherapy was targeted against the GCT (3), the SMT (6), or both components (3). The last patient received surgery exclusively. Partial or complete response to chemotherapy was observed in 5/10 assessable cases: 2/3 patients treated with GCT-dedicated chemotherapy, 3/6 patients treated with SMT-dedicated therapy, and 0/1 treated with combined therapy. In addition, 2 patients with mediastinal GCT primary had metachronous SMT, with acute myeloid leukemia and thyroid papillary adenocarcinoma, 8 months and 8 years, respectively, after the diagnoses of GCT. Two patients (1 synchronous and 1 metachronous) were cured with surgery exclusively. At the end of follow-up, 6 patients died of their disease including all 4 with postsurgical macroscopic residue. CONCLUSIONS: GCT with SMT constitutes a very rare entity in children and adolescents. Surgical removal of the tumor is the cornerstone of the treatment and might be sufficient in selected cases. In the remaining cases, the best management is still unknown and should take into account both components and their respective chemosensitivity. Long-term surveillance is advised for patient with unresected teratoma as late transformation can occur.


Assuntos
Transformação Celular Neoplásica , Neoplasias Embrionárias de Células Germinativas , Adolescente , Transformação Celular Neoplásica/patologia , Criança , Pré-Escolar , Feminino , França , Humanos , Lactente , Masculino , Neoplasias Embrionárias de Células Germinativas/mortalidade , Neoplasias Embrionárias de Células Germinativas/patologia , Neoplasias Embrionárias de Células Germinativas/terapia , Estudos Retrospectivos , Procedimentos Cirúrgicos Operatórios , Taxa de Sobrevida , Resultado do Tratamento
12.
Kidney Int ; 92(1): 214-226, 2017 07.
Artigo em Inglês | MEDLINE | ID: mdl-28318622

RESUMO

Antibody-mediated rejection is associated with heterogeneous kidney allograft outcomes. Accurate evaluation of risk for graft loss at time of diagnosis is necessary to offer personalized treatment. In contrast with serological and molecular assessment, morpho-histological evaluation of antibody-mediated rejection lesions has not significantly evolved. This relies on Banff classifications designed to be of diagnostic discriminatory power rather than prognostic and face quantitative and qualitative limitations. Here we developed a method of Computer-assisted Analysis of Graft Inflammation (CAGI) to improve the classification of allograft inflammation. Digitization of immunostained biopsy sections, image processing and algorithm-driven analysis allowed quantification of macrophages, T cells, B cells, and granulocytes per unit surface of interstitium, capillaries or glomeruli. CAGI was performed on biopsy specimens of 52 patients with extensively phenotyped antibody-mediated rejection. Macrophage numbers in capillaries and interstitium, but not Banff scores or the amount of other immune cell subsets, correlated with donor-specific antibody (DSA) mean fluorescence intensity and DSA-C3d status. The quantity of macrophages in the interstitium and DSA-C3d status were the only independent predictors for significant allograft loss at the time of antibody-mediated rejection diagnosis (hazard ratio 3.71 and 2.34, respectively). A significant strategy integrating the DSA-C3d assay and the quantification of interstitial macrophages allowed identification of three groups with distinct renal prognosis: DSA-C3d-, DSA-C3d+/macrophages-low and DSAC3d+/macrophages-high. Thus, CAGI brings a missing piece to the antibody-mediated rejection puzzle by identifying morpho-histological processes that bridge in vitro parameters of DSA pathogenicity and graft loss. Hence, this approach could be useful in future integrated strategies of risk evaluation.


Assuntos
Diagnóstico por Computador/métodos , Glomerulonefrite/diagnóstico , Rejeição de Enxerto/diagnóstico , Interpretação de Imagem Assistida por Computador/métodos , Imunidade Humoral , Imuno-Histoquímica/métodos , Transplante de Rim/efeitos adversos , Rim/patologia , Adulto , Algoritmos , Aloenxertos , Biomarcadores/análise , Biópsia , Complemento C3d/análise , Feminino , Glomerulonefrite/imunologia , Glomerulonefrite/patologia , Rejeição de Enxerto/imunologia , Rejeição de Enxerto/patologia , Sobrevivência de Enxerto , Humanos , Isoanticorpos/análise , Estimativa de Kaplan-Meier , Rim/imunologia , Masculino , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Prognóstico , Fatores de Tempo , Resultado do Tratamento , Adulto Jovem
13.
Pediatr Nephrol ; 32(6): 1023-1028, 2017 06.
Artigo em Inglês | MEDLINE | ID: mdl-28236143

RESUMO

BACKGROUND: Eculizumab may be used to treat C3-glomerulopathy (C3G), a rare but severe glomerular disease. DIAGNOSIS AND TREATMENT: Patients 1, 2 and 3 were diagnosed with nephritic syndrome with alternative complement pathway activation (low C3, C3Nef-positive) and C3G at the age of 9, 13 and 12 years, respectively. Treatment with eculizumab normalized proteinuria within 1, 2 and 7 months, respectively. Proteinuria relapsed when eculizumab was withdrawn, but the re-introduction of eculizumab normalized proteinuria. Patient 4 was diagnosed with C3G at 9 years of age, with progression to end-stage renal disease within 2 years, followed by a first renal transplantation (R-Tx) with early disease recurrence and graft loss within 39 months. After a second R-Tx, she rapidly presented with biological and histological recurrence: therapy with eculizumab was started, with no effect on proteinuria after 5 months, in a complex clinical setting (i.e. association of C3G recurrence, humoral rejection and BK nephritis). Eculizumab was withdrawn due to multiple viral reactivations, but the re-introduction of the drug a few months later enabled a moderate decrease in proteinuria. CONCLUSION: These cases illustrate the efficacy of eculizumab, at least on native kidneys, in paediatric C3G. However, larger international studies are warranted to confirm the benefit and safety of eculizumab therapy.


Assuntos
Anticorpos Monoclonais Humanizados/uso terapêutico , Glomerulonefrite Membranoproliferativa/tratamento farmacológico , Falência Renal Crônica/terapia , Proteinúria/tratamento farmacológico , Adolescente , Criança , Complemento C3/antagonistas & inibidores , Complemento C3/imunologia , Fator Nefrítico do Complemento 3 , Via Alternativa do Complemento/efeitos dos fármacos , Feminino , Glomerulonefrite Membranoproliferativa/complicações , Glomerulonefrite Membranoproliferativa/imunologia , Glomerulonefrite Membranoproliferativa/urina , Rejeição de Enxerto/tratamento farmacológico , Rejeição de Enxerto/imunologia , Humanos , Imunidade Humoral/efeitos dos fármacos , Rim/patologia , Falência Renal Crônica/etiologia , Transplante de Rim/efeitos adversos , Masculino , Uso Off-Label , Recidiva , Resultado do Tratamento
14.
Am J Med Genet A ; 173(3): 654-660, 2017 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-28160395

RESUMO

We report a novel syndromic disorder of sex development observed in three male siblings, presenting with the association of micropenis without hypospadias, cryptorchidism, very low level of antimüllerian hormone in the neonatal period, and no persistent müllerian duct structures, suggesting a progressive regression of testicular function. The patients described here showed a striking neurological involvement including bilateral periventricular cysts observed in the anterior part of the frontal horns prenatally and increasing in size and number over time, associated with infra and supratentorial parenchymal atrophy, dilated ventricular system, corpus callosum hypoplasia, severe intellectual disability, and epilepsy. Associated features included a distinctive facies, joint contractures, retinopathy, and hearing loss. Pathological examination was consistent with testicular dysgenesis and leukoencephalopathy with spongiosis and microcalcifications. To the best of our knowledge, this disease, characterized by a recognizable pattern of malformations, has not been previously reported. An exhaustive genetic and metabolic evaluation was normal. Autosomal recessive inheritance was considered to be likely, on the basis of SNP studies. We hope that the detailed description provided here of the clinical, radiological, and pathological findings observed in this family will help to identify further unrelated patients, and ultimately, to clarify the genetic basis of this condition. © 2017 Wiley Periodicals, Inc.


Assuntos
Transtornos do Desenvolvimento Sexual/diagnóstico , Transtornos do Desenvolvimento Sexual/genética , Disgenesia Gonadal/diagnóstico , Disgenesia Gonadal/genética , Leucoencefalopatias/diagnóstico , Leucoencefalopatias/genética , Fenótipo , Testículo/anormalidades , Encéfalo/patologia , Pré-Escolar , Facies , Evolução Fatal , Doenças dos Genitais Masculinos/patologia , Hormônios Esteroides Gonadais/sangue , Humanos , Recém-Nascido , Imagem por Ressonância Magnética , Masculino , Pênis/anormalidades , Pênis/patologia , Irmãos , Síndrome
15.
Pediatr Infect Dis J ; 36(8): 805-808, 2017 08.
Artigo em Inglês | MEDLINE | ID: mdl-28134743

RESUMO

This first observation of donor-transmitted coccidioidomycosis in a pediatric liver-transplant recipient underlines a rare condition in transplanted patients in a nonendemic area. This transmission was observed after a liver split, the patient being contaminated by the left liver while the right-liver recipient was not.


Assuntos
Coccidioidomicose/transmissão , Transplante de Fígado/efeitos adversos , Transplantes/parasitologia , Criança , Feminino , Humanos
16.
Cancer Chemother Pharmacol ; 78(2): 419-26, 2016 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-27371224

RESUMO

PURPOSE: Vemurafenib (VMF) is a B-RAF inhibitor used in the treatment of B-RAF-V600-mutant metastatic melanomas. Reports of acute kidney injury (AKI) in patients treated with VMF are scarce. METHODS: To investigate the incidence and severity of AKI, we conducted a retrospective, observational, monocentric study in the Lyon Sud Hospital University, France, which included 74 patients with metastatic B-RAF-mutated melanomas treated with VMF, between June 2011 and August 2014. According to the Kidney Disease Improving Global Outcomes Guidelines, AKI is defined as an increase in serum creatinine concentration exceeding the baseline concentration by 1.5 fold. Serum creatinine was thus determined before treatment, on a monthly basis during treatment, and 3 months after treatment discontinuation. Patients were divided into two main groups: AKI-positive (AKI+) and AKI-negative (AKI-) and further subdivided into three groups according to AKI severity (stage 1, 2 or 3). To visualize the tissue damage caused by VMF, kidney biopsies were performed for two stage 1 AKI+ patients. RESULTS: Of the 74 patients, 30 (40.5 %) were AKI-, and of the 44 AKI+ patients (59.5 %), 29 (66 %) were diagnosed within the first three months of treatment. There were significantly more men in the AKI+ group: n = 33 (75 %) versus n = 12 (40 %) women, p = 0.004 with an odds ratio for developing AKI of 4.6 (95 % CI 1.48-14.23). Most AKI + cases were considered as stage 1 (n = 40; 91 %) and the remaining four (9 %) as stage 2 AKI. Kidney biopsies revealed interstitial fibrosis and acute focal tubular damage. However, renal failure was reversible in 80 % of patients within 3 months of VMF discontinuation. CONCLUSIONS: We observed frequent, reversible, moderately severe AKI with some histological evidence of tubular and interstitial damage in VMF-treated patients, suggesting that renal function should be carefully monitored in male patients, especially during the first 3 months.


Assuntos
Lesão Renal Aguda/induzido quimicamente , Antineoplásicos/efeitos adversos , Indóis/efeitos adversos , Melanoma/tratamento farmacológico , Sulfonamidas/efeitos adversos , Lesão Renal Aguda/epidemiologia , Lesão Renal Aguda/fisiopatologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos/administração & dosagem , Creatinina/sangue , Feminino , França , Humanos , Incidência , Indóis/administração & dosagem , Masculino , Melanoma/genética , Melanoma/patologia , Pessoa de Meia-Idade , Mutação , Metástase Neoplásica , Proteínas Proto-Oncogênicas B-raf/antagonistas & inibidores , Proteínas Proto-Oncogênicas B-raf/genética , Estudos Retrospectivos , Índice de Gravidade de Doença , Sulfonamidas/administração & dosagem , Fatores de Tempo , Vemurafenib
17.
J Clin Oncol ; 34(25): 3023-30, 2016 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-27382093

RESUMO

PURPOSE: Langerhans cell histiocytosis (LCH) is an inflammatory myeloid neoplasia with a broad spectrum of clinical manifestations and outcomes in children. The somatic BRAF(V600E) mutation occurs frequently, but clinical significance remains to be determined. PATIENTS AND METHODS: BRAF(V600E) 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 BRAF(V600E) mutation. Patients with BRAF(V600E) manifested more severe disease than did those with wild-type BRAF. Patients with BRAF(V600E) 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). BRAF(V600E) 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 BRAF(V600E) 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, BRAF(V600E) 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.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Histiocitose de Células de Langerhans/tratamento farmacológico , Histiocitose de Células de Langerhans/genética , Mutação , Proteínas Proto-Oncogênicas B-raf/genética , Adolescente , Corticosteroides/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Criança , Pré-Escolar , Estudos de Coortes , Resistencia a Medicamentos Antineoplásicos , Feminino , França/epidemiologia , Histiocitose de Células de Langerhans/enzimologia , Histiocitose de Células de Langerhans/epidemiologia , Humanos , Lactente , Recém-Nascido , Masculino , Terapia de Alvo Molecular , Proteínas Proto-Oncogênicas B-raf/antagonistas & inibidores , Sistema de Registros , Vimblastina/administração & dosagem
18.
Mod Pathol ; 29(11): 1399-1414, 2016 11.
Artigo em Inglês | MEDLINE | ID: mdl-27469328

RESUMO

Disorders of sex development are defined as congenital conditions with discordance between the phenotype, the genotype, the karyotype, and the hormonal profile. The disorders of sex development consensus classification established in 2005 are mainly based on chromosomal and biological data. However, histological anomalies are not considered. The aims of this study were to define the specific pathological features of gonads in various groups of disorders of sex development in order to clarify the nosology of histological findings and to evaluate the tumor risk in case of a conservative approach. One hundred and seventy-five samples from 86 patients with disorders of sex development were analyzed following a strict histological reading protocol. The term 'gonadal dysgenesis' for the histological analysis was found confusing and therefore excluded. The concept of 'dysplasia' was subsequently introduced in order to describe the architectural disorganization of the gonad (various degrees of irregular seminiferous tubules, thin albuginea, fibrous interstitium). Five histological types were identified: normal gonad, hypoplastic testis, dysplastic testis, streak gonad, and ovotestis. The analysis showed an association between undifferentiated gonadal tissue, a potential precursor of gonadoblastoma, and dysplasia. Dysplasia and undifferentiated gonadal tissue were only encountered in cases of genetic or chromosomal abnormality ('dysgenesis' groups in the disorders of sex development consensus classification). 'Dysgenetic testes', related to an embryonic malformation of the gonad, have variable histological presentations, from normal to streak. Conversely, gonads associated with hormonal deficiencies always display a normal architecture. A loss of expression of AMH and α-inhibin was identified in dysplastic areas. Foci of abnormal expression of the CD117 and OCT4 immature germ cells markers in dysplasia and undifferentiated gonadal tissue were associated with an increased risk of neoplasia. This morphological analysis aims at clarifying the histological classification and gives an indication of tumor risk of gonads in disorders of sex development.


Assuntos
Transtornos do Desenvolvimento Sexual/classificação , Transtornos do Desenvolvimento Sexual/patologia , Gônadas/patologia , Adolescente , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Recém-Nascido , Masculino
19.
Pathol Oncol Res ; 22(4): 847-52, 2016 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-27230613

RESUMO

Metastatic status, histologic response, and quality of surgical resection are prognostic factors for osteosarcomas. Pathology reports sometimes describe peritumoral vascular invasion on surgical specimens after neoadjuvant chemotherapy but their prognostic significance as an independent parameter has never been reported. The aim of this study was to evaluate how the presence of this peritumoral vascular invasion could influence survival. We retrospectively analyzed histology, demographics, and outcomes of pediatric patients treated for osteosarcoma in our institutions between January 2007 and December 2012. A single pathologist analyzed the resection specimens after neoadjuvant chemotherapy. Fifty-one osteosarcomas were diagnosed over a 6-year period; nine had metastatic disease at diagnosis. Surgery was performed after neoadjuvant chemotherapy in all cases. We identified peritumoral vascular invasion in the surgical specimens in 15 cases. Two-year event-free survival (EFS) was 78 % (CI95%[64;93]) for patients without vascular invasion versus 48 % (CI95% [21;75]) in patients with vascular invasion, and 2-year overall survival (OS) was 94 % (CI95%[86;100]) for those without vascular invasion versus 79 % (CI95%[57;100]) for others. Multivariate analysis demonstrated correlation of metastatic status and presence of vascular invasion with survival. The histopathological description of peritumoral vascular invasion in surgical specimens of osteosarcoma after neoadjuvant chemotherapy can be considered a prognostic factor and could indicate modification of the postoperative therapeutic strategy.


Assuntos
Neoplasias Ósseas/patologia , Invasividade Neoplásica/patologia , Neovascularização Patológica/patologia , Osteossarcoma/patologia , Adolescente , Adulto , Criança , Pré-Escolar , Intervalo Livre de Doença , Feminino , Humanos , Masculino , Terapia Neoadjuvante/métodos , Prognóstico , Estudos Retrospectivos , Adulto Jovem
20.
J Am Soc Nephrol ; 27(12): 3539-3544, 2016 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-27153925

RESUMO

Most patients with idiopathic membranous nephropathy (IMN) have IgG4 autoantibodies against phospholipase A2 receptor (PLA2R). C3 and C5b-9 are found in immune deposits of IMN kidney biopsy specimens, but the pathway of complement activation in IMN remains elusive. We report the case of a patient who developed IMN with intense staining for PLA2R, IgG4, C3, C5b-9, factor B, and properdin and very weak staining for C1q, C4d, and IgG1. Measurement of mannan binding lectin (MBL) antigenic level and activity revealed MBL deficiency. Genotyping revealed a heterozygous (A/C) polymorphism in codon 57 of MBL2 exon 1 associated with homozygous and heterozygous variations in the promoter region at -550 (L/L) and -221 (X/Y), respectively, suggesting that the patient harbored the LXA/LYC haplotypes linked to MBL deficiency. Genetic sequencing in 77 consecutive patients with IMN identified four patients with MBL2 promoter and coding region variations associated with MBL deficiency and the same complement pattern in immune deposits as the index patient. In contrast, patients with wild-type MBL2 had immune deposits with intense Cd4 staining. Thus, IMN can develop in patients with complete MBL deficiency, with complement activated mainly by the alternative pathway, whereas the lectin pathway is also activated in those with wild-type MBL2.


Assuntos
Glomerulonefrite Membranosa/etiologia , Lectina de Ligação a Manose/deficiência , Receptores da Fosfolipase A2/fisiologia , Adulto , Glomerulonefrite Membranosa/genética , Glomerulonefrite Membranosa/metabolismo , Humanos , Masculino , Lectina de Ligação a Manose/genética
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