RESUMEN
We report a large series of 40 patients presenting EPAS1-mutated paraganglioma (PGL) in whom we investigated a cause underlying chronic hypoxia. Four patients suffered from hypoxaemic heart disease. In patients with available haemoglobin electrophoresis results, 59% presented with a haemoglobin disorder, including six with sickle cell disease, five with sickle cell trait and two with heterozygous haemoglobin C disease. Histological and transcriptomic characterization of EPAS1 tumours revealed increased angiogenesis and high similarities with pseudohypoxic PGLs caused by VHL gene mutations. Sickle haemoglobinopathy carriers could thus be at increased risk for developing EPAS1-PGLs, which should be taken into account in their management and surveillance.
Asunto(s)
Neoplasias de las Glándulas Suprarrenales , Hemoglobinopatías , Paraganglioma , Humanos , Hemoglobinas/genética , Hipoxia/genética , Mutación , Paraganglioma/genética , Paraganglioma/patologíaRESUMEN
BACKGROUND: Anaplastic thyroid carcinoma (ATC) is a rare tumor, with poorly defined oncogenic molecular mechanisms and limited therapeutic options contributing to its poor prognosis. The aims of this retrospective study were to determine the frequency of anaplastic lymphoma kinase (ALK) translocations and to identify the mutational profile of ATC including TERT promoter mutations. METHODS AND MATERIALS: One hundred and forty-four ATC cases were collected from 10 centers that are a part of the national French network for management of refractory thyroid tumors. Fluorescence in situ hybridization analysis for ALK rearrangement was performed on tissue microarrays. A panel of 50 genes using next-generation sequencing and TERT promoter mutations using Sanger sequencing were also screened. RESULTS: Fluorescence in situ hybridization was interpretable for 90 (62.5%) cases. One (1.1%) case was positive for an ALK rearrangement with a borderline threshold (15% positive cells). Next-generation sequencing results were interpretable for 94 (65.3%) cases, and Sanger sequencing (TERT) for 98 (68.1%) cases. A total of 210 mutations (intronic and exonic) were identified. TP53 alterations were the most frequent (54.4%). Forty-three percent harbored a mutation in the (H-K-N)RAS genes, 13.8% a mutation in the BRAF gene (essentially p.V600E), 17% a PI3K-AKT pathway mutation, 6.4% both RAS and PI3K pathway mutations, and 4.3% both TP53 and PTEN mutations. Nearly 10% of the cases showed no mutations of the RAS, PI3K-AKT pathways, or TP53, with mutations of ALK, ATM, APC, CDKN2A, ERBB2, RET, or SMAD4, including mutations not yet described in thyroid tumors. Genes encoding potentially druggable targets included: mutations in the ATM gene in four (4.3%) cases, in ERBB2 in one (1.1%) case, in MET in one (1.1%) case, and in ALK in one (1.1%) case. A TERT promoter alteration was found in 53 (54.0%) cases, including 43 C228T and 10 C250T mutations. Three out of our cases did not harbor mutations in the panel of genes with therapeutic interest. CONCLUSION: This study confirms that ALK rearrangements in ATC are rare and that the mutational landscape of ATC is heterogeneous, with many genes implicated in the follicular epithelial cell dedifferentiation process. This may explain the limited effectiveness of targeted therapeutic options tested so far.
Asunto(s)
Proteínas Tirosina Quinasas Receptoras/genética , Telomerasa/genética , Carcinoma Anaplásico de Tiroides/genética , Neoplasias de la Tiroides/genética , Adulto , Anciano , Anciano de 80 o más Años , Quinasa de Linfoma Anaplásico , Femenino , Humanos , Masculino , Persona de Mediana Edad , Patología Molecular , Fosfatidilinositol 3-Quinasas/genética , Regiones Promotoras Genéticas , Proteínas Proto-Oncogénicas B-raf/genética , Estudios Retrospectivos , Transducción de Señal/genética , Carcinoma Anaplásico de Tiroides/patología , Neoplasias de la Tiroides/patologíaRESUMEN
OBJECTIVES: Graves' ophthalmopathy occurs in 50% of Graves' disease cases. Treatment is based on smoking cessation, and control of the euthyroidism and ocular repercussions associated with the disease. The active orbital forms are treated with glucocorticoids. Non-validated therapies have also been recently tested. Rituximab has been effectively used several times to treat corticosteroid-resistant Graves' ophthalmopathy associated with an optic neuropathy, but its use could be proposed only in inflammatory ophthalmopathies after failure of the corticosteroids. We present six cases treated since early 2012 at the University Hospital Center of Tours, France. METHODS: Six patients were treated at the University Hospital Center of Tours, France, between September 2012 and April 2014. The patients had a Mourits' score greater than three after treatment with corticosteroids and/or a severe NOSPECS score and/or orbital inflammation resistant to maximal treatment with intravenous injections of methylprednisolone and an optic neuropathy. They twice received one gram of rituximab by slow intravenous injection two weeks apart. Efficacy was assessed by a decrease of the orbital inflammatory clinical Mourits' score, and visual acuity and visual field testing. RESULTS: The inflammatory score of patients improved and treatment helped to stop the progression of the sequelae due to neuropathy. The orbital inflammatory clinical score, and the visual acuity and visual field improved but orbital decompression was necessary to complete the treatment. CONCLUSION: Rituximab has been used for the treatment of active corticosteroid-resistant Graves' ophthalmopathies. We also had positive results on patients with visual threat and optic neuropathy, when combined with surgical decompression.
Asunto(s)
Resistencia a Medicamentos , Glucocorticoides/uso terapéutico , Oftalmopatía de Graves/tratamiento farmacológico , Rituximab/uso terapéutico , Adulto , Anciano , Resistencia a Medicamentos/efectos de los fármacos , Femenino , Francia , Humanos , Masculino , Persona de Mediana Edad , Resultado del TratamientoAsunto(s)
Neoplasias de las Glándulas Suprarrenales/diagnóstico , Dopamina/análogos & derivados , Dopamina/metabolismo , Paraganglioma/diagnóstico , Feocromocitoma/diagnóstico , Neoplasias de las Glándulas Suprarrenales/metabolismo , Neoplasias de las Glándulas Suprarrenales/orina , Dopamina/orina , Humanos , Paraganglioma/metabolismo , Paraganglioma/orina , Feocromocitoma/metabolismo , Feocromocitoma/orina , Estudios RetrospectivosRESUMEN
BACKGROUND: A randomized phase III trial demonstrated that vandetanib treatment is effective in patients with metastatic medullary thyroid cancer (MTC), leading to regulatory approval, but its use may be associated with toxicities that require specific monitoring and management. The objective of the present study performed in France was to describe the toxicity profile and efficacy of vandetanib treatment when given outside any trial. METHODS: Sixty-eight patients were treated with vandetanib in the frame of a temporary use authorization (ATU) in France from August 2010 to February 2012, when the drug was available on request for patients with locally advanced or metastatic MTC. Patients were registered by the French health authorities, and characteristics, treatment parameters, toxicity profile, and efficacy were retrospectively reviewed. Eight patients were excluded from the analysis because vandetanib treatment was not administered (n=3), had been given in a trial before ATU (n=3), or was given for a non-MTC cancer (n=2). RESULTS: Data from the 60 MTC patients were analyzed. Mean age was 58 years (range 11-83 years), 39 patients were male, and six had hereditary MTC. Fifty-six (93%) had metastatic disease in the mediastinum (82%), bones (65%), liver (53%), or lung (53%), and four had only locally advanced disease. At the time of study evaluation, with a median follow-up of 20 months and a median duration of treatment of 9.7 months (range 0.3-36 months), 15 patients were continuing vandetanib treatment (range 18-36 months). Median progression-free survival was 16.1 months. Twenty-five patients discontinued treatment for disease progression (range 0.3-29 months). Best tumor response was a complete response in one patient, a partial response in 12 (20%), stable disease in 33 (55%), and progression in seven patients (12%). All patients had at least one adverse event (AE) during treatment. The main AEs were skin toxicity, diarrhea, and asthenia. Sixteen patients (27%) discontinued treatment for toxicity, and one patient died from vandetanib-induced cardiac toxicity. CONCLUSIONS: Vandetanib is an effective option for patients with advanced MTC. AEs should be monitored carefully and should be minimized by educating both patients and care providers and by applying symptomatic treatment and dose reduction.
Asunto(s)
Antineoplásicos/uso terapéutico , Carcinoma Neuroendocrino/tratamiento farmacológico , Piperidinas/uso terapéutico , Inhibidores de Proteínas Quinasas/uso terapéutico , Quinazolinas/uso terapéutico , Neoplasias de la Tiroides/tratamiento farmacológico , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Antineoplásicos/efectos adversos , Carcinoma Neuroendocrino/mortalidad , Carcinoma Neuroendocrino/patología , Niño , Femenino , Francia , Humanos , Masculino , Persona de Mediana Edad , Piperidinas/efectos adversos , Inhibidores de Proteínas Quinasas/efectos adversos , Quinazolinas/efectos adversos , Estudios Retrospectivos , Factores de Riesgo , Neoplasias de la Tiroides/mortalidad , Neoplasias de la Tiroides/patología , Factores de Tiempo , Resultado del Tratamiento , Adulto JovenRESUMEN
CONTEXT: Mitotane is an adrenolytic and anticortisolic drug used in adrenocortical carcinoma (ACC), Cushing's disease (CD), and ectopic ACTH syndrome. Its effects on the ovaries are unknown. OBJECTIVE: To evaluate the ovarian and gonadotrope effects of mitotane therapy in premenopausal women. PATIENTS: We studied 21 premenopausal women (ACC: n=13; CD: n=8; median age 33 years, range 18-45 years) receiving mitotane at a median initial dose of 3âg/day (range 1.5-6âg/day). METHODS: Gynecological history was collected and ovarian ultrasound was performed. Four women also underwent ovarian CT or magnetic resonance imaging. Serum gonadotropin, estradiol (E2), androgens, sex hormone-binding globulin (SHBG), and circulating mitotane levels were determined at diagnosis and during mitotane therapy. RESULTS: In the women included, ovarian macrocysts (bilateral in 51%) were detected after a median 11 months (range: 3-36) of mitotane exposure. The median number of macrocysts per woman was two (range: 1-4) and the median diameter of the largest cysts was 50âmm (range: 26-90). Menstrual irregularities and/or pelvic pain were present in 15 out of 21 women at macrocyst diagnosis. In two women, the macrocysts were revealed by complications (ovarian torsion and hemorrhagic macrocyst rupture) that required surgery. Mitotane therapy was associated with a significant decrease in androstenedione and testosterone levels and a significant increase in LH levels. Serum FSH and E2 levels were also increased, and SHBG levels rose markedly. CONCLUSIONS: Mitotane therapy causes significant morphological and ovarian/gonadotrope hormonal abnormalities in premenopausal women. Follicular thecal steroid synthesis appears to be specifically altered and the subsequent increase in gonadotropins might explain the development of macrocysts. The mechanisms underlying these adverse effects, whose exact prevalence in this population still needs to be determined, are discussed.
Asunto(s)
Carcinoma Corticosuprarrenal/sangre , Antineoplásicos Hormonales/uso terapéutico , Gonadotropinas/sangre , Mitotano/uso terapéutico , Quistes Ováricos/sangre , Hipersecreción de la Hormona Adrenocorticotrópica Pituitaria (HACT)/sangre , Premenopausia/sangre , Adolescente , Carcinoma Corticosuprarrenal/diagnóstico , Carcinoma Corticosuprarrenal/tratamiento farmacológico , Adulto , Antineoplásicos Hormonales/efectos adversos , Antineoplásicos Hormonales/farmacología , Biomarcadores/sangre , Femenino , Humanos , Persona de Mediana Edad , Mitotano/efectos adversos , Mitotano/farmacología , Quistes Ováricos/inducido químicamente , Quistes Ováricos/diagnóstico , Ovario/efectos de los fármacos , Ovario/metabolismo , Hipersecreción de la Hormona Adrenocorticotrópica Pituitaria (HACT)/diagnóstico , Hipersecreción de la Hormona Adrenocorticotrópica Pituitaria (HACT)/tratamiento farmacológico , Premenopausia/efectos de los fármacos , Estudios RetrospectivosRESUMEN
BACKGROUND: Increasing physical activity and decreasing sedentary time are cornerstones in the management of type 2 diabetes (T2DM). However, there are few instruments available to measure physical activity in this population. We translated the long version of the International Physical Activity Questionnaire (IPAQ-L) into French and studied its reproducibility and validity in patients with T2DM. METHODS: Reproducibility was studied by 2 telephone administrations, 8 days apart. Concurrent validity was tested against pedometry for 7 days during habitual life. RESULTS: One-hundred forty-three patients with T2DM were recruited (59% males; age: 60.9 ± 10.5 years; BMI: 31.2 ± 5.2 kg/m2; HbA1c: 7.4 ± 1.2%). Intraclass correlation coefficients (95% CI) for repeated administration (n = 126) were 0.74 (0.61-0.83) for total physical activity, 0.72 (0.57-0.82) for walking, and 0.65 (0.51-0.78) for sitting time. Total physical activity and walking (MET-min·week-1) correlated with daily steps (Spearman r = .24 and r = .23, respectively, P < .05). Sitting time (min·week-1) correlated negatively with daily steps in women (r = -0.33; P < .05). CONCLUSION: Our French version of the IPAQ-L appears reliable to assess habitual physical activity and sedentary time in patients with T2DM, confirming previous data in nonclinical populations.