RESUMO
PURPOSE: Mitotane is the only approved treatment for metastatic adrenocortical carcinoma (ACC). Monitoring plasma levels is recommended, but its predictive value is insufficient. METHODS: This prospective study of the French ENDOCAN-COMETE network aimed to investigate the prognostic role of plasma mitotane levels pharmacokinetics and free or bound to lipoprotein fraction measurements during six consecutive months. Lipoprotein fractions were isolated by ultracentrifugation, and mitotane level was determined by HPLC-UV. Total, free, and lipoprotein fraction bound plasma mitotane were monitored every two months for six months with morphological assessment. The primary endpoint was overall survival (OS). RESULTS: 21 patients with metastatic ACC were included. Median overall survival was 23 months. The median free mitotane level per patient was 12% (± 7%), and the majority (88%) was bound to lipoprotein fractions. Several pharmacokinetics measures of total mitotane were related to OS: first level at one month (p = 0.026), mean level (p = 0.055), and area under the curve (AUC) (p = 0.048), with higher exposure associated to longer OS. Free mitotane (not bounded) and mitotane bounded to lipoprotein subfraction added no prognostic values. The relationship between the mitotane level and OS suggested a minimum "effective" threshold of 10-15 mg/L or an area under the curve above 100 mg/L/month with no individualized maximum value. CONCLUSION: This prospective study did not identify any added prognostic value of free mitotane level over the total level. Early total mitotane level measurements (before 3-6 months) were related to OS with a higher and faster exposure related to more prolonged survival.
RESUMO
PURPOSE: Specific recommendations on screening modalities for paraganglioma (PGL) and phaeochromocytoma (PCC) in asymptomatic SDHx mutation carriers (relatives) are still lacking. We evaluated the added value of (18)F-FDG PET/CT in comparison with morphological imaging at initial diagnosis and 1 year of follow-up in this population. METHODS: The study included 30 consecutive relatives with a proven SDHx mutation who were investigated by (18)F-FDG PET/CT, gadolinium-enhanced magnetic resonance angiography of the head and neck, thoracic/abdominal/pelvic (TAP) contrast-enhanced CT and/or TAP MRI. (123)I-MIBG scintigraphy was performed in 20 subjects and somatostatin receptor scintigraphy (SRS) in 20 subjects. The gold standard was based on pathology or a composite endpoint as defined by any other positive imaging method and persistent tumour on follow-up. Images were considered as false-positive when the lesions were not detected by another imaging method or not confirmed at 1 year. RESULTS: At initial work-up, an imaging abnormality was found in eight subjects (27%). The final diagnosis was true-positive in five subjects (two with abdominal PGL, one with PCC and two with neck PGL) and false-positives in the other three subjects (detected with (18)F-FDG PET/CT in two and TAP MRI in one). At 1 year, an imaging abnormality was found in three subjects of which one was an 8-mm carotid body PGL in a patient with SDHD mutaion and two were considered false-positive. The tumour detection rate was 100% for (18)F-FDG PET/CT and conventional imaging, 80% for SRS and 60% for (123)I-MIBG scintigraphy. Overall, disease was detected in 4% of the subjects at the 1-year follow-up. CONCLUSION: (18)F-FDG PET/CT demonstrated excellent sensitivity but intermediate specificity justifying combined modality imaging in these patients. Given the slow progression of the disease, if (18)F-FDG PET/CT and MRI are normal at baseline, the second imaging work-up should be delayed and an examination that does not expose the patient to radiation should be used.
Assuntos
Neoplasias das Glândulas Suprarrenais/diagnóstico por imagem , Fluordesoxiglucose F18 , Heterozigoto , Feocromocitoma/diagnóstico por imagem , Tomografia por Emissão de Pósitrons , Compostos Radiofarmacêuticos , Succinato Desidrogenase/genética , 3-Iodobenzilguanidina , Adolescente , Neoplasias das Glândulas Suprarrenais/genética , Neoplasias das Glândulas Suprarrenais/patologia , Adulto , Idoso , Doenças Assintomáticas , Feminino , Humanos , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Imagem Multimodal , Mutação , Linhagem , Feocromocitoma/genética , Feocromocitoma/patologia , Tomografia Computadorizada por Raios XRESUMO
OBJECTIVE: Adrenocortical carcinoma (ACC) has an aggressive but variable clinical course. Prognostic stratification based on the European Network for the Study of Adrenal Tumours stage and Ki67 index is limited. We aimed to demonstrate the prognostic role of a points-based score (S-GRAS) in a large cohort of patients with ACC. DESIGN: This is a multicentre, retrospective study on ACC patients who underwent adrenalectomy. METHODS: The S-GRAS score was calculated as a sum of the following points: tumour stage (1-2 = 0; 3 = 1; 4 = 2), grade (Ki67 index 0-9% = 0; 10-19% = 1; ≥20% = 2 points), resection status (R0 = 0; RX = 1; R1 = 2; R2 = 3), age (<50 years = 0; ≥50 years = 1), symptoms (no = 0; yes = 1), and categorised, generating four groups (0-1, 2-3, 4-5, and 6-9). Endpoints were progression-free survival (PFS) and disease-specific survival (DSS). The discriminative performance of S-GRAS and its components was tested by Harrell's Concordance index (C-index) and Royston-Sauerbrei's R2D statistic. RESULTS: We included 942 ACC patients. The S-GRAS score showed superior prognostic performance for both PFS and DSS, with best discrimination obtained using the individual scores (0-9) (C-index = 0.73, R2D = 0.30, and C-index = 0.79, R2D = 0.45, respectively, all P < 0.01vs each component). The superiority of S-GRAS score remained when comparing patients treated or not with adjuvant mitotane (n = 481 vs 314). In particular, the risk of recurrence was significantly reduced as a result of adjuvant mitotane only in patients with S-GRAS 4-5. CONCLUSION: The prognostic performance of S-GRAS is superior to tumour stage and Ki67 in operated ACC patients, independently from adjuvant mitotane. S-GRAS score provides a new important guide for personalised management of ACC (i.e. radiological surveillance and adjuvant treatment).
Assuntos
Neoplasias do Córtex Suprarrenal/diagnóstico , Carcinoma Adrenocortical/diagnóstico , Técnicas de Diagnóstico Endócrino , Neoplasias do Córtex Suprarrenal/mortalidade , Neoplasias do Córtex Suprarrenal/patologia , Neoplasias do Córtex Suprarrenal/cirurgia , Adrenalectomia , Carcinoma Adrenocortical/mortalidade , Carcinoma Adrenocortical/patologia , Carcinoma Adrenocortical/cirurgia , Adulto , Idoso , Idoso de 80 Anos ou mais , Progressão da Doença , Humanos , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/diagnóstico , Recidiva Local de Neoplasia/mortalidade , Recidiva Local de Neoplasia/patologia , Estadiamento de Neoplasias , Prognóstico , Projetos de Pesquisa , Estudos Retrospectivos , Análise de SobrevidaRESUMO
PURPOSE: Differentiated thyroid cancer (DTC) patients with an unresectable primary tumor cannot benefit from curative surgery, and radioiodine treatment for locoregional and distant disease is not possible with the thyroid gland still in place. Due to local invasion, these patients cannot be included in clinical trials, so that treatment options are limited. The aim of this study was to describe the characteristics and the prognosis of patients with these locally unresectable DTC. PATIENTS AND METHODS: A retrospective and multicentric analysis of consecutive cases of unresectable DTC diagnosed between 2000 and 2015 was performed. RESULTS: The study population consisted in 22 patients, 13 females (59%); median age: 77 years (range: 52-91). Thyroid tumors were papillary in six, follicular in seven, Hürthle cell in one and poorly differentiated in eight patients. Patients were treated with external beam radiation therapy (EBRT) (57%), locoregional therapy of distant metastases (41%), cytotoxic chemotherapy (38%) and tyrosine kinase inhibitors (TKIs) (33%). TKI treatment resulted in median disease control duration of 7 months with a grade 3-4 toxicity rate of 44%. Only one patient had a total thyroidectomy after neo-adjuvant EBRT. The 1, 3 and 5-year cumulative survival rate was 81%, 27.7% and 21.5%, respectively. The cause of death was DTC in 11 cases (local progression in 7), and to other causes in 7 cases; no patient died from treatment toxicity. CONCLUSIONS: Clinical trials and approved treatments are lacking for unresectable DTC. TKI treatment may allow prolonged disease control with acceptable toxicity.
Assuntos
Radioisótopos do Iodo , Neoplasias da Glândula Tireoide , Idoso , Feminino , Humanos , Radioisótopos do Iodo/uso terapêutico , Estudos Retrospectivos , Neoplasias da Glândula Tireoide/cirurgia , Tireoidectomia , Resultado do TratamentoRESUMO
BACKGROUND: Antiangiogenic tyrosine kinase inhibitors (TKIs) are the mainstay of advanced thyroid cancer (TC) treatment. Concern is rising about TKI-related toxicity. OBJECTIVE: To determine the incidence and to investigate the risk factors of hemoptysis in TC patients during TKI treatment. METHODS: We analyzed consecutive TC patients treated with TKI in our center between 2005 and 2013 and performed an independent review of computed tomography scan images for airway invasion assessment. Occurrence of grade 1-2 or grade 3-5 hemoptysis according to Common Terminology Criteria for Adverse Events version 4.03 and risk factors for hemoptysis were investigated. RESULTS: A total of 140 patients (89 males; median age, 52 y) with medullary (56%), differentiated (33%), and poorly differentiated (11%) TC were enrolled. Thyroidectomy±neck dissection was performed in 123 patients and neck/mediastinum external-beam radiotherapy in 41 (32% with therapeutic purpose and 68% with adjuvant purpose). Patients received from 1 to 4 lines of TKI (median 1). Median follow-up was 24 months. Airway invasion was found in 65 (46%) cases. Hemoptysis occurred in 9 patients: grade 1-2 in 7 cases (5%) and grade 3-5 in 2 (1.4%) cases (fatal in 1). Hemoptysis was associated with presence of airway invasion (P = .04), poorly differentiated pathology (P = .03), history of therapeutic external-beam radiotherapy (P = .003), and thyroidectomy without neck dissection (P = .02). CONCLUSION: Airway invasion, poorly differentiated pathology, therapeutic external-beam radiotherapy, and thyroidectomy without neck dissection are associated with and increased risk of hemoptysis in TC patients during antiangiogenic TKI treatment. Further research is needed to confirm this data and to sort out interactions between these risk factors. A careful assessment of airway invasion is mandatory before TKI introduction.
Assuntos
Inibidores da Angiogênese/uso terapêutico , Resistencia a Medicamentos Antineoplásicos , Hemoptise/epidemiologia , Inibidores de Proteínas Quinases/uso terapêutico , Neoplasias da Glândula Tireoide/tratamento farmacológico , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Inibidores da Angiogênese/efeitos adversos , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Feminino , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Inibidores de Proteínas Quinases/efeitos adversos , Proteínas Tirosina Quinases/antagonistas & inibidores , Radioterapia Adjuvante , Fatores de Risco , Neoplasias da Glândula Tireoide/epidemiologia , Neoplasias da Glândula Tireoide/radioterapia , Neoplasias da Glândula Tireoide/cirurgia , Tireoidectomia , Falha de Tratamento , Adulto JovemRESUMO
INTRODUCTION: The prognostic value of serum calcitonin (CT) and carcinoembryonic antigen (CEA) doubling time has been recently demonstrated in medullary thyroid carcinoma (MTC) patients. No study has yet validated the surrogate role of these markers for survival during treatment. The aim of this study was to evaluate, in patients with advanced MTC treated with cytotoxic chemotherapy, the relationship between early changes of serum CT or CEA levels and progression-free survival (PFS). PATIENTS AND METHODS: The files of 28 consecutive metastatic MTC patients with progressive disease, treated with cytotoxic chemotherapy in a single tertiary referral center between 2000 and 2010, were retrospectively reviewed. Serum CT and CEA measurements and radiological Response Evaluation Criteria in Solid Tumors (RECIST) evaluations were collected every 3 months. The relationship between changes in serum CT and CEA levels at 3 months, defined by an increase or a decrease of at least 20%, and PFS according to RECIST 1.0, was estimated using Kaplan-Meier curves and log-rank test. RESULTS: The median follow-up for the 28 patients was 68 months. According to RECIST, a partial response, a stabilization or a progression was observed in 14, 43, and 43% of cases respectively. Median PFS from the initiation of cytotoxic chemotherapy was 4.5 months. Median PFS among patients with and without significant CT increase at 3 months was 4.6 and 3.3 months respectively (P=0.75). Median PFS among patients with a significant CEA increase at 3 months was 2.7 months, whereas it was 19.1 months in patients in whom CEA did not increase (P=0.02). CONCLUSION: At 3 months, an increase of serum CEA but not of CT levels appears as a valuable surrogate marker of short PFS in MTC patients treated with cytotoxic chemotherapy. A prospective validation is expected.
Assuntos
Calcitonina/sangue , Antígeno Carcinoembrionário/sangue , Carcinoma Medular/sangue , Neoplasias da Glândula Tireoide/sangue , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carcinoma Medular/tratamento farmacológico , Carcinoma Medular/mortalidade , Progressão da Doença , Intervalo Livre de Doença , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico , Estudos Retrospectivos , Neoplasias da Glândula Tireoide/tratamento farmacológico , Neoplasias da Glândula Tireoide/mortalidadeRESUMO
CONTEXT: Thyroglobulin (Tg) measurement is a major tool for the follow-up of differentiated thyroid cancer (DTC) patients; however, in patients who do not undergo radioactive iodine (RAI) ablation, normal ultrasensitive Tg levels measured under levothyroxine treatment (usTg/l-T4) are not well defined. OBJECTIVE AND DESIGN: This single-center retrospective study assessed usTg/l-T4 level in 86 consecutive patients treated with total thyroidectomy without RAI ablation for low-risk DTC (n=77) or for tumors of uncertain malignant potential (TUMP) (n=9). RESULTS: DTCS were classified as PT1, PT2, and PT3 in 75, 1, and 1 case respectively and PN0, PN1, and PNX in 40, 6, and 31 respectively. following surgery, ten patients had TG antibodieS (TGAB). Among those without TGAB, the first USTG/L-T4 determination obtained at a mean time of 9 months after surgery was 0.1NG/ML in 62% of cases, 0.3NG/ML in 82% of cases, 1NG/ML in 91%, and 2NG/ML in 96% of cases. after a median follow-up of 2.5 years (range: 0.6-7.2 years), one patient had persistent disease with an usTg/l-T4 at 11 ng/ml and an abnormal neck ultrasonography (US) and two patients had usTg/l-T4 level >2 ng/ml (3.9 and 4.9 ng/ml) with a normal neck US. Within the first 2 years following total thyroidectomy without RAI ablation, usTg/l-T4 level is ≤2 ng/ml in 96% of the cases. CONCLUSION: After total thyroidectomy, sensitive serum Tg/l-T4 level is ≤2 ng/ml in most patients and can be used for patient follow-up.
Assuntos
Tireoglobulina/sangue , Neoplasias da Glândula Tireoide/sangue , Neoplasias da Glândula Tireoide/cirurgia , Tireoidectomia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Seguimentos , Humanos , Radioisótopos do Iodo , Excisão de Linfonodo , Masculino , Pessoa de Meia-Idade , Pescoço/diagnóstico por imagem , Estudos Retrospectivos , Neoplasias da Glândula Tireoide/diagnóstico por imagem , Tiroxina/sangue , Ultrassonografia , Adulto JovemRESUMO
CONTEXT: Mitotane plasma concentrations ≥ 14 mg/l have been shown to predict tumor response and better survival in patients with advanced adrenocortical carcinoma (ACC). A correlation between mitotane concentrations and patient outcome has not been demonstrated in an adjuvant setting. OBJECTIVE: To compare recurrence-free survival (RFS) in patients who reached and maintained mitotane concentrations ≥ 1 4 mg/l vs patients who did not. DESIGN AND SETTING: Retrospective analysis at six referral European centers. PATIENTS: Patients with ACC who were radically resected between 1995 and 2009 and were treated adjuvantly with mitotane targeting concentrations of 14-20 mg/l. MAIN OUTCOME MEASURES: RFS (primary) and overall survival (secondary). RESULTS: Of the 122 patients included, 63 patients (52%) reached and maintained during a median follow-up of 36 months the target mitotane concentrations (group 1) and 59 patients (48%) did not (group 2). ACC recurrence was observed in 22 patients of group 1 (35%) and 36 patients in group 2 (61%). In multivariable analysis, the maintenance of target mitotane concentrations was associated with a significantly prolonged RFS (hazard ratio (HR) of recurrence: 0.418, 0.22-0.79; P=0.007), while the risk of death was not significantly altered (HR: 0.59, 0.26-1.34; P=0.20). Grades 3-4 toxicity was observed in 11 patients (9%) and was managed with temporary mitotane discontinuation. None of the patients discontinued mitotane definitively for toxicity. CONCLUSIONS: Mitotane concentrations ≥ 14 mg/l predict response to adjuvant treatment being associated with a prolonged RFS. A monitored adjuvant mitotane treatment may benefit patients after radical removal of ACC.
Assuntos
Neoplasias do Córtex Suprarrenal/tratamento farmacológico , Córtex Suprarrenal/efeitos dos fármacos , Carcinoma Adrenocortical/tratamento farmacológico , Antineoplásicos Hormonais/sangue , Mitotano/sangue , Adolescente , Córtex Suprarrenal/patologia , Córtex Suprarrenal/cirurgia , Neoplasias do Córtex Suprarrenal/sangue , Neoplasias do Córtex Suprarrenal/prevenção & controle , Neoplasias do Córtex Suprarrenal/cirurgia , Carcinoma Adrenocortical/sangue , Carcinoma Adrenocortical/prevenção & controle , Carcinoma Adrenocortical/cirurgia , Adulto , Idoso , Antineoplásicos Hormonais/efeitos adversos , Antineoplásicos Hormonais/farmacocinética , Antineoplásicos Hormonais/uso terapêutico , Quimioterapia Adjuvante , Monitoramento de Medicamentos , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Mitotano/efeitos adversos , Mitotano/farmacocinética , Mitotano/uso terapêutico , Recidiva Local de Neoplasia/prevenção & controle , Estadiamento de Neoplasias , Estudos Retrospectivos , Análise de Sobrevida , Adulto JovemRESUMO
CONTEXT: Medullary thyroid carcinoma (MTC) is characterized by proto-oncogene RET mutations in almost all hereditary cases as well as in more than 40% of sporadic cases. Recently, a high prevalence of RAS mutations was reported in sporadic MTC, suggesting an alternative genetic event in sporadic MTC tumorigenesis. OBJECTIVE: This study aimed to extend this observation by screening somatic mutational status of RET, BRAF, and the three RAS proto-oncogenes in a large series of patients with MTC. MATERIALS AND METHODS: Direct sequencing of RET (exons 8, 10, 11, 13, 14, 15, 16), BRAF (exons 11 and 15), and KRAS, HRAS, and NRAS genes (exons 2, 3, and 4) was performed on DNA prepared from 50 MTC samples, including 30 sporadic cases. RESULTS: Activating RET mutations were detected in the 20 hereditary cases (germline mutations) and in 14 sporadic cases (somatic mutations). Among the 16 sporadic MTC without any RET mutation, eight H-RAS mutations and five K-RAS mutations were found. Interestingly, nine RAS mutations correspond to mutation hot spots in exons 2 and 3, but the other four mutations were detected in exon 4. The RET and RAS mutations were mutually exclusive. No RAS gene mutation was found in hereditary MTC, and no BRAF or NRAS mutation was observed in any of the 50 samples. CONCLUSIONS: Our study confirms that RAS mutations are frequent events in sporadic MTC. Moreover, we showed that RAS mutation analysis should not be limited to the classical mutational hot spots of RAS genes and should include analysis of exon 4.
Assuntos
Carcinoma Medular/genética , Proteínas Proto-Oncogênicas c-ret/genética , Proteínas Proto-Oncogênicas p21(ras)/genética , Proteínas Proto-Oncogênicas/genética , Neoplasias da Glândula Tireoide/genética , Proteínas ras/genética , Adulto , Idoso , Carcinoma Neuroendócrino , Criança , Éxons/genética , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Proto-Oncogene Mas , Proteínas Proto-Oncogênicas B-raf/genética , Adulto JovemRESUMO
Activated Ras oncogene induces DNA-damage response by triggering reactive oxygen species (ROS) production and this is critical for oncogene-induced senescence. Until now, little connections between oncogene expression, ROS-generating NADPH oxidases and DNA-damage response have emerged from different studies. Here we report that H-RasV12 positively regulates the NADPH oxidase system NOX4-p22(phox) that produces H(2)O(2). Knocking down the NADPH oxidase with small interference RNA decreases H-RasV12-induced DNA-damage response detected by γ-H2A.X foci analysis. Using HyPer, a specific probe for H(2)O(2), we detected an increase in H(2)O(2) in the nucleus correlated with NOX4-p22(phox) perinuclear localization. DNA damage response can be caused not only by H-RasV12-driven accumulation of ROS but also by a replicative stress due to a sustained oncogenic signal. Interestingly, NOX4 downregulation by siRNA abrogated H-RasV12 regulation of CDC6 expression, an essential regulator of DNA replication. Moreover, senescence markers, such as senescence-associated heterochromatin foci, PML bodies, HP1ß foci and p21 expression, induced under H-RasV12 activation were decreased with NOX4 inactivation. Taken together, our data indicate that NADPH oxidase NOX4 is a critical mediator in oncogenic H-RasV12-induced DNA-damage response and subsequent senescence.
Assuntos
Senescência Celular/genética , Dano ao DNA , NADPH Oxidases/genética , NADPH Oxidases/metabolismo , Proteínas Proto-Oncogênicas p21(ras)/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Pontos de Checagem do Ciclo Celular/genética , Homólogo 5 da Proteína Cromobox , Humanos , Peróxido de Hidrogênio/metabolismo , NADPH Oxidase 4 , NADPH Oxidases/antagonistas & inibidores , OxirreduçãoRESUMO
OBJECTIVE: To make the specificity of fluorodesoxyglucose ((18)FDG) positron emission tomography (PET) precise, in the follow-up of patients with adrenal cancer. DESIGN: This single centre retrospective study assessed the frequency and outcome of (18)FDG uptake in the remaining adrenal glands after adrenalectomy for adrenocortical carcinoma (ACC) or malignant phaeochromocytoma (PH). RESULTS: Two hundred and ten (18)FDG PET scans in 62 ACC patients, all under 1,ortho-1,para'-dichloro-diphenyl-dichloro-ethane (o,p'-DDD) treatment, and 30 (18)FDG PET scans in 8 PH patients were reviewed. Abnormal (18)FDG uptake in the remaining adrenal glands was found in 19 (8%) (18)FDG PET scans, in 10 (16%) ACC patients and in none of the PH patients. (18)FDG uptake was found in 4% of the patients before the onset of o,p'-DDD, in 29% of the patients 0-6 months after the onset of o,p'-DDD (P=0.05), in 26% of the patients 6-12 months (P=0.072) after the onset of o,p'-DDD and in 14% of the patients 12-24 months after the onset of o,p'-DDD. It was never found later than 24 months after the onset of o,p'-DDD. Adrenal glands with (18)FDG uptake were normal on computed tomography scans with i.v. contrast agent in all cases. (18)FDG uptake in the remaining adrenal glands decreased and disappeared on subsequent FDG PET imaging in eight of the patients with follow-up available. CONCLUSIONS: (18)FDG uptake in the remaining adrenal glands occurred in 14-29% of the patients followed for ACC within 24 months after adrenalectomy and onset of o,p'-DDD. This uptake is transient and should not be considered as suspicious for malignancy.
Assuntos
Neoplasias do Córtex Suprarrenal/diagnóstico por imagem , Glândulas Suprarrenais/diagnóstico por imagem , Glândulas Suprarrenais/metabolismo , Adrenalectomia , Carcinoma Adrenocortical/diagnóstico por imagem , Fluordesoxiglucose F18 , Feocromocitoma/diagnóstico por imagem , Tomografia por Emissão de Pósitrons , Neoplasias do Córtex Suprarrenal/metabolismo , Neoplasias do Córtex Suprarrenal/cirurgia , Carcinoma Adrenocortical/metabolismo , Carcinoma Adrenocortical/cirurgia , Adulto , Idoso , Feminino , Fluordesoxiglucose F18/metabolismo , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Feocromocitoma/metabolismo , Feocromocitoma/cirurgia , Tomografia por Emissão de Pósitrons/métodos , Compostos Radiofarmacêuticos , Estudos Retrospectivos , Sensibilidade e Especificidade , Fatores de TempoRESUMO
The aim of this study is to search for relationships between histology, radioiodine ((131)I) uptake, fluorodeoxyglucose (FDG) uptake, and disease outcome in patients with metastatic thyroid cancer. Eighty patients with metastatic thyroid cancer (34 males, 46 females, mean age at the time of the diagnosis of metastases: 55 years) were retrospectively studied. All patients were treated with radioactive iodine and evaluated by FDG-positron emission tomography (PET). Primary tumor tissue sample was available in all cases. Forty-five patients (56%) had a papillary, 12 (15%) a follicular, and 23 (29%) a poorly differentiated thyroid cancer. Cellular atypias, necrosis, mitoses, thyroid capsule infiltration, and vascular invasion were frequently detected (70, 44, 52, 60, and 71% respectively). Metastases disclosed FDG uptake in 58 patients (72%) and (131)I uptake in 37 patients (45%). FDG uptake was the only significant prognostic factor for survival (P=0.02). The maximum standardized uptake value and the number of FDG avid lesions were also related to prognosis (P=0.03 and 0.009). Age at the time of the diagnosis of metastases (P=0.001) and the presence of necrosis (P=0.002) were independent predictive factors of FDG uptake. Radioiodine uptake was prognostic for stable disease (P=0.001) and necrosis for progressive disease at 1 year (P=0.001). Histological subtype was not correlated with in vivo tumor metabolism and prognosis. In conclusion, FDG uptake in metastatic thyroid cancer is highly prognostic for survival. Histological subtype alone does not correlate with (131)I/FDG uptake pattern and patient outcome. Well-differentiated thyroid cancer presenting histological features such as necrosis and FDG uptake on PET scan should be considered aggressive differentiated cancers.
Assuntos
Fluordesoxiglucose F18/farmacocinética , Radioisótopos do Iodo/farmacocinética , Adenocarcinoma Folicular , Adulto , Idoso , Biomarcadores Tumorais/análise , Biomarcadores Tumorais/metabolismo , Feminino , Seguimentos , Humanos , Imuno-Histoquímica , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Metástase Neoplásica , Estadiamento de Neoplasias/métodos , Prognóstico , Estudos Retrospectivos , Neoplasias da Glândula Tireoide/diagnóstico por imagem , Neoplasias da Glândula Tireoide/metabolismo , Neoplasias da Glândula Tireoide/patologia , Tomografia Computadorizada de EmissãoRESUMO
The prognosis of advanced adrenocortical carcinoma (ACC) is dismal but heterogeneous. In 2011, mitotane is the only drug approved in Europe and US for the treatment of advanced ACC. Mitotane exerts both antisecretory and antiproliferative effects, which are delayed over time, and requires careful biological and morphological evaluations coupled with mitotane plasma measurement monitoring. In the absence of demonstration of any superior activity of combined polychemotherapy, the least toxic regimen should be considered in routine care. Locoregional therapies, including surgery of the primary tumor and metastases, should be considered part of the therapeutic arsenal. A prolonged survival can be observed in the case of tumor objective response and/or high plasma mitotane levels. New protocols are urgently needed, coupled with ancillary studies dedicated to progress in the findings of predictors or surrogates. International networks and comprehensive databases gathering clinical and biological data constitute the prerequisites for progress.
Assuntos
Neoplasias das Glândulas Suprarrenais/diagnóstico , Neoplasias das Glândulas Suprarrenais/tratamento farmacológico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carcinoma Adenoide Cístico/diagnóstico , Carcinoma Adenoide Cístico/tratamento farmacológico , Mitotano/administração & dosagem , Neoplasias das Glândulas Suprarrenais/patologia , Neoplasias das Glândulas Suprarrenais/fisiopatologia , Adulto , Animais , Carcinoma Adenoide Cístico/patologia , Carcinoma Adenoide Cístico/fisiopatologia , Cisplatino/administração & dosagem , Cisplatino/efeitos adversos , Ensaios Clínicos como Assunto , Humanos , Mitotano/efeitos adversos , Estadiamento de Neoplasias , Prognóstico , Carga Tumoral/efeitos dos fármacosRESUMO
(131)I is given in differentiated thyroid cancer (DTC) without taking into account thyroglobulin (Tg) levels at the time of ablation, whereas 6-18 months later it is a major criterion for cure. This single-center retrospective study assessed the frequency and risk factors for persistent disease on postablation whole body scan (WBS) and postoperative neck ultrasonography (n-US) and for recurrent disease during the subsequent follow-up, in patients with DTC and undetectable TSH-stimulated Tg level (TSH-Tg) in the absence of Tg antibodies (TgAb) at the time of ablation. Among 1031 patients ablated, 242 (23%) consecutive patients were included. Persistent disease occurred in eight cases (3%) (seven abnormal WBS and one abnormal n-US), all with initial neck lymph node metastases (N1). N1 was a major risk factor for persistent disease. Among 203 patients with normal WBS and a follow-up over 6 months, TSH-Tg 6-18 months after ablation was undetectable in the absence of TgAb in 173 patients, undetectable with TgAb in 1 patient and equal to 1.2 âng/ml in 1 patient. n-US was normal in 152 patients and falsely positive in 3 patients. After a mean follow-up of 4 years, recurrence occurred in two cases (1%), both with aggressive histological variants. The only risk factor for recurrence was an aggressive histological variant (P = 0.03). In conclusion, undetectable postoperative TSH-Tg in the absence of TgAb at the time of ablation is frequent. In these patients, repeating TSH-Tg 6-18 months after ablation is not useful. (131)I ablation could be avoided in the absence of N1 and aggressive histological variant.
Assuntos
Carcinoma Papilar, Variante Folicular/cirurgia , Radioisótopos do Iodo/efeitos adversos , Complicações Pós-Operatórias/etiologia , Tireoglobulina/sangue , Neoplasias da Glândula Tireoide/cirurgia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Algoritmos , Carcinoma Papilar, Variante Folicular/diagnóstico por imagem , Carcinoma Papilar, Variante Folicular/patologia , Diferenciação Celular/fisiologia , Progressão da Doença , Feminino , Humanos , Radioisótopos do Iodo/uso terapêutico , Masculino , Pessoa de Meia-Idade , Complicações Pós-Operatórias/epidemiologia , Cintilografia , Radiocirurgia/efeitos adversos , Radiocirurgia/métodos , Recidiva , Estudos Retrospectivos , Neoplasias da Glândula Tireoide/diagnóstico por imagem , Neoplasias da Glândula Tireoide/patologia , Ultrassonografia , Regulação para Cima/efeitos da radiação , Adulto JovemRESUMO
CONTEXT: Peritoneal carcinomatosis (PC) is a rare site of distant metastases in patients with adrenocortical cancer (ACC). One preliminary study suggests an increased risk of PC after laparoscopic adrenalectomy (LA) for ACC. OBJECTIVE: The objective of the study was to search for risk factors of PC including surgical approach. DESIGN: This was a retrospective cohort study conducted in an institutional practice. PATIENTS: Sixty-four consecutive patients with ACC seen at our institution between 2003 and 2009 were included. Mean tumor size was 132 mm. Patients had stage I disease in 2 cases, stage II disease in 32 cases, stage III disease in 7 cases, stage IV disease in 21 cases, and unknown stage disease in 2 cases. Surgery was open in 58 cases and laparoscopic in 6 cases. MAIN OUTCOME: The main outcome was the risk factors of PC. RESULTS: PC occurred in 18 (28%) patients. It was present at initial diagnosis in three cases and occurred during follow-up in 15 cases. The only risk factor of PC occurring during follow-up was the surgical approach with a 4-year rate of PC of 67% (95% confidence interval (CI), 30-90%) for LA and 27% (95% CI, 15-44%) for open adrenalectomy (P=0.016). Neither tumor size, stage, functional status, completeness of surgery, nor plasma level of op'DDD was associated with the occurrence of PC. CONCLUSION: We found an increased risk of PC after LA for ACC. Whether this is related to an inappropriate surgical approach or to insufficient experience in ACC surgery should be clarified by a prospective program.
Assuntos
Neoplasias do Córtex Suprarrenal/cirurgia , Adrenalectomia/efeitos adversos , Carcinoma Adrenocortical/cirurgia , Laparoscopia/efeitos adversos , Neoplasias Peritoneais/etiologia , Neoplasias Peritoneais/secundário , Neoplasias do Córtex Suprarrenal/patologia , Carcinoma Adrenocortical/secundário , Adulto , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Seleção de Pacientes , Estudos Retrospectivos , Resultado do TratamentoRESUMO
CA15-3, a peptide derived from MUC-1, an hormonally-regulated protein, is the most widely used serum marker of breast cancer. CA15-3 level increases at the metastatic phase in 50-80% breast cancer patients. Although rise of CA15-3 precede symptoms of metastasis by a mean time of 2-9 months, current international guidelines do not recommend its routine use for screening for metastases because of moderate sensitivity and absence of clinical impact. We conducted a retrospective study among all patients with metastatic breast cancer seen by three senior breast oncologists during a 4-month period. We evaluated correlation of CA15-3 level at the time of metastatic relapse with ER, PgR and Her2 expressions, tumor type, size and nodal status at initial diagnosis, and sites of metastases. CA15-3 was increased in 168/272 patients (62%) at diagnosis of metastases. ER/PgR positivity was strongly correlated with elevated CA15-3 at this time (P < 0.0001). CA 15-3 was elevated in 69% of the cases of HR+ Her2- primary tumors at time of metastatic relapse. It was elevated in 56% of HR+ Her2+++, 46% of HR- Her2+++ cases and only in 41% of triple-negative cases (P = 0.003). these data confirm that CA 15-3 is very variably elevated at time of metastatic relapse of breast cancer, and this is dependant on HR status.
Assuntos
Biomarcadores Tumorais/sangue , Neoplasias da Mama/sangue , Mucina-1/sangue , Adulto , Idoso , Idoso de 80 Anos ou mais , Neoplasias Ósseas/secundário , Neoplasias Encefálicas/secundário , Neoplasias da Mama/química , Neoplasias da Mama/patologia , Neoplasias da Mama Masculina/sangue , Neoplasias da Mama Masculina/patologia , Carcinoma Ductal de Mama/sangue , Carcinoma Ductal de Mama/química , Carcinoma Ductal de Mama/secundário , Carcinoma Lobular/sangue , Carcinoma Lobular/química , Carcinoma Lobular/secundário , Proteínas de Ligação a DNA , Feminino , Humanos , Neoplasias Hepáticas/secundário , Neoplasias Pulmonares/secundário , Masculino , Pessoa de Meia-Idade , Membro 1 do Grupo A da Subfamília 4 de Receptores Nucleares , Receptor ErbB-2/análise , Receptores de Estrogênio/análise , Receptores de Progesterona/análise , Receptores de Esteroides , Estudos Retrospectivos , Neoplasias Cutâneas/secundário , Carga TumoralRESUMO
AIMS: To determine whether cell size is related to HER-2/neu status and/or to Akt activation in breast carcinomas. HER-2/neu overexpression is observed in 20-30% of invasive breast carcinomas with poor pronostic features, but little is known about the cell phenotype associated with HER-2/neu activation. Akt has been found to be involved in the HER-2/neu signal transduction pathway and Akt activation has been associated with increased cell size in various models. METHODS AND RESULTS: A case-control study of invasive ductal carcinoma of the breast was carried out, including 21 cases displaying HER-2/neu overexpression and 20 HER-2/neu negative controls. Cytoplasmic and nuclear sizes were measured on digitized histological pictures using cell image analysis software. Akt expression analysis was performed by immunohistochemistry on formalin-fixed histological sections using an anti-phosphorylated-Akt (Ser473) antibody. RESULTS: HER-2/neu-overexpressing carcinomas had a mean nuclear size of 75 +/- 22.2 micro m(2) and a mean cytoplasmic size of 187 +/- 52.3 micro m(2). Both values were higher than the nuclear and cytoplasmic size of HER-2/neu-negative cases (nucleus = 58 +/- 24.5 micro m(2), cytoplasm = 133 +/- 56.6 micro m(2); P = 0.02 and P =0.003, respectively). Up to 75% of the tumours with a cell size over 140 micro m(2) were HER-2/neu-positive. Immunohistochemical Akt expression was observed in 19/40 (47.5%) cases. The immunoreactivity was localized in the cytoplasm in eight cases, on the cell membrane in four cases and at both sites in seven cases. One case was not interpretable. Comparison between HER-2/neu and Akt status showed that Akt was detectable at the cell membrane in 43% (9/21) of HER-2/neu-positive and in 10% (2/19) of HER-2/neu-negative cases (P = 0.02). CONCLUSIONS: HER-2/neu overexpression was consistently associated with increased cell size in invasive ductal carcinoma of the breast. This increase may be related to concomitant Akt activation. The assessment of activated pathways in HER-2/neu-overexpressing breast carcinomas may provide useful information for optimized individual HER-2/neu-targeted therapy.