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INTRODUCTION: Survival of childhood cancer has increased over the past decades. This has led to the development of strategies aiming to enhance follow-up care and research, for which priorities may vary globally. We explored perspectives of an international healthcare workers panel. METHODS: Attendants of a meet-the-expert session on childhood cancer survivorship at the 2018 SIOP conference completed a survey about their view on important follow-up care and research aspects for survivors below and over 18 years. We analysed overarching categories and subtopics, and compared Asian versus European and North American healthcare workers. RESULTS: A total of 58 participants from different medical specialties (67.2% paediatric oncologists) and continents (48.3% Asia, 39.7% Europe/North America) responded. Follow-up care priorities for survivors below and over 18 years included physical care (39.3% ≤18 years, 35.9% >18 years) and healthcare structure (29.4%, 26.0%). Physical care was also the most important research aspect for both age groups (52.5%, 50.7%). Psychological support was the most frequently reported subtopic. Asian clinicians (n = 22) primarily prioritized physical care aspects of follow-up care, whereas European/North American (n = 19) clinicians underscored the importance of healthcare structure. CONCLUSION: Physical care is the most important aspect of survivorship care and research according to clinicians from several continents. Asian and European/North American respondents shared most priorities, however, healthcare structure was a more important category for European/North American clinicians. The most common subtopic was psychological support, underlining also the need to involve psychologists in follow-up.
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Sobreviventes de Câncer , Neoplasias , Assistência ao Convalescente , Criança , Humanos , Neoplasias/terapia , Inquéritos e Questionários , SobreviventesRESUMO
INTRODUCTION AND BACKGROUND: Normative data for the iSYS IGF-I assay have been published both in the VARIETE cohort and by Bidlingmaier et al. OBJECTIVE: To investigate whether normative data of the VARIETE cohort lead to differences in Z-scores for total IGF-I and clinical interpretation compared to normative data of Bidlingmaier et al. DESIGN: We used total IGF-I values previously measured by the IDS-iSYS assay in 102 GH-deficient subjects before starting GH treatment and after 12 months of GH treatment. Z-scores were calculated for all samples by using the normative data of the VARIETE cohort and by the normative data reported by Bidlingmaier et al. RESULT: Before GH treatment, Z-scores calculated by using the normative data of the VARIETE cohort were significantly lower than those calculated by the normative data of Bidlingmaier et al: -2.40 (-4.52 to +1.31) (mean [range]) vs. -1.41 (-3.14 to +1.76); P < .001). After 12 months of GH treatment, again the Z-scores based on the normative data of the VARIETE cohort were significantly lower than those based on the normative data of Bidlingmaier et al: -0.65 (-4.32 to +2.79) vs 0.21 (-3.00 to +3.28); P < .001). CONCLUSION: IGF-I Z-scores in 102 GH-deficient subjects differed significantly when normative data from two different sources were used. In daily clinical practice, this would most likely have led to different clinical interpretations and GH dose adjustments.
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Interpretação Estatística de Dados , Hormônio do Crescimento Humano/administração & dosagem , Hormônio do Crescimento Humano/deficiência , Fator de Crescimento Insulin-Like I/normas , Adulto , Estudos de Coortes , Biologia Computacional , Feminino , Humanos , Fator de Crescimento Insulin-Like I/análise , Masculino , Pessoa de Meia-Idade , Reprodutibilidade dos TestesRESUMO
BACKGROUND: Hypothalamic obesity is a devastating consequence of craniopharyngioma. Bariatric surgery could be a promising therapeutic option. However, its efficacy and safety in patients with craniopharyngioma-related hypothalamic obesity remain largely unknown. OBJECTIVES: We investigated the efficacy of bariatric surgery for inducing weight loss in patients with craniopharyngioma-related hypothalamic obesity. In addition, we studied the safety of bariatric surgery regarding its effects on hormone replacement therapy for pituitary insufficiency. METHODS: In this retrospective matched case-control study, we compared weight loss after bariatric surgery (that is, Roux-en-Y gastric bypass and sleeve gastrectomy) between eight patients with craniopharyngioma-related hypothalamic obesity and 75 controls with 'common' obesity during 2 years of follow-up. We validated our results at 1 year of follow-up in a meta-analysis. In addition, we studied alterations in hormone replacement therapy after bariatric surgery in patients with craniopharyngioma. RESULTS: Mean weight loss after bariatric surgery was 19% vs 25% (difference -6%, 95% confidence of interval (CI) -14.1 to 4.6; P=0.091) at 2 years of follow-up in patients with craniopharyngioma-related hypothalamic obesity compared with control subjects with 'common' obesity. Mean weight loss was 25% vs 29% (difference -4%, 95% CI -11.6 to 8.1; P=0.419) after Roux-en-Y gastric bypass and 10% vs 20% (difference -10%, 95% CI -14.1 to -6.2; P=0.003) after sleeve gastrectomy at 2 years of follow-up in patients with craniopharyngioma-related hypothalamic obesity vs control subjects with 'common' obesity. Our meta-analysis demonstrated significant weight loss 1 year after Roux-en-Y gastric bypass, but not after sleeve gastrectomy. Seven patients with craniopharyngioma suffered from pituitary insufficiency; three of them required minor adjustments in hormone replacement therapy after bariatric surgery. CONCLUSIONS: Weight loss after Roux-en-Y gastric bypass, but not sleeve gastrectomy, was comparable between patients with craniopharyngioma-related hypothalamic obesity and control subjects with 'common' obesity at 2 years of follow-up. Bariatric surgery seems safe regarding its effects on hormone replacement therapy.
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Craniofaringioma/complicações , Gastrectomia , Derivação Gástrica , Obesidade/etiologia , Neoplasias Hipofisárias/complicações , Adolescente , Adulto , Estudos de Casos e Controles , Criança , Pré-Escolar , Craniofaringioma/tratamento farmacológico , Craniofaringioma/cirurgia , Feminino , Seguimentos , Humanos , Masculino , Países Baixos/epidemiologia , Obesidade/cirurgia , Neoplasias Hipofisárias/tratamento farmacológico , Neoplasias Hipofisárias/cirurgia , Estudos Retrospectivos , Suécia/epidemiologia , Resultado do Tratamento , Redução de Peso , Adulto JovemRESUMO
STUDY QUESTION: Is the long-term decline of ovarian function, as reflected by a decrease in serum anti-Müllerian hormone (AMH) concentration, accelerated over time in female childhood cancer survivors (CCS) as compared to healthy women of the same age? SUMMARY ANSWER: The median decline of AMH levels in long-term female CCS is not accelerated and similar to that observed in healthy controls. WHAT IS KNOWN ALREADY: Gonadal function is compromised in female CCS treated with chemotherapy and/or radiation therapy. Ovarian function is most compromised in survivors treated with total body irradiation, abdominal or pelvic irradiation, stem cell transplantation or high doses of alkylating agents. STUDY DESIGN SIZE, DURATION: Longitudinal single-centre cohort study in 192 CCS in Rotterdam, The Netherlands, between 2001 and 2014. PARTICIPANTS/MATERIALS, SETTING, METHODS: Serum AMH levels of 192 adult female CCS were assessed, at least five years after cessation of treatment and at a follow-up visit with a median of 3.2 years (range: 2.1-6.0) later and were compared to the age-based P50 of AMH in healthy controls. MAIN RESULTS AND THE ROLE OF CHANCE: Median AMH levels were below the P50 at both visit 1 (-0.59 µg/L) and at visit 2 (-0.22 µg/L). In women with a sustained ovarian function (AMH > 1.0 µg/L), the decline in AMH is similar to that in the normal population (difference in decline per year: -0.07 µg/L (range: -2.86 to 4.92), P = 0.75). None of the treatment modalities was correlated with a significant acceleration of decline of AMH per year. LIMITATIONS REASONS FOR CAUTION: We selected CCS that visited our late effect outpatient clinic and who had two AMH levels available. It is conceivable that women without any apparent late effects of treatment as well as women with extreme late effects, which might be the ones with the largest impact on ovarian function, could be more likely to be lost to follow-up. However, general characteristics did not differ between the included and excluded patients. WIDER IMPLICATIONS OF THE FINDINGS: While prospective longitudinal research is required to strengthen our findings, they may help physicians to counsel female CCS about their expected reproductive lifespan. STUDY FUNDING/COMPETING INTERESTS: A.L.F.v.d.K., M.M.v.d.H.-E. and S.M.F.P. are supported by FP7-PanCare LIFE. J.S.E.L. has received grants from the following companies (in alphabetical order): Ferring, Merck Serono, Merck Sharp and Dome, Organon, Serono, Shering Plough and Shering. The other authors have no conflicts of interest to declare.
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Hormônio Antimülleriano/sangue , Sobreviventes de Câncer , Reserva Ovariana/fisiologia , Ovário/patologia , Adolescente , Adulto , Criança , Pré-Escolar , Feminino , Seguimentos , Humanos , Lactente , Estudos Longitudinais , Pessoa de Meia-Idade , Adulto JovemRESUMO
BACKGROUND AND PURPOSE: Aneurysmal subarachnoid hemorrhage (SAH) survivors often complain of fatigue, which is disabling. Fatigue is also a common symptom of pituitary dysfunction (PD), in particular in patients with growth hormone deficiency (GHD). A possible association between fatigue after SAH and long-term pituitary deficiency in SAH survivors has not yet been established. METHODS: A single center observational study was conducted amongst 84 aneurysmal SAH survivors to study the relationship between PD and fatigue over time after SAH, using mixed model analysis. Fatigue was measured with the Fatigue Severity Scale and its relationships with other clinical variables were studied. RESULTS: Three-quarters of respondents (76%) have pathological fatigue directly after SAH and almost two-thirds (60%) of patients still have pathological levels of fatigue after 14 months. The severity of SAH measured with a World Federation of Neurosurgical Societies (WFNS) score higher than 1 (P = 0.008) was associated with long-term fatigue. There is no statistically significant effect of PD (P = 0.8) or GHD (P = 0.23) on fatigue in SAH survivors over time. CONCLUSIONS: Fatigue is a common symptom amongst SAH survivors. WFNS is a usable clinical determinant of fatigue in SAH survivors. Neither PD nor GHD has a significant effect on long-term fatigue after SAH.
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Fadiga/etiologia , Hipopituitarismo/complicações , Hemorragia Subaracnóidea/complicações , Adulto , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , SobreviventesRESUMO
SUMMARY: More than 45 % of long-term childhood cancer survivors (CCS) were diagnosed with osteopenia. Our data suggest that greater awareness for osteopenia is warranted in long-term CCS, especially in survivors who are older than 30 years, male, and underweight and were treated with cranial-spinal radiotherapy and/or steroids. INTRODUCTION: Osteopenia is a potential complication of childhood cancer treatment, but the magnitude of this problem in survivors is unknown. We examined (determinants of) bone mineral density (BMD) status in long-term survivors of adult childhood cancer. METHODS: This retrospective single-centre cohort study included 346 subjects with the most common types of childhood cancer. Subjects had a median age at diagnosis of 7.0 years (range 0.1-16.8 years), a median age at follow-up of 24.5 years (range 18.0-47.6 years) and a median follow-up time of 16.7 years (range 5.6-39.9 years). Total body BMD (BMDTB) and BMD of the lumbar spine (BMDLS) were measured by dual X-ray absorptiometry. Osteopenia was defined as BMD standardized deviation score (SDS) below -1. RESULTS: Survivors had a lower BMDTB and BMDLS (mean SDS -0.55; p<0.001 and -0.30; p<0.001, respectively) as compared to healthy peers. Osteopenia (BMDTB and/or BMDLS) was present in 45% of the survivors. Multivariate logistic regression analyses identified age at diagnosis<12 years, age>30 years at follow-up, male gender, underweight at follow-up and treatment with cranial-spinal radiotherapy or prednisone as independent prognostic factors for osteopenia. CONCLUSIONS: This large cohort of childhood cancer survivors identified osteopenia in 45% of CCS. This indicates that greater awareness is warranted, especially in survivors who are older than 30 years, male, have underweight and were treated with cranial-spinal radiotherapy and/or steroids.
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Doenças Ósseas Metabólicas/diagnóstico por imagem , Neoplasias/terapia , Absorciometria de Fóton , Adolescente , Adulto , Densidade Óssea/fisiologia , Doenças Ósseas Metabólicas/complicações , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Vértebras Lombares/diagnóstico por imagem , Masculino , Pessoa de Meia-Idade , Neoplasias/complicações , Estudos Retrospectivos , Fatores de Risco , Sobreviventes , Resultado do Tratamento , Adulto JovemRESUMO
OBJECTIVE: We describe the occurrence and course of anterior pituitary dysfunction (PD) after aneurysmal subarachnoid haemorrhage (SAH), and identify clinical determinants for PD in patients with recent SAH. METHODS: We prospectively collected demographic and clinical parameters of consecutive survivors of SAH and measured fasting state endocrine function at baseline, 6 and 14â months. We included dynamic tests for growth-hormone function. We used logistic regression analysis to compare demographic and clinical characteristics of patients with SAH with and without PD. RESULTS: 84 patients with a mean age of 55.8 (±11.9) were included. Thirty-three patients (39%) had PD in one or more axes at baseline, 22 (26%) after 6â months and 6 (7%) after 14â months. Gonadotropin deficiency in 29 (34%) patients and growth hormone deficiency (GHD) in 26 (31%) patients were the most common deficiencies. PD persisted until 14â months in 6 (8%) patients: GHD in 5 (6%) patients and gonadotropin deficiency in 4 (5%). Occurrence of a SAH-related complication was associated with PD at baseline (OR 2.6, CI 2.2 to 3.0). Hydrocephalus was an independent predictor of PD 6â months after SAH (OR 3.3 CI 2.7 to 3.8). PD was associated with a lower score on health-related quality of life at baseline (p=0.06), but not at 6 and 14â months. CONCLUSIONS: Almost 40% of SAH survivors have PD. In a small but substantial proportion of patients GHD or gonadotropin deficiency persists over time. Hydrocephalus is independently associated with PD 6â months after SAH. TRIAL REGISTRATION NUMBER: NTR 2085.
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Doenças da Hipófise/etiologia , Adeno-Hipófise , Hemorragia Subaracnóidea/complicações , Feminino , Gonadotropinas/deficiência , Humanos , Hidrocefalia/complicações , Hidrocefalia/etiologia , Masculino , Pessoa de Meia-Idade , Doenças da Hipófise/fisiopatologia , Adeno-Hipófise/fisiopatologia , Estudos Prospectivos , Fatores de RiscoRESUMO
BACKGROUND: Aim of this study was to investigate the long-term endocrine effects of treatment of childhood non-Hodgkin lymphoma (NHL). PATIENTS AND METHODS: A single-center cohort of 84 survivors (22 females) was included in this retrospective study. Median age was 21 years (9-40 years) and time after cessation of therapy 12 years (4-30 years). Height, weight, percentage fat, lean body mass (LBM), bone mineral content (BMC), bone mineral density of total body (BMD(TB)) and bone mineral density of lumbar spine (BMD(LS)) were measured. Thyroid-stimulating hormone (TSH), free thyroxin (fT4), insulin-like growth factor-1 (IGF-1), inhibin B and anti-müllerian hormone (AMH) levels were measured. Results were compared with Dutch controls. RESULTS: Height was lower in survivors [mean standard deviation score (SDS) -0.36, P = 0.002], but further analysis showed that shorter stature was already present at diagnosis (mean SDS -0.28, P = 0.023). Body mass index, percentage fat, BMC, BMD(TB) and BMD(LS) were not different from controls. LBM was lower in survivors (mean SDS -0.47, P = 0.008). TSH, fT4 and IGF-1 were normal in all survivors. Three of 20 adult females had low AMH levels and 23 of 42 adult males had low inhibin B levels. CONCLUSIONS: Twelve years after cessation of treatment, NHL survivors did not develop adiposity, osteoporosis or thyroid disease. Male survivors may be at risk for infertility.
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Antineoplásicos/efeitos adversos , Hormônios/sangue , Linfoma não Hodgkin/tratamento farmacológico , Sobreviventes , Adolescente , Adulto , Antineoplásicos/uso terapêutico , Composição Corporal , Pesos e Medidas Corporais , Densidade Óssea , Estudos de Casos e Controles , Criança , Pré-Escolar , Sistema Endócrino/efeitos dos fármacos , Feminino , Seguimentos , Humanos , Vértebras Lombares/diagnóstico por imagem , Linfoma não Hodgkin/sangue , Masculino , Radiografia , Adulto JovemRESUMO
Disease activity of acromegaly can be measured in many ways. Growth hormone (GH) and insulin-like growth factor 1 (IGF1) concentrations are the main biochemical markers used to measure the response to treatment. Both GH and IGF1 have been associated with prognosis, in particular mortality. In this review, we discuss the available parameters to assess disease activity in acromegaly.
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Acromegalia/metabolismo , Biomarcadores/metabolismo , Hormônio do Crescimento Humano/metabolismo , Fator de Crescimento Insulin-Like I/metabolismo , Acromegalia/diagnóstico , Acromegalia/tratamento farmacológico , Hormônio do Crescimento Humano/análogos & derivados , Hormônio do Crescimento Humano/uso terapêutico , Humanos , Avaliação de Resultados em Cuidados de Saúde/métodos , Prognóstico , Qualidade de Vida , Inquéritos e QuestionáriosRESUMO
In children with cancer, the heterogeneity in ototoxicity occurrence after similar treatment suggests a role for genetic susceptibility. Using a genome-wide association study (GWAS) approach, we identified a genetic variant in TCERG1L (rs893507) to be associated with hearing loss in 390 non-cranial irradiated, cisplatin-treated children with cancer. These results were replicated in two independent, similarly treated cohorts (n = 192 and 188, respectively) (combined cohort: P = 5.3 × 10-10, OR 3.11, 95% CI 2.2-4.5). Modulating TCERG1L expression in cultured human cells revealed significantly altered cellular responses to cisplatin-induced cytokine secretion and toxicity. These results contribute to insights into the genetic and pathophysiological basis of cisplatin-induced ototoxicity.
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BACKGROUND: Adult survivors of childhood cancer have been reported to have an increased risk of late sequels. A cluster of abnormalities that contribute to the metabolic syndrome may be expressed at a higher level and therefore result in an increased risk for diabetes mellitus and cardiovascular diseases. PATIENTS AND METHODS: We investigated a single-centre cohort of 500 adult survivors (228 females) of childhood cancer, median age 28 years (range 18-59 years) and median follow-up time 19 years (range 6-49 years). We measured total cholesterol, high-density lipoprotein-cholesterol, systolic and diastolic blood pressure, body mass index and the prevalence of diabetes mellitus. Data from the epidemiological Monitoring van Risicofactoren en Gezondheid in Nederland (MORGEN) study were used to calculate standard deviation scores as normative values. RESULTS: The criteria of the metabolic syndrome were met in 13% of the total cohort. Acute lymphoblastic leukaemia (ALL) survivors treated with cranial irradiation had an increased risk of developing the metabolic syndrome compared with ALL survivors not treated with cranial irradiation (23% versus 7%, P = 0.011), probably determined by higher prevalence of overweight and hypertension. CONCLUSION: Adult survivors of childhood cancer, especially those treated with cranial irradiation, are at increased risk of developing the metabolic syndrome.
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Doenças Cardiovasculares/etiologia , Diabetes Mellitus/etiologia , Síndrome Metabólica/etiologia , Neoplasias/complicações , Neoplasias/terapia , Sobreviventes , Adolescente , Adulto , Antineoplásicos/efeitos adversos , Pressão Sanguínea , Índice de Massa Corporal , Estudos de Coortes , Terapia Combinada , Irradiação Craniana/efeitos adversos , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Neoplasias/mortalidade , Prognóstico , Taxa de Sobrevida , Adulto JovemRESUMO
PURPOSE: Acromegaly is a rare disease due to growth hormone (GH)-secreting pituitary adenoma. GH and IGF-1 levels are usually congruent, indicating either remission or active disease; however, a discrepancy between GH and IGF-1 may occur. We aimed to evaluate the outcome of diabetes mellitus (DM) and hypertension (HT) in acromegalic patients with congruent GH and/or IGF-1 levels vs. discordant biochemical parameters. METHODS: Retrospective analysis of the data of 3173 patients from the Liege Acromegaly Survey (LAS) allowed us to include 190 patients from 8 tertiary referral centers across Europe, treated by surgery, with available data concerning DM and HT both at diagnosis and at the last follow-up (LFU). We recorded the number of anti-HT and anti-DM drugs used at the first evaluation and at LFU for every patient. RESULTS: Ninety-nine patients belonged to the REM group (concordant parameters), 65 patients were considered as GHdis (high random GH/controlled IGF-1), and 26 patients were considered as IGF-1dis (high IGF-1/controlled random GH). At diagnosis, 72 patients (37.8%) had HT and 54 patients had DM (28.4%). There was no statistically significant difference in terms of the number of anti-HT and anti-DM drugs at diagnosis versus LFU (mean duration: 7.3 ± 4.5 years) between all three groups. CONCLUSION: The long-term outcome of DM and HT in acromegaly does not tend to be more severe in patients with biochemical discordance in comparison with patients considered as in remission on the basis of concordant biological parameters, suggesting that patients with biochemical discordance do not require a closer follow-up.
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Acromegalia , Adenoma , Diabetes Mellitus , Hormônio do Crescimento Humano , Hipertensão , Acromegalia/complicações , Acromegalia/epidemiologia , Diabetes Mellitus/epidemiologia , Europa (Continente) , Humanos , Hipertensão/complicações , Hipertensão/epidemiologia , Fator de Crescimento Insulin-Like I , Estudos Retrospectivos , RiscoRESUMO
PURPOSE: Augmented survival of childhood nephroblastoma and neuroblastoma has increased long-term side effects such as metabolic syndrome (MetS). Risk stratification is difficult after abdominal radiation because waist circumference underestimates adiposity. We aimed to develop a strategy for determining MetS in irradiated survivors using an integrated biomarker profile and vascular ultrasonography. METHODS: The NCEP-ATPIII MetS-components, 14 additional serum biomarkers and 9 vascular measurements were assessed in a single-centre cohort of childhood nephroblastoma (n = 67) and neuroblastoma (n = 36) survivors and controls (n = 61). Multivariable regression models were used to study treatment effects. Principal component analysis (PCA) was used to study all biomarkers in a combined analysis, to identify patterns and correlations. RESULTS: After 27.5 years of follow-up, MetS occurred more often in survivors (14%) than controls (3%). Abdominal radiotherapy and nephrectomy, to a lesser extent, were associated with MetS and separate components and with several biomarker abnormalities. PCA of biomarkers revealed a pattern on PC1 from favourable lipid markers (HDL-cholesterol, adiponectin) towards unfavourable markers (triglycerides, LDL-cholesterol, apoB, uric acid). Abdominal radiotherapy was associated with the unfavourable biomarker profile (ß = 1.45, P = 0.001). Vascular measurements were not of added diagnostic value. CONCLUSIONS: Long-term childhood nephro- and neuroblastoma survivors frequently develop MetS. Additional assessment of biomarkers identified in PCA - adiponectin, LDL, apoB, and uric acid - may be used especially in abdominally irradiated survivors, to classify MetS as alternative for waist circumference. Vascular ultrasonography was not of added value.
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PURPOSE: Germline mutations in the aryl-hydrocarbon receptor interacting protein (AIP) have been identified often in the setting of familial isolated pituitary adenoma (FIPA). To date there is no strong evidence linking germline AIP mutations to other neoplasms apart from the pituitary. Our primary objective was to investigate the prevalence of AIP gene mutations and mutations in genes that have been associated with neuroendocrine tumors in series of tumors from patients presenting with both pituitary adenomas and differentiated thyroid carcinomas (DTCs). METHODS: Pathology samples were retrieved from all pituitary adenomas in patients with concomitant DTCs, including one with a known germline AIP variant. Subsequently, two additional patients with known germline AIP variants were included, of which one presented only with a follicular thyroid carcinoma (FTC). RESULTS: In total, 17 patients (14 DTCs and 15 pituitary adenomas) were investigated by targeted next generation sequencing (NGS). The pituitary tumor samples revealed no mutations, while among the thyroid tumor samples BRAF (6/14, 42.9%) was the most frequently mutated gene, followed by NRAS (3/11, 27.3%). In one AIP-mutated FIPA kindred, the AIP-variant c.853C>T; p.Q285* was confirmed in the FTC specimen, including evidence of loss of heterozygosity (LOH) at the AIP locus in the tumor DNA. CONCLUSION: Although most observed variants in pituitary adenomas and DTCs were similar to those of sporadic DTCs, we confirmed in one AIP mutation-positive case the AIP-variant and LOH at this locus in an FTC specimen, which raises the potential role of the AIP mutation as a rare initiating event.
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Adenoma Hipofisário Secretor de Hormônio do Crescimento , Neoplasias Hipofisárias , Neoplasias da Glândula Tireoide , Mutação em Linhagem Germinativa , Humanos , Mutação , Países Baixos , Neoplasias Hipofisárias/genética , Sistema de Registros , Neoplasias da Glândula Tireoide/genéticaRESUMO
Ectopic adrenocorticotropin (ACTH) secretion accounts for less than 10% of all causes of endogenous Cushing's syndrome (CS) and is usually associated with neuroendocrine tumors and small cell carcinoma of the lung. We report the case of a 62-year-old man with CS due to ectopic ACTH production by small cell carcinoma of the prostate. He presented with severe hypercortisolism and associated symptoms. Plasma neuron specific enolase (NSE) was grossly elevated. Despite performing a laparoscopic bilateral adrenalectomy, the patient died as a result of sepsis with multi-organ failure. Post-mortem immunohistochemical staining of prostate tumor tissue showed ACTH expression. ACTH staining was also performed in four additional patients with small cell carcinoma of the urinary tract without CS. None of these additional cases showed a positive staining for ACTH. Although a rare cause of ectopic ACTH production, neuroendocrine prostate carcinoma should be considered in male patients with Cushing's syndrome, in particular in those with an occult source of ACTH overproduction.
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Hormônio Adrenocorticotrópico/metabolismo , Síndrome de Cushing/etiologia , Síndrome de Cushing/metabolismo , Neoplasias da Próstata/complicações , Neoplasias da Próstata/metabolismo , Carcinoma de Pequenas Células do Pulmão/metabolismo , Síndrome de Cushing/patologia , Evolução Fatal , Humanos , Masculino , Pessoa de Meia-IdadeRESUMO
Over the past decades, survival rates of childhood cancer have increased considerably from 5 to 30% in the early seventies to current rates exceeding 80%. This is due to the development of effective chemotherapy, surgery, radiotherapy and stem cell transplantation, combined with an optimized stratification of therapy and better supportive care regimens. As a consequence, active surveillance strategies of late sequelae have been developed to improve the quality of survival. Several epidemiological studies have reported an increased incidence of (components of) metabolic syndrome (MetS) and cardiovascular disease in childhood cancer survivors (CCS). Growth hormone deficiency (GHD) after cranial radiotherapy (CRT) has been previously described as an important cause of MetS. New insights suggest a role for abdominal radiotherapy as a determinant for MetS as well. The role of other risk factors, such as specific chemotherapeutic agents, steroids, gonadal impairment, thyroid morbidity and genetics, warrants further investigation. This knowledge is important to define subgroups of CCS that are at risk to develop (subclinical) MetS features. These survivors might benefit from standard surveillance and early interventions, for example lifestyle and diet advice and medical treatment, thereby preventing the development of cardiovascular disease.
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Sobreviventes de Câncer , Doenças Cardiovasculares/epidemiologia , Síndrome Metabólica/epidemiologia , Neoplasias/epidemiologia , Adulto , Idade de Início , Sobreviventes de Câncer/estatística & dados numéricos , Doenças Cardiovasculares/etiologia , Criança , Humanos , Incidência , Síndrome Metabólica/complicações , Neoplasias/complicações , Fatores de RiscoRESUMO
OBJECTIVE: The objective of the study was to assess whether weekly administration of 40 mg pegvisomant (PEG-V) improves quality of life (QoL) and metabolic parameters in acromegalic patients with normal age-adjusted IGF-I concentrations during long-acting somatostatin analog (SSA) treatment. DESIGN: This was a prospective, investigator-initiated, double blind, placebo-controlled, crossover study. Twenty acromegalic subjects received either PEG-V or placebo for two consecutive treatment periods of 16 wk, separated by a washout period of 4 wk. Efficacy was assessed as change between baseline and end of each treatment period. QoL was assessed by the Acromegaly Quality of Life Questionnaire (AcroQoL) and the Patient-Assessed Acromegaly Symptom Questionnaire (PASQ). RESULTS: The AcroQoL (P = 0.008) and AcroQoL physical (P = 0.002) improved significantly after PEG-V was added. The addition of PEG-V also significantly improved the PASQ (P = 0.038) and the single PASQ questions, perspiration (P = 0.024), soft tissue swelling (P = 0.036), and overall health status (P = 0.035). No significant change in Z-score of IGF-I (P = 0.34) was observed during addition of PEG-V. Transient liver enzyme elevations were observed in five subjects (25%). CONCLUSION: Improvement in quality of life was observed without significant change in IGF-I after the addition of 40 mg pegvisomant weekly to monthly SSA therapy in acromegalic patients who had normalized IGF-I on SSA monotherapy. These data question the current recommendations in how to assess disease activity in acromegaly. Moreover, the findings question the validity of the current approach of medical treatment in which pegvisomant is used only when SSA therapy has failed to normalize IGF-I.
Assuntos
Acromegalia/tratamento farmacológico , Antagonistas de Hormônios/administração & dosagem , Hormônio do Crescimento Humano/análogos & derivados , Qualidade de Vida , Somatostatina/análogos & derivados , Acromegalia/psicologia , Adulto , Idoso , Estudos Cross-Over , Método Duplo-Cego , Esquema de Medicação , Combinação de Medicamentos , Feminino , Antagonistas de Hormônios/efeitos adversos , Hormônio do Crescimento Humano/administração & dosagem , Hormônio do Crescimento Humano/efeitos adversos , Humanos , Masculino , Pessoa de Meia-Idade , Placebos , Somatostatina/administração & dosagem , Somatostatina/efeitos adversos , Fatores de TempoRESUMO
INTRODUCTION: The variability in late toxicities among childhood cancer survivors (CCS) is only partially explained by treatment and baseline patient characteristics. Inter-individual variability in the association between treatment exposure and risk of late toxicity suggests that genetic variation possibly modifies this association. We reviewed the available literature on genetic susceptibility of late toxicity after childhood cancer treatment related to components of metabolic syndrome, bone mineral density, gonadal impairment and hearing impairment. METHODS: A systematic literature search was performed, using Embase, Cochrane Library, Google Scholar, MEDLINE, and Web of Science databases. Eligible publications included all English language reports of candidate gene studies and genome wide association studies (GWAS) that aimed to identify genetic risk factors associated with the four late toxicities, defined as toxicity present after end of treatment. RESULTS: Twenty-seven articles were identified, including 26 candidate gene studies: metabolic syndrome (nâ¯=â¯6); BMD (nâ¯=â¯6); gonadal impairment (nâ¯=â¯2); hearing impairment (nâ¯=â¯12) and one GWAS (metabolic syndrome). Eighty percent of the genetic studies on late toxicity after childhood cancer had relatively small sample sizes (nâ¯<â¯200), leading to insufficient power, and lacked adjustment for multiple comparisons. Only four (4/26â¯=â¯15%) candidate gene studies had their findings validated in independent replication cohorts as part of their own report. CONCLUSION: Genetic susceptibility associations are not consistent or not replicated and therefore, currently no evidence-based recommendations can be made for hearing impairment, gonadal impairment, bone mineral density impairment and metabolic syndrome in CCS. To advance knowledge related to genetic variation influencing late toxicities among CCS, future studies need adequate power, independent cohorts for replication, harmonization of disease outcomes and sample collections, and (international) collaboration.
Assuntos
Sobreviventes de Câncer , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/genética , Variação Genética/fisiologia , Transtornos de Início Tardio/genética , Neoplasias/genética , Lesões por Radiação/genética , Densidade Óssea/genética , Sobreviventes de Câncer/estatística & dados numéricos , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/epidemiologia , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Humanos , Transtornos de Início Tardio/epidemiologia , Síndrome Metabólica/epidemiologia , Síndrome Metabólica/etiologia , Síndrome Metabólica/genética , Neoplasias/epidemiologia , Neoplasias/terapia , Lesões por Radiação/epidemiologia , Fatores de TempoRESUMO
BACKGROUND: Effective treatment of acromegaly with pegvisomant (PEGV), a growth hormone receptor antagonist, requires an appropriate dose titration. PEGV doses vary widely among individual patients, and various covariates may affect its dosing and pharmacokinetics. OBJECTIVE: To identify predictors of the PEGV dose required to normalize insulin-like growth factor I (IGF-I) levels during PEGV monotherapy and in combination with long-acting somatostatin analogues (LA-SSAs). DESIGN: Two retrospective cohorts (Rotterdam + Liège Acromegaly Survey (LAS), total n = 188) were meta-analyzed as a form of external replication to study the predictors of PEGV dosing in addition to LA-SSA, the LAS (n = 83) was used to study the predictors of PEGV monotherapy dosing. Multivariable regression models were used to identify predictors of the PEGV dose required to normalize IGF-I levels. RESULTS: For PEGV dosing in combination with LA-SSA, IGF-I levels, weight, height and age, were associated with the PEGV normalization dosage (P ≤ 0.001, P ≤ 0.001, P = 0.028 and P = 0.047 respectively). Taken together, these characteristics predicted the PEGV normalization dose correctly in 63.3% of all patients within a range of ±60 mg/week (21.3% within a range of ±20 mg/week). For monotherapy, only weight was associated with the PEGV normalization dose (P ≤ 0.001) and predicted this dosage correctly in 77.1% of all patients within a range of ±60 mg/week (31.3% within a range of ±20 mg/week). CONCLUSION: In this study, we show that IGF-I levels, weight, height and age can contribute to define the optimal PEGV dose to normalize IGF-I levels in addition to LA-SSA. For PEGV monotherapy, only the patient's weight was associated with the IGF-I normalization PEGV dosage.
Assuntos
Acromegalia/tratamento farmacológico , Hormônio do Crescimento Humano/análogos & derivados , Modelos Biológicos , Somatostatina/análogos & derivados , Somatostatina/administração & dosagem , Acromegalia/sangue , Adulto , Quimioterapia Combinada , Feminino , Hormônio do Crescimento Humano/administração & dosagem , Humanos , Fator de Crescimento Insulin-Like I/metabolismo , Masculino , Pessoa de Meia-Idade , Estudos RetrospectivosRESUMO
Treatment of acromegaly with monotherapy long-acting somatostatin analogues (LA-SSA) as primary treatment or after neurosurgery can only achieve complete normalization of insulin-like growth factor I (IGF-I) in roughly 40 % of patients. Recently, one of the acromegaly consensus groups has recommended switching to combined treatment of LA-SSA and pegvisomant (PEGV) in patients with partial response to LA-SSAs. This combination of LA-SSA and PEGV, a growth hormone receptor antagonist, can normalize IGF-I levels in virtually all patients, requiring that the adequate dose of PEGV is used. The required PEGV dose varies significantly between individual acromegaly patients. One of the advantages of the combination therapy is that tumor size control or even tumor shrinkage can be observed in a vast majority of patients. The main side effects of the combination treatment are gastrointestinal symptoms, lipohypertrophy and transient elevated liver transaminases. In this review we provide an overview of the efficacy and safety of the combined treatment of LA-SSAs with PEGV.