Neggers, S.J.C.M.M.

Endocrine sequelae and metabolic syndrome in adult long-term survivors of childhood acute myeloid leukemia (Article)

2013-04-01T00:00:00Z

This study focuses on the effect of chemotherapy on endocrinopathies and the metabolic syndrome in adult survivors of childhood acute myeloid leukemia (AML). Endocrine function and metabolic syndrome were evaluated in 12 AML survivors, treated with chemotherapy, and in 9 survivors of myeloid leukemias treated with stem cell transplantation (SCT), after a median follow-up time of 20 years (range 9-31). In survivors treated with chemotherapy, no endocrinopathies or metabolic syndrome were present, although AMH and Inhibin B levels tended to be lower than in controls. In SCT survivors, pituitary deficiencies and metabolic syndrome were more frequent.

Gonadal function recovery in very long-term male survivors of childhood cancer (Article)

2013-04-01T00:00:00Z

Background: Although gonadal toxicity has been reported, no data are available on recovery of gonadal function in very long-term survivors of childhood cancer. Inhibin B is a novel reliable serum marker which has been shown to be of value in childhood cancer survivor studies to identify risk groups for impaired gonadal function, but consecutive long-term follow-up studies using serum inhibin B as a marker are not available. Objective: To evaluate possible recovery of gonadal dysfunction over time in adult male survivors of childhood cancer. Methods: In this retrospective study, adult male long-term childhood cancer survivors (n = 201) who visited our outpatient late effects clinic were included and we used inhibin B as a surrogate marker for gonadal function. Results: Median age at diagnosis was 5.9 years (range 0.0-17.5) and discontinuation of treatment was reached at a median age of 8.2 years (range 0.0-20.8). Inhibin B levels were first measured after a median follow-up time of 15.7 years (range 3.0-37.0). Median interval between the first (T1) and second measurement (T2) was 3.3 years (range 0.7-11.3). Median inhibin B level was 127 ng/L (range 5-366) at T1 and 155 ng/L (range 10-507) at T2. The prediction model suggests that inhibin B levels do not normalise in survivors with a very low Inhibin B level at T1. Conclusions: Our results suggest that recovery of gonadal function is possible even long after discontinuation of treatment. However, this recovery does not seem to occur in survivors who already reached critically low inhibin B levels after discontinuation of treatment.

Treatment factors rather than genetic variation determine metabolic syndrome in childhood cancer survivors (Article)

2013-02-01T00:00:00Z

Background: Genetic variation that regulates insulin resistance, blood pressure and adiposity in the normal population might determine differential vulnerability for metabolic syndrome after treatment for childhood cancer. Objective: To evaluate the contribution of candidate single nucleotide polymorphisms (SNPs) relevant for metabolic syndrome in our single centre cohort of adult long-term childhood cancer survivors. Methods: In this retrospective study 532 survivors were analysed. Median age at diagnosis was 5.7 years (range 0.0-17.8 years), median follow-up time was 17.9 years (range 5.0-48.8) and median age at follow-up was 25.6 years (range 18.0-50.8). JAZF1 gene rs864745, THADA gene rs7578597, IRS1 gene rs2943641, TFAP2B gene rs987237, MSRA gene rs7826222, ATP2B1 gene rs2681472 and rs2681492 were genotyped. The association of genotypes with total cholesterol levels, blood pressure, body mass index, waist circumference and frequency of diabetes were assessed. Results: Metabolic syndrome was more frequent in cranially (23.3%, P = 0.002) and abdominally (23.4%, P = 0.009) irradiated survivors as compared with non-irradiated survivors (10.0%). Association of allelic variants in rs2681472 and rs2681492 with hypertension, rs987237 and rs7826222 with waist circumference and rs864745, rs7578597 and rs2943641 with diabetes were not significant. None of the SNPs was associated with the metabolic syndrome. Adjusting for age, sex, follow-up time, cranial irradiation and abdominal irradiation did not change these results. Conclusions: Treatment factors and not genetic variation determine hypertension, waist circumference, diabetes and metabolic syndrome in adult long-term survivors of childhood cancer.

Pegvisomant and improvement of quality of life in acromegalic patients (Article)

2011-07-01T00:00:00Z

Background: Acromegaly is a growth disorder, but mostly it is a metabolic disease related to excessive production of growth hormone (GH). It is characterized by progressive somatic disfigurement in combination with sometimes severe systemic manifestations. Long-acting somatostatin analog (SSA) therapy normalizes serum insulin-like growth factor I (IGF-I) levels in approximately 55% of patients, but we postulate that these patients still have acromegaly in many tissues other than the liver. Direct and indirect effects of SSA reduce hepatic IGF-I generation and make the liver behave as if it is GH resistant. The remaining 'peripheral' or non-hepatic acromegaly has a significant negative impact on the quality of life of these patients. Conclusions: Pegvisomant is the most effective medical treatment for acromegaly. Due to its mode of action and pharmacodynamic properties, it is the ideal partner for combination therapy with an SSA for acromegalic patients with a remaining, peripheral form of the disease.

New Insights into Medical Treatment of Acromegaly (Doctoral Thesis)

2011-06-10T00:00:00Z

Giants and Acromegalics fascinated people, since ancient times. Historical artifacts, paintings, illustrations, photographs or articles have documented many. The earliest medical reports date back to 1516. In 1864 Verga was the first to describe an acromegalic in medical literature and called it “prosopectasia”. However the article did not really characterize the disease. Pierre Marie was the first to do so and describe the disease and gave it the final name “acromegalie”, in 1886. Although Pierre Marie was aware of the enlarged pituitary gland he did not describe this as cause of the disease. In 1887 Minkowski was the first to suggest a pituitary origin of acromegaly. Later Massalongo also described the pituitary origin and additional the relationship between acromegaly and Gigantism. So at the end of the 19th century the disease and origin were unraveled. A decade later Harvey Cushing was the first to observe partial reversal of clinical symptoms after partial hypophysectomy, and the first form of effective treatment was born.

Combination treatment with somatostatin analogues and pegvisomant in acromegaly (Article)

2011-06-01T00:00:00Z

Mono-therapy using long-acting somatostatin analogues and surgery cannot provide optimal biochemical control in a large proportion of patients with acromegaly. This results in increased mortality, poor control of signs and symptoms of disease and decreased quality of life. Combined treatment with somatostatin analogues and pegvisomant (a growth-hormone-receptor antagonist) seems to be an attractive option. Combination treatment is highly effective at normalising the level of insulin-like growth factor 1 in over 90% of patients and has a favourable effect on quality of life in those with biochemically controlled acromegaly. Moreover, combination therapy with somatostatin analogues results in a clinically relevant decrease in tumour size in about 20% of patients, whereas pegvisomant (PEG-V) mono-therapy does not decrease pituitary tumour size. Transient elevations in the levels of transaminases are the main adverse effects of combination treatment, which occur in about 11-15% of patients.

Coadministration of lanreotide Autogel and pegvisomant normalizes IGF1 levels and is well tolerated in patients with acromegaly partially controlled by somatostatin analogs alone (Article)

2011-03-01T00:00:00Z

Objective: To evaluate the efficacy and safety of coadministered lanreotide Autogel (LA; 120 mg/month) and pegvisomant (40-120 mg/week) in acromegaly. Design: This is a 28-week, multicenter, open-label, single-arm sequential study. Methods: Patients (n=92) biochemically uncontrolled, on somatostatin analogs (SSAs) or using pegvisomant monotherapy entered a 4-month run-in taking LA (120 mg/month). Patients uncontrolled after the run-in period (n=57) entered a 28-week coadministration period, receiving LA 120 mg/month plus pegvisomant (60 mg once weekly, adapted every 8 weeks based on IGF1 levels to 40-80 mg once weekly or 40 or 60 mg twice weekly). Results: In total, 33 (57.9%) patients had normalized IGF1 following coadministration (P<0.0001 versus 30% minimum clinically relevant); median pegvisomant dose in normalized patients was 60 mg/week. IGF1 normalized at any time during coadministration in 45 (78.9%) patients (P<0.0001) with median pegvisomant dose at 60 mg/week. Being nondiabetic (odds ratio (OR): 4.65) and older (OR, upper versus lower quartile: 3.40) showed increased likelihood of normalization. Symptom reduction was greatest for arthralgia (-0.6±1.6) and soft tissue swelling (-0.6±1.8). Five patients reported treatment-emergent adverse events causing treatment withdrawal: three serious (treatment related - thrombocytopenia, urticaria; not treatment related - abdominal pain/vomiting) and two nonserious (hepatotoxicity and cytolytic hepatitis, both elevating alanine aminotransferase to >5X upper limit of normal with normalization after withdrawal). Conclusions: In patients partially controlled by SSAs, LA (120 mg/month) plus pegvisomant normalized IGF1 in 57.9% of patients after 7 months, at a median effective pegvisomant dose of 60 mg/week, and 78.9% at any time. In these patients, results suggest a pegvisomant-sparing effect versus daily pegvisomant monotherapy.

Conversion of daily pegvisomant to weekly pegvisomant combined with long-acting somatostatin analogs, in controlled acromegaly patients (Article)

2011-01-11T00:00:00Z

The efficacy of combined treatment in active acromegaly with both long-acting somatostatin analogs (SRIF) and pegvisomant (PEG-V) has been well established. The aim was to describe the PEG-V dose reductions after the conversion from daily PEG-V to combination treatment. To clarify the individual beneficial and adverse effects, in two acromegaly patients, who only normalized their insulin like growth factor (IGF-I) levels with high-dose pegvisomant therapy. We present two cases of a 31 and 44 years old male with gigantism and acromegaly that were controlled subsequently by surgery, radiotherapy, SRIF analogs and daily PEG-V treatment. They were converted to combined treatment of monthly SSA and (twice) weekly PEG-V. High dose SSA treatment was added while the PEG-V dose was decreased during carful monitoring of the IGF-I. After switching from PEG-V monotherapy to SRIF analogs plus pegvisomant combination therapy IGF-I remained normal. However, the necessary PEG-V dose, to normalize IGF-I differed significantly between these two patients. One patient needed twice weekly 100 mg, the second needed 60 mg once weekly on top of their monthly lanreotide Autosolution injections of 120 mg. The weekly dose reduction was 80 and 150 mg. After the introducing of lanreotide, fasting glucose and glycosylated haemoglobin concentrations increased. Diabetic medication had to be introduced or increased. No changes in liver tests or in pituitary adenoma size were observed. In these two patients, PEG-V in combination with long-acting SRIF analogs was as effective as PEG-V monotherapy in normalizing IGF-I levels, although significant dose-reductions in PEG-V could be achieved. However, there seems to be a wide variation in the reduction of PEG-V dose, which can be obtained after conversion to combined treatment.

Hypothesis: Extra-hepatic acromegaly: A new paradigm? (Article)

2011-01-01T00:00:00Z

Medical treatment of acromegaly with long-acting somatostatin analogs (LA-SMSA) and the GH receptor antagonist, pegvisomant (PEGV), has made it possible to achieve normal serum IGF1 concentrations in a majority of patients with acromegaly. These two compounds, however, impact the GH-IGF1 axis differently, which challenges the traditional biochemical assessment of the therapeutic response.We postulate that LA-SMSA in certain patients normalizes serum IGF1 levels in the presence of elevated GH actions in extra-hepatic tissues. This may result in persistent disease activity for which we propose the term extra-hepatic acromegaly. PEGV, on the other hand, blocks systemic GH actions, which are not necessarily reliably reflected by serum IGF1 levels, and this treatment causes a further elevation of serum GH levels. Medical treatment is therefore difficult to monitor with the traditional biomarkers. Moreover, the different modes of actions of LA-SMSA and PEGV make it attractive to use the two drugs in combination.We believe that it is time to challenge the existing concepts of treatment and monitoring of patients with acromegaly.

Modulation of glucocorticoid metabolism by the GH-IGF-I axis (Article)

2010-12-01T00:00:00Z

Growth hormone (GH) can generate insulin-like growth factor-I production, provided that the liver encounters portal insulin as a permissive factor that switches on the liver sensitivity for GH. This phenomenon is important for a proper insight into the pathophysiology of diseases as type 1 and 2 diabetes which differ in portal insulin levels. Also, acromegaly and obesity can be better understood when this effect of insulin on liver sensitivity for GH is taken into account. Moreover, as all of these factors seem to influence activity of the 11β-hydroxysteroid dehydrogenase (11β-HSD) type 1 (and 2), an extensive knowledge on the interplay between them is crucial as nowadays treatment options for obesity using the 11β-HSD1 are emerging. Copyright

The metabolic syndrome in adult survivors of childhood cancer, a review (Article)

2010-04-01T00:00:00Z

The number of adult survivors of childhood cancer in the general population has increased. As reports on the prevalence of the metabolic syndrome in adult survivors of childhood cancer are scarce, we reviewed the available literature on the components of the metabolic syndrome in adult survivors of childhood cancer. Although there is a lack of studies estimating the prevalence of metabolic syndrome directly, especially prevalence of insulin resistance, obesity, and dyslipidemia is increased in certain groups. Therefore, adult survivors of childhood cancer are at increased risk of developing cerebrovascular and cardiovascular diseases. Accordingly, it is important to identify the predisposing factors of the metabolic syndrome in cohorts of survivors, to introduce medical interventions, and to subsequently decrease the risk of cerebrovascular and cardiovascular events. Copyright

Medical therapy of acromegaly: Efficacy and safety of somatostatin analogues (Article)

2009-11-04T00:00:00Z

Acromegaly is a chronic disease with signs and symptoms due to growth hormone (GH) excess. The most frequent cause of acromegaly is a GH-producing pituitary adenoma. Chronic GH excess is accompanied by long-term complications of the locomotor (arthrosis) and cardiovascular (atherosclerosis, cardiomyopathy) systems and is, when untreated, associated with an increased mortality. The aim of treatment of acromegaly is to improve symptoms, to achieve local tumour mass control, and to decrease morbidity and mortality. Treatment options include surgery, medical therapy and radiotherapy.Transsphenoidal surgery is the first choice of treatment when a definitive cure can be achieved, particularly in the case of microadenomas and when decompression of surrounding structures (optic chiasm, ophthalmic motor nerves) is indicated. Primary medical therapy has been increasingly applied in recent years, especially when a priori chances of surgical cure are low (because of adenoma size and localization) and in patients with advanced age andor serious co-morbidity. In addition, preoperative primary medical therapy may result in tumour shrinkage, facilitating tumour resection, and may reduce perioperative complications due to GH excess. Within the spectrum of medical therapy, long-acting somatostatin analogues (somatostatins) are considered as first-line treatment. Treatment with somatostatin analogues results in GH control in approximately 60 of patients. In addition, somatostatin analogues induce tumour shrinkage in 3050 of patients, particularly when applied as primary therapy. Prolonged treatment with somatostatin analogues appears to be safe and is usually well tolerated.The currently available somatostatin analogues, octreotide and lanreotide, seem to be equally effective; however, this should still be evaluated in prospective, randomized trials evaluating efficacy with respect to GH control and tumour shrinkage. In patients with an insufficient clinical and biochemical response to somatostatin analogues, combination therapy with dopamine receptor agonists or the GH receptor antagonist pegvisomant usually leads to disease control. New developments in the medical therapy of acromegaly include the universal somatostatin receptor agonist pasireotide, which has a broader affinity for all somatostatin receptor (sst) subtypes compared with the currently available somatostatin analogues with preferential affinity for the sst2 receptor, and chimeric compounds that interact with both somatostatin and dopamine receptors with synergizing effects on GH secretion.

Components of the metabolic syndrome in 500 adult long-term survivors of childhood cancer (Article)

2009-10-22T00:00:00Z

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.

Somatostatin analog and pegvisomant combination therapy for acromegaly (Article)

2009-10-01T00:00:00Z

Optimal biochemical control cannot be attained by long-acting somatostatin analog monotherapy in a large proportion of patients with acromegaly. Such therapy might result in increased mortality, poor control of signs and symptoms of disease and decreased quality of life. Combination treatment with somatostatin analogs and pegvisomant (a growth-hormone-receptor antagonist) is, however, highly effective at normalizing the level of insulin-like growth factor I in over 90% of patients and might also have a favorable effect on quality of life in those with biochemically controlled acromegaly. Moreover, whereas pegvisomant monotherapy does not lead to a decrease in the size of the pituitary tumor, combination therapy with somatostatin analogs results in a clinically relevant decrease in tumor size in about 20% of patients. The main adverse effects of combination treatment are transient elevations in the levels of transaminases, which occur in about 15% of patients, especially in those with diabetes mellitus. In this Review, we discuss the available data on the long-term efficacy and safety of somatostatin analog-pegvisomant combination treatment and its potential use in patients with acromegaly.

Combined treatment for acromegaly with long-acting somatostatin analogs and pegvisomant: long-term safety for up to 4.5 years (median 2.2 years) of follow-up in 86 patients. (Article)

2009-09-08T00:00:00Z

BACKGROUND: We previously reported on the efficacy, safety, and quality of life (QoL) of long-acting somatostatin analogs (SSA) and (twice) weekly pegvisomant (PEG-V) in acromegaly and improvement after the addition of PEG-V to long-acting SSA. OBJECTIVE: To assess the long-term safety in a larger group of acromegalic patients over a larger period of time: 29.2 (1.2-57.4) months (mean (range)). DESIGN: Pegvisomant was added to SSA monotherapy in 86 subjects (37 females), to normalize serum IGF1 concentrations (n=63) or to increase the QoL. The median dosage was 60.0 (20-200) mg weekly. RESULTS: After a mean treatment period of 29.2 months, 23 patients showed dose-independent PEG-V related transient liver enzyme elevations (TLEE). TLEE occurred only once during the continuation of combination therapy, but discontinuation and re-challenge induced a second episode of TLEE. Ten of these patients with TLEE also suffered from diabetes mellitus (DM). In our present series, DM had a 2.28 odds ratio (CI 1.16-9.22; p=0.03) higher risk for developing TLEE. During the combined therapy, a clinical significant decrease in tumor size by more than 20% was observed in 14 patients. Two of these patients were previously treated by pituitary surgery, 1 with additional radiotherapy and all other patients received primary medical treatment. CONCLUSION: Long-term combined treatment with SSA and twice weekly PEG-V up to more than 4 years seems to be safe. Patients with both acromegaly and DM have a 2.28 higher risk of developing TLEE. Clinical significant tumor shrinkage was observed in 14 patients during combined treatment.

Cranial irradiation does not result in pituitary-gonadal axis dysfunction in very long-term male survivors of childhood acute lymphoblastic leukemia (Article)

2009-09-03T00:00:00Z

Cushing's syndrome due to ectopic ACTH production by (neuroendocrine) prostate carcinoma (Article)

2009-01-01T00:00:00Z

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.

Quality of life in acromegalic patients during long-term somatostatin analog treatment with and without pegvisomant (Article)

2008-10-01T00:00:00Z

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.

Long-term efficacy and safety of combined treatment of somatostatin analogs and pegvisomant in acromegaly (Article)

2007-12-01T00:00:00Z

Background: We previously reported the efficacy of a combined treatment of active acromegaly with both long-acting somatostatin analogs (SSA) and pegvisomant (PEG-V). Objective: Our objective was to assess long-term efficacy and safety in a larger group of acromegalic patients after a period of 138 (35-149) wk [median (range)]. Design: PEG-V was added to high-dose SSA treatment in 32 subjects (13 females) who had not shown a normalization in serum IGF-I concentrations during SSA monotherapy. PEG-V dosage was increased until IGF-I concentration normalized. The maximal dose was 80 mg twice weekly. Results: After dose finding, IGF-I remained within the normal range in all subjects with PEG-V administered once (n = 24) or twice (n = 8) weekly, on a total weekly dose of 60 (40-160) mg. Baseline IGF-I levels were positively correlated with the required dosage of PEG-V (r = 0.48; P = 0.006). PEG-V-dependent liver enzyme disturbances were observed in 11 (6 diabetic) subjects, of which symptomatic gallstones explained two cases. These liver enzyme disturbances were transient in all subjects without discontinuation or dose adaptation of PEG-V. In our series, diabetic patients had a 5.1 times (odds ratio) (confidence interval, 1.02-25.54; P < 0.05) higher risk for developing liver enzyme disturbances. These liver enzyme disturbances seemed to occur earlier. Pituitary adenoma size decreased in four patients. No increase in tumor size was observed in any of the patients. Conclusion: Long-term combined treatment with long-acting SSA and (twice) weekly PEG-V for active acromegaly seems to be effective and safe. Patients with acromegaly and diabetes seem to have a higher risk of developing transient liver enzyme disturbances. Copyright