Prolactinoma, the most common pituitary adenoma, is usually treated with dopamine agonist (DA) therapy like cabergoline. Surgery is second-line therapy, and radiotherapy is used if surgical treatment ...fails or in relapsing macroprolactinoma.
This study aimed to provide economic evidence for the management of prolactinoma in Italy, using a cost-of-illness and cost-utility analysis that considered various treatment options, including cabergoline, bromocriptine, temozolomide, radiation therapy, and surgical strategies.
The researchers conducted a systematic literature review for each research question on scientific databases and surveyed a panel of experts for each therapeutic procedure's specific drivers that contributed to its total cost.
The average cost of the first year of treatment was €2,558.91 and €3,287.40 for subjects with microprolactinoma and macroprolactinoma, respectively. Follow-up costs from the second to the fifth year after initial treatment were €798.13 and €1,084.59 per year in both groups. Cabergoline had an adequate cost-utility profile, with an incremental cost-effectiveness ratio (ICER) of €3,201.15 compared to bromocriptine, based on a willingness-to-pay of €40,000 per quality-adjusted life year (QALY) in the reference economy. Endoscopic surgery was more cost-effective than cabergoline, with an ICER of €44,846.64. Considering a willingness-to-pay of €40,000/QALY, the baseline findings show cabergoline to have high cost utility and endoscopic surgery just a tad above that.
Due to the favorable cost-utility profile and safety of surgical treatment, pituitary surgery should be considered more frequently as the initial therapeutic approach. This management choice could lead to better outcomes and an appropriate allocation of healthcare resources.
Prolactinomas are the most frequent pituitary adenomas. Prolactinoma may occur in different clinical settings and always require an individually tailored approach. This is the reason why a panel of ...Italian neuroendocrine experts was charged with the task to provide indications for the diagnostic and therapeutic approaches that can be easily applied in different contexts. The document provides 15 recommendations for diagnosis and 54 recommendations for treatment, issued according to the GRADE system. The level of agreement among panel members was formally evaluated by RAND-UCLA methodology. In the last century, prolactinomas represented the paradigm of pituitary tumors for which the development of highly effective drugs obtained the best results, allowing to avoid neurosurgery in most cases. The impressive improvement of neurosurgical endoscopic techniques allows a far better definition of the tumoral tissue during surgery and the remission of endocrine symptoms in many patients with pituitary tumors. Consequently, this refinement of neurosurgery is changing the therapeutic strategy in prolactinomas, allowing the definitive cure of some patients with permanent discontinuation of medical therapy.
Despite being a classical growth disorder, pituitary gigantism has not been studied previously in a standardized way. We performed a retrospective, multicenter, international study to characterize a ...large series of pituitary gigantism patients. We included 208 patients (163 males; 78.4%) with growth hormone excess and a current/previous abnormal growth velocity for age or final height >2 s.d. above country normal means. The median onset of rapid growth was 13 years and occurred significantly earlier in females than in males; pituitary adenomas were diagnosed earlier in females than males (15.8 vs 21.5 years respectively). Adenomas were ≥10 mm (i.e., macroadenomas) in 84%, of which extrasellar extension occurred in 77% and invasion in 54%. GH/IGF1 control was achieved in 39% during long-term follow-up. Final height was greater in younger onset patients, with larger tumors and higher GH levels. Later disease control was associated with a greater difference from mid-parental height (r=0.23, P=0.02). AIP mutations occurred in 29%; microduplication at Xq26.3 – X-linked acrogigantism (X-LAG) – occurred in two familial isolated pituitary adenoma kindreds and in ten sporadic patients. Tumor size was not different in X-LAG, AIP mutated and genetically negative patient groups. AIP-mutated and X-LAG patients were significantly younger at onset and diagnosis, but disease control was worse in genetically negative cases. Pituitary gigantism patients are characterized by male predominance and large tumors that are difficult to control. Treatment delay increases final height and symptom burden. AIP mutations and X-LAG explain many cases, but no genetic etiology is seen in >50% of cases.
Context: AIP mutations (AIPmut) give rise to a pituitary adenoma predisposition that occurs in familial isolated pituitary adenomas and less often in sporadic cases. The clinical and therapeutic ...features of AIPmut-associated pituitary adenomas have not been studied comprehensively.
Objective: The objective of the study was to assess clinical/therapeutic characteristics of AIPmut pituitary adenomas.
Design: This study was an international, multicenter, retrospective case collection/database analysis.
Setting: The study was conducted at 36 tertiary referral endocrine and clinical genetics departments.
Patients: Patients included 96 patients with germline AIPmut and pituitary adenomas and 232 matched AIPmut-negative acromegaly controls.
Results: The AIPmut population was predominantly young and male (63.5%); first symptoms occurred as children/adolescents in 50%. At diagnosis, most tumors were macroadenomas (93.3%); extension and invasion was common. Somatotropinomas comprised 78.1% of the cohort; there were also prolactinomas (n = 13), nonsecreting adenomas (n = 7), and a TSH-secreting adenoma. AIPmut somatotropinomas were larger (P = 0.00026), with higher GH levels (P = 0.00068), more frequent extension (P = 0.018) and prolactin cosecretion (P = 0.00023), and occurred 2 decades before controls (P < 0.000001). Gigantism was more common in the AIPmut group (P < 0.000001). AIPmut somatotropinoma patients underwent more surgical interventions (P = 0.00069) and had lower decreases in GH (P = 0.00037) and IGF-I (P = 0.028) and less tumor shrinkage with somatostatin analogs (P < 0.00001) vs. controls. AIPmut prolactinomas occurred generally in young males and frequently required surgery or radiotherapy.
Conclusions: AIPmut pituitary adenomas have clinical features that may negatively impact treatment efficacy. Predisposition for aggressive disease in young patients, often in a familial setting, suggests that earlier diagnosis of AIPmut pituitary adenomas may have clinical utility.
Pituitary adenomas in patients with germline AIP mutations have an aggressive clinical course.
It is debated if acromegalic patients have an increased risk to develop malignancies. The aim of the present study was to assess the standardized incidence ratios (SIRs) of different types of cancer ...in acromegaly on a large series of acromegalic patients managed in the somatostatin analogs era. It was evaluated the incidence of cancer in an Italian nationwide multicenter cohort study of 1512 acromegalic patients, 624 men and 888 women, mean age at diagnosis 45 ± 13 years, followed up for a mean of 10 years (12573 person-years) in respect to the general Italian population. Cancer was diagnosed in 124 patients, 72 women and 52 men. The SIRs for all cancers was significantly increased compared to the general Italian population (expected: 88, SIR 1.41; 95% CI, 1.18–1.68, P < 0.001). In the whole series, we found a significantly increased incidence of colorectal cancer (SIR 1.67; 95% CI, 1.07–2.58, P = 0.022), kidney cancer (SIR 2.87; 95% CI, 1.55–5.34, P < 0.001) and thyroid cancer (SIR 3.99; 95% CI, 2.32–6.87, P < 0.001). The exclusion of 11 cancers occurring before diagnosis of acromegaly (all in women) did not change remarkably the study outcome. In multivariate analysis, the factors significantly associated with an increased risk of malignancy were age and family history of cancer, with a non-significant trend for the estimated duration of acromegaly before diagnosis. In conclusion, we found evidence that acromegaly in Italy is associated with a moderate increase in cancer risk.
Data on osteoporotic fractures in hyperprolactinemia are limited. An increased prevalence of radiological vertebral fractures was recently observed in women with prolactin (PRL)-secreting adenoma, ...whereas it is unknown whether this observation may reflect a more general increased risk of fractures in this disease and whether the prevalence of fractures in males is affected by gonadal status. Thirty-two males (median age 47 years, range: 22–79) with PRL-secreting pituitary adenoma (10 with microadenoma and 22 with macroadenoma) and 64 control males, with normal PRL values and with comparable age to patients with hyperprolactinemia, were evaluated for vertebral fractures by a morphometric approach and for bone mineral density (BMD) by a dual-energy X-ray absorptiometry at lumbar spine. Vertebral fractures were shown in 12 patients with PRL-secreting adenoma (37.5%) and in 5 controls (7.8%,
P
< 0.001). Fractured patients had lower BMD T-score (
P
= 0.007) and longer duration of disease (
P
< 0.001) as compared to patients who did not fracture. Fractures occurred more frequently (
P
= 0.03) in patients with untreated hyperprolactinemia versus patients treated with cabergoline whose frequency of vertebral fractures was still higher than control subjects. The prevalence of vertebral fractures was not significantly different between eugonadal and hypogonadal patients (33.3% vs. 38.5%;
P
= 0.8). Moreover, no significant (
P
= 0.4) difference in serum testosterone values was found between fractured and not fractured males. Hyperprolactinemia is associated with high prevalence of radiological vertebral fractures in men with PRL-secreting adenoma. These findings would also suggest that PRL excess may produce negative skeletal effects independently of hypogonadism.
Pituitary adenomas are common in the general population. Although most of them are sporadic, some occur in a familial setting. In familial pituitary adenoma patients it is common that no germline ...defects are found after screening of aryl hydrocarbon receptor interacting protein (AIP) and other genes known to underlie the condition, suggesting the existence of yet unknown predisposition genes. Recently, the RET proto-oncogene was found to be a novel in vivo interaction partner of AIP in the pituitary gland. Here, we have screened patients from 16 AIP mutation negative (AIPmut−) pituitary adenoma families for RET germline mutations to assess whether RET could play a role in pituitary adenoma predisposition, similar to AIP. We found five novel germline RET changes: one in RET Exon 4 and the rest in noncoding regions of RET. Two changes, c.1560*G>A and −1285G>A, were segregated in affected family members. We also analyzed the RET region with enhancer element locator (EEL) to identify RET regulatory elements, and to see whether the changes resided in these. None of the variants mapped to the regions predicted by EEL. Expression of RET was examined in ten AIPmut− and seven AIP mutation positive (AIPmut+) somatotropinomas by immunohistochemistry, with a trend showing reduced expression in the latter (P=0.05). We conclude that the RET variants are presumably not related to pituitary adenoma predisposition, although reduced RET expression may play a role in AIP-related genesis of somatotropinomas.
Pituitary adenomas are common in the general population, and understanding their molecular basis is of great interest. Combining chip-based technologies with genealogy data, we identified germline ...mutations in the aryl hydrocarbon receptor interacting protein (AIP) gene in individuals with pituitary adenoma predisposition (PAP). AIP acts in cytoplasmic retention of the latent form of the aryl hydrocarbon receptor and also has other functions. In a population-based series from Northern Finland, two AIP mutations account for 16% of all patients diagnosed with pituitary adenomas secreting growth hormone and for 40% of the subset of patients who were diagnosed when they were younger than 35 years of age. Typically, PAP patients do not display a strong family history of pituitary adenoma; thus, AIP is an example of a low-penetrance tumor susceptibility gene.
Sommario
La polidipsia primaria (PP) è un condizione clinica rilevante per la frequenza con cui si manifesta nei pazienti psichiatrici e per le conseguenze gravi e potenzialmente fatali legate allo ...sviluppo di iponatriemia. Sebbene l’80% dei pazienti con PP siano schizofrenici, essa può presentarsi in un ampio spettro di malattie psichiatriche e anche nei decadimenti cognitivi. La PP ha una prevalenza del 20% nei pazienti istituzionalizzati ma è presente anche nel 15% dei pazienti ambulatoriali. Il quadro clinico può evolvere dalla semplice polidipsia con poliuria, allo sviluppo di iponatremia di varia severità fino al quadro della
water intoxication
. La PP si pone in diagnosi differenziale con le sindromi poliuriche-polidipsiche che, escluse le forme osmotiche o legate a disionie, comprendono le forme complete o parziali di diabete insipido centrale e nefrogenico. Il test indiretto, test all’assetamento seguito da somministrazione di desmopressina, e i test diretti, dosaggio AVP e copeptin, sono utili ma presentano limiti di accuratezza nella diagnosi differenziale della PP. Pertanto necessitano di essere integrati da dati anamnestici, di imaging ipotalamo-ipofisario e, talora, da terapia
ex adjuvantibus
con desmopressina. La terapia comportamentale risulta efficace ma è molto spesso difficile da attuare e deve essere supportata dal trattamento farmacologico antipsicotico, anche se gli studi clinici sono scarsi. In caso di presenza di iponatriemia si dovranno seguire le corrispettive linee guida tenendo presente il rischio di mielinolisi.
Summary
Objective This prospective randomized study evaluated the efficacy and safety of octreotide LAR vs. surgery in newly diagnosed acromegalic patients.
Methods Totally 104 male and female ...patients were enrolled in a 50‐week, exploratory, open‐label and randomized study. Eligible patients were randomized to receive either octreotide LAR 20 mg every 28 days or to undergo surgery. Efficacy was assessed by changes in mean GH and IGF‐I serum concentrations, at weeks 12, 24 and 48. Tumour volume was assessed by contrast‐enhanced MRI. In both groups, treatment adjustment was performed for patients uncontrolled at week 12 or 24. Octreotide LAR patients received a dose increased to 30 mg or, if already receiving this dose, investigator and patients could decide to cross‐over to surgery. Patients uncontrolled after surgery received octreotide LAR 20 mg, increased to 30 mg if acromegaly was still uncontrolled.
Results Overall success rates at weeks 24 and 48 were 25% and 28% for the octreotide LAR group and 49% and 39% for the surgery group. Only the difference observed at week 24 was statistically significant (P = 0·047). Both groups had a significant (> 20%) tumour shrinkage: 73% of patients in the octreotide LAR group and 95% in the surgery group. Major differences between octreotide LAR and surgery group in the occurrence of adverse events were gastrointestinal (71%vs. 27%), hepatobiliary (41%vs. 8%) and respiratory (5%vs. 28%).
Conclusion This first randomized study in unselected patients indicates that the 48‐week treatment outcome of octreotide LAR as first‐line treatment of acromegaly does not significantly differ from surgery. As a complete response to surgery in GH‐secreting macro‐adenomas can be difficult, first‐line therapy with octreotide LAR can be considered as a viable alternative for most patients with acromegaly, due to its low complication rate.
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