Mark R. Postma

Background: Accurate interpretation of insulin-like growth factor-1 (IGF1) requires both analytically robust measurement and appropriate reference data. Most available IGF1 normative datasets are based on ligand-binding assays (LBA), limiting their applicability to liquid chromatography-tandem mass spectrometry (LC-MS/MS) methods that provide higher analytical specificity. Objective: To evaluate the clinical performance of an in-house developed LC-MS/MS IGF1 assay in combination with a method-matched normative dataset derived from the Dutch Lifelines cohort, and to compare it with a commonly used LBA. Methods: Paired IGF1 results (n = 2057) were obtained using LC-MS/MS and the IDS iSYS LBA. Standard deviation scores (SDS) were calculated using assay-specific normative datasets. Agreement was assessed by regression, Bland-Altman, and weighted Cohen's κ analyses. Clinical validity was evaluated by comparing extreme SDS values with diagnostic categories adjudicated by endocrinologists. Results: The LC-MS/MS method showed a proportional bias of −27% versus IDS iSYS and yielded symmetrically distributed SDS around zero, whereas IDS iSYS results were positively skewed. Categorical agreement was fair (κ = 0.39). LC-MS/MS-derived SDS corresponded more closely with clinical diagnoses across adult and pediatric groups, including acromegaly, growth hormone (GH) deficiency, and GH replacement therapy. Conclusions: Our LC-MS/MS IGF1 assay integrated with its own population-based normative dataset demonstrated superior alignment with clinical assessment compared with LBA results. In our setting, this method provides a clinically reliable benchmark for IGF1 interpretation and may serve as a reference for IGF1 harmonization and broader adoption of the Lifelines normative dataset in routine endocrinology.

Differentiation of pituitary neuroendocrine tumor (PitNET) tissue from surrounding normal tissue during surgery is challenging. A number of fluorescent agents is available for visualization of tissue discrepancy, with the potential of improving total tumor resection. This review evaluates the availability, clinical and technical applicability of the various fluorescent agents within the field of pituitary surgery. According to PRISMA guidelines, a systematic review was performed to identify reports describing results of in vivo application of fluorescent agents. In this review, 15 publications were included. Sodium Fluorescein (FNa) was considered in two studies. The first study reported noticeable fluorescence in adenoma tissue, the second demonstrated the strongest fluorescence in non-functioning pituitary adenomas. 5-Aminolevulinic acid (5-ALA) was investigated in three studies. One study compared laser-based optical biopsy system (OBS) with photo-diagnostic filter (PD) and found that the OBS was able to detect all microadenomas, even when MRI was negative. The second study retrospectively analyzed twelve pituitary adenomas and found only one positive for fluorescence. The third investigated fifteen pituitary adenomas of which one displayed vague fluorescence. Indocyanine green (ICG) was researched in four studies with variable results. Second-Window ICG yielded no significant difference between functioning and non-functioning adenomas in one study, while a second study displayed 4 times higher fluorescence in tumor tissue than in normal tissue. In three studies, OTL38 showed potential in non-functioning pituitary adenomas. At present, evidence for fluorescent agents to benefit total resection of PitNETs is lacking. OTL38 can potentially serve as a selective fluorescent agent in non-functioning pituitary adenomas in the near future.

Summary In July 2017, a 35-year-old woman was referred to our care for treatment of a large pituitary mass with an unusually high growth rate. She presented with right-sided ptosis and diplopia (n. III palsy), increasing retrobulbar pain and vertigo. Although laboratory investigations were consistent with acromegaly, she exhibited no clear phenotypic traits. During transsphenoidal surgery aimed at biopsy, typical adenomatous tissue was encountered, upon which it was decided to proceed to debulking. Histopathological analysis demonstrated a poorly differentiated plurihormonal Pit-1-positive adenoma with focal growth hormone (GH) and prolactin positivity, positive SSTR2 staining and a Ki-67 of 20–30%. Postoperative magnetic resonance imaging (MRI) examination revealed a large tumour remnant within the sella invading the right cavernous sinus with total encasement of the internal carotid artery and displacement of the right temporal lobe. As a consequence, she was treated additionally with radiotherapy, and a long-acting first-generation somatostatin analogue was prescribed. Subsequently, the patient developed secondary hypocortisolism and diabetes mellitus despite adequate suppression of GH levels. In September 2019, her symptoms recurred. Laboratory evaluations indicated a notable loss of biochemical control, and MRI revealed tumour progression. Lanreotide was switched to pasireotide, and successful removal of the tumour remnant and decompression of the right optic nerve was performed. She received adjuvant treatment with temozolomide resulting in excellent biochemical and radiological response after three and six courses. Symptoms of right-sided ptosis and diplopia remained. Evidence for systemic therapy in case of tumour progression after temozolomide is currently limited, although various potential targets can be identified in tumour tissue. Learning points Poorly differentiated plurihormonal Pit-1-positive adenoma is a potentially aggressive subtype of pituitary tumours. This subtype can express somatostatin receptors, allowing treatment with somatostatin analogues. A multidisciplinary approach involving an endocrinologist, neurosurgeon, pituitary pathologist, neuroradiologist, radiation oncologist and medical oncologist is key for the management of patients with aggressive pituitary tumours, allowing the successful application of multimodality treatment. Temozolomide is first-line chemotherapy for aggressive pituitary tumours and carcinomas. Further development of novel targeted therapies, such as peptide receptor radionuclide therapy (PRRT), vascular endothelial growth factor (VEGF) receptor-targeted therapy, tyrosine kinase inhibitors, mammalian target of rapamycin (mTOR) inhibitors and immune checkpoint inhibitors, is needed. Abstract Summary In July 2017, a 35-year-old woman was referred to our care for treatment of a large pituitary mass with an unusually high growth rate. She presented with right-sided ptosis and diplopia (n. III palsy), increasing retrobulbar pain and vertigo. Although laboratory investigations were consistent with acromegaly, she exhibited no clear phenotypic traits. During transsphenoidal surgery aimed at biopsy, typical adenomatous tissue was encountered, upon which it was decided to proceed to debulking. Histopathological analysis demonstrated a poorly differentiated plurihormonal Pit-1-positive adenoma with focal growth hormone (GH) and prolactin positivity, positive SSTR2 staining and a Ki-67 of 20–30%. Postoperative magnetic resonance imaging (MRI) examination revealed a large tumour remnant within the sella invading the right cavernous sinus with total encasement of the internal carotid artery and displacement of the right temporal lobe. As a consequence, she was treated additionally with radiotherapy, and a long-acting first-generation somatostatin analogue was prescribed. Subsequently, the patient developed secondary hypocortisolism and diabetes mellitus despite adequate suppression of GH levels. In September 2019, her symptoms recurred. Laboratory evaluations indicated a notable loss of biochemical control, and MRI revealed tumour progression. Lanreotide was switched to pasireotide, and successful removal of the tumour remnant and decompression of the right optic nerve was performed. She received adjuvant treatment with temozolomide resulting in excellent biochemical and radiological response after three and six courses. Symptoms of right-sided ptosis and diplopia remained. Evidence for systemic therapy in case of tumour progression after temozolomide is currently limited, although various potential targets can be identified in tumour tissue. Learning points Poorly differentiated plurihormonal Pit-1-positive adenoma is a potentially aggressive subtype of pituitary tumours. This subtype can express somatostatin receptors, allowing treatment with somatostatin analogues. A multidisciplinary approach involving an endocrinologist, neurosurgeon, pituitary pathologist, neuroradiologist, radiation oncologist and medical oncologist is key for the management of patients with aggressive pituitary tumours, allowing the successful application of multimodality treatment. Temozolomide is first-line chemotherapy for aggressive pituitary tumours and carcinomas. Further development of novel targeted therapies, such as peptide receptor radionuclide therapy (PRRT), vascular endothelial growth factor (VEGF) receptor-targeted therapy, tyrosine kinase inhibitors, mammalian target of rapamycin (mTOR) inhibitors and immune checkpoint inhibitors, is needed.

Context Transsphenoidal surgery (TSS) is the primary treatment of choice in acromegaly. It is important to identify patients in whom surgical cure is not attainable at an early stage, both to inform patients on expected treatment outcome and to select those who are more likely to need additional therapy. Objective To identify predictors for remission after TSS in acromegaly. Methods Large multicenter study with retrospective data collection from 3 tertiary neurosurgical referral centers in The Netherlands. We analyzed clinical data since 2000 from 3 cohorts (Groningen, Nijmegen, and Rotterdam, total n = 282). Multivariate regression models were used to identify predictors of early biochemical remission (12 weeks to 1 year postoperatively) according to the 2010 consensus criteria, long-term remission (age- and sex-normalized insulin-like growth factor 1 [IGF-1] and the absence of postoperative treatment until last follow-up), and relative IGF-1 and growth hormone [GH] reduction. Results A larger maximum tumor diameter (odds ratio [OR] 0.91, 95% CI 0.87-0.96, P ≤ .0001) was associated with a lower chance of early biochemical remission. A larger maximum tumor diameter (OR 0.93, 95% CI 0.89-0.97, P = .0022) and a higher random GH concentration at diagnosis (OR 0.98, 95% CI 0.96-0.99, P = .0053) were associated with a lower chance of long-term remission. Conclusion Maximum tumor diameter and random GH concentration at diagnosis are the best predictors for remission after TSS in acromegaly.

Introduction: Adult-onset growth hormone deficiency (AGHD) is usually the last deficiency to be substituted in hypopituitarism. In children with documented GH deficiency, treatment without delay is crucial for achieving optimal effects on growth and development. In adults, it is not known whether a delay in treatment initiation influences biochemical response and the favourable physiological effects resulting from GH replacement therapy (GHRT). Methods:: A total of 1085 GH-deficient adults from KIMS (Pfizer International Metabolic Database) were included, adequately replaced with all pituitary hormones except for GH at baseline. Patients were stratified by sex and age (20–50 years and ≥50 years) and subsequently divided into two groups below and above the median duration of unsubstituted AGHD for that subgroup. The median time of unsubstituted GHD for the total cohort was 2.53 years (P5 = 0.35, P95 = 24.42). Results:: Beneficial effects of 4 years of GHRT were observed on lipids and quality of life in all subgroups. A decrease in waist circumference was observed only in older (>50 years) patients. There was no difference in IGF-I SDS and in GH dose required to normalize IGF-I in patients with a duration of unsubstituted AGHD above or below the median. No relevant differences were found between the groups for anthropometric measures, cardiovascular risk factors and quality of life scores. Conclusion:: In contrast to GHD in children and adolescents, no difference could be established in treatment response between early or late initiation of GHRT in AGHD in terms of required GH dose, IGF-I, metabolic health and quality of life.

Background/Aims: It is unknown whether long-term growth hormone replacement therapy (GHRT) affects body composition in an age- or sex-dependent manner. We aimed to study the effects of 4 years of GHRT on body composition in a large cohort of patients with hypopituitarism compared to a reference population matched by age and sex. Methods: A total of 964 GH-deficient adults from KIMS (Pfizer International Metabolic Database) with adult-onset hypopituitarism, adequately replaced with all pituitary hormones except for GH at baseline were included. A random sample of the general population (2,301 subjects) from a similar time period was used as reference. Patients and controls were grouped by sex in 5 age cohorts of 10 years. Main outcome measures were changes in BMI and waist circumference after 4 years of GHRT. Results: In younger patients (28–47 years), 4 years of GHRT resulted in a BMI increase similar to that observed in the reference population, but older patients (48–67 years) had significantly less BMI increase than age-matched healthy controls. Significant differences were seen in waist circumference in patients of all age cohorts who showed virtually no change after 4 years of GHRT compared to approximately 4 cm of increase in the reference population. Conclusion: Four years of GHRT resulted in improvements in BMI and waist circumference in patients with adult-onset hypopituitarism compared to age-matched controls observed during the same follow-up time. Despite these beneficial effects on body composition, BMI and waist circumference remained higher in patients on GHRT compared to healthy controls.

OBJECTIVE: To assess the effect of somatostatin analogs (SSA) on mortality in relation to disease control of acromegaly after pituitary surgery. DESIGN: A retrospective study in two large tertiary referral centers in The Netherlands. METHODS: 319 patients with acromegaly in whom pituitary surgery was performed as primary therapy between January 1980 and July 2017 were included. Postoperative treatment with SSA was prescribed to 174 (55%) patients because of persistent or recurrent disease. Disease control at last visit was assessed by IGF1 standard deviation score (SDS). Adequate disease control was defined as IGF1 SDS ≤ 2. Univariate determinants of mortality and standardized mortality ratios (SMR) were calculated for groups with and without SSA at any moment postoperatively and at last visit. RESULTS: In total, 27 deaths were observed. In univariate analysis, determinants of mortality were inadequate disease control (RR 3.41, P=0.005), surgery by craniotomy (RR 3.53, P=0.013) and glucocorticoid substitution (RR 2.11, P=0.047). There was a strong trend towards increased mortality for patients who used SSA (RR 2.01, P=0.067) and/or dopamine agonists (RR 2.54, P=0.052) at last visit. The SMR of patients with adequate disease control who used SSA at any moment postoperatively (1.07, P=0.785) and at last visit (1.19; P=0.600) was not increased. Insufficiently controlled patients had a significantly raised SMR (3.92, P=0.006). CONCLUSIONS: Postoperative use of SSA is not associated with increased mortality in patients with acromegaly who attain adequate disease control. In contrast, inadequate disease control, primary surgery by craniotomy, and glucocorticoid substitution are associated with increased mortality.

Objective: To assess the effect of somatostatin analogs (SSTA) on mortality in relation to metabolic control of acromegaly after pituitary surgery. Design: A retrospective study in two large tertiary referral centers in The Netherlands. Patients and methods: Three hundred and nineteen patients with acromegaly in whom pituitary surgery was performed as primary therapy between January 1980 and July 2017 were included (total follow-up: 3887 patient years). Postoperative treatment with SSTA was prescribed to 174 (55%) patients because of persistent or recurrent disease. Metabolic control at last visit was assessed by local IGF1 standard deviation score (SDS). Adequate metabolic control was defined as an IGF-1 SDS ≤ 2. Univariate determinants of mortality and standardized mortality ratios (SMR) were calculated for groups with and without SSTA at any moment postoperatively and at last visit. Results: In total, 27 deaths were observed. SSTA use was not associated with increased mortality. In univariate analysis, determinants of mortality were inadequate metabolic control (RR 3.41, P=0.005), surgery by craniotomy/combined approach (RR 3.53, P=0.013) and glucocorticoid substitution (RR 2.11, P=0.047). The SMR of patients with adequate metabolic control who used SSTA at any moment postoperatively (1.06, P=0.959) and at last visit (1.19; P=0.769) was not increased. Insufficiently controlled patients had a significantly raised SMR (3.94, P<0.001). Conclusion: Postoperative use of SSTA is not associated with increased mortality in patients with acromegaly when adequately controlled. In contrast, inadequate metabolic control, primary surgery by craniotomy/combined approach, and glucocorticoid substitution are associated with increased mortality.