First-generation somatostatin analogs (SSAs), such as octreotide (OCT), are the first line medical therapy for acromegaly. Pasireotide (PAS), a newly developed SSA, has shown promising results in the ...treatment of acromegaly.
To compare the antisecretory effect of OCT and PAS in primary cultures of growth hormone (GH)-secreting pituitary adenomas (GH-omas). To correlate responses with the adenoma somatostatin receptor (SSTR) profile.
The effect of OCT and PAS on GH (and PRL) secretion was tested in 33 GH-oma cultures. SSTR expression was evaluated in adenoma samples.
Patients with acromegaly referred to the Erasmus Medical Center (Rotterdam, The Netherlands).
OCT and PAS treatment for 72 hours (10 nM).
GH (and PRL) concentrations in cell culture media. SSTR expression in adenoma samples.
The overall effect of OCT (-36.8%) and PAS (-37.1%) on GH secretion was superimposable. We identified three adenoma groups: PAS+ (PAS more effective than OCT), n = 6; PAS = OCT, n = 22; and OCT+ (OCT more effective than PAS), n = 5. PAS+ adenomas showed lower somatostatin receptor subtype (sst)2 messenger RNA (mRNA) and sst2/sst5 mRNA ratio, compared with the other groups (P < 0.05). PAS inhibited PRL hypersecretion more than OCT (P < 0.01).
Overall, OCT and PAS equally reduced GH secretion in vitro. Adenomas with lower sst2 mRNA expression and lower sst2/sst5 mRNA ratio were better responders to PAS compared with OCT. SSTR evaluation in GH-omas may become a tool for tailored SSA treatment in acromegaly.
Acromegaly is a rare disorder caused by chronic growth hormone (GH) hypersecretion. While diagnostic and therapeutic methods have advanced, little information exists on trends in acromegaly ...characteristics over time. The
, a relational database, is designed to assess the profile of acromegaly patients at diagnosis and during long-term follow-up at multiple treatment centers. The following results were obtained at diagnosis. The study population consisted of 3173 acromegaly patients from ten countries; 54.5% were female. Males were significantly younger at diagnosis than females (43.5 vs 46.4 years;
< 0.001). The median delay from first symptoms to diagnosis was 2 years longer in females (
= 0.015). Ages at diagnosis and first symptoms increased significantly over time (
< 0.001). Tumors were larger in males than females (
< 0.001); tumor size and invasion were inversely related to patient age (
< 0.001). Random GH at diagnosis correlated with nadir GH levels during OGTT (
< 0.001). GH was inversely related to age in both sexes (
< 0.001). Diabetes mellitus was present in 27.5%, hypertension in 28.8%, sleep apnea syndrome in 25.5% and cardiac hypertrophy in 15.5%. Serious cardiovascular outcomes like stroke, heart failure and myocardial infarction were present in <5% at diagnosis. Erythrocyte levels were increased and correlated with IGF-1 values. Thyroid nodules were frequent (34.0%); 820 patients had colonoscopy at diagnosis and 13% had polyps. Osteoporosis was present at diagnosis in 12.3% and 0.6-4.4% had experienced a fracture. In conclusion, this study of >3100 patients is the largest international acromegaly database and shows clinically relevant trends in the characteristics of acromegaly at diagnosis.
How to Position Pasireotide LAR Treatment in Acromegaly Coopmans, Eva C; Muhammad, Ammar; van der Lely, Aart J ...
The journal of clinical endocrinology and metabolism,
2019-June, Letnik:
104, Številka:
6
Journal Article
Recenzirano
Odprti dostop
Abstract
Context
Pasireotide long-acting release (LAR) is a somatostatin multireceptor ligand, and in the current consensus criteria pasireotide LAR is considered the second-line medical treatment ...for acromegaly. We present in this article our recommendations to define the position of pasireotide LAR in the treatment of acromegaly and provide recommendations for the management of pasireotide-induced hyperglycemia.
Evidence Acquisition
Our recommendations are based on our experiences with the pasireotide LAR and pegvisomant (PEGV) combination study and the available basic or clinical articles published in peer-reviewed international journals on pasireotide LAR and acromegaly.
Evidence Synthesis
In accordance with the current consensus criteria, we recommend pasireotide LAR monotherapy as a second-line therapy in young patients who show tumor growth during first-generation somatostatin receptor ligand (SRL) therapy and in patients who show tumor growth during PEGV therapy. In addition, we recommend pasireotide LAR monotherapy in patients with headache not responsive to first-generation SRL therapy and in patients who experience side effects or are intolerant to PEGV monotherapy. In contrast to the current consensus criteria, we recommend considering combination therapy with pasireotide LAR and PEGV as third-line treatment in patients without diabetes at low PEGV dosages (≤80 mg/week) and in patients with tumor growth or symptoms of active acromegaly during first-generation SRL and PEGV combination therapy. With respect to pasireotide-induced hyperglycemia, we recommend a more liberal strategy of blood glucose monitoring during pasireotide treatment.
Conclusions
In contrast to the current consensus criteria, we recommend a more reluctant use of pasireotide LAR therapy for the treatment of acromegaly.
Based on our experiences with the Pasireotide LAR and Pegvisomant Study in Acromegaly and on the currently available literature, we provide recommendations to define the position of pasireotide long-acting release in the treatment of acromegaly.
Purpose Childhood cancer survivors (CCSs) are at increased risk for subsequent malignant neoplasms (SMNs). We evaluated the long-term risk of SMNs in a well-characterized cohort of 5-year CCSs, with ...a particular focus on individual chemotherapeutic agents and solid cancer risk. Methods The Dutch Childhood Cancer Oncology Group-Long-Term Effects After Childhood Cancer cohort includes 6,165 5-year CCSs diagnosed between 1963 and 2001 in the Netherlands. SMNs were identified by linkages with the Netherlands Cancer Registry, the Dutch Pathology Registry, and medical chart review. We calculated standardized incidence ratios, excess absolute risks, and cumulative incidences. Multivariable Cox proportional hazard regression analyses were used to evaluate treatment-associated risks for breast cancer, sarcoma, and all solid cancers. Results After a median follow-up of 20.7 years (range, 5.0 to 49.8 years) since first diagnosis, 291 SMNs were ascertained in 261 CCSs (standardized incidence ratio, 5.2; 95% CI, 4.6 to 5.8; excess absolute risk, 20.3/10,000 person-years). Cumulative SMN incidence at 25 years after first diagnosis was 3.9% (95% CI, 3.4% to 4.6%) and did not change noticeably among CCSs treated in the 1990s compared with those treated earlier. We found dose-dependent doxorubicin-related increased risks of all solid cancers ( P
< .001) and breast cancer ( P
< .001). The doxorubicin-breast cancer dose response was stronger in survivors of Li-Fraumeni syndrome-associated childhood cancers (leukemia, CNS, and non-Ewing sarcoma) versus survivors of other cancers ( P
= .008). In addition, cyclophosphamide was found to increase sarcoma risk in a dose-dependent manner ( P
= .01). Conclusion The results strongly suggest that doxorubicin exposure in CCSs increases the risk of subsequent solid cancers and breast cancer, whereas cyclophosphamide exposure increases the risk of subsequent sarcomas. These results may inform future childhood cancer treatment protocols and SMN surveillance guidelines for CCSs.
Psychopathology in Acromegaly—Real and Perceived Pivonello, Rosario; Neggers, Sebastian J C M M; Imran, Syed Ali
The journal of clinical endocrinology and metabolism,
09/2023, Letnik:
108, Številka:
10
Journal Article
Recenzirano
Abstract
Acromegaly is a chronic condition caused by the excessive production of growth hormone and is characterized by progressive morphological and systemic complications, as well as increased ...prevalence of psychopathologies, which markedly affect patients’ quality of life. The advancing multimodal therapies, while significantly improving the morbidity and mortality, have limited impact on psychopathologies, which often persist despite disease remission. The most common psychopathologies in acromegaly include depression, anxiety and affective disorders, together with sexual dysfunction, which may be considered as either a consequence or potentially even a contributory factor to these psychopathologies. Approximately one-third of patients with acromegaly manifest depression, whereas two-thirds of patients display anxiety, with both conditions tending to be more prevalent and severe in younger patients with shorter duration of disease. Apparently, a major impact of psychological discomfort in women compared with men appears to be the fact that women tend to internalize whereas men tend to externalize their distress. Personality disorders also commonly associated with acromegaly, especially due to body image suffering, are linked to sexual dysfunction, which seems to affect women more than men. In summary, psychopathology in acromegaly is a major determinant of the quality of life and a complex array of psychological abnormalities are associated with acromegaly.
The response to first-generation somatostatin receptor ligands (SRLs) treatment in acromegaly correlates with expression of somatostatin receptor subtype 2 (SSTR2). However, pasireotide shows the ...highest binding affinity for SSTR subtype 5 (SSTR5). It has been suggested that in acromegaly, SSTR5 expression is better at predicting the response to pasireotide long-acting release (PAS-LAR) treatment than SSTR2 expression.
To investigate in patients with active acromegaly whether response to SRL treatment correlates to PAS-LAR treatment and to what extent SSTR2 and SSTR5 expression are correlated to the response to PAS-LAR treatment.
We included 52 patients from a cohort that initially received SRL treatment, followed by SRL and pegvisomant combination treatment, and finally PAS-LAR treatment. The long-term response to PAS-LAR was evaluated using a PAS-LAR score. In 14 out of 52 patients, somatotroph adenoma tissue samples were available to evaluate SSTR2 and SSTR5 expression using a previously validated immunoreactivity score (IRS).
The percentage IGF-I (times the upper limit of normal) reduction, which was observed after SRL treatment, correlated with PAS-LAR response score during follow-up (r = 0.40; P = 0.003; n = 52). After exclusion of SRL-pretreated patients, SSTR2 IRS was positively correlated to PAS-LAR score (r = 0.58; P = 0.039; n = 9), whereas SSTR5 IRS showed no relation (r = 0.35; P = 0.36; n = 9).
In a cohort of patients partially responsive to SRLs, the IGF-I-lowering effects of PAS-LAR treatment correlated with the effect of SRL treatment and seemed to be mainly driven by SSTR2 expression instead of SSTR5.
Context:
Somatostatin receptor subtype 2 (sst2A) protein expression has been demonstrated to positively correlate with somatostatin analog treatment outcome in GH-secreting adenomas. Recently, a new ...rabbit monoclonal anti-sst2A antibody (clone UMB-1) has been validated as a reliable method to selectively detect sst2A protein levels in formalin-fixed tissues.
Objective:
The aim of the study was to establish whether the evaluation of sst2A protein levels, assessed with a routine reproducible immunohistochemistry protocol using UMB-1 antibody, may predict the successful adjuvant therapy with somatostatin analogs in acromegalic patients.
Design, Setting, and Patients:
Thirty-six acromegalic patients from our referral hospital were evaluated retrospectively. Sst2A expression analysis was performed by immunohistochemistry in 25 patients and by quantitative RT-PCR in 26 patients. Sst2A immunoreactivity was evaluated using an immunoreactivity score (IRS), which takes into account both the percentage of positive cells and staining intensity.
Interventions:
Patients with persistent disease after surgery (n = 26) were treated with somatostatin analogs for a median duration of 6 months.
Main Outcome Measure:
GH and IGF-I levels were measured before and after postoperative treatment.
Results:
Sst2A IRS showed a significant positive correlation with both GH (P = 0.039) and IGF-I (P = 0.001) suppression by octreotide. Sst2A IRS was negatively associated with IGF-I levels reached after treatment (P = 0.001), and patients that achieved IGF-I normalization showed significantly higher sst2A IRS compared to the group that was not normalized (P = 0.002). A sst2A IRS of at least 5 showed a sensitivity of 86% and a specificity of 91% in predicting IGF-I normalization during adjuvant octreotide treatment.
Conclusion:
Sst2A IRS with the anti-sst2A antibody UMB-1 represents a valid tool in the clinical practice to identify acromegalic patients likely to be responders to adjuvant therapy with the currently available somatostatin analogs.
Abstract
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.
Abstract
Context
Cabergoline (CAB) is an off-label medical therapy for acromegaly, overshadowed by first-generation somatostatin receptor ligands, eg, octreotide (OCT).
Objective
This was a ...head-to-head comparison between OCT and CAB in inhibiting growth hormone (GH) secretion in primary cultures of GH- and GH/prolactin (PRL)-secreting tumors; we also investigated the role of somatostatin (SST) and dopamine type 2 (D2R) receptor expression.
Methods
We evaluated the antisecretory effect of OCT and CAB, together with receptor mRNA expression, in 23 tumor cultures obtained from acromegaly patients referred to the Erasmus Medical Center (Rotterdam, The Netherlands). GH concentrations in cell culture media were determined after 72-hour OCT and CAB treatment (10 nM).
Results
OCT showed a slightly higher efficacy compared with CAB (GH decrease −39.5% vs −32.5%, P = 0.079). The effect of the 2 drugs was superimposable in GH/PRL co-secreting tumors (−42.1% vs −44.8%), where SST1 and D2R had a higher expression compared with the pure GH-secreting tumors (P = 0.020 and P = 0.026). OCT was more effective than CAB in 8/23 cultures, while CAB was more effective than OCT in 3/23 (CAB+ group). In CAB+ tumors, SST1 expression was higher compared with the other groups (P = 0.034). At receiver operating characteristic (ROC) curve analysis, SST1 and D2R discriminated between GH and GH/PRL co-secretion (AUC 0.856, P = 0.013; AUC 0.822, P = 0.024). SST1 was the best predictor of CAB response (≥50% GH reduction, AUC 0.913, P = 0.006; 80% sensitivity, 94% specificity).
Conclusion
OCT is 5% to 10% more effective than CAB in vitro. SST1 mRNA expression can represent a reliable marker of GH/PRL co-secreting tumors showing a preferential response to CAB treatment.
Childhood cancer patients and their families are increasingly offered oncofertility care including information regarding their risk of gonadal damage by paediatric oncologists, fertility counselling ...by fertility specialists and fertility preservation options. However, experiences regarding oncofertility care are underreported. We aimed to summarize the available evidence of experiences of female childhood cancer patients and survivors regarding oncofertility care.
Manuscripts were systematically identified using the PubMed and Embase database. From, respectively, 1256 and 3857 manuscripts, 7 articles were included and assessed, including risk of bias assessment. Outcome measures included data describing experiences of female childhood cancer patients and survivors, regarding fertility information, counselling and/or preservation.
Female patients and survivors are variably satisfied with fertility information, report challenges in communication with healthcare professionals and prefer to receive general information at diagnosis and detailed fertility information later. Regrets after fertility counselling are underreported, but are associated with refusing fertility preservation. Lastly, regardless of counselling, female patients and survivors report fertility concerns about their future children's health and effect on relationships.
Currently, the satisfaction with oncofertility care varies and female patients or survivors report regrets and concerns regardless of receiving fertility information or counselling. These results may help to improve the content of fertility information, communication skills of healthcare professionals and timing of counselling.
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