Biochemical Remission Of Acromegaly Research Articles

Somatotroph Adenomas have a Predilection to Invade the Cavernous Sinus and Resection of the Medial Wall of the Cavernous Sinus Offers the Highest Potential for Biochemical Remission in Acromegaly

Recurrence and remission rates vary widely among different histological subtypes of pituitary adenoma. Invasion of the medial wall of the cavernous sinus is a known mechanism that may account for such failed clinical outcomes as its removal has long been considered unattainable. The use of modern endoscopic techniques allows for direct intraoperative evaluation of invasion and resection of the medial wall of the cavernous sinus with low morbidity when performed by highly experienced surgeons. In this retrospective study we evaluated 105 consecutive primary pituitary adenomas operated by a single surgeon including 28 corticotroph, 27 gonadotroph, 24 somatotroph, 15 lactotroph, 5 null-cell, 5 plurihormonal, and 1 dual adenoma; 53 caused hypersecretory syndromes, specifically acromegaly (30), hyperprolactinemia (15) and Cushing’s disease (8). In each case, we performed meticulous intraoperative inspection of the medial wall with its surgical removal when invasion was suspected, regardless of functional status. Medial wall resection was performed in 46% of pituitary adenomas, and 38/48 walls confirmed pathologic evidence of invasion rendering a positive predictive value of intraoperative evaluation of medial wall invasion of 79%. Furthermore, we show for the first time that the rate of medial wall invasion among pathological subtypes is dramatically different. Somatotroph tumors invaded the medial wall much more often than other adenoma subtypes, 83% intraoperatively and 71% histologically, followed by plurihormonal tumors (40%) and gonadotrophs (33%), both with intraoperative positive predictive value of 100%. The least likely to invade were corticotroph, at a rate of 32% intraoperatively and 21% histologically, and null-cell adenomas at 0%. Removal of the medial wall caused no permanent morbidity with no carotid artery injuries and 2 patients with transient diplopia. We report that resecting the medial wall of the cavernous sinus in acromegaly offers the highest potential for biochemical remission with average postoperative day 1 GH levels at 0.96 ug/l and early surgical remission rates at 90% (100% with adjuvant therapy) based on normalization of IGF-1 levels 3 to 6 months after surgery; these results are significantly better than previously reported but longer follow-up is required for definitive conclusions. Our findings may explain the failed biochemical remission rates seen in acromegaly and illustrate the relevance of advanced surgical techniques for successful outcomes in pituitary surgery.

Diverse Manifestation of Acromegaly With Suspicion of Ectopic GHRH Secretion. Report of Two Cases

Introduction: Acromegaly can rarely be caused by an ectopic production of GH or GHRH by various neoplasms, most commonly neuroendocrine tumors of pancreatic or pulmonary origin. Squamous cell carcinoma of the lung has not been associated with ectopic GHRH secretion yet. The authors present two cases of acromegaly with suspicion of GHRH ectopy. Presentation of the Cases: Case 1. A male born in 1945 presenting with typical morphologic features of acromegaly. Pituitary MRI revealed a cuneatic-shaped, hypointense focal lesion (8x7x6 mm) in the right posterior part of the anterior pituitary lobe, radiologically interpreted as either hyperplasia of the intermediate lobe or atypical adenoma in a normal-sized pituitary. IGF-1 and no suppression of GH secretion after oral glucose load were observed. Furthermore, a polycyclic tumor in the 2nd segment of the right lung with pathological metabolic activity in 18FDG- PET/CT was discovered. Ga68- DOTA TATE PET/CT revealed no pathological accumulation of the tracer. After upper right lobectomy, squamous cell carcinoma, non-keratinizing, G3, with a negative immunohistochemical reaction for GH was confirmed. IHC for GHRH and serum GHRH have been scheduled. After surgery and chemotherapy, no biochemical remission of acromegaly was observed and the pituitary MRI showed stable radiological image of the pituitary tumor, suggesting rather a possible metastasis to the pituitary. Due to unfavorable prognosis, the patient was disqualified from neurosurgical resection of the pituitary tumor. Case 2. a male born in 1948 with typical symptoms of acromegaly, elevation of IGF-1 and no suppression of GH in OGTT. Due to MRI contraindications, only CT of the head was performed- it revealed partially empty sella, compressed pituitary with maximal diameter 3 mm and no focal lesions. Treatment with somatostatin analogue was introduced, however, only partial biochemical control was achieved. Ga68- DOTA TATE PET/CT performed after 8 years showed pathological expression of somatostatin receptors in the pancreatic tail. Abdominal CT confirmed a focal lesion in this location, 14x9 mm, with a strong enhancement after contrast administration, suggesting a neuroendocrine tumor. The patient refused to undergo any invasive procedures and remains treated with SRL. Serum GHRH has been scheduled. Conclusion: The authors report two cases of ectopic acromegaly suspicion, with an ambiguous clinical and radiological presentation. In unclear cases of acromegaly, ectopic production of GHRH should be taken into consideration.

Predictors of postoperative biochemical remission in acromegaly.

Acromegaly is a rare neuroendocrine condition that can lead to significant morbidity. Despite China's vast population size, studies on acromegaly remain sparse. This study aimed to investigate the clinical characteristics and predictors of biochemical remission after surgery for acromegaly using the China Acromegaly Patient Association (CAPA) database. A retrospective nationwide study was conducted using patient-reported data from CAPA database between 1998 and 2018. The principal component analysis (PCA) and logistic regression analysis were employed to determine independent predictors of biochemical remission at 3months in patients after surgery. Of the 546 surgical cases (mean age: 36.8years; 59.5% females), macroadenomas and invasive tumors (Knosp score 3-4) were 83.9% and 64.1%, respectively. Ninety-five percent of patients were treated with endonasal surgery and 36.8% exhibited biochemical remission at 3-months postoperatively. The following independent predictors of biochemical remission were identified: preoperative growth hormone (GH) levels between 12 and 28μg/L [odds ratio (OR) = 0.58; 95% confidence interval (CI), 0.37-0.92; p = 0.021], preoperative GH levels > 28μg/L (OR = 0.55; 95% CI, 0.34-0.88; p = 0.013), macroadenoma (OR = 0.56; 95% CI, 0.32-0.96; p = 0.034), giant adenomas (OR = 0.14; 95% CI, 0.05-0.38; p < 0.001), Knosp score 3-4 (OR = 0.37; 95% CI, 0.24-0.57; p < 0.001), and preoperative medication usage (OR = 2.32; 95% CI, 1.46-3.70; p < 0.001). In this nationwide study spanning over two decades, we highlight that higher preoperative GH levels, large tumor size, and greater extent of tumor invasiveness are associated with a lower likelihood of biochemical remission at 3-months after surgery, while preoperative medical therapy increases the chance of remission.

MON-436 Clinical Phenotypes of GNAS Gene Mutations in Acromegalic Patients

Introduction Acromegaly is mostly caused by growth hormone (GH) hypersecretion. Guanine nucleotide-binding protein, α stimulating (GNAS) gene have been reported to be associated with GH secreting pituitary adenoma. Approximately 40% of patients with acromegaly have GNAS mutation. In this study, we investigated the prevalence of GNAS mutation in Korean acromegalic patients and assessed whether mutation status correlated with the biochemical or clinical characteristics. Method We studied acromegalic patients who underwent surgery between from July 2005 to January 2007 in Severance Hospital. Tumor genomic DNA was extracted using QIAamp DNA FFPE Tissue Kit from paraffin blocks of surgically resected tissue. GNAS gene analysis was performed with amplications of regions containing hotspot 2 sites of activating somatic mutations in codons 201 and 227. We evaluated the age, gender, GH, IGF-1 levels and immunohistochemical staining results of tumor. Biochemical remission of acromegaly was defined as a normal serum IGF-1 level or nadir GH after oral glucose tolerance test (OGTT) was less than 1ng/ml. Biochemical characteristics had been followed up at least 10 years. Result We analyzed 126 patients. GNAS mutations were present in 75 of the 126 acromegalic pateints (59.5%). Among the GNAS mutant patient, 61 subjects (81%) had mutation in codon 201. Patients with and without GNAS mutations were similar in age distribution and Hardy classification. The mutation negative group was 76.5% female and the mutation positive group was 48.0% female (p=0.006). GNAS mutant group had higher prevalence of overall GH expression in immunohistochemical staining (98.7% vs. 92.2%, p = 0.015). GNAS mutant patients are associated with higher IGF-1 level preoperatively (791.3 vs. 697.0ng/ml, p=0.045). Immediate postoperative basal GH (0.9 vs. 1.0ng/ml, p = 0.191) and nadir GH (0.3 vs. 0.6ng/ml, p=0.012) in OGTT was lower in GNAS mutant patients. Surgical remission rates were significantly higher in GNAS mutant patients, evaluated both at immediately and at 6 months after operation (70.7% vs. 54.9%, p=0.011; 85.3% vs. 82.4%, p=0.007, respectively). Conclusion In conclusion, GNAS mutation was more frequently found in Korean acromegalic patients. GNAS mutation positive tumors tended to have higher preoperative IGF-1 level, surgical remission rate and lower immediate postoperative nadir GH on OGTT. Identifying the GNAS mutation would be helpful in predicting patient’s clinical features and prognosis.

Acromegaly surgery in Manchester revisited – The impact of reducing surgeon numbers and the 2010 consensus guidelines for disease remission

Surgical remission rates for acromegaly vary and are dependent on the tumour morphology, biochemical definition of disease remission and surgical expertise. A previous report from the Manchester region in 1998 reported an overall surgical remission rate of 27% using accepted criteria for biochemical remission at the time. The establishment of the 2010 Consensus guidelines further tightens biochemical criteria for remission. This report aims to assess the impact of establishing a specialist pituitary surgery service in Manchester in 2005, with reduced surgeon numbers on the remission rates for acromegaly surgery. Patients with acromegaly undergoing first time endoscopic transsphenoidal surgery between 2005 and 2010 were studied. Surgery was performed by a single surgeon. Review of a prospectively collected acromegaly surgery database was performed with documentation of pre- and postoperative biochemical tests [oral glucose tolerance test (oGTT) and IGF-1], as well as clinical, pathological and radiological data. Definition of disease remission was according to the 2010 Consensus criteria (GH nadir <0·4 μg/l following an oGTT and normalized population matched IGF-1). There were 43 consecutive patients with acromegaly, with 13 (30%) microadenomas and 12 (28%) invasive adenomas. Overall, surgical remission was achieved in 29 (67%) patients. The remission rates were similar between micro (77%), macro (63%) and giant (67%) adenomas. There were nonsignificant trends towards higher remission rates for noninvasive tumours compared with invasive tumours (74%vs 50%) and for patients with a preoperative GH nadir <10 μg/l (73%vs 54%) and IGF-1 standard deviation score <15 (72%vs 54%). Remission rates for acromegaly surgery have improved following establishment of a specialist surgical service, with a reduction in surgeon numbers. Endoscopic trans-sphenoidal surgery remains an effective first-line treatment for achieving biochemical remission in acromegaly, despite the introduction of the more stringent 2010 consensus guidelines.

Secondary erythrocytosis in patient with acromegaly

A 53-year old man with acromegaly was referred for neurosurgical treatment. At admission: growth hormone (GH) 240 ME/l at all time points of glucose tolerance test, IGF-1 - 415,1 ng/ml, brain MRI showed pituitary adenoma 34×32×27 mm extending suprasellar, deforming and displacing optic chiasm, parasellar to both cavernous sinuses and surrounding left internal carotid artery. Clinical blood tests revealed marked erythrocytosis - 6.1×1012, Hb - 200 g/l, HCT - 62%; urobilinigen 50 mmol/l was found in urine; otherwise the tests were normal. For exclusion of erythraemia the patient underwent trepanobiopsy of bone marrow which showed normal haemopoesis and suggested a secondary nature of erythrocytosis. In preoperative period 1100 ml of blood were evacuated by phlebotomy in 4 sessions, which resulted in reduction of erythrocyte count to 5,1×1012, Hb 160 g/l, HCT 50% and disappearance of urobilinigen. The patient was then operated by transnasal approach with debulking of most adenomatous tissue but without biochemical remission of acromegaly (GH 92-99 at glucose tolerance test). A week after surgery - erythrocytes 4,5×1012, Hb - 141 g/l, HCT - 44,1%. The patient was prescribed a octreotide depo (Sandostatin LAR) injections 20 mg/mth and at 6 months from operation was feeling well, with clinical remission of acromegaly and normalization of IGF-1 and all blood count parameters.

Tumor Volume of Growth Hormone-Secreting Pituitary Adenomas during Treatment with Pegvisomant: A Prospective Multicenter Study

Clinical and biochemical remission in acromegaly can frequently be achieved with the recombinant GH receptor antagonist pegvisomant, even when other treatments fail. However, increases in tumor volume have been reported. Because previous studies suffer from inhomogenous magnetic resonance imaging (MRI) protocols, this prospective study examined the long-term course of adenoma volume during pegvisomant therapy by standardized MRI. Five centers in Germany participated. High-resolution MRI was performed at baseline and 6, 12, and 24 months after enrollment. Patients were outpatients, and pegvisomant is third-line therapy in most of the cases. The primary end point was tumor volume at 24 month follow-up, measured by a single, double-blinded rater. Forty-five of 61 patients completed 24 months' follow-up (73.8%). Tumor volume increase greater than 25% during the study was observed in three of 61 patients (4.9%), all during the first year of enrollment. All three patients had had octreotide treatment before initiation of pegvisomant; none of them had had radiotherapy. All volumetric findings were comparable with clinical radiological interpretations. ANOVA revealed no significant change in tumor volume after 24 months (n = 45). This study shows that pegvisomant therapy infrequently coincides with tumor growth during long-term treatment of acromegaly. Because all significant tumor volume increases occurred during the first year, these changes might correlate to the change of medication and thus be the result of a rebound from somatostatin-induced shrinkage.

Cardiac manifestations of GH deficiency after treatment for acromegaly: a comparison to patients with biochemical remission and controls

Both GH excess and GH deficiency (GHD) lead to specific cardiac pathology. The aim of this study was to evaluate cardiac morphology and function in patients with GHD after treatment for acromegaly. Cross-sectional study. Cardiac parameters were studied by conventional two-dimensional echocardiography and tissue Doppler imaging in 53 patients with acromegaly (16 patients with GHD, 20 patients with biochemical remission, and 17 patients with active disease). Patients with GHD were also compared with age- and gender-matched controls. Left ventricular (LV) dimensions, wall thickness, and mass did not differ between the three groups, or between the patients with GHD and healthy controls. Systolic function, assessed by LV ejection fraction, tended to be lower in patients with GHD compared with patients with biochemical remission (65.9+/-7.3% vs 72.4+/-8.5%, P=0.070), but was higher when compared with active acromegaly (58.8+/-9.3%, P=0.047). No differences were found with healthy controls. Diastolic function, measured with early diastolic velocity (E'), was lower in patients with GHD when compared with both patients with biochemical remission (6.0+/-2.1 cm/s vs 8.3+/-1.5 cm/s, P=0.005) and healthy controls (8.1+/-1.9 cm/s, P=0.006). GHD after acromegaly results in a specific decrease in diastolic function compared with patients with biochemical remission of acromegaly and healthy controls. In addition, systolic function tends to be decreased in patients with GHD compared with patients with biochemical remission, but was higher than that in patients with active acromegaly.

Clinical indicators of biochemical remission in acromegaly: does incomplete disease control always mean therapeutic failure?

Correction of GH and IGF-I levels are associated with improvements in insulin secretion, cardiac performance and body composition in patients with acromegaly, but whether these parallel post-treatment levels of GH-IGF-I axis activity is undefined. We investigate whether various biochemical outcomes after transsphenoidal pituitary surgery (TSS) in these patients are associated with clinically relevant differences in cardiac performance, insulin resistance and body composition. Cross-sectional study of consecutive patients with acromegaly admitted to the hospital between 2001 and 2002. Forty-one patients after TSS for somatotroph pituitary adenoma and 23 patients with naive acromegaly serving as positive controls were enrolled in the study. Mean daily GH levels (mGH), IGF-I, leptin and lipid levels, glucose, insulin and GH concentrations during oral glucose tolerance test (oGTT) were measured in all study participants. Insulin resistance was measured by homeostatic model index (R(HOMA)). Body composition was assessed by dual-energy X-ray absorptiometry. Left ventricular mass index (LVM(i)) and cardiac index (C(i)) were determined by echocardiography. We found no difference in cardiac indices, insulin resistance, body composition and leptin levels between patients with complete biochemical remission and those with inadequately controlled disease (P > 0.05 for all) after TSS. Cured patients had lower values (mean +/- SD) of cardiac index (2.2 +/- 0.7 vs. 3.0 +/- 1.0 l/min/m(2); P = 0.04) compared with naive patients. A similar decrease in LVM(i) was observed in controlled (108.4 +/- 30.0 g/m(2); P = 0.015) and inadequately controlled disease (108.8 +/- 30.7 g/m(2); P = 0.03) in comparison with naive disease (160.3 +/- 80.6 g/m(2)). Insulin resistance and leptin changed in opposite ways. In controlled and inadequately controlled disease, R(HOMA) index was lower (2.2 +/- 1.4; P = 0.001 and 3.1 +/- 2.0; P = 0.05 vs. 5.1 +/- 3.1) while leptin concentration was higher (14.9 +/- 8.7 microg/l, P = 0.004 and 12.8 +/- 7.8 microg/l, P = 0.05 vs. 7.4 +/- 3.8 microg/l) than in naive disease. In all patients, leptin correlated negatively with cardiac index (r = -0.46; P = 0.001) and IGF-I levels (r = -0.45; P < 0.001). Independent predictors of biochemical remission, based on normal IGF-I levels only, were cardiac [P = 0.04, odds ratio (OR) 0.4; 95% confidence interval (CI) 0.2-0.9] and R(HOMA) index (P = 0.009, OR 0.6; 95% CI 0.4-0.8). Similar results were obtained if the definition of cure included both normal IGF-I levels and the ability to achieve GH nadir < 1 microg/l during oGTT. Insulin resistance (P = 0.02, OR 0.6; 95% CI 0.4-0.9) and leptin level (P = 0.002, OR 1.3; 95% CI 1.1-1.6) were independent predictors of normalized mGH values. This study shows that cardiac indices, insulin resistance and body composition were not different between patients with complete biochemical remission and those with discordant GH and IGF-I levels. It appears that even incomplete disease control after TSS can result in improvement of these clinical markers.

Comment on Long-Acting Lanreotide Inducing Clinical and Biochemical Remission of Acromegaly Caused by Disseminated GHRH Secreting Carcinoid

Comment on Long-Acting Lanreotide Inducing Clinical and Biochemical Remission of Acromegaly Caused by Disseminated GHRH Secreting Carcinoid

Comment on Long-Acting Lanreotide Inducing Clinical and Biochemical Remission of Acromegaly Caused by Disseminated GHRH Secreting Carcinoid

Comment on Long-Acting Lanreotide Inducing Clinical and Biochemical Remission of Acromegaly Caused by Disseminated GHRH Secreting Carcinoid

Long-Acting Lanreotide Induces Clinical and Biochemical Remission of Acromegaly Caused by Disseminated Growth Hormone-Releasing Hormone-Secreting Carcinoid

Long-Acting Lanreotide Induces Clinical and Biochemical Remission of Acromegaly Caused by Disseminated Growth Hormone-Releasing Hormone-Secreting Carcinoid

Heel pad thickness is an insensitive index of biochemical remission in acromegaly

The value of serial measurements of heel pad thickness as a clinical predictor of biochemical remission in acromegaly was assessed in 25 patients followed for up to 20 years after treatment by interstitial irradiation using yttrium-90 implantation. Growth hormone (GH) levels fell to 50% of baseline values within 12 months of therapy (P less than 0.001) and to 21% at 5 years, reaching normal levels after 10 years, constituting a biochemical cure maintained to the end of the study period. By contrast, heel pad thickness remained relatively stable, falling to 95% of baseline after 5 years (P less than 0.05) and to 87% after 20 years. There was no overall correlation between the measured parameters (r = 0.033, P greater than 0.05) suggesting that heel pad thickness is a poor predictor of biochemical remission in acromegaly.