Role of biological effective dose for prediction of endocrine remission in acromegaly patients treated with stereotactic radiosurgery.

PURPOSE: Stereotactic radiosurgery (SRS) can be used in acromegaly patients to achieve endocrine remission. In this study we evaluate the biological effective dose (BED) as a predictor of SRS outcomes for acromegaly. METHOD: This retrospective, single-center study included patients treated with single-fraction SRS with growth hormone secreting pituitary adenomas and available endocrine follow-up. Kaplan-Meier analysis was used to study endocrine remission, new pituitary deficit, and tumor control. Cox analyses were performed using two models [margin dose (model 2) versus BED (model 1)]. RESULTS: Sixty-seven patients (53.7% male) with a median age of 46.8 years (IQR 21.2) were treated using a median dose of 25 Gy (IQR 5), and a median BED of 171.9Gy2.47 (IQR 66.0). Five (7.5%) were treated without stopping antisecretory medication. The cumulative probability of maintained endocrine remission off suppressive medications was 62.5% [47.9-73.0] at 3 years and 76.5% [61.0-85.9] at 5 years. IGF1i > 1.5 was a predictor of treatment failure [Hazard ratio (HR) 0.40 (0.21-0.79) in model 1, p = 0.00783]. Margin dose > 22 Gy [HR 2.33 (1.06-5.13), p = 0.03593] or a BED > 170Gy2.47 [HR 2.02 (1.06-3.86), p = 0.03370] were associated with endocrine remission. The cumulative probability of new hypopituitarism after SRS was 36.8% (CI 95% 22.4-45.9) at 3 years and 53.2% (CI 95% 35.6-66) at 5 years. BED or margin dose were not associated with new hypopituitarism. CONCLUSION: BED is a strong predictor of endocrine remission in patients treated with SRS. Dose planning and optimization of the BED to > 170Gy2.47 give a greater probability of endocrine remission in acromegalic patients.

Radiosurgery as primary management for acromegaly.

OBJECTIVE: Transsphenoidal surgery (TSS) remains the recommended primary treatment for acromegaly. Long-term outcome data are not available for patients treated with gamma knife radiosurgery (STRS) as a primary treatment. DESIGN: Retrospective cohort study. DATA COLLECTION: notes review, laboratory results, general physician notes, patient questionnaire and death certification. PATIENTS: Twenty acromegaly patients underwent primary STRS at the National Centre for Radiosurgery, Sheffield, UK, between 1985 and 2015. MEASUREMENTS: Biochemical control (GH/IGF1), hypopituitarism, morbidity and mortality were all recorded. RESULTS: At 20 years of follow-up, control was seen in all on acromegaly-specific medication (n = 12) and 75% of those off medication (3/4). Time for 50% to achieve control on medication was 3 years, and 7.4 years off medication. Median marginal radiation dose was 27.5 Gy, and median follow-up was 166.5 months. 53% of patients developed new hypopituitarism at a median follow-up of 146 months, and the development of first onset of hypopituitarism occurred as late as 20 years after treatment. With MRI planning, no other complications were noted. Three patients underwent subsequent TSS due to poor biochemical control. During follow-up, 7 patients died at a median age of 65 years. There were no STRS-related deaths. CONCLUSION: This is the longest follow-up of patients who have undergone primary STRS for acromegaly. It shows low morbidity, but significant latency to biochemical control and new-onset hypopituitarism. This mandates very long-term follow-up for these patients. STRS has shown good long-term efficacy providing initial control can be afforded by optimal medical management. While TSS remains best practice, STRS offers an alternative for those in whom surgery is not an option.

Safety and efficacy of repeat radiosurgery for acromegaly: an International Multi-Institutional Study.

PURPOSE: Surgical resection is the first line treatment for growth hormone (GH) secreting tumors. Stereotactic radiosurgery (SRS) is recommended for patients who do not achieve endocrine remission after resection. The purpose of this study was to evaluate safety and efficacy of repeat radiosurgery for acromegaly. METHODS: Three hundred and ninety-eight patients with acromegaly treated with the Gamma Knife radiosurgery (Elekta AB, Stockholm) were identified from the International Gamma Knife Research Foundation database. Among these, 21 patients underwent repeated SRS with sufficient endocrine follow-up and 18 patients had sufficient imaging follow-up. Tumor control was defined as lack of adenoma progression on imaging. Endocrine remission was defined as a normal IGF-1 concentration while off medical therapy. RESULTS: Median time from initial SRS to repeat SRS was 5.0 years. The median imaging and endocrine follow-up duration after repeat SRS was 3.4 and 3.8 years, respectively. The median initial marginal dose was 17 Gy, and the median repeat marginal dose was 23 Gy. Of the 18 patients with adequate imaging follow up, 15 (83.3%) patients had tumor control and of 21 patients with endocrine follow-up, 9 (42.9%) patients had endocrine remission at last follow-up visit. Four patients (19.0%) developed new deficits after repeat radiosurgery. Of these, 3 patients had neurologic deficits and 1 patient had endocrine deficit. CONCLUSIONS: Repeat radiosurgery for persistent acromegaly offers a reasonable benefit to risk profile for this challenging patient cohort. Further studies are needed to identify patients best suited for this type of approach.

Radiotherapy in acromegaly: Long-term brain parenchymal and vascular magnetic resonance changes.

BACKGROUND: Radiation therapy (RT) effectiveness on hormonal reduction is proven in acromegaly; however, collateral long-term effects are still undetermined. This transversal neuroimaging study on a large cohort of acromegalic patients aimed to investigate the rate of parenchymal and vascular changes after RT. MATERIALS AND METHODS: Thirty-six acromegalic patients underwent RT (RT+) after unsuccessful surgery and were compared to RT- acromegalic patients matched for age, gender, adenoma features, clinical and surgical history. All patients underwent magnetic resonance angiography (MRA) to investigate intracranial artery abnormalities and FLAIR sequence to assess white matter changes according to the Wahlund scale. RESULTS: RT+ acromegalic patients had a higher rate of controlled disease (29/36 vs. 12/36, P<0.001). RT+ acromegalic patients had MRI/MRA evaluation 15.3±9.6 years after RT. RT+ acromegalic patients had a significantly higher Wahlund score than RT- acromegalic patients (6.03±6.41 vs. 2.53±3.66, P=0.006) due to increased white matter signal abnormalities at the level of the temporal lobes, the basal ganglia (insula) and the infratentorial regions, bilaterally. Among RT+ patients one died because of temporo-polar anaplastic astrocytoma, one suffered from a stroke due to right internal carotid artery occlusion, one presented with cystic degeneration of the temporal poles. Long-dated RT (>10 years before MR evaluation) was associated with a higher rate of RT-related white matter changes (P=0.0004). CONCLUSIONS: RT seems to have created a cohort of patients with brain parenchymal changes whose clinical and cognitive impact is still unknown. These patients might require a prolonged MRI and MRA follow-up to promptly detect delayed RT-related complications and minimize their clinical consequences.

Updates in outcomes of stereotactic radiation therapy in acromegaly.

Purpose Treatment of acromegaly has undergone important progress in the last 20 years mainly due to the development of new medical options and advances in surgical techniques. Pituitary surgery is usually first-line therapy, and medical treatment is indicated for persistent disease, while radiation (RT) is often used as third-line therapy. The benefits of RT (tumor volume control and decreased hormonal secretion) are hampered by the long latency of the effect and the high risk of adverse effects. Stereotactic RT methods have been developed with the aim to provide more precise targeting of the tumor with better control of the radiation dose received by the adjacent brain structures. The purpose of this review is to present the updates in the efficacy and safety of pituitary RT in acromegalic patients, with an emphasis on the new stereotactic radiation techniques. Methods A systematic review was performed using PubMed and articles/abstracts and reviews detailing RT in acromegaly from 2000 to 2016 were included. Results Stereotactic radiosurgery and fractionated stereotactic RT (FSRT) for patients with persistent active acromegaly after surgery and/or during medical therapy provide comparable high rates of tumor control, i.e. stable or decrease in size of the tumor in 93-100% of patients at 5-10 years and endocrinological remission in 40-60% of patients at 5 years. Hypofractionated RT is an optimal option for tumors located near the optic structures, due to its lower toxicity for the optic nerves compared to single-dose radiosurgery. The rate of new hypopituitarism varies from 10 to 50% at 5 years and increases with the duration of follow-up. The risk for other radiation-induced complications is usually low (0-5% for new visual deficits, cranial nerves damage or brain radionecrosis and 0-1% for secondary brain tumors) and risk of stroke may be higher in FSRT. Conclusion Although the use of radiotherapy in patients with acromegaly has decreased with advances in medical treatments, it remains an effective treatment option after unsuccessful surgery and/or resistance or unavailability of medical therapy. Long-term studies evaluating secondary morbidity and mortality rate after the new stereotactic techniques are needed, in order to evaluate their potential brain-sparing effect.

Management of aggressive growth hormone secreting pituitary adenomas.

Aggressive GH-secreting pituitary adenomas (GHPAs) represent an important clinical problem in patients with acromegaly. Surgical therapy, although often the mainstay of treatment for GHPAs, is less effective in aggressive GHPAs due to their invasive and destructive growth patterns, and their proclivity for infrasellar invasion. Medical therapies for GHPAs, including somatostatin analogues and GH receptor antagonists, are becoming increasingly important adjuncts to surgical intervention. Stereotactic radiosurgery serves as an important fallback therapy for tumors that cannot be cured with surgery and medications. Data suggests that patients with aggressive and refractory GHPAs are best treated at dedicated tertiary pituitary centers with multidisciplinary teams of neuroendocrinologists, neurosurgeons, radiation oncologists and other specialists who routinely provide advanced care to GHPA patients. Future research will help clarify the defining features of "aggressive" and "atypical" PAs, likely based on tumor behavior, preoperative imaging characteristics, histopathological characteristics, and molecular markers.

HIGH-PRECISION CONFORMAL FRACTIONATED RADIOTHERAPY IS EFFECTIVE IN ACHIEVING REMISSION IN PATIENTS WITH ACROMEGALY AFTER FAILED TRANSSPHENOIDAL SURGERY.

OBJECTIVE: Variable efficacy of pituitary radiotherapy in acromegaly is reported. Here we sought to assess the efficacy of high-precision conformal fractionated radiotherapy (CRT) in patients with acromegaly after failed TSS. METHODS: A retrospective analysis was conducted a in tertiary care referral center between 1999 to 2013 on 36 acromegaly patients (M: 16, F: 20; median age: 36.0 years) with macroadenoma and mean growth hormone (GH) and insulin-like growth factor-1 (IGF1) upper limits of normal (ULN) of 15.9 ± 14.3 ng/mL and 1.74 ± 0.43, respectively. The cohort was divided into 2 groups: 30 patients (M: 13, F: 17) who were medical treatment naïve, and 6 patients (M: 3, F: 3) who received medical treatment after CRT. RESULTS: Normalization of GH (fasting GH <1 ng/mL), normalization of IGF1 (ULN <1), and remission (normalization of GH and IGF1) were achieved in 20 (55%), 23 (63%) and 20 (55%) patients, respectively. The mean time required to achieve remission was 63 ± 33.4 months. Follow-up duration was the only predictor of achieving remission. GH level declined exponentially by 65% and 89% at 2 and 5 years, respectively. New onset hypopituitarism was noted in 33% of patients. Tumor control was achieved in 100% of patients. In groups 1 and 2, 18 (60%) and 2 (33.3%) achieved remission post-CRT, and the mean times required to achieve remission were 58.6 ± 30.7 months and 102 ± 42.4 months, respectively. CONCLUSION: High-precision CRT is an effective modality to achieve remission in patients with acromegaly after failed TSS.

Associations of coefficient of variation of serum GH with previous radiotherapy, hypopituitarism and cardiac disease in patients with treated acromegaly.

BACKGROUND: Cardiovascular complications represent the biggest cause of mortality in acromegaly. It is therefore important to optimally stratify acromegalic patients according to disease activity and complication risk. GH is secreted in a pulsatile manner from the pituitary gland, but GH pulsatility is not routinely assessed clinically. The coefficient of variation of serum GH (GHCV) during oral glucose tolerance test (OGTT) quantifies the variation of GH secretion in patients with acromegaly, but has not been reported previously. AIM: To investigate whether GHCV during OGTT is associated with clinical parameters predicted to relate with hypothalamo-pituitary dysfunction during acromegaly, such as radiotherapy treatment, pituitary deficiency and cardiac disease. METHODS: GHCV was calculated during 584 OGTTs and compared with nadir serum GH and IGF-1 in 111 acromegalic patients treated at a single centre. RESULTS: Acromegalic patients treated with radiotherapy had a 37% lower level of GHCV when compared to the nonradiotherapy group (mean GHCV: 0·298 ± 0·015, no radiotherapy; 0·189 ± 0·007, radiotherapy; P < 0·001). Neither serum IGF-1 nor nadir GH was significantly altered in the radiotherapy group. Mean GHCV was 50% lower in the acromegalic patients with cardiac failure when compared to acromegalic patients with normal echocardiogram (0·161 ± 0·034 vs 0·297 ± 0·055; P < 0·05). Neither serum IGF-1 nor nadir GH was significantly altered during cardiac failure. CONCLUSION: Our preliminary data suggest that GHCV during OGTT may be reduced during acromegaly in patients with previous radiotherapy, pituitary deficiencies and cardiac disease. Larger studies are required to determine whether GHCV could provide help to assess the morbidity status of patients with treated acromegaly.

The quality of life in acromegalic patients with biochemical remission by surgery alone is superior to that in those with pharmaceutical therapy without radiotherapy, using the newly developed Japanese version of the AcroQoL.

PURPOSE: To develop a Japanese version of the acromegaly quality of life (QoL) questionnaire (AcroQoL) and investigate the factors associated with impaired QoL in patients with acromegaly. METHODS: We developed a Japanese version of the AcroQoL by a forward-backward method and evaluated QoL in 38 patients with acromegaly who had been followed up at an outpatient clinic at Kobe University Hospital. Its reliability was examined with Cronbach's alpha and item-total correlations. Second examination was performed for concurrent validity by assessment of correlations with the Short Form-36 (SF-36) and longitudinal analysis of the AcroQoL in 25 patients. RESULTS: Cronbach's alpha and item-total correlations showed a range of 0.76-0.93 and 0.20-0.84, respectively, and significant correlations were found between the AcroQoL and the SF-36. Younger age and a history of radiotherapy were associated with worse total score by the multivariate linear regression analysis (p = 0.020 and p = 0.042, respectively). Intriguingly, in the biochemically-controlled group after the exclusion of patients who received radiotherapy, patients who underwent surgery alone exhibited a higher psychological (75.0 vs. 65.7 %, p = 0.036) and appearance (64.3 vs. 53.6 %, p = 0.036) score than those who are treating with pharmaceutical therapy. CONCLUSIONS: The reliability of the Japanese version of the AcroQoL was satisfactory. Younger age and a history of radiotherapy were associated with lower QoL in patients with acromegaly. In biochemically-controlled acromegaly, patients who underwent surgery alone exhibited better QoL than those under pharmaceutical therapy.

RADIOTHERAPY VERSUS RADIOSURGERY IN TREATING PATIENTS WITH ACROMEGALY: A SYSTEMATIC REVIEW AND META-ANALYSIS.

OBJECTIVE: When patients with acromegaly have residual disease following surgery, adjuvant radiation therapy is considered. Both stereotactic radiosurgery (SRS) and conventional fractionated radiotherapy (RT) are utilized. We conducted a systematic review and meta-analysis to synthesize the existing evidence and compare outcomes for SRS and RT in patients with acromegaly. METHODS: We searched Medline In-Process & Other Non-Indexed Citations, MEDLINE, EMBASE, Cochrane Central Register of Controlled Trials, Cochrane Database of Systematic Reviews, and Scopus through April 2014 for studies in which SRS or RT were used in patients with acromegaly. Outcomes evaluated were serum insulin-like growth factor-I (IGF-I) and growth hormone (GH) levels, biochemical remission, all-cause mortality, hypopituitarism, headaches, and secondary malignancies. We pooled outcomes using a random-effects model. RESULTS: The final search yielded 30 eligible studies assessing 2,464 patients. Compared to RT, SRS was associated with a nonsignificant increase in remission rate at the latest follow-up period (52% vs. 36%; P = .14) and a significantly lower follow-up IGF-I level (-409.72 µg/L vs. -102 µg/L, P = .002). SRS had a lower incidence of hypopituitarism than RT; however, the difference was not statistically significant (32% vs. 51%, respectively; P = .05). CONCLUSION: SRS may be associated with better biochemical remission, and it had a lower risk of hypopituitarism with at least 1 deficient axis when compared with RT; however, the confidence in such evidence is very low due to the noncomparative nature of the studies, high heterogeneity, and imprecision.

Changes in acromegaly treatment over four decades in Spain: analysis of the Spanish Acromegaly Registry (REA).

Since 1997 there is an online National Registry of acromegalic patients in Spain (REA). We aimed to study changes in acromegaly treatment and outcomes over the last four decades in Spain. In REA clinical and biochemical data are collected at diagnosis and updated every one to 2 years. We analyzed the first treatment received and the different treatments administered according to decade of diagnosis of acromegaly: prior to 1980, 1980-1989, 1990-1999 and 2000-2009. Surgical cure rates according to pretreatment with long-acting somatostatin receptor ligands (SRLs) were also analyzed. 1,658 patients were included of which 698 had accurate follow-up data. Treatment of acromegaly changed over time. Surgery was the main treatment option (83.8 %) and medical treatment was widely used (74.7 %) both maintained over decades, while radiation therapy declined (62.8, 61.6, 42.2 and 11.9 % over decades, p < 0.001). First treatment type also changed: surgery was the first line option up until the last decade in which medical treatment was preferred (p < 0.001). Radiotherapy was barely used as first treatment. Treatment combinations changed over time (p < 0.001). The most common treatment combination (surgery plus medical therapy), was received by 24.4, 16.4, 25.3 and 56.5 % of patients over decades. Medical treatment alone was performed in 7.3, 6, 7.2 and 14.7 % over decades. Type of medical treatment also changed, SRLs becoming the first medical treatment modality in the last decades, whereas dopamine agonist use declined (p < 0.001). Surgical cure rates improved over decades (21, 21, 36 and 38 %, p = 0.002) and were not influenced by SRL pre-surgical use. Acromegaly treatment has changed in Spain in the last four decades. Surgery has been the main treatment option for decades; however, medical therapy has replaced surgery as first line in the last decade and radiotherapy rates have clearly declined. SRLs are the most used medical treatment.

Endoscopic endonasal approach for growth hormone secreting pituitary adenomas: outcomes in 53 patients using 2010 consensus criteria for remission.

We report the outcomes of the endoscopic endonasal approach (EEA) for resection of growth hormone secreting pituitary adenomas using 2010 consensus criteria. We also assess outcomes with additional medical therapy and radiosurgery (RS) for patients not achieving remission with EEA alone. A retrospective review of 53 patients who had follow up endocrinologic data at least 3 months post-surgery was performed among patients who were treated by EEA between 1998 and 2012. Data were analyzed for remission using GH and IGF-I levels based on 2010 consensus criteria. We also analyzed the outcomes using 2000 consensus criteria for ease in comparison to prior studies of outcomes of surgery for acromegaly. In this series of mostly large (88.2% macroadenomas), invasive (46.9% Hardy-Wilson C, D, E) adenomas, there were 27 patients (50.9%) who achieved remission after EEA only. For patients who had no remission with EEA alone, RS and/or medical therapy were used and 37 patients (69.8 %) achieved remission overall. Statistical analysis showed larger tumor size, Hardy Stages C, D, E and Knosp Scores 3, 4 to be predictive against remission for EEA only and EEA with other modalities. The volume of residual tumor after EEA was not found to be predictive of remission with additional therapies. We used stringent consensus criteria from 2010 in a series which included a high proportion of invasive GH secreting adenomas to show that EEA alone or combined with other modalities results in comparable remission rates to earlier studies which used less strict criteria, while retaining low complication rates.

Medical treatment of acromegaly-experience from the Croatian acromegaly registry.

PURPOSE: The aim of this study was to review therapeutic outcomes of the medical treatment of patients with acromegaly based on real-world data from the Croatian Acromegaly Registry. METHODS: In this retrospective study we investigated 163 patients (101 female, 62 male, age at diagnosis 47.2 ± 13.4 years) treated between 1990 and 2020, of which 53 were treated medically (32.5%). The duration of follow-up was 115.8 ± 304.4 months. The remission rate after the pituitary surgery was achieved in 66.5% (n = 105/158; 5 patients refused surgery). Patients who did not achieve disease remission or had a relapse during follow-up (n = 2), underwent reoperation (n = 18/60, 30%) and/or radiotherapy (n = 33/60, 55%) and/or medical treatment (n = 53/60, 88.3%). One patient refused further treatment after the failure of the first pituitary surgery. RESULTS: Out of 53 patients treated with medical therapy, monotherapy was used in 34 (64.2%) and combination therapy in 19 (35.8%) patients. Remission (IGF-I < 1.2 upper limit of normal, ULN) was achieved in 51 patients (96.2%). Out of 53 patients, 21 (39.6%) were treated with first-generation somatostatin receptor ligand (SRL-1) monotherapy, 10 (18.9%) with dopamine agonist (DA) monotherapy, one (1.9%) with pegvisomant monotherapy, 13 (24.4%) with a combination of SRL-1 and DA, three (5.7%) with a combination of SRL-1, DA and pegvisomant, two (3.8%) with a combination of second-generation somatostatin receptor ligand (SRL-2), DA and pegvisomant and in one (1.9%) temozolomide was added on top of SRL-1 and DA. Two patients currently have active disease, both on SRL-1 monotherapy, of whom one is non-adherent to the treatment. Radiotherapy was applied to 27 (50.9%) patients on medical therapy. CONCLUSION: Our results indicate that almost all patients with active acromegaly after pituitary surgery can achieve biochemical control with medical treatment.

Characterization of management and outcomes of patients with acromegaly in Vancouver over 30 years.

PURPOSE: The purpose of this study was to characterize the management and outcomes of patients with acromegaly seen in single center in Vancouver, British Columbia, Canada over a 30 year period. METHODS: The study involved retrospective data collection from charts of patients diagnosed with acromegaly since 1980: 130 patients (63 male and 67 female) were included in the analysis, with a mean age at diagnosis of 43 years (male) and 47 years (female). RESULTS: The most common presenting features included acral enlargement, coarse facial features, sweating/oily skin and headache. All cases were caused by pituitary adenomas, of which 58.5% were macroadenomas and of these, 30.8% were invasive. The most common co-morbidities were hypertension 31.5%, arthralgia 28%, diabetes 27.7% and sleep apnea 23.8%. The vast majority (88.5%) of patients was treated surgically and of these patients, 21.5% also received radiotherapy and 66.9% received medical therapy. When stringent cure criteria were applied (based on latest growth hormone (GH) and IGF-1 results) the outcomes were 35.4% cured or controlled, 30% remained active, 15.4 discordant results and 19.2 % with no results reported. Twenty eight percent of patients who underwent surgery and 32% of patients who underwent radiotherapy were not cured but symptoms were moderately well controlled with medical therapy. CONCLUSION: Based on the size of population studied, this study showed a prevalence of acromegaly of 29 per million. The cure rate was low following surgery but with adjuvant medical treatment disease control was achieved in most individuals.

Growth of an aggressive tumor during pregnancy in an acromegalic patient.

Pregnancy in acromegalic patients is a rare event, but is usually uneventful, with stable GH and IGF-I levels and no tumor enlargement. Medical treatment can usually be withdrawn without problems and although no major adverse event has been reported, the suspension of drug treatments is generally recommended. No case report exists in the literature regarding evolution of a somatotropinoma with invasiveness markers throughout pregnancy. We report a case of an acromegalic patient who was submitted to surgery and treated with octreotide LAR maintaining a stable residual tumor and an IGF-I close to the normal levels. Her tumor presented with a high Ki-67 (11.6%) and a low aryl hydrocarbon receptor-interacting protein (AIP) expression. When she became pregnant, octreotide LAR was withdrawn, and despite remaining asymptomatic during pregnancy, tumor growth occurred with compression of surrounding structures. In conclusion, pregnancy in acromegalic patients has usually a favorable prognosis with no tumor growth. However, in the presence of high Ki-67 labeling index and low AIP expression, tumor enlargement may occur and somatostatin analogue treatment throughout the pregnancy should be considered.

Lack of delayed neurocognitive side effects of Gamma Knife radiosurgery in acromegaly: the Later-Ac study.

INTRODUCTION: Persistent growth hormone hypersecretion can be observed in roughly 50% of patients operated for somatotroph adenomas, requiring additional treatments. Despite its proven antisecretory efficacy, the use of Gamma Knife radiosurgery (GK) is limited probably due to the lack of data on long-term side effects, including potential cognitive consequences. METHODS: The LATe Effects of Radiosurgery in Acromegaly study was a cross-sectional exposed/unexposed non-randomized study. The primary objective was to determine the long-term neurocognitive effects of GK focusing on memory, executive functions, and calculation ability. Exposed patients had been treated by GK for acromegaly at least 5 years before inclusion. Unexposed patients (paired for age) had to be cured or controlled at last follow-up without any radiation technique. Patients of both groups were cured or controlled at the last follow-up. RESULTS: Sixty-four patients were evaluated (27 exposed and 37 unexposed). Mean follow-up after GK was 13 ± 6 years (including 24 patients followed for at least 10 years). While up to 23.8% of the patients of the whole cohort presented at least one abnormal cognitive test, we did not observe any significant difference in neurocognitive function between both groups. During the follow-up, 11 patients presented at least one new pituitary deficiency (P = 0.009 for thyroid-stimulating hormone deficiency with a higher rate in exposed patients), two presented a stroke (1 in each group), and one presented a meningioma (12 years after GK). CONCLUSIONS: While GK exposes patients to a well-known risk of pituitary deficiency, it does not seem to induce long-term cognitive consequences in patients treated for acromegaly.

Discordant nadir GH after oral glucose and IGF-I levels on treated acromegaly: refining the biochemical markers of mild disease activity.

Biochemical markers for remission on acromegaly activity are controversial. We studied a subset of treated acromegalic patients with discordant nadir GH levels after oral glucose tolerance test (oGTT) and IGF-I values to refine the current consensus on acromegaly remission. We also compared GH results by two GH immunoassays. From a cohort of 75 treated acromegalic patients, we studied 13 patients who presented an elevated IGF-I despite post-oGTT nadir GH of < or =1 microg/l. The 12-h daytime GH profile (GH-12 h), nadir GH after oGTT, and basal IGF-I levels were studied in patients and controls. Bland-Altman method showed high concordance between GH assays. Acromegalic patients showed higher mean GH-12 h values (0.71+/-0.36 vs. 0.31+/-0.28 microg/l; p<0.05) and nadir GH after oGTT (0.48+/-0.32 vs. 0.097+/-0.002 microg/l; p<0.05) as compared to controls. Nadir GH correlated with mean GH-12 h (r=0.92, p<0.05). The mean GH-12 h value from upper 95% CI of controls (0.54 microg/l) would correspond to a theoretical normal nadir GH of < or =0.27 microg/l. Patients with GH nadir < or =0.3 microg/l had IGF-I between 100-130% ULNR (percentage of upper limit of normal range) and mean GH-12 h of 0.35+/-0.15, and patients with GH nadir >0.3 and < or =1 microg/l had IGF-I >130% ULNR and mean GH-12 h of 0.93+/-0.24 microg/l. Our data integrate daytime GH secretion, nadir GH after oGTT, and plasma IGF-I concentrations showing a continuum of mild residual activity in a subgroup of treated acromegaly with nadir GH values < or =1 microg/l. The degree of increased IGF-I levels and nadir GH after oGTT are correlated with the subtle abnormalities of daytime GH secretion.

Management of acromegaly in Latin America: expert panel recommendations.

Although there are international guidelines orienting physicians on how to manage patients with acromegaly, such guidelines should be adapted for use in distinct regions of the world. A panel of neuroendocrinologists convened in Mexico City in August of 2007 to discuss specific considerations in Latin America. Of major discussion was the laboratory evaluation of acromegaly, which requires the use of appropriate tests and the adoption of local institutional standards. As a general rule to ensure diagnosis, the patient's GH level during an oral glucose tolerance test and IGF-1 level should be evaluated. Furthermore, to guide treatment decisions, both GH and IGF-1 assessments are required. The treatment of patients with acromegaly in Latin America is influenced by local issues of cost, availability and expertise of pituitary neurosurgeons, which should dictate therapeutic choices. Such treatment has undergone profound changes because of the introduction of effective medical interventions that may be used after surgical debulking or as first-line medical therapy in selected cases. Surgical resection remains the mainstay of therapy for small pituitary adenomas (microadenomas), potentially resectable macroadenomas and invasive adenomas causing visual defects. Radiotherapy may be indicated in selected cases when no disease control is achieved despite optimal surgical debulking and medical therapy, when there is no access to somatostatin analogues, or when local issues of cost preclude other therapies. Since not all the diagnostic tools and treatment options are available in all Latin American countries, physicians need to adapt their clinical management decisions to the available local resources and therapeutic options.

Radiation treatment strategies for acromegaly.

The high morbidity and mortality associated with acromegaly can be addressed with multiple treatment modalities, including surgery, medicines, and radiation therapy. Radiation was initially delivered through conventional fractionated radiotherapy, which targets a wide area over many treatment sessions and has been shown to induce remission in 50%–60% of patients with acromegaly. However, conventional fractionated radiotherapy takes several years to achieve remission in patients with acromegaly and carries a risk of hypopituitarism that may limit its use. Stereotactic radiosurgery, of which there are several forms, including Gamma Knife surgery, CyberKnife therapy, and proton beam therapy, offers slightly attenuated efficacy but achieves remission in less time and provides more precise targeting of the adenoma with better control of the dose of radiation received by adjacent structures such as the pituitary stalk, pituitary gland, optic chiasm, and cranial nerves in the cavernous sinus. Of the forms of stereotactic radiosurgery, Gamma Knife surgery is the most widely used and, because of its long-term follow-up in clinical studies, is the most likely to compete with medical therapy for first-line adjuvant use after resection. In this review, the authors outline the major modes of radiation therapies in clinical use today, and they critically assess the feasibility of these modalities for acromegaly treatment. Acromegaly is a multisystem disorder that demands highly specialized treatment protocols including neurosurgical and endocrinological intervention. As more efficient forms of pituitary radiation develop, acromegaly treatment options may continue to change with radiation therapies playing a more prominent role.

The role of stereotactic radiosurgery in the multimodal management of growth hormone-secreting pituitary adenomas.

Growth hormone (GH)-secreting pituitary adenomas represent a common source of GH excess in patients with acromegaly. Whereas surgical extirpation of the culprit lesion is considered first-line treatment, as many as 19% of patients develop recurrent symptoms due to regrowth of previously resected adenomatous tissue or to continued growth of the surgically inaccessible tumor. Although medical therapies that suppress GH production can be effective in the management of primary and recurrent acromegaly, these therapies are not curative, and lifelong treatment is required for hormonal control. Stereotactic radiosurgery has emerged as an effective adjunctive treatment modality, and is an appealing alternative to conventional fractionated radiation therapy. The authors reviewed the growing body of literature concerning the role of radiosurgical procedures in the treatment armamentarium of acromegaly, and identified more than 1350 patients across 45 case series. In this review, the authors report that radiosurgery offers true hormonal normalization in 17% to 82% of patients and tumor growth control in 37% to 100% of cases across all series, while minimizing adverse complications. As a result, stereotactic radiosurgery represents a safe and effective treatment option in the multimodal management of primary or recurrent acromegaly secondary to GH-secreting pituitary adenomas.