Multidisciplinary Approach for Acromegaly: A Single Tertiary Center's Experience

Accepted Manuscript Multidisciplinary approach for acromegaly: a single tertiary center’s experience Ozlem Haliloglu, Enis Kuruoglu, Hande Mefkure Ozkaya, Fatma Ela Keskin, Omur Gunaldi, Buge Oz, Nurperi Gazioglu, Pinar Kadioglu, Necmettin Tanriover PII:

S1878-8750(16)00010-3

DOI:

10.1016/j.wneu.2015.12.092

Reference:

WNEU 3597

To appear in:

World Neurosurgery

Received Date: 13 November 2015 Revised Date:

25 December 2015

Accepted Date: 26 December 2015

Please cite this article as: Haliloglu O, Kuruoglu E, Ozkaya HM, Keskin FE, Gunaldi O, Oz B, Gazioglu N, Kadioglu P, Tanriover N, Multidisciplinary approach for acromegaly: a single tertiary center’s experience, World Neurosurgery (2016), doi: 10.1016/j.wneu.2015.12.092. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

ACCEPTED MANUSCRIPT Haliloglu

1

Multidisciplinary approach for acromegaly: a single tertiary center’s experience

1

2

1

1

2

3

2

1

Oz , Nurperi Gazioglu , Pinar Kadioglu , Necmettin Tanriover

1

2

RI PT

Ozlem Haliloglu , Enis Kuruoglu , Hande Mefkure Ozkaya , Fatma Ela Keskin , Omur Gunaldi , Buge

Division of Endocrinology-Metabolism and Diabetes, Department of Internal Medicine, Cerrahpasa

Medical Faculty, Istanbul University, Istanbul, Turkey

SC

2

Department of Neurosurgery, Cerrahpasa Medical Faculty, Istanbul University, Istanbul, Turkey Department of Pathology, Cerrahpasa Medical Faculty, Istanbul University, Istanbul, Turkey

M AN U

3

Corresponding Author Necmettin Tanriover, MD

Telephone: +90212 4143000

AC C

EP

E-mail: [email protected]

TE D

Eflatun street, Leylak apartment blocks, Block B, D:2, Fenerbahce, Istanbul, Turkey

1

ACCEPTED MANUSCRIPT Haliloglu

2

Abstract Background: Acromegaly is a multisystemic disease that requires a multidisciplinary approach. The aim of

RI PT

this study was to determine early and late remissions of patients who underwent surgery at our center, and to evaluate relations between pathologic and radiologic properties of adenoma and medical and radiosurgical treatments with remissions.

Methods: The medical records of 103 patients with acromegaly who underwent endoscopic endonasal

SC

transsphenoidal surgery in Cerrahpasa Medical Faculty, Istanbul University, between 2007-2014 were

M AN U

reviewed. Clinical, biochemical, radiologic, and pathologic properties were determined. Results: The total median follow-up time was 38 months [IQR: 24-53.5 months]. Thirty-two percent of the adenomas were microadenomas and 68% were macroadenomas The early remission rate was 51.5% and late remission was 75.2%. The sellar floor invasion was significantly lower in patients with early and rd

late remissions (p= 0.01 and p= 0.009, respectively). The initial GH (p< 0.001), first day GH (p= 0.03), 3 th

month GH (p= 0.001), IGF-1 (p= 0.004), and 6 month IGF-1 (p= 0.02) levels were significantly higher in

TE D

patients with sellar floor invasion. The late remission rates (p= 0.004) were higher and re-operation needs (p= 0.05) were lower in patients with Ki-67 <3% than in patients with ≥3%. Seventy (68.6%) patients needed medical therapy during follow-up.

EP

Conclusions: Late remission was achieved using a multi-diciplinary approach in 75.2% of 103 patients with acromegaly, and young age, male sex, high Ki-67 and mitosis indices, and cavernous sinus and

AC C

sellar floor invasion had negative effects on clinical and biochemical control of the disease. Keywords: Acromegaly; early remission; late remission; proliferation indices

2

ACCEPTED MANUSCRIPT Haliloglu

3

Abbreviations and Acronyms EETSS: Endoscopic endonasal transsphenoidal surgery

RI PT

GH: Growth hormone IGF-1: Insulin like growth factor-1

SC

OGTT: Oral glucose tolerance test

AC C

EP

TE D

M AN U

RT: Radiotherapy

3

ACCEPTED MANUSCRIPT Haliloglu

4

INTRODUCTION Acromegaly is a rare disease that results from excessive growth hormone (GH) secretion, generally by a pituitary adenoma, and can affect multiple organ systems via the effects of insulin like

RI PT

growth factor-1 (IGF-1). Hypersecretion of IGF-1 can lead to physical changes, comorbidities, and premature mortality. Acromegaly is a multisystemic disease and needs to be managed with a multidisiplinary approach (1-3).

SC

The main dual goals of acromegaly treatment are tumor resection while preserving pituitary function and biochemical hormonal normalizaton; thereby reducing disease-related mortality. Transsphenoidal surgery

M AN U

is the gold standard primary treatment in acromegaly because its superiority over medical treatment has repeatedly been proved (4-6). Endoscopic endonasal transsphenoidal surgery (EETSS) is a novel technique in which the target tissue can be approached with a wider angle and a clearer deep view. The unique ability of the EETSS facilitates the resection of the macroadenomas, which occur in nearly 80% of patients with acromegaly (7). In addition to the sellar cavity, the medial walls of bilateral cavernous sinuses

TE D

and the suprasellar region can be approached safely under direct endoscopic vision with EETSS. The remission rates of acromegaly in experienced centers has escalated to 85% in microadenomas and 4050% in macroadenomas (8-10).

Medical therapy is the second-line treatment strategy in the management of acromegaly if surgery cannot

EP

be performed because of the patient’s clinical status or the tumor’s characteristics, or if the patient does not achieve remission. Although there are several different drug choices in acromegaly, some patients fail

AC C

to reach remission, which can necessitate radiotherapy, of which there are 2 different types: conventional or stereotactic radiosurgical techniques. The multidiciplinary approach towards acromegaly in our tertiary referral center was reviewed in this study.

SUBJECTS AND METHODS Subjects and Study Design One-hundred three patients with long follow-up duration, out of 159, with acromegaly who had undergone EETSS in Cerrahpasa Medical Faculty, Istanbul University, between 2007-2014, were retrospectively

4

ACCEPTED MANUSCRIPT Haliloglu

5

reviewed. Two senior neurosurgeons (NG, NT) began endoscopic endonasal skull base surgery in October 2007, and performed 502 EETSS procedures on 453 patients with pituitary adenomas, among which 159 were GH-secreting adenomas. The Department of Neurosurgery of Cerrahpasa Medical

RI PT

Faculty, Istanbul University is a referral center and receives patients with pituitary adenomas from all over the country, as such, we excluded patients who had undergone surgery in our department but were followed-up in other endocrinology clinics (35% of the surgical series). All 159 patients were reached by

SC

phone, mail or addresses and asked to share the disease states. Eight of these patients agreed to come and share their results but the rest of 56 patients didn’t want to be involved.

The medical records of patients in the Endocrinology and Metabolism outpatient clinic were

M AN U

retrospectively reviewed and the clinical, biochemical, pathologic, and radiologic data found in the medical files were recorded. Ki-67, p53, mitosis, hypercellularity, intraoperative and pathologic fibrosis, sellar floor and dural invasions, and immunohistochemical properties were evaluated in the pathologic data. The pre-operative MR images were re-evaluated in 97 patients and the size, cavernous sinus invasion in relation to the Knosp classification, and the suprasellar extension of the tumors were

TE D

determined. The sizes of tumors were grouped as; 1 (0-1 cm), 2 (1-2 cm), 3 (2-3 cm), 4 (3-4 cm), and 5 (>4cm), and these were re-evaluated in two groups; small and moderate adenomas, and large and giant adenomas. Knosp classification was re-evaluated as adenomas without (Knosp 0-2) and with (Knosp 3-4)

EP

cavernous sinus invasion (11).

AC C

Endocrine Assessment

The patients’ pre-operative, post-operative first day, third month, sixth month, and the latest GH and ageadjusted IGF-1 values were documented. Postoperative day 1 GH levels operated at our neurosurgery clinic were also reviewed in all 159 patients, including those – 103 patients – not involved for long time follow-up and presented in this study. GH levels during 75 gram oral glucose tolerance test (OGTT) of <1ng/mL and age-adjusted IGF-1 levels in the normal range in the third post-operative month were accepted as “early remission.” Patients were identified who were cured by surgery and did not need medication. Patients who needed medical therapy or radiosurgery, or a second operation were assessed

5

ACCEPTED MANUSCRIPT Haliloglu

6

and the medical treatment type, whether it had begun before or after the surgery, and the type of radiosurgery were evaluated. Patients who had residual post-operative adenoma and did not achieve remission even after appropriate medical therapy underwent radiosurgical assessment. Patients were

RI PT

excluded from the statistical analysis of first day GH and IGF-1 data if they required pre-operative somatostatin analog treatment due to a relatively long surgery waiting time.

SC

Statistical Analyses

The data were statistically analyzed using the Statistical Package for Social Sciences for Windows version 21.0 (SPSS, Chicago, IL) program. Normality of distribution was assessed using the Kolmogorov-

M AN U

Smirnov test. Variables that had normal distribution were detected using an independent t-test; the results were presented as mean and standard deviation and nonparametric tests (Mann-Whitney U test for comparison of 2 groups and Kruskal Wallis test for 3) were used when the distribution was not normal and presented as median and interquartile range [IQR]. The categoric variables were assessed using Chi-square test or Fisher’s exact test when appropriate. For the multivariate analysis, the possible factors

TE D

that were identified with univariate analyses were further entered into the logistic regression analysis to determine independent predictors of patient outcomes. Logistic regression analysis was used to determine predictors that affected early- and late-stage remission status.

EP

The study was approved by the local ethics committee of Cerrahpasa Medical Faculty, Istanbul

AC C

University, and was carried out in accordance with the Declaration of Helsinki.

RESULTS

A total of 103 patients, out of 159 operated during same time period, with acromegaly were assessed for long follow-up duration. The baseline demographics, laboratory, and radiologic characteristics of the patients are summarized in Table 1. The total median follow-up time between diagnosis and the present was 38 months [IQR: 24-53.5 months]. The first day GH levels, an important predictive of remission, were determined in all 159 patients operated at our clinic during the same time period and the median postoperative day 1 GH levels were 1.02 [0.5-

6

ACCEPTED MANUSCRIPT Haliloglu

7

3.3]ng/mL. Postoperative day GH levels were ≤ 1 ng/mL in nearly half of the 159 patients (48.2%). Importantly, the commonly accepted cut-off level for early remisson – postoperative day 1 GH ≤ 2 ng/mL – was achieved in 106 (67%) out of 159 patients (8, 12).

RI PT

In this series, 32% of the 103 pituitary adenomas were micro- and the remaining 68% were macroadenomas. Approximately, one-third of the patients had large or giant pituitary adenomas (tumor size ≥ 3cm), twelve of which (12%) were considered as giant pituitary adenomas. An apparent suprasellar

SC

extension in relation to the level of the planum sphenoidale in sagittal MRI views were noted in 25% of the patients. Radiologic cavernous sinus invasion was present in 28% of the patients in this series. The pathologic characteristics of the adenomas were evaluated and immuno-histochemical staining

M AN U

showed GH-secreting adenomas in 55%; GH and prolactin co-secretion in 36%; GH and TSH cosecretion in 3%; and GH, prolactin, and TSH co-secretion in 6% of patients. Sellar floor and dural invasions were seen in 27% and 55% of patients, respectively. In regard to proliferative indices, 20.6% of the cases in this series had Ki67 scores ≥ 3%; 79.4% of patients had p53 scores ≥1%; and 59.8% had mitosis ≥1/high power field (HPF).

TE D

Some 51.5% of patients achieved early remission in the 3

rd

month and this was considered as the

surgical remission rate. In the preoperative period, somatostatin analog therapy was used in 35 patients (34%) and the median preoperative use was 4 months [IQR: 2-6.6 months]. Overall, 70 patients (68.6%)

EP

needed additional medical therapy during the follow-up period. The medical therapy requirements and types are shown in Table 2. One in ten patients who used pegvisomant therapy showed tumor growth, 9

AC C

patients needed re-operation, and 9 patients needed radiotherapy (3 gamma-knife, 7 cyberknife) during the follow-up. The mean radiotherapy time after surgery was 18.6 ± 8.7 months. All patients who needed radiotherapy had residual tumors after surgery. In this series, the late remission rate of 103 patients was 75% with a combination of surgery and medicalradiosurgical adjunctive therapies when needed. Among the patients with early surgical remission, 29% lost biochemical control and strikingly, did not end up with late remission. The parameters that affected early and late remissions are summarized in Tables 3 and 4. It was found that Ki-67 score did not differ in patients with and without early remission; however, late remission rates

7

ACCEPTED MANUSCRIPT Haliloglu

8

(p= 0.004) were higher and requirement for re-operation (p= 0.05) was lower in patients with Ki-67 < 3% than in patients with ≥ 3%. p53 values did not differ in patients with and without early and late remissions, respectively. There were no correlations between fibrosis, hypercellularity, immunohistochemistry, and

RI PT

dural invasion of adenoma in patients with and without early and late remissions (p > 0.05). Sellar floor invasion was significantly higher in patients without early (p= 0.01) and late remissions (p= 0.009). In rd

addition to this, the initial GH (p < 0.001), first day GH (p= 0.03), 3 month GH (p= 0.001), IGF-1 (p= th

SC

0.004), and 6 month IGF-1 (p= 0.02) levels were significantly higher in patients with sellar floor invasion. When tumor size was subclassified into two groups as small/moderate and large/giant (72% and 28% of cases, respectively) adenomas, it was seen that early (3

rd

month) IGF-1 normalization was lower (p= rd

M AN U

0.01), and the initial GH (p = 0.01), mitosis index (p= 0.02) and 3 month GH (p= 0.04) were higher in patients with large/giant adenomas. When cavernous sinus invasion was considered, early (p= 0.05) and rd

th

late (p= 0.04) remissions were lower and 3 month GH (p= 0.003), 6 month IGF-1 (p= 0.05) levels were higher in patients with cavernous invasion. Younger patients had larger adenomas (p= 0.004), more cavernous sinus invasion (p= 0.02), more re-operations (p= 0.01), and radiotherapy (p= 0.04) needs.

TE D

Accordingly, younger patients expressed less early (p< 0.001) and late (p= 0.01) remission rates. Male rd

patients had higher initial GH (p= 0.05), initial IGF-1 (p< 0.001), first day IGF-1 (<0.001), 3 month IGF-1 (p= 0.007), and 6th month IGF-1 (p= 0.01) levels than female patients.

EP

The patients who needed medical therapy had lower early (p< 0.001) and late (p= 0.001) remission rates and their first day GH levels were higher (p< 0.02) than patients who did not require drugs. There was no

AC C

difference between octreotide or lanreotide use in terms of remission. Patients with early remissions had lower dopamine agonist use than the non-remission ones (p< 0.001) and none of the patients who rd

needed pegvisomant therapy had normal 3 month IGF-1 levels. The patients who needed reoperation and radiotherapy (RT) had significantly higher values of IGF-1 (p< rd

0.001 and p= 0.003, respectively), GH levels at the 3 month (p< 0.001 and p= 0.002, respectively), and th

IGF-1 levels at the 6 month (p< 0.001 and p= 0.004, respectively). Ki-67 scores in patients treated with RT were also higher than patients not treated with RT (p= 0.04).

8

ACCEPTED MANUSCRIPT Haliloglu

9

We found that the late remission rates in patients with early remission were higher than in patients without early remission (p< 0.001). Ki-67 scores and mitosis indices were lower in patients with late remission

between patients with and without late remission. (p= 0.4).

RI PT

(p= 0.004 and p< 0.03, respectively). There was no difference in preoperative somatostatin analog use

Logistic regression analysis revealed that patients without sellar floor invasion entered early stage

SC

remission 8.2 times (p= 0.02; [95% CI: 1.2-54]) more than patients with sellar floor invasion.

M AN U

DISCUSSION

In this study, we evaluated early and late remission in 103 patients with acromegaly who underwent surgery and followed up at our center. Surgical remission was achieved in 51.5% of patients in the postoperative 3rd month, despite the fact that almost 70% of these tumors were macroadenomas and 30% showed cavernous sinus invasion. Due to recurrence during the follow-up period, only 30% of patients were cured with EETSS alone and required no further adjunctive therapies. The combination of medical

TE D

and radiation therapies with surgery normalized the GH and IGF-1 levels during follow-up in three out of four patients in this series. Thus, we observed 75% late remission in 103 patients with acromegaly with a combination of surgery and medical and/or radiosurgical adjunctive therapies when required. This study

EP

remarkably depicted that young age and male sex were associated with more invasive tumors and difficult-to-control disease in acromegaly. The proliferation indices, Ki-67 and mitosis of tumors in

AC C

pathological examinations, were lower in patients with late remission than in the non-remission group. Sellar floor invasion was found to be very significant both in early and late remissions. The panoramic view and ability to assess and follow the lateral and superior extensions of tumors have been prosposed as the hallmarks of endoscopic endonasal approaches to the sellar, supra-, and parasellar regions (9, 13-16). Fathalla et al. showed that the endoscopic approach was superior to the microscopic trans-sphenoidal approach, especially in large tumors and with cavernous sinus invasion (17). Remission rates with EETSS range between 46-75% in the literature (8, 12, 14, 18-23). Some of these studies used 2000 consensus criteria, whereas others used 2010 criteria, and the number of cases

9

ACCEPTED MANUSCRIPT Haliloglu

10

were small in most of these series. In our study, we used the 2014 Endocrine Society consensus criteria to determine remission (1) and found 51.5% early surgical remission and 75.2% late remission rates, despite the high numbers of macroadenomas and cavernous sinus invasion. It should be emphasized

RI PT

that our series included challenging patients with acromegaly in regard to tumor characteristics as a tertiary pituitary center. Furthermore, our study intentionally included patients who were surgically treated at the beginning of the EETSS learning curve, when it was first introduced in our clinic. The number of

SC

surgeries were not evenly distributed through the years, although the surgical approach evolved over the initial three years. The explicit remission rates of the modified EETSS technique, which include the extended endoscopic approaches in GH-secreting adenomas performed since 2011, along with

M AN U

postoperative pituitary function and surgical complications, will be presented in a separate publication. It has been shown that GH and IGF-1 secretion is affected by sex in both healthy and patients with acromegaly (24-26). There are several studies in the literature that show that male patients have higher preoperative GH and IGF-1 levels and are diagnosed at a younger age than female patients (27, 28). In a

TE D

German acromegaly register study, 1485 patients were analyzed and it was demonstrated that men had higher GH values than women, and sex was an independent risk factor for biochemical activity (29). In contrast to these studies, Colao et al. showed that GH levels were similar in 151 patients but IGF-1 values were higher in males (24). In the present study, we also found that males had higher initial GH,

EP

IGF-1 and significantly higher first day, third and sixth month IGF-1 levels than females, which is in accordance with literature. Another interesting finding in our study pinpoints the relationship between

AC C

young age and the invasiveness of tumors. Younger age and male sex in acromegaly tends to be affiliated with more invasive tumors, thus the disease is difficult to control. We found that younger patients had lower remission rates than older ones, which could be related to the more invasive nature of adenomas as determined by their size and cavernous invasion. The need for additional radiotherapy and reoperation were also higher in younger patients than those who were older. Consistent with our study, it was shown that age was inversely correlated with both GH and IGF-1 levels (29). Several studies have tried to explain young age as a determinant of aggressive disease in acromegaly owing to the increased incidence of large pituitary adenomas in this age group (29-31).

10

ACCEPTED MANUSCRIPT Haliloglu

11

Authors have also tried to establish pathologic factors to predict the aggresiveness of tumors and the prognosis of disease. Ki-67, p53, and mitotic activity indices of adenomas were shown to be related with invasiveness (32, 33). Sarkar et al. revealed increased mitotic activity and p53 expression as higher

RI PT

proliferation indices, but found no correlation between Ki-67 and invasiveness of adenomas in 101 patients with acromegaly. Yilmaz et al. found no correlation between Ki-67 and cavernous sinus invasion and remission(34). In our study, we found that high Ki-67 and mitotic activity results in lower late

SC

remissions; however, there was no correlation detected between p53 index and remission rates. The proliferation indices and mitosis were lower in patients with late remission than in the non-remission

M AN U

group.

Cavernous sinus invasion has long been shown to be a predictor of remission (10, 35). In our study, we also revealed that both early and late remissions were lower in patients with cavernous sinus invasion. Surprisingly, sellar floor invasion was found to be a major determinant in terms of both early and late remissions. Sellar floor invasion was significantly higher in patients who did not have early and late

TE D

remissions. Shirvani, et al. found that cavernous sinus extension was related with higher recurrence rates, but suprasellar or sellar floor invasion did not predict poor outcomes (36). To our knowledge, ours is the first study to delineate sellar floor invasion as a predictive factor of remission rates in patients with

EP

acromegaly.

Our study had some limitations due to its retrospective design and the relatively small number of patients from a single center. Furthermore, although surgical remission at the postoperative 3rd month was 52%,

AC C

only 30% of the series were cured soley with the use of EETSS. Accordingly, nearly 20% of the tumors that were totally surgically resected (with a remission at the 3rd month) seemed to recur during the followup period, and constituted a major problem in terms of late remission. CONCLUSIONS

A 75% late remission rate was achieved in 103 patients with acromegaly with a combination of surgery and other treatments in our study. The results of the study undoubtedly bring great expectations for good outcomes of this complex disease because three out of four patients with acromegaly can be cured with

11

ACCEPTED MANUSCRIPT Haliloglu

12

EETSS and adjunctive therapies such as somatostatin analogs, dopamine agonists, pegvisomant, and radiotherapy. Considering the complexity of the disease in terms of radiologic, surgical and pathologic characteristics, a multidisciplinary approach by an experienced and a dedicated team is a prerequisite to

RI PT

accomplish the best remission rates. Finally, young age, male sex, high Ki-67 and mitosis indices, and cavernous sinus and sellar floor invasions all play negative roles in the clinical and biochemical control of this disease.

M AN U

Figure.1 GH and IGF-1 changes during the follow up

SC

Figure Legends:

rd

Figure.2 Remissions with combination of all treatment modalities. The 3 month remission was assessed th

by surgery only, the 6 month remission was by combination of surgery and medical therapies and the

REFERENCES 1.

TE D

recent one was by combination of all surgery, medical and radiosurgical treatment modalities.

Katznelson L, Laws ER, Jr., Melmed S, Molitch ME, Murad MH, Utz A, Wass JA. Acromegaly: an

endocrine society clinical practice guideline. J Clin Endocrinol Metab 99(11):3933-3951,2014. Melmed S. Medical progress: Acromegaly. N Engl J Med 355(24):2558-2573,2006.

3.

Ribeiro-Oliveira A, Jr., Barkan A. The changing face of acromegaly--advances in diagnosis and

EP

2.

4.

AC C

treatment. Nat Rev Endocrinol 8(10):605-611,2012. Abu Dabrh AM, Mohammed K, Asi N, Farah WH, Wang Z, Farah MH, Prokop LJ, Katznelson L,

Murad MH. Surgical interventions and medical treatments in treatment-naive patients with acromegaly: systematic review and meta-analysis. J Clin Endocrinol Metab 99(11):4003-4014,2014. 5.

Zada G, Cavallo LM, Esposito F, Fernandez-Jimenez JC, Tasiou A, De Angelis M, Cafiero T,

Cappabianca P, Laws ER. Transsphenoidal surgery in patients with acromegaly: operative strategies for overcoming technically challenging anatomical variations. Neurosurg Focus 29(4):E8,2010.

12

ACCEPTED MANUSCRIPT Haliloglu 6.

13

Melmed S, Colao A, Barkan A, Molitch M, Grossman AB, Kleinberg D, Clemmons D, Chanson P,

Laws E, Schlechte J, Vance ML, Ho K, Giustina A. Guidelines for acromegaly management: an update. J Clin Endocrinol Metab 94(5):1509-1517,2009. Mestron A, Webb SM, Astorga R, Benito P, Catala M, Gaztambide S, Gomez JM, Halperin I,

RI PT

7.

Lucas-Morante T, Moreno B, Obiols G, de Pablos P, Paramo C, Pico A, Torres E, Varela C, Vazquez JA, Zamora J, Albareda M, Gilabert M. Epidemiology, clinical characteristics, outcome, morbidity and

REA). Eur J Endocrinol 151(4):439-446,2004. 8.

SC

mortality in acromegaly based on the Spanish Acromegaly Registry (Registro Espanol de Acromegalia,

Jane JA, Jr., Starke RM, Elzoghby MA, Reames DL, Payne SC, Thorner MO, Marshall JC, Laws

M AN U

ER, Jr., Vance ML. Endoscopic transsphenoidal surgery for acromegaly: remission using modern criteria, complications, and predictors of outcome. J Clin Endocrinol Metab 96(9):2732-2740,2011. 9.

Starke RM, Raper DM, Payne SC, Vance ML, Oldfield EH, Jane JA, Jr. Endoscopic vs

microsurgical transsphenoidal surgery for acromegaly: outcomes in a concurrent series of patients using modern criteria for remission. J Clin Endocrinol Metab 98(8):3190-3198,2013. Kreutzer J, Vance ML, Lopes MB, Laws ER, Jr. Surgical management of GH-secreting pituitary

TE D

10.

adenomas: an outcome study using modern remission criteria. J Clin Endocrinol Metab 86(9):40724077,2001.

Knosp E, Steiner E, Kitz K, Matula C. Pituitary adenomas with invasion of the cavernous sinus

EP

11.

space: a magnetic resonance imaging classification compared with surgical findings. Neurosurgery

12.

AC C

33(4):610-617; discussion 617-618,1993. Hazer DB, Isik S, Berker D, Guler S, Gurlek A, Yucel T, Berker M. Treatment of acromegaly by

endoscopic transsphenoidal surgery: surgical experience in 214 cases and cure rates according to current consensus criteria. J Neurosurg 119(6):1467-1477,2013. 13.

Bohinski RJ, Warnick RE, Gaskill-Shipley MF, Zuccarello M, van Loveren HR, Kormos DW, Tew

JM, Jr. Intraoperative magnetic resonance imaging to determine the extent of resection of pituitary macroadenomas during transsphenoidal microsurgery. Neurosurgery 49(5):1133-1143; discussion 11431134,2001.

13

ACCEPTED MANUSCRIPT Haliloglu 14.

14

Hofstetter CP, Mannaa RH, Mubita L, Anand VK, Kennedy JW, Dehdashti AR, Schwartz TH.

Endoscopic endonasal transsphenoidal surgery for growth hormone-secreting pituitary adenomas. Neurosurg Focus 29(4):E6,2010. Schwartz TH, Anand VK. The endoscopic endonasal transsphenoidal approach to the suprasellar

cistern. Clin Neurosurg 54:226-235,2007.

Theodosopoulos PV, Leach J, Kerr RG, Zimmer LA, Denny AM, Guthikonda B, Froelich S, Tew

JM. Maximizing

the extent

of tumor resection

during transsphenoidal surgery for pituitary

SC

16.

RI PT

15.

macroadenomas: can endoscopy replace intraoperative magnetic resonance imaging? J Neurosurg 112(4):736-743,2010.

Fathalla H, Cusimano MD, Di Ieva A, Lee J, Alsharif O, Goguen J, Zhang S, Smyth H.

M AN U

17.

Endoscopic versus microscopic approach for surgical treatment of acromegaly. Neurosurg Rev,2015. 18.

Albarel F, Castinetti F, Morange I, Conte-Devolx B, Gaudart J, Dufour H, Brue T. Outcome of

multimodal therapy in operated acromegalic patients, a study in 115 patients. Clin Endocrinol (Oxf) 78(2):263-270,2013.

Gondim JA, Almeida JP, de Albuquerque LA, Gomes E, Schops M, Ferraz T. Pure endoscopic

TE D

19.

transsphenoidal surgery for treatment of acromegaly: results of 67 cases treated in a pituitary center. Neurosurg Focus 29(4):E7,2010.

Minniti G, Jaffrain-Rea ML, Esposito V, Santoro A, Tamburrano G, Cantore G. Evolving criteria

EP

20.

for post-operative biochemical remission of acromegaly: can we achieve a definitive cure? An audit of

21.

AC C

surgical results on a large series and a review of the literature. Endocr Relat Cancer 10(4):611-619,2003. Nomikos P, Buchfelder M, Fahlbusch R. The outcome of surgery in 668 patients with acromegaly

using current criteria of biochemical 'cure'. Eur J Endocrinol 152(3):379-387,2005. 22.

Shin SS, Tormenti MJ, Paluzzi A, Rothfus WE, Chang YF, Zainah H, Fernandez-Miranda JC,

Snyderman CH, Challinor SM, Gardner PA. Endoscopic endonasal approach for growth hormone secreting pituitary adenomas: outcomes in 53 patients using 2010 consensus criteria for remission. Pituitary 16(4):435-444,2013.

14

ACCEPTED MANUSCRIPT Haliloglu 23.

15

Kwon O, Song YD, Kim SY, Lee EJ, Rare Disease Study Group S, Research Committee KES.

Nationwide survey of acromegaly in South Korea. Clin Endocrinol (Oxf) 78(4):577-585,2013. 24.

Colao A, Amato G, Pedroncelli AM, Baldelli R, Grottoli S, Gasco V, Petretta M, Carella C, Pagani

RI PT

G, Tambura G, Lombardi G. Gender- and age-related differences in the endocrine parameters of acromegaly. Journal of endocrinological investigation 25(6):532-538,2002. 25.

Landin-Wilhelmsen K, Wilhelmsen L, Lappas G, Rosen T, Lindstedt G, Lundberg PA, Bengtsson

SC

BA. Serum insulin-like growth factor I in a random population sample of men and women: relation to age, sex, smoking habits, coffee consumption and physical activity, blood pressure and concentrations of plasma lipids, fibrinogen, parathyroid hormone and osteocalcin. Clin Endocrinol (Oxf) 41(3):351-

26.

M AN U

357,1994.

Tanaka S, Fukuda I, Hizuka N, Takano K. Gender differences in serum GH and IGF-I levels and

the GH response to dynamic tests in patients with acromegaly. Endocrine journal 57(6):477-483,2010. 27.

Parkinson C, Ryder WD, Trainer PJ, Sensus Acromegaly Study G. The relationship between

5244,2001. 28.

TE D

serum GH and serum IGF-I in acromegaly is gender-specific. J Clin Endocrinol Metab 86(11):5240-

Kauppinen-Makelin R, Sane T, Reunanen A, Valimaki MJ, Niskanen L, Markkanen H, Loyttyniemi

E, Ebeling T, Jaatinen P, Laine H, Nuutila P, Salmela P, Salmi J, Stenman UH, Viikari J, Voutilainen E. A

29.

EP

nationwide survey of mortality in acromegaly. J Clin Endocrinol Metab 90(7):4081-4086,2005. Petersenn S, Buchfelder M, Gerbert B, Franz H, Quabbe HJ, Schulte HM, Grussendorf M,

AC C

Reincke M, Participants of the German Acromegaly R. Age and sex as predictors of biochemical activity in acromegaly: analysis of 1485 patients from the German Acromegaly Register. Clin Endocrinol (Oxf) 71(3):400-405,2009. 30.

van der Lely AJ, Harris AG, Lamberts SW. The sensitivity of growth hormone secretion to medical

treatment in acromegalic patients: influence of age and sex. Clin Endocrinol (Oxf) 37(2):181-185,1992. 31.

Turner HE, Adams CB, Wass JA. Pituitary tumours in the elderly: a 20 year experience. Eur J

Endocrinol 140(5):383-389,1999.

15

ACCEPTED MANUSCRIPT Haliloglu 32.

16

Fusco A, Zatelli MC, Bianchi A, Cimino V, Tilaro L, Veltri F, Angelini F, Lauriola L, Vellone V,

Doglietto F, Ambrosio MR, Maira G, Giustina A, degli Uberti EC, Pontecorvi A, De Marinis L. Prognostic

Metab 93(7):2746-2750,2008. 33.

RI PT

significance of the Ki-67 labeling index in growth hormone-secreting pituitary adenomas. J Clin Endocrinol

Chacko G, Chacko AG, Kovacs K, Scheithauer BW, Mani S, Muliyil JP, Seshadri MS. The clinical

significance of MIB-1 labeling index in pituitary adenomas. Pituitary 13(4):337-344,2010. Yilmaz

M,

Vural

E,

Koc

K,

Ceylan

S.

Cavernous

sinus

invasion

and

effect

of

SC

34.

immunohistochemical features on remission in growth hormone secreting pituitary adenomas. Turkish neurosurgery 25(3):380-388,2015.

Bourdelot A, Coste J, Hazebroucq V, Gaillard S, Cazabat L, Bertagna X, Bertherat J. Clinical,

M AN U

35.

hormonal and magnetic resonance imaging (MRI) predictors of transsphenoidal surgery outcome in acromegaly. Eur J Endocrinol 150(6):763-771,2004. 36.

Shirvani M, Motiei-Langroudi R. Transsphenoidal surgery for growth hormone-secreting pituitary

AC C

EP

TE D

adenomas in 130 patients. World neurosurgery 81(1):125-130,2014.

16

ACCEPTED MANUSCRIPT Table 1 Baseline characteristics, laboratory and radiologic findings of patients Patients with acromegalic (N=103) Age (years) *

44.2 ± 11.5

Sex (F/M)

60 /43

Initial IGF-1 (ng/mL)

9.8 [4.2-27.1] †

740 [502-996] (n)

RI PT

Cavernous sinus invasion (Knosp class.) 0

40

1

21

2

9

3

10

4

17

Tumor size (Modified Hardy classification) 1

M AN U

3 4 5 Suprasellar extansion A

TE D

B

D

*Data was expressed as mean ±SD †

(n) 31

2

C

SC

Initial GH ( ng/mL)

†

AC C

EP

Data was expressed as median and IQR

39 15 10 2

(n) 73 19 4 1

ACCEPTED MANUSCRIPT Table 2 Medical therapy types Patients (n) Somatostatin analogue use

69

Octreotide*

38 1

20mg

9

RI PT

10mg

30mg

11

40mg

6

Lanreotide*

31 2

60mg

8

SC

90mg 120mg

17 1

Beginning of somatostatin analog Pre-operative Post-operative Cabergoline use

Pegvisomant use

15mg 20mg

TE D

10mg

M AN U

180mg

35 34 38

10 5 1 4

*These data presents the somatostatin analog use at the most recent visit. Nine patients in the octreotide group and 3 patients in the lanreotide group started to use the treatments but stopped

AC C

EP

treatment during their follow-up because of remission.

ACCEPTED MANUSCRIPT Table 3 Parameters that affected early remission Patients without early

remission

remission

48.6 ± 10.6

40.0 ± 10.7

<0.001

5.8 [2.4-14.4]

16,7 [6.5-40]

<0.001

706.9 ± 346.0

823.5 ± 254.2

0.01

†‡

0.6 [0.2-0.9]

3.3 [1.7-6.1]

<0.001

†

0.2 [0.0-0.8]

2.1 [1.0-4.7]

<0.001

0.4 [0.1-0.8]

1.6 [0.9-2.5]

<0.001

176.8 [114.2-249.5]

278.1 [178.2-398.9]

Initial GH (ng/mL)

†

Initial IGF-1 (ng/mL)* First day GH (ng/mL) th

6 month GH (ng/mL) Last GH (ng/mL)

†

Last IGF-1 (ng/mL)

†

M AN U

*Data expressed as mean ±SD

SC

Age*

†

Data expressed as median and IQR

EP

TE D

‡ Data of patients who did not use pre-operative somatostatin analog treatment

AC C

p value

RI PT

Patients with early

<0.001

ACCEPTED MANUSCRIPT Table 4 Parameters that affected late remission Patients without late

remission

remission

45.8 ± 11.4

39.5 ± 11.1

0.01

728.6 ± 310.5

887.7 ± 264.1

0.02

†‡

0.8 [0.4-2.1]

2.7 [1.7-4.5]

0.016

†

0.8 [0.2-3.4]

5.1[3.0-19.3]

0.001

323.5 ± 244.5

620.9 ± 249.7

<0,001

0.5 [0.1-1.7]

3.1 [1.1-5.4]

<0.001

236.2 ± 208.3

483.8 ± 298.6

<0.001

0.5 [0.3-1.2]

2.3 [1.4-4.2]

<0.001

First day GH (ng/mL) rd

3 month GH (ng/mL) rd

3 month IGF-1 (ng/mL) th

6 month GH (ng/mL) th

†

6 month IGF-1 (ng/mL) Last GH (ng/mL)

*

*

†

Last IGF-1 (ng/mL)

†

178.6 [123.7-248.5]

*Data expressed as mean ±SD †

SC

Initial IGF-1 (ng/mL)*

M AN U

Age*

415.7 [340.0-572.9]

Data expressed as median and IQR

EP

TE D

‡ Data of patients who did not use pre-operative somatostatin analog treatment

AC C

p value

RI PT

Patients with late

<0.001

ACCEPTED MANUSCRIPT

IGF-1 (ng/ml)

12

800 700 600 500 400 300 200 100 0

10 8 6 4 2 0 3rd 6th Recent month month

Initial 1st day

3rd 6th Recent month month

AC C

EP

TE D

M AN U

SC

Initial 1st day

RI PT

GH (ng/ml)

ACCEPTED MANUSCRIPT 75%

80 64.9%

70 60

51.5%

50 40 30 10 0 6th month

Recent

AC C

EP

TE D

M AN U

SC

3rd month

RI PT

20

ACCEPTED MANUSCRIPT

Highlights:

2. Late remission rate was 75.2% by multi-diciplinary approach.

RI PT

1. Surgical remission rate was 51.5% at 3rd month of surgery.

AC C

EP

TE D

M AN U

SC

3. Cavernous sinus and sellar floor invasion had negative effects on remission.