- Email: [email protected]
Outcome of Endoscopic Transsphenoidal Surgery for Acromegaly
Accepted Manuscript Outcome of Endoscopic Transsphenoidal Surgery for Acromegaly Jung Hee Kim, MD, PhD, Kyu Yeon Hur, MD, PhD, Jung Hyun Lee, RN, Ji Hyun Lee, MD, Young-Bem Se, MD, Hey In Kim, MD, Seung Hoon Lee, MD, Do-Hyun Nam, MD, PhD, Seong Yeon Kim, MD, PhD, Kwang-Won Kim, MD, PhD, Doo-Sik Kong, MD, PhD, Yong Hwy Kim, MD, PhD PII:
S1878-8750(17)30649-6
DOI:
10.1016/j.wneu.2017.04.141
Reference:
WNEU 5660
To appear in:
World Neurosurgery
Received Date: 13 February 2017 Revised Date:
20 April 2017
Accepted Date: 21 April 2017
Please cite this article as: Kim JH, Hur KY, Lee JH, Lee JH, Se Y-B, Kim HI, Lee SH, Nam D-H, Kim SY, Kim K-W, Kong D-S, Kim YH, Outcome of Endoscopic Transsphenoidal Surgery for Acromegaly, World Neurosurgery (2017), doi: 10.1016/j.wneu.2017.04.141. 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.
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Outcome of Endoscopic Transsphenoidal Surgery for Acromegaly
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Jung Hee Kim
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Seung Hoon Lee , Do-Hyun Nam , Seong Yeon Kim , Kwang-Won Kim , Doo-Sik Kong , Yong
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Hwy Kim
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, Kyu Yeon Hur , Jung Hyun Lee , Ji Hyun Lee , Young-Bem Se , Hey In Kim , 5
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University College of Medicine
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Department of Internal Medicine, Pituitary Center, Department of Neurosurgery, Seoul National 5
Department of Medicine, Department of Neurosurgery, Samsung Medical Center, Sungkyunkwan
University School of Medicine, Seoul, Republic of Korea
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University of Medicine and Science, Incheon, Korea
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Jung Hee Kim and Kyu Yeon Hur equally contributed to this work.
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Corresponding authors to whom reprint requests should be addressed:
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Yong Hwy Kim, MD
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Department of Neurosurgery, Seoul National University College of Medicine
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101 Daehak-ro, Jongno-gu, Seoul, 03080, Republic of Korea
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Tel: +82-2-2072-4062/Fax: +82-2-744-8459/e-mail: [email protected]
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Doo-Sik Kong, MD
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Department of Neurosurgery, Samsung Medical Center, Sungkyunkwan University School of
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Medicine, Seoul, Republic of Korea
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Tel:
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email: [email protected]/ [email protected]
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Department of Endocrinology and Metabolism, Gachon University Gil Medical Center, Gachon
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+82-2-3410-3499
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Key words: endoscopic transsphenoidal surgery, acromegaly
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Short Title: Endoscopic transsphenoidal surgery for acromegaly
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Highest academic degrees for all authors.
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Jung Hee Kim, MD, PhD, Kyu Yeon Hur, MD, PhD, Jung Hyun Lee, RN, Ji Hyun Lee, MD, Young-
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Bem Se, MD, Hey In Kim, MD, Seung Hoon Lee, MD, Do-Hyun Nam, MD, PhD, Seong Yeon Kim,
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MD, PhD Kwang-Won Kim, MD, PhD Doo-Sik Kong, MD, PhD Yong Hwy Kim, MD, PhD
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Abstract
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Objective: Endoscopic transsphenoidal surgery has recently been introduced in pituitary surgery. We investigated outcomes and complications of endoscopic surgery in two referral centers in Korea.
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Methods: We enrolled 134 patients with acromegaly (microadenomas, n=15; macroadenomas,
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n=119) who underwent endoscopic transsphenoidal surgery at Seoul National University Hospital
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(n=74) and Samsung Medical center (n=60) between Jan 2009 and Mar 2016. Remission was defined
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as having a normal IGF-1 and a suppressed GH less than 1 ng/mL during an oral glucose tolerance
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test.
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Results: Remission was achieved in 73.1% of patients, including 13/15 microadenoma patients
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(86.7%) and 86/119 macroadenoma patients (72.3%). A multivariate analysis to determine a predictor
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of biochemical remission demonstrated that absence of cavernous sinus invasion and immediate
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postoperative GH levels of < 2.5 ng/dL were significant predictors of remission (adjusted odds ratios
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[ORs], 5.14 [1.52-17.3] and 9.60 [3.41-26.9], respectively). After surgery, normal pituitary function
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was maintained in 34 patients (25.4%). Sixty-four patients (47.7%) presented complete (n=59, 44.0%)
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or incomplete (n=5, 3.7%) recovery of pituitary function. Hypopituitarism persisted in 20 patients
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(14.9%) and worsened in 16 patients (11.9%). Postoperatively, transient diabetes insipidus was
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reported in 52 patients (38.8%) but only persisted in 2 patients (1.5%). Other postoperative
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complications were epistaxis (n=2), cerebral fluid leakage (n=4), infection (n=1), and intracerebral
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hemorrhage (n=1).
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Conclusions: Endoscopic transsphenoidal surgery for acromegaly presented high remission rates
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and a low incidence of endocrine deficits and complications. Regardless of surgical techniques,
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invasive pituitary tumors were associated with poor outcome.
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Introduction Patients with acromegaly have a considerable burden of complications, including cardiovascular
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diseases, respiratory complications, metabolic syndrome, malignancy, and musculoskeletal pain.1
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These factors contribute to increased mortality rates in patients with acromegaly. Thus, treatment
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goals of acromegaly are to control growth hormone (GH) and insulin-like growth factor-1 (IGF-1)
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secretion, reduce tumor growth, and preserve pituitary hormone function.2
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Surgical removal of GH-secreting pituitary adenomas is the primary therapy in most patients.2
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Transsphenoidal microscopic surgery has been the standard surgical approach in acromegalic patients.
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The surgical success rate of microscopic surgery has been reported at 67-95% for microadenomas and
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47-68% for macroadenomas (overall, 42-72%), based on large sample-sized data including up to 506
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patients.3-7. Recently, endoscopic transsphenoidal surgery has been adopted for pituitary adenomas.
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When compared with a traditional microscopic approach, the endoscope provides a relatively wide
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view of the surgical site and enhances visualization of the lateral aspect of the cavernous sinus and
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suprasellar compartment of large tumors.8,9 But, there is still no evidence that the endoscopic
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approach is superior to the microscopic approach in terms of efficacy or safety for pituitary adenoma
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surgery.2,9-11 Favorable outcomes are largely dependent on the surgical skill and experience of the
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neurosurgeon. Single-surgeon treatment series can represent a personalized treatment outcome. Data
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from single-surgeon series have several limitations that result from the limited sample size and
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inconsistencies in data collection. In contrast, outcomes from registry data of surgeries performed by
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heterogeneous surgeons can provide a sufficient number of serial surgeries with broader applications
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of the results. This study represents the only comprehensive review of outcomes and complications
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after endoscopic pituitary surgery for acromegaly across a heterogeneous group of surgeons and
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patients. Here, we retrospectively investigated the initial surgical outcomes and complications of
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endoscopic pituitary surgery in the second largest data set of acromegaly patients from two referral
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centers, and elucidated which parameters affected biochemical remission.
2 Materials and Methods
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Study subjects
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We retrospectively included 134 acromegalic patients who underwent endoscopic transsphenoidal
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surgery (ETS) at Seoul National University Hospital (SNUH) (n=74) and Samsung Medical Center
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(SMC) (n=60) between January 2009 and March 2016, consecutively. All patients were followed up
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within at least 6 months after surgery. We excluded patients lost to follow-up (n=5), lack of MRI or
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biochemical data (n=7), and with the previous surgery in another hospital (n=3). The surgical
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procedures were performed by 5 neurosurgeons (1 from SNUH and 4 surgeons from SMC), and all
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data were retrieved from medical records and imaging studies. The study was approved by the
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Institutional Review Board of each institution (IRB no. 1503-040-654 and SMC 011-02).
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Study subjects underwent neuro-opthalmological and endocrinological evaluations before and after
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surgery. Visual acuity and Goldmann perimetry testing were performed in patients with
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macroadenomas or microadenomas abutting the optic chiasms. Decreased visual acuity or visual field
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defects were considered visual deficits.
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All pituitary adenomas were visible on preoperative magnetic resonance imaging (MRI). Dynamic
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MRIs of the sella turcica and parasellar region were performed in sagittal and coronal planes both
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before and after administration of gadolinium contrast. The tumor size was presented as maximal
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tumor diameter based on MRI. Pituitary adenomas of <10 mm in maximal diameter were designated
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as microadenomas, while adenomas ≥10 mm in maximal diameter were defined as macroadenomas.
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Macroadenomas were categorized into three groups: 10–20 mm, 20–30 mm, and greater than 30 mm.
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The lateral extension of tumor was graded with the modified Knosp grading system based on coronal
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T1-weighted contrasted imaging and only the complete encasement of internal carotid artery was
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regarded as grade 4.12
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Hormone assessment was performed in all patients pre- and post-operatively. Biochemical
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ng/mL after a 75-g oral glucose load, and plasma insulin like growth factor -1 (IGF-1) levels within
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the normal range for age at about 12 weeks.2 GH levels were measured by an immunoradiometric
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assay kit (Izotop, Budapest, Hungary). The intra-assay coefficients of variations (CVs) were 1.5-3.5%
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and the inter-assay CVs were 2.5-3.3%. IGF-1 levels were measured by an immunoradiometric assay
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kit (Beckman Coulter, California, USA). The intra-assay CVs were below or equal to 5.6%, and the
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inter-assay CVs were below or equal to 8.3%. The lowest detectable levels of GH and IGF-1 were
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0.02 and 4.55 ng/mL. The World Health Organization international standards for GH (98/574) and for
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IGF-I (91/554) measurement were used. IGF-1 levels were presented as times of upper limit of
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normal (x ULN). Immediate postoperative GH levels were measured in the early morning of
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postoperative day 1 or day 2.
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Hypopituitarism was assessed in all patients pre- and post-operatively, except the GH-IGF-1 axis.
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Luteinizing hormone (LH), follicle-stimulating hormone (FSH), estradiol (E2) or total testosterone,
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prolactin, free T4, thyroid-stimulating hormone (TSH), adrenocorticotropic hormone (ACTH), and
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serum cortisol levels were measured by radioimmunoassay (RIA) and immunoradiometric assay
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(IRMA) between 8:00 a.m. and 10:00 a.m. ACTH deficiency was defined as peak cortisol levels of ≤
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18 µg/dL following a short Synacthen test, or in cases where dynamic testing was not available, a low
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morning cortisol level (< 5 µg/dL) with a low-normal ACTH level (10-65 pg/mL). TSH deficiency
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was defined according to a low free T4 level (< 0.70 ng/dL) under a low-normal TSH level (reference
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range, 0.4−4.1 µIU/mL). Normal menopause was defined by FSH > 30 mIU/mL and estradiol < 50
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pg/mL in hypopituitary patients. Premenopausal women with FSH/LH sufficiency were considered to
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have no menstrual disorders. In men, low testosterone levels under a low-normal FSH/LH level
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indicated a need to assess central hypogonadism. In patients with water diuresis and polydipsia,
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diabetes insipidus was considered. We defined transient (< 1 month) or permanent (≥ 3 months) post-
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operative diabetes insipidus based on the usage of desmopressin, because the management protocols
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of post-operative diuresis were different between the two institutions. Endocrinological outcomes
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normalized hypopituitarism: hypopituitarism recovered completely after ETS, (3) improved
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hypopituitarism: hypopituitarism resolved, but incompletely, (4) persistent hypopituitarism: the
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number of deficient axes of pituitary hormone did not change after ETS, and (5) worsened
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hypopituitarism: the number of deficient axes of pituitary hormone worsened after ETS.13
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Surgical procedures
The surgical procedures performed in this study aligned with those detailed in the current
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literature.14,15 All surgical procedures were initiated though the bi-nostril pure endonasal or trans-
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septal routes, under the view of endoscope, and all turbinates were preserved without posterior
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septectomy. We preferred to halt the bleeding from the nasal mucosa with hemostatic material, and
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tried to avoid coagulation to prevent post-operative synechiae and preserve mucosal function. The
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bony sella opening was performed enough to identify the superior intercavernous sinus and bilateral
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cavernous sinus. We attempted to find the pseudocapsule of the tumor after wide dural incision. The
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extracapsular dissection is considered a yardstick procedure in surgical dissection of tumors; however,
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the sharp dissection procedure with microdissector was performed in cases in which the
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pseudocapsule was not in direct surgical view. Blind curettement with sharp and angled ring curettage
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procedures was not performed at all. The tumor in the cavernous sinus was dissected and removed
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with the two-suction technique after confirmation of the exact location of the interval carotid artery,
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obtained by neuronavigation and intraoperative Doppler ultrasonograph. The medial to lateral
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approach was the most frequently used surgical route to the tumor in the cavernous sinuses; however,
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we performed the lateral to lateral approach in cases where the tumor completely covered the anterior
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surface of cavernous ICA, or the tumor thickness in the lateral cavernous sinus was more than 3 mm
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in axial plane as determined by MRI. The visible residual tumor in the cavernous sinus was confirmed
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by viewing with an angled endoscope. The sellar floor was usually reconstructed with multi-layers of
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absorbable fibrin silant (Tachosil®,Takeda Pharma); however, we relied on the pedicled nasoseptal
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flap in cases with high-flow CSF leakage.
3 Statistical analysis
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All data were presented as n (%) for categorical variables or mean ± standard deviation. The
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independent-samples t-test for normally distributed continuous variables and the Mann-Whitney U
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test for non-parametric variables were used. For categorical variables, the χ2 test for nominally
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distributed variables and Fisher’s exact test for non-parametric variables were applied. Receiver
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operator characteristic (ROC) analysis was performed to determine the optimal cut-off values of
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immediate postoperative GH levels for predicting biochemical remission. The optimal cut-off point
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was obtained from the Youden index [maximum (sensitivity + specificity − 1)].16 Binary univariate
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and multivariate logistic regression models were analyzed to determine the predictive factors for
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biochemical remission. All statistical analyses were performed using SPSS software (version 22;
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SPSS Inc., Chicago, IL), and differences with a P-value of < .05 were considered statistically
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significant.
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Results
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All patients underwent pure endoscopic pituitary surgeries without prior medical or gamma-knife
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radiosurgery. One-hundred thirty-four acromegalic patients aged 46 ± 13.5 were included in this study.
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Of the participants, 60 were men and 74 women; 60 of the patients were included from SMC, and 74
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patients from SNUH. Maximal diameter of the tumors was 20.1 (± 10.4) mm, and 88.8% (119/134) of
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patients had macroadenomas (≥ 10 mm). Cavernous sinus invasion was observed in 35.1% (47/134)
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of patients. Eighteen of the 134 patients (13.4%) complained of visual deficits. The mean preoperative
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GH and IGF-1 levels were 34.9 (± 48.1) and 796 (± 344) ng/mL. When comparing the two centers,
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preoperative IGF-1 levels were significantly higher in SNUH patients than SMC patients, but other
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variables were not significantly different between the two centers (Table 1).
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ACCEPTED MANUSCRIPT Biochemical remission was achieved in 73.1% (99/134) of patients, including 13 of 15 (86.7%)
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microadenoma patients and 86 of 119 (72.3%) macroadenoma patients (Fig. 1). The recurrence rate
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among the remission group was 3% (3/99) during a median follow-up period of 31 (7-80) months
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despite the pseudocapsule resection in all 3 cases. The remission rates were 70.0% in SMC and 77.0%
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in SNUH, which were not significantly different. In patients with tumors larger than 30 mm, the
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remission rate was significantly lower than in those with tumors smaller than 30 mm (48.0% vs.
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79.8%). Only 46.8% (22/47) of tumors with cavernous sinus invasion achieved remission compared
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with noninvasive tumors (88.5%, 77/87) and 23.8% (5/21) of Knosp grade 4 tumors did it. However,
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the remission rate of noninvasive macroadenomas was similar to that of microadenomas (88.9%
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[64/72] vs. 86.7% [13/15]).
Patients achieving remission had significantly smaller maximal tumor diameters than those who
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failed to attain remission (18.1 ± 8.9 vs. 25.7 ± 12.2 mm, P=0.001). Cavernous sinus invasion was
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associated with lower rates of remission (22 of 47, 46.8%) compared with intrasellar location (77 of
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87, 88.5%) (P<.001). The rate of pseudocapsule resection was higher in the remission group than the
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non-remission group (92.9% vs. 7.1%, P<.001). Preoperative GH levels and nadir GH levels during
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the oral glucose tolerance test were significantly lower in the remission group than in the non-
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remission group (26.1 ± 32.3 vs. 59.6 ± 71.9 ng/mL, P<.001; 20.6 ± 26.2 vs. 53.4 ± 77.2 ng/mL,
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P<.001, respectively). However, preoperative IGF-1 and prolactin levels were not different between
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the two groups. Preoperative hormone deficiency and postoperative diabetes insipidus were not
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related to surgical outcome. GH levels at postoperative day 1 or 2 were significantly lower in patients
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achieving remission than in those who failed to attain remission (1.9 ± 2.9 vs. 11.6 ± 19.5 ng/mL,
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P<.001) (Table 2). We performed ROC analysis to determine the cut-off value of immediate
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postoperative GH levels that would predict biochemical remission. The area under the curve was
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0.883 (95% CI, 0.824-0.942). Immediate postoperative GH levels <2.5 ng/mL and absence of
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cavernous sinus invasion were significant predictors for biochemical remission (adjusted ORs, 5.14
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[1.52-17.3] and 9.60 [3.41-26.9], respectively) in multivariate analysis adjusted for tumor size or
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preoperative GH levels. Successful pseudocapsule resection led to a high rate of biochemical
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remission by 52-fold. (Table 3). In Fig. 2, endocrinological outcomes of endoscopic transsphenoidal surgery were presented.
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Preoperatively, 1 patient experienced diabetes insipidus but normalized after surgery. After
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endoscopic surgery, normal pituitary function was maintained in 34 patients (25.4%). Sixty-four
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patients (47.7%) presented complete (n=59, 44.0%) or incomplete (n=5, 3.7%) recovery of pituitary
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function. Hypopituitarism persisted in 20 patients (14.9%) and worsened in 16 patients (11.9%).
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Gonadotropin deficiency was the most recovered (n=43, 32.1%) and most worsened (n=16, 11.9%)
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axis among the ACTH, TSH, and gonadotropin axes. Five patients showed decreased function in the
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ACTH and TSH axes after surgery. The most common complications were transient diabetes insipidus
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(n=52, 38.8%), followed by epistaxis (n=2), cerebral fluid leakage (n=4), infection (n=1), and
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intracerebral hemorrhage (n=1). However, among patients with transient diabetes insipidus, only 2
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patients (1.5%) presented persistent diabetes insipidus.
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14 Discussion
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The present study demonstrated that the endoscopic transsphenoidal surgery achieved an initial
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biochemical remission rate in 73.1% of acromegalic patients. The remission rate was higher in cases
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of relatively low preoperative GH levels, tumor size < 3 cm, and an absence of cavernous sinus
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invasion. Immediate postoperative GH levels < 2.5 ng/mL predicted biochemical remission.
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Several researchers have reported on the postoperative remission rates of GH-producing pituitary
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adenomas treated with endoscopic transsphenoidal surgery, which ranged between 13 and 100%
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remission for microadenomas and 44 and 80% remission for macroadenomas.9,17-23 (Table 4)
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Remission rates have been reported quite differently depending on inclusion criteria, remission
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criteria, and the proportions of macroadenomas and invasive tumors. Here, we present similar data
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(86.7% for microadenomas and 72.3% for macroadenomas), although 88% of our study subjects had
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macroadenomas. Most previous studies included a small number of patients. To our knowledge, only
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ACCEPTED MANUSCRIPT one study had a larger sample size than our study.23 Hazer et al. reported remission rates in 214
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acromegalic patients based on the stringent 2010 criteria (62.6%, 134/214) but after re-analyzing
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according to the 2000 remission criteria, remission was achieved in 75.2% of 214 patients, which was
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similar to our findings.23 However, the proportions of macroadenomas (76.2%) and invasive tumors
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(25.2%) were less than those of our study.
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In the present study, we did not compare the outcome between endoscopic and microscopic
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transsphenoidal surgery. However, several series of the microsurgical approach have reported
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remission rates of 67-95% for microadenomas and 47-68% for macroadenomas (overall, 42-72%). 3-7
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There is still no evidence that the endoscopic approach is superior to the microscopic approach in
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terms of efficacy or safety.2,9-11 In subgroup analysis in our study, the remission rate of noninvasive
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macroadenomas was similar to that of microadenomas. A recent meta-analysis also reported that the
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endoscopic group achieved remission in patients with noninvasive macroadenomas at the high rate of
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83.3% (80.6-87.1), which was significantly higher than that in the microscopic group (66.9% [60.2%-
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73.6%], P<.001).11 Thus, for noninvasive macroadenomas, endoscopic surgery may be superior to
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microscopic surgery. However, another systemic review suggested that for small intrasellar adenomas
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can be removed in experienced surgeons by either the endoscopic or microscopic surgery, but for
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larger adenomas with extrasellar extension, the endoscopic surgery may have better outcomes and less
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complications.24
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A number of studies have investigated the predictive markers for postsurgical remission,9,17,23
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although the most important determinant for surgical outcome is the experience and skill of the
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neurosurgeon.25 Larger tumor size and cavernous sinus invasion were the most important parameters
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to determine the surgical outcome in our study. Sarkar et al. suggested that adenomas < 20 mm in size
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elevated the remission rate.10 Similarly, we demonstrated that the remission rate of adenomas < 30
24
mm in size was similar to that of microadenomas. Absence of cavernous invasion (Knosp score of 0-2)
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increased the probability for remission (OR=6.8, P <.001),9 which was comparable to the predictive
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power of cavernous sinus invasion in our study (OR=8.75). Although the endoscope offers a more
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panoramic view and enhances the visualization of the lateral extent of large tumors,8 the endoscopic
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view did not change the intrinsic tumor behavior and overcome the unresectability of invasiveness.
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The surgical outcome for invasive pituitary tumors was similar in both endoscopic and microscopic
4
surgeries.5,26,27 In previous studies, preoperative GH levels may have also predicted biochemical remission.9,10 On
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the other hand, Shirvani et al. reported that neither preoperative GH nor IGF-1 predicted surgical
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outcomes.27 We confirmed the predictive value of preoperative GH levels for remission, but failed to
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find the cut-off value. Moreover, in multivariate analyses, cavernous sinus invasion and immediate
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postoperative GH levels were more significant for predicting surgical outcomes than preoperative GH
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levels. Unlike GH levels, we were not able to demonstrate the predictive power of preoperative IGF-1
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levels.
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Immediate postoperative GH levels were useful as an early marker for predicting remission in the
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present study. Other researchers have also mentioned that immediate postoperative GH levels might
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be the predictor for remission, but the cut-off values are controversial. Hazer et al. suggested that the
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cut-off value of postoperative GH levels in predicting remission was 2.33 ng/mL on the first day.23
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Instead, Starke et al. showed that immediate postoperative GH levels less than 1.15 ng/mL provided
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the best predictor of surgical remission (OR=7.7, P<.001; sensitivity of 73%, specificity of 85%).9
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However, Jane et al. reported that a cut-off value of 2.5 ng/ml was the best predictor of remission.17 In
19
our ROC analysis using the Youden index, the optimal cut-off value of immediate postoperative GH
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level as a predictor was 2.5 ng/mL. Therefore, despite the different cut-off values, measurements of
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GH levels at postoperative day 1 or day 2 were fundamental to assessing surgical outcome.
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We reaffirmed the importance of successful pseudocapsule resection. Previous literature also
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demonstrated the value of pseudocapsule resection in tumor recurrence and biochemical remission in
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pituitary adenoma surgery.28,29 However, the pseudocapsules were not always formed in all cases and
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there were still concerns regarding cerebrospinal fluid leak and hypopituitarism..
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Regarding endocrinological outcomes, previous studies have indicated a range of novel, post-
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ACCEPTED MANUSCRIPT operative anterior pituitary deficiency rates, between 4.1 and 21.3%.5,9,10,17 Our data showed that
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hypopituitarism worsened in 16/134 (11.9%) patients, which is similar to findings from other studies.
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Similar to the study performed by Jane et al.,17 32.1% of patients with hypogonadism recovered,
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although novel, post-operative hypogonadism occurred in 11.9% of patients. Postoperative
5
complications were similar to those reported in previous studies. The incidence of transient diabetes
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insipidus appeared to be higher than expected, and desmopressin use was a criterion to define
7
transient diabetes insipidus. However, diabetes insipidus persisted in only 2 patients (1.5%), which
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was lower than the results of previous studies (around 5%).9,10,17
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Our study had several limitations worth mentioning. The surgical outcome was short-term, and
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long-term data such as recurrence or delayed remission were not shown. Given that no patients had
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pre-operative radiation or medical therapy, the selection bias may exist. Several surgeons performed
12
the endoscopic surgery, and there may be inter-individual variation according to surgical skill and
13
experience. The discrepancy between preoperative GH and IGF-1 levels as predictors for remission
14
was clearly unexplainable. GH levels represent the tumor size and characteristics, whereas IGF-1
15
levels are affected by several extrinsic factors such as gender, nutrition, and diabetes.30 As the
16
biochemical remission criteria, we did not follow the guideline published in 2010. The 2014
17
Endocrine Society Guideline admitted that many GH assays do not have sufficient accuracy at GH
18
levels < 1.0 µg/L. In addition, GH assays in our institutes did not achieve satisfactory accuracy at low
19
GH level. Therefore, we adhere to the cut-off value with a nadir GH < 1.0 µg/L for remission.
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We conducted a study with the second largest sample size regarding endoscopic surgical outcome
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in acromegaly, and the first study in Korea. Endoscopic transsphenoidal surgery for acromegaly
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presented high remission rates and a low incidence of endocrine deficits and complications. Absence
25
of cavernous sinus invasion and immediate postoperative GH levels < 2.5 ng/mL may predict
26
biochemical remission after endoscopic surgery.
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Disclosure: All authors state that they have no conflicts of interest.
4 5
Acknowledgments
6
supported by a grant from the Korea Health Technology R&D Project through the Korea Health
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Industry Development Institute (KHIDI), funded by the Ministry of Health & Welfare, Republic of
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Korea (grant number: HI16C-1111-020016 to Kim YH).
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We thank all colleagues who contributed to the study. This research was
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acromegaly complications. Pituitary. 2013;16(3):294-302. 2.
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practice guideline. J Clin Endocrinol Metab. 2014;99(11):3933-3951. 3.
7 8
Kim MS, Jang HD, Kim OL. Surgical results of growth hormone-secreting pituitary adenoma. J Korean Neurosurg Soc. 2009;45(5):271-274.
4.
9 10
Katznelson L, Laws ER, Jr., Melmed S, et al. Acromegaly: an endocrine society clinical
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Melmed S, Casanueva FF, Klibanski A, et al. A consensus on the diagnosis and treatment of
Ludecke DK, Abe T. Transsphenoidal microsurgery for newly diagnosed acromegaly: a personal view after more than 1,000 operations. Neuroendocrinology. 2006;83(3-4):230-239.
5.
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Beauregard C, Truong U, Hardy J, Serri O. Long-term outcome and mortality after transsphenoidal adenomectomy for acromegaly. Clin Endocrinol (Oxf). 2003;58(1):86-91.
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Kreutzer J, Vance ML, Lopes MB, Laws ER, Jr. Surgical management of GH-secreting
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Oldfield EH. Editorial: Unresolved issues: radiosurgery versus radiation therapy; medical
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suppression of growth hormone production during radiosurgery; and endoscopic surgery
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versus microscopic surgery. Neurosurg Focus. 2010;29(4):E16.
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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
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Sarkar S, Rajaratnam S, Chacko G, Chacko AG. Endocrinological outcomes following
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endoscopic and microscopic transsphenoidal surgery in 113 patients with acromegaly. Clin
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Phan K, Xu J, Reddy R, Kalakoti P, Nanda A, Fairhall J. Endoscopic endonasal versus
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microsurgical transphenoidal approach for growth hormone-secreting pituitary adenomas -
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systematic review and meta-analysis. World Neurosurg. 2016.
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Micko AS, Wohrer A, Wolfsberger S, Knosp E. Invasion of the cavernous sinus space in pituitary adenomas: endoscopic verification and its correlation with an MRI-based
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Ku CR, Kim EH, Oh MC, Lee EJ, Kim SH. Surgical and endocrinological outcomes in the treatment of growth hormone-secreting pituitary adenomas according to the shift of surgical
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paradigm. Neurosurgery. 2012;71(2 Suppl Operative):ons192-203; discussion ons203.
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Hwang JM, Kim YH, Kim JW, Kim DG, Jung HW, Chung YS. Feasibility of endoscopic endonasal approach for recurrent pituitary adenomas after microscopic trans-sphenoidal
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approach. J Korean Neurosurg Soc. 2013;54(4):317-322.
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Hong SD, Nam DH, Kong DS, Kim HY, Chung SK, Dhong HJ. Endoscopic Modified Transseptal Transsphenoidal Approach for Maximal Preservation of Sinonasal Quality of Life
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and Olfaction. World Neurosurg. 2016;87:162-169.
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Jane JA, Jr., Starke RM, Elzoghby MA, et al. Endoscopic transsphenoidal surgery for acromegaly: remission using modern criteria, complications, and predictors of outcome. J
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Clin Endocrinol Metab. 2011;96(9):2732-2740. 18.
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pituitary adenomas: early surgical results in 200 patients and comparison with previous
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Dehdashti AR, Ganna A, Karabatsou K, Gentili F. Pure endoscopic endonasal approach for
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microsurgical series. Neurosurgery. 2008;62(5):1006-1015; discussion 1015-1007.
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Cappabianca P, Cavallo LM, Colao A, et al. Endoscopic endonasal transsphenoidal approach:
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outcome analysis of 100 consecutive procedures. Minim Invasive Neurosurg. 2002;45(4):193-
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200.
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Frank G, Pasquini E. Endoscopic endonasal cavernous sinus surgery, with special reference to
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pituitary adenomas. Front Horm Res. 2006;34:64-82. 21.
Gondim JA, Almeida JP, de Albuquerque LA, Gomes E, Schops M, Ferraz T. Pure endoscopic
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transsphenoidal surgery for treatment of acromegaly: results of 67 cases treated in a pituitary
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center. Neurosurg Focus. 2010;29(4):E7. 22.
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Kabil MS, Eby JB, Shahinian HK. Fully endoscopic endonasal vs. transseptal transsphenoidal
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pituitary surgery. Minim Invasive Neurosurg. 2005;48(6):348-354. 23.
Hazer DB, Isik S, Berker D, et al. Treatment of acromegaly by endoscopic transsphenoidal surgery: surgical experience in 214 cases and cure rates according to current consensus
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criteria. J Neurosurg. 2013;119(6):1467-1477. 24.
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endoscopic versus microscopic. J Neurooncol. 2016;130(2):309-317. 25.
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Singh H, Essayed WI, Cohen-Gadol A, Zada G, Schwartz TH. Resection of pituitary tumors:
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McLaughlin N, Laws ER, Oyesiku NM, Katznelson L, Kelly DF. Pituitary centers of excellence. Neurosurgery. 2012;71(5):916-924; discussion 924-916.
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Petrossians P, Borges-Martins L, Espinoza C, et al. Gross total resection or debulking of pituitary adenomas improves hormonal control of acromegaly by somatostatin analogs. Eur J
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Endocrinol. 2005;152(1):61-66. 27.
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pituitary adenomas in 130 patients. World Neurosurg. 2014;81(1):125-130. 28.
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Kim EH, Ku CR, Lee EJ, Kim SH. Extracapsular en bloc resection in pituitary adenoma surgery. Pituitary. 2015;18(3):397-404.
29.
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Xie T, Liu T, Zhang X, et al. Time to Revive the Value of the Pseudocapsule in Endoscopic Endonasal Transsphenoidal Surgery for Growth Hormone Adenomas. World Neurosurg.
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Shirvani M, Motiei-Langroudi R. Transsphenoidal surgery for growth hormone-secreting
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Zeinalizadeh M, Habibi Z, Fernandez-Miranda JC, Gardner PA, Hodak SP, Challinor SM.
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Discordance between growth hormone and insulin-like growth factor-1 after pituitary surgery
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for acromegaly: a stepwise approach and management. Pituitary. 2015;18(1):48-59.
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ACCEPTED MANUSCRIPT Fig. 1. Remission rates according to centers, tumor size, and cavernous sinus invasion
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* P <0.05
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Fig. 2. Endocrinological outcomes of endoscopic transsphenoidal surgery
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Variables
SMC
SNUH
(n=60)
(n=74)
p Value
46.1 ± 13.5
45.1 ± 13.3
46.9 ± 13.8
0.426
Male
60 (44.8%)
27 (45.0%)
33 (44.6%)
0.963
Maximal diameter of tumor (mm)
20.1 ± 10.4
20.0 ± 10.6
20.1 ± 10.3
0.132
Macroadenoma (≥10 mm)
119 (88.8%)
52 (86.7%)
67 (90.5%)
0.479
Cavernous sinus invasion
47 (35.1%)
16 (26.7%)
31 (41.9%)
0.066
Visual deficit
18 (13.4%)
6 (10.0%)
12 (16.2%)
0.396
GH (ng/mL)
34.9 ± 48.1
28.6 ± 42.8
40.1 ± 51.9
0.172
Nadir GH during OGTT
28.5 ± 14.5
23.8 ± 42.4
32.6 ± 49.0
0.304
IGF-1 (ng/mL)
796 ± 344
656 ± 195
908 ± 395
<0.001
IGF-I (% of ULN)
263 ± 228
209 ± 70
307 ± 155
<0.001
Prolactin (ng/mL)
23.5 ± 59.7
18.0 ± 36.7
0.241
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Age (years)
30.2 ± 79.0
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ACCEPTED MANUSCRIPT Table 2. Comparison of parameters between remission and non-remission group Remission
Non-remission
(n=99)
(n=35)
Age (years)
47.0 ± 12.5
43.5 ± 15.9
0.194
Male
55 (55.6%)
19 (54.3%)
0.897
Maximal diameter of tumor (mm)
18.1 ± 8.9
25.7 ± 12.2
0.001
Macroadenoma (≥10 mm)
86 (86.9%)
33 (94.3%)
0.006
20-30 mm
19 (19.2%)
≥30 mm
12 (12.1%)
Cavernous sinus invasion
22 (22.2%)
Pseudocapsule resection
91 (92.9%)
Nadir GH during OGTT (ng/mL) Preoperative IGF-1 (ng/mL) Preoperative IGF-I (% of ULN) Prolactin (ng/mL)
13 (37.1%)
<0.001
7 (7.1%)
<0.001
10 (28.6%)
0.027
26.1 ± 32.3
59.6 ± 71.9
<0.001
20.6 ± 26.2
53.4 ± 77.2
<0.001
774.0 ± 357.8
860.5 ± 298.9
0.209
252.9 ± 132.4
294.1 ± 132.9
0.121
21.1 ± 56.6
30.1 ± 68.2
0.449
20 (20.2%)
11 (31.4%)
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Preoperative ACTH deficiency
8 (22.9%)
25 (71.4%)
8 (8.1%)
Preoperative GH (ng/mL)
12 (34.3%)
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55 (55.6%)
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10-19 mm
p Value
Preoperative TSH deficiency
19 (19.2%)
8 (27.9%)
0.642
Preoperative FSH/LH deficiency
45 (45.5%)
16 (45.7%)
0.979
1.9 ± 2.9
11.6 ± 19.5
<0.001
33 (33.3%)
13 (37.1%)
0.683
Immediate postoperative GH (ng/mL)
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Postoperative diabetes insipidus
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Table 3. Multivariate analysis for predictors for biochemical remission Unadjusted ORs
Adjusted ORs
0.55 (0.37-0.81)
1.29 (0.70-2.36)
Absence of cavernous sinus invasion
8.75 (3.65-20.9)
5.14 (1.52-17.3)
Preoperative GH (ng/mL) (per 5 ng/dL increase)
0.93 (0.89-0.98)
0.97 (0.91-1.02)
Immediate postoperative GH (ng/mL)< 2.5 ng/dL
14.9 (5.70-38.7)
9.60 (3.41-26.9)
Pseudocapsule resection
52.0 (16.0-169.1)
38.9 (9.1-166.6)
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Tumor size (per 10 mm increase)
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Data are shown as odds ratios (95% confidence interval). ORs = odds ratios.
ACCEPTED MANUSCRIPT in more than 30 Remission criteria nadir GH <1.0 nadir GH <1.0 nadir GH <1.0 nadir GH <1.0 nadir GH <1.0 nadir GH <0.4 nadir GH <0.4 nadir GH <0.4 nadir GH <0.4 nadir GH <1.0 nadir GH <0.4
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Table 4. Literature review of biochemical remission after endoscopic surgery acromegalic patients Number of Macro Micro Reference Year n macro Overall adenoma adenoma adenoma Cappabianca et al. 2002 36 30 64% 60% 83% Kabil et al. 2005 48 35 85% 80% 100% Frank et al. 2006 83 59 70% 65% 83% Dehdashi et al. 2008 34 26 71% 65% 83% Gondim et al. 2010 67 53 75% 72% 86% Jane et al. 2011 60 46 70% 61% 10% Starke et al. 2013 72 59 71% 66% 88% Hazer et al 2013 214 163 63% 63% 63% Sarkar et al. 2014 66 34 29% 44% 13% 73% 72% 87% Current study 2017 134 119 48% 45% 67%
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ACCEPTED MANUSCRIPT Highlights
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The main contribution of our study was the initial surgical outcomes and complications of endoscopic pituitary surgery in the second largest data set of acromegaly patients from two referral centers. In addition, we elucidated that low preoperative GH levels, tumor size < 3 cm, an absence of cavernous sinus invasion, and immediate postoperative GH levels < 2.5 ng/mL predicted biochemical remission.
ACCEPTED MANUSCRIPT Abbreviations list GH: Growth hormone IGF-1: Insulin-like growth factor-1 SNUH : Seoul National University Hospital
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SMC: Samsung Medical Center ETS : Transsphenoidal surgery MRI : Magnetic resonance imaging
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CVs : Coefficients of variations LH : Luteinizing hormone
E2: Estradiol TSH: Thyroid-stimulating hormone ACTH: Adrenocorticotropic hormone RIA: Radioimmunoassay
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IRMA: Immunoradiometric assay
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FSH : follicle-stimulating hormone
S1878-8750(17)30649-6
DOI:
10.1016/j.wneu.2017.04.141
Reference:
WNEU 5660
To appear in:
World Neurosurgery
Received Date: 13 February 2017 Revised Date:
20 April 2017
Accepted Date: 21 April 2017
Please cite this article as: Kim JH, Hur KY, Lee JH, Lee JH, Se Y-B, Kim HI, Lee SH, Nam D-H, Kim SY, Kim K-W, Kong D-S, Kim YH, Outcome of Endoscopic Transsphenoidal Surgery for Acromegaly, World Neurosurgery (2017), doi: 10.1016/j.wneu.2017.04.141. 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.
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Outcome of Endoscopic Transsphenoidal Surgery for Acromegaly
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Jung Hee Kim
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Seung Hoon Lee , Do-Hyun Nam , Seong Yeon Kim , Kwang-Won Kim , Doo-Sik Kong , Yong
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Hwy Kim
1,2
4
2
1
3
4
, Kyu Yeon Hur , Jung Hyun Lee , Ji Hyun Lee , Young-Bem Se , Hey In Kim , 5
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2,3
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1
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University College of Medicine
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2
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Department of Internal Medicine, Pituitary Center, Department of Neurosurgery, Seoul National 5
Department of Medicine, Department of Neurosurgery, Samsung Medical Center, Sungkyunkwan
University School of Medicine, Seoul, Republic of Korea
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6
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University of Medicine and Science, Incheon, Korea
14
Jung Hee Kim and Kyu Yeon Hur equally contributed to this work.
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Corresponding authors to whom reprint requests should be addressed:
16
Yong Hwy Kim, MD
17
Department of Neurosurgery, Seoul National University College of Medicine
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101 Daehak-ro, Jongno-gu, Seoul, 03080, Republic of Korea
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Tel: +82-2-2072-4062/Fax: +82-2-744-8459/e-mail: [email protected]
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Doo-Sik Kong, MD
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Department of Neurosurgery, Samsung Medical Center, Sungkyunkwan University School of
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Medicine, Seoul, Republic of Korea
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Tel:
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email: [email protected]/ [email protected]
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Department of Endocrinology and Metabolism, Gachon University Gil Medical Center, Gachon
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+82-2-3410-3499
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Key words: endoscopic transsphenoidal surgery, acromegaly
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Short Title: Endoscopic transsphenoidal surgery for acromegaly
28 1
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Highest academic degrees for all authors.
2
Jung Hee Kim, MD, PhD, Kyu Yeon Hur, MD, PhD, Jung Hyun Lee, RN, Ji Hyun Lee, MD, Young-
3
Bem Se, MD, Hey In Kim, MD, Seung Hoon Lee, MD, Do-Hyun Nam, MD, PhD, Seong Yeon Kim,
4
MD, PhD Kwang-Won Kim, MD, PhD Doo-Sik Kong, MD, PhD Yong Hwy Kim, MD, PhD
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Abstract
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Objective: Endoscopic transsphenoidal surgery has recently been introduced in pituitary surgery. We investigated outcomes and complications of endoscopic surgery in two referral centers in Korea.
9
Methods: We enrolled 134 patients with acromegaly (microadenomas, n=15; macroadenomas,
10
n=119) who underwent endoscopic transsphenoidal surgery at Seoul National University Hospital
11
(n=74) and Samsung Medical center (n=60) between Jan 2009 and Mar 2016. Remission was defined
12
as having a normal IGF-1 and a suppressed GH less than 1 ng/mL during an oral glucose tolerance
13
test.
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Results: Remission was achieved in 73.1% of patients, including 13/15 microadenoma patients
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(86.7%) and 86/119 macroadenoma patients (72.3%). A multivariate analysis to determine a predictor
16
of biochemical remission demonstrated that absence of cavernous sinus invasion and immediate
17
postoperative GH levels of < 2.5 ng/dL were significant predictors of remission (adjusted odds ratios
18
[ORs], 5.14 [1.52-17.3] and 9.60 [3.41-26.9], respectively). After surgery, normal pituitary function
19
was maintained in 34 patients (25.4%). Sixty-four patients (47.7%) presented complete (n=59, 44.0%)
20
or incomplete (n=5, 3.7%) recovery of pituitary function. Hypopituitarism persisted in 20 patients
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(14.9%) and worsened in 16 patients (11.9%). Postoperatively, transient diabetes insipidus was
22
reported in 52 patients (38.8%) but only persisted in 2 patients (1.5%). Other postoperative
23
complications were epistaxis (n=2), cerebral fluid leakage (n=4), infection (n=1), and intracerebral
24
hemorrhage (n=1).
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Conclusions: Endoscopic transsphenoidal surgery for acromegaly presented high remission rates
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and a low incidence of endocrine deficits and complications. Regardless of surgical techniques,
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invasive pituitary tumors were associated with poor outcome.
2 3
Introduction Patients with acromegaly have a considerable burden of complications, including cardiovascular
5
diseases, respiratory complications, metabolic syndrome, malignancy, and musculoskeletal pain.1
6
These factors contribute to increased mortality rates in patients with acromegaly. Thus, treatment
7
goals of acromegaly are to control growth hormone (GH) and insulin-like growth factor-1 (IGF-1)
8
secretion, reduce tumor growth, and preserve pituitary hormone function.2
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Surgical removal of GH-secreting pituitary adenomas is the primary therapy in most patients.2
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Transsphenoidal microscopic surgery has been the standard surgical approach in acromegalic patients.
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The surgical success rate of microscopic surgery has been reported at 67-95% for microadenomas and
12
47-68% for macroadenomas (overall, 42-72%), based on large sample-sized data including up to 506
13
patients.3-7. Recently, endoscopic transsphenoidal surgery has been adopted for pituitary adenomas.
14
When compared with a traditional microscopic approach, the endoscope provides a relatively wide
15
view of the surgical site and enhances visualization of the lateral aspect of the cavernous sinus and
16
suprasellar compartment of large tumors.8,9 But, there is still no evidence that the endoscopic
17
approach is superior to the microscopic approach in terms of efficacy or safety for pituitary adenoma
18
surgery.2,9-11 Favorable outcomes are largely dependent on the surgical skill and experience of the
19
neurosurgeon. Single-surgeon treatment series can represent a personalized treatment outcome. Data
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from single-surgeon series have several limitations that result from the limited sample size and
21
inconsistencies in data collection. In contrast, outcomes from registry data of surgeries performed by
22
heterogeneous surgeons can provide a sufficient number of serial surgeries with broader applications
23
of the results. This study represents the only comprehensive review of outcomes and complications
24
after endoscopic pituitary surgery for acromegaly across a heterogeneous group of surgeons and
25
patients. Here, we retrospectively investigated the initial surgical outcomes and complications of
26
endoscopic pituitary surgery in the second largest data set of acromegaly patients from two referral
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centers, and elucidated which parameters affected biochemical remission.
2 Materials and Methods
4
Study subjects
5
We retrospectively included 134 acromegalic patients who underwent endoscopic transsphenoidal
6
surgery (ETS) at Seoul National University Hospital (SNUH) (n=74) and Samsung Medical Center
7
(SMC) (n=60) between January 2009 and March 2016, consecutively. All patients were followed up
8
within at least 6 months after surgery. We excluded patients lost to follow-up (n=5), lack of MRI or
9
biochemical data (n=7), and with the previous surgery in another hospital (n=3). The surgical
10
procedures were performed by 5 neurosurgeons (1 from SNUH and 4 surgeons from SMC), and all
11
data were retrieved from medical records and imaging studies. The study was approved by the
12
Institutional Review Board of each institution (IRB no. 1503-040-654 and SMC 011-02).
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Study subjects underwent neuro-opthalmological and endocrinological evaluations before and after
14
surgery. Visual acuity and Goldmann perimetry testing were performed in patients with
15
macroadenomas or microadenomas abutting the optic chiasms. Decreased visual acuity or visual field
16
defects were considered visual deficits.
17
All pituitary adenomas were visible on preoperative magnetic resonance imaging (MRI). Dynamic
18
MRIs of the sella turcica and parasellar region were performed in sagittal and coronal planes both
19
before and after administration of gadolinium contrast. The tumor size was presented as maximal
20
tumor diameter based on MRI. Pituitary adenomas of <10 mm in maximal diameter were designated
21
as microadenomas, while adenomas ≥10 mm in maximal diameter were defined as macroadenomas.
22
Macroadenomas were categorized into three groups: 10–20 mm, 20–30 mm, and greater than 30 mm.
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The lateral extension of tumor was graded with the modified Knosp grading system based on coronal
24
T1-weighted contrasted imaging and only the complete encasement of internal carotid artery was
25
regarded as grade 4.12
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Hormone assessment was performed in all patients pre- and post-operatively. Biochemical
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2
ng/mL after a 75-g oral glucose load, and plasma insulin like growth factor -1 (IGF-1) levels within
3
the normal range for age at about 12 weeks.2 GH levels were measured by an immunoradiometric
4
assay kit (Izotop, Budapest, Hungary). The intra-assay coefficients of variations (CVs) were 1.5-3.5%
5
and the inter-assay CVs were 2.5-3.3%. IGF-1 levels were measured by an immunoradiometric assay
6
kit (Beckman Coulter, California, USA). The intra-assay CVs were below or equal to 5.6%, and the
7
inter-assay CVs were below or equal to 8.3%. The lowest detectable levels of GH and IGF-1 were
8
0.02 and 4.55 ng/mL. The World Health Organization international standards for GH (98/574) and for
9
IGF-I (91/554) measurement were used. IGF-1 levels were presented as times of upper limit of
10
normal (x ULN). Immediate postoperative GH levels were measured in the early morning of
11
postoperative day 1 or day 2.
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Hypopituitarism was assessed in all patients pre- and post-operatively, except the GH-IGF-1 axis.
13
Luteinizing hormone (LH), follicle-stimulating hormone (FSH), estradiol (E2) or total testosterone,
14
prolactin, free T4, thyroid-stimulating hormone (TSH), adrenocorticotropic hormone (ACTH), and
15
serum cortisol levels were measured by radioimmunoassay (RIA) and immunoradiometric assay
16
(IRMA) between 8:00 a.m. and 10:00 a.m. ACTH deficiency was defined as peak cortisol levels of ≤
17
18 µg/dL following a short Synacthen test, or in cases where dynamic testing was not available, a low
18
morning cortisol level (< 5 µg/dL) with a low-normal ACTH level (10-65 pg/mL). TSH deficiency
19
was defined according to a low free T4 level (< 0.70 ng/dL) under a low-normal TSH level (reference
20
range, 0.4−4.1 µIU/mL). Normal menopause was defined by FSH > 30 mIU/mL and estradiol < 50
21
pg/mL in hypopituitary patients. Premenopausal women with FSH/LH sufficiency were considered to
22
have no menstrual disorders. In men, low testosterone levels under a low-normal FSH/LH level
23
indicated a need to assess central hypogonadism. In patients with water diuresis and polydipsia,
24
diabetes insipidus was considered. We defined transient (< 1 month) or permanent (≥ 3 months) post-
25
operative diabetes insipidus based on the usage of desmopressin, because the management protocols
26
of post-operative diuresis were different between the two institutions. Endocrinological outcomes
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2
normalized hypopituitarism: hypopituitarism recovered completely after ETS, (3) improved
3
hypopituitarism: hypopituitarism resolved, but incompletely, (4) persistent hypopituitarism: the
4
number of deficient axes of pituitary hormone did not change after ETS, and (5) worsened
5
hypopituitarism: the number of deficient axes of pituitary hormone worsened after ETS.13
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Surgical procedures
The surgical procedures performed in this study aligned with those detailed in the current
9
literature.14,15 All surgical procedures were initiated though the bi-nostril pure endonasal or trans-
10
septal routes, under the view of endoscope, and all turbinates were preserved without posterior
11
septectomy. We preferred to halt the bleeding from the nasal mucosa with hemostatic material, and
12
tried to avoid coagulation to prevent post-operative synechiae and preserve mucosal function. The
13
bony sella opening was performed enough to identify the superior intercavernous sinus and bilateral
14
cavernous sinus. We attempted to find the pseudocapsule of the tumor after wide dural incision. The
15
extracapsular dissection is considered a yardstick procedure in surgical dissection of tumors; however,
16
the sharp dissection procedure with microdissector was performed in cases in which the
17
pseudocapsule was not in direct surgical view. Blind curettement with sharp and angled ring curettage
18
procedures was not performed at all. The tumor in the cavernous sinus was dissected and removed
19
with the two-suction technique after confirmation of the exact location of the interval carotid artery,
20
obtained by neuronavigation and intraoperative Doppler ultrasonograph. The medial to lateral
21
approach was the most frequently used surgical route to the tumor in the cavernous sinuses; however,
22
we performed the lateral to lateral approach in cases where the tumor completely covered the anterior
23
surface of cavernous ICA, or the tumor thickness in the lateral cavernous sinus was more than 3 mm
24
in axial plane as determined by MRI. The visible residual tumor in the cavernous sinus was confirmed
25
by viewing with an angled endoscope. The sellar floor was usually reconstructed with multi-layers of
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absorbable fibrin silant (Tachosil®,Takeda Pharma); however, we relied on the pedicled nasoseptal
2
flap in cases with high-flow CSF leakage.
3 Statistical analysis
5
All data were presented as n (%) for categorical variables or mean ± standard deviation. The
6
independent-samples t-test for normally distributed continuous variables and the Mann-Whitney U
7
test for non-parametric variables were used. For categorical variables, the χ2 test for nominally
8
distributed variables and Fisher’s exact test for non-parametric variables were applied. Receiver
9
operator characteristic (ROC) analysis was performed to determine the optimal cut-off values of
10
immediate postoperative GH levels for predicting biochemical remission. The optimal cut-off point
11
was obtained from the Youden index [maximum (sensitivity + specificity − 1)].16 Binary univariate
12
and multivariate logistic regression models were analyzed to determine the predictive factors for
13
biochemical remission. All statistical analyses were performed using SPSS software (version 22;
14
SPSS Inc., Chicago, IL), and differences with a P-value of < .05 were considered statistically
15
significant.
17
Results
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All patients underwent pure endoscopic pituitary surgeries without prior medical or gamma-knife
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radiosurgery. One-hundred thirty-four acromegalic patients aged 46 ± 13.5 were included in this study.
20
Of the participants, 60 were men and 74 women; 60 of the patients were included from SMC, and 74
21
patients from SNUH. Maximal diameter of the tumors was 20.1 (± 10.4) mm, and 88.8% (119/134) of
22
patients had macroadenomas (≥ 10 mm). Cavernous sinus invasion was observed in 35.1% (47/134)
23
of patients. Eighteen of the 134 patients (13.4%) complained of visual deficits. The mean preoperative
24
GH and IGF-1 levels were 34.9 (± 48.1) and 796 (± 344) ng/mL. When comparing the two centers,
25
preoperative IGF-1 levels were significantly higher in SNUH patients than SMC patients, but other
26
variables were not significantly different between the two centers (Table 1).
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ACCEPTED MANUSCRIPT Biochemical remission was achieved in 73.1% (99/134) of patients, including 13 of 15 (86.7%)
2
microadenoma patients and 86 of 119 (72.3%) macroadenoma patients (Fig. 1). The recurrence rate
3
among the remission group was 3% (3/99) during a median follow-up period of 31 (7-80) months
4
despite the pseudocapsule resection in all 3 cases. The remission rates were 70.0% in SMC and 77.0%
5
in SNUH, which were not significantly different. In patients with tumors larger than 30 mm, the
6
remission rate was significantly lower than in those with tumors smaller than 30 mm (48.0% vs.
7
79.8%). Only 46.8% (22/47) of tumors with cavernous sinus invasion achieved remission compared
8
with noninvasive tumors (88.5%, 77/87) and 23.8% (5/21) of Knosp grade 4 tumors did it. However,
9
the remission rate of noninvasive macroadenomas was similar to that of microadenomas (88.9%
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[64/72] vs. 86.7% [13/15]).
Patients achieving remission had significantly smaller maximal tumor diameters than those who
12
failed to attain remission (18.1 ± 8.9 vs. 25.7 ± 12.2 mm, P=0.001). Cavernous sinus invasion was
13
associated with lower rates of remission (22 of 47, 46.8%) compared with intrasellar location (77 of
14
87, 88.5%) (P<.001). The rate of pseudocapsule resection was higher in the remission group than the
15
non-remission group (92.9% vs. 7.1%, P<.001). Preoperative GH levels and nadir GH levels during
16
the oral glucose tolerance test were significantly lower in the remission group than in the non-
17
remission group (26.1 ± 32.3 vs. 59.6 ± 71.9 ng/mL, P<.001; 20.6 ± 26.2 vs. 53.4 ± 77.2 ng/mL,
18
P<.001, respectively). However, preoperative IGF-1 and prolactin levels were not different between
19
the two groups. Preoperative hormone deficiency and postoperative diabetes insipidus were not
20
related to surgical outcome. GH levels at postoperative day 1 or 2 were significantly lower in patients
21
achieving remission than in those who failed to attain remission (1.9 ± 2.9 vs. 11.6 ± 19.5 ng/mL,
22
P<.001) (Table 2). We performed ROC analysis to determine the cut-off value of immediate
23
postoperative GH levels that would predict biochemical remission. The area under the curve was
24
0.883 (95% CI, 0.824-0.942). Immediate postoperative GH levels <2.5 ng/mL and absence of
25
cavernous sinus invasion were significant predictors for biochemical remission (adjusted ORs, 5.14
26
[1.52-17.3] and 9.60 [3.41-26.9], respectively) in multivariate analysis adjusted for tumor size or
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preoperative GH levels. Successful pseudocapsule resection led to a high rate of biochemical
2
remission by 52-fold. (Table 3). In Fig. 2, endocrinological outcomes of endoscopic transsphenoidal surgery were presented.
4
Preoperatively, 1 patient experienced diabetes insipidus but normalized after surgery. After
5
endoscopic surgery, normal pituitary function was maintained in 34 patients (25.4%). Sixty-four
6
patients (47.7%) presented complete (n=59, 44.0%) or incomplete (n=5, 3.7%) recovery of pituitary
7
function. Hypopituitarism persisted in 20 patients (14.9%) and worsened in 16 patients (11.9%).
8
Gonadotropin deficiency was the most recovered (n=43, 32.1%) and most worsened (n=16, 11.9%)
9
axis among the ACTH, TSH, and gonadotropin axes. Five patients showed decreased function in the
10
ACTH and TSH axes after surgery. The most common complications were transient diabetes insipidus
11
(n=52, 38.8%), followed by epistaxis (n=2), cerebral fluid leakage (n=4), infection (n=1), and
12
intracerebral hemorrhage (n=1). However, among patients with transient diabetes insipidus, only 2
13
patients (1.5%) presented persistent diabetes insipidus.
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14 Discussion
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The present study demonstrated that the endoscopic transsphenoidal surgery achieved an initial
17
biochemical remission rate in 73.1% of acromegalic patients. The remission rate was higher in cases
18
of relatively low preoperative GH levels, tumor size < 3 cm, and an absence of cavernous sinus
19
invasion. Immediate postoperative GH levels < 2.5 ng/mL predicted biochemical remission.
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Several researchers have reported on the postoperative remission rates of GH-producing pituitary
21
adenomas treated with endoscopic transsphenoidal surgery, which ranged between 13 and 100%
22
remission for microadenomas and 44 and 80% remission for macroadenomas.9,17-23 (Table 4)
23
Remission rates have been reported quite differently depending on inclusion criteria, remission
24
criteria, and the proportions of macroadenomas and invasive tumors. Here, we present similar data
25
(86.7% for microadenomas and 72.3% for macroadenomas), although 88% of our study subjects had
26
macroadenomas. Most previous studies included a small number of patients. To our knowledge, only
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ACCEPTED MANUSCRIPT one study had a larger sample size than our study.23 Hazer et al. reported remission rates in 214
2
acromegalic patients based on the stringent 2010 criteria (62.6%, 134/214) but after re-analyzing
3
according to the 2000 remission criteria, remission was achieved in 75.2% of 214 patients, which was
4
similar to our findings.23 However, the proportions of macroadenomas (76.2%) and invasive tumors
5
(25.2%) were less than those of our study.
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In the present study, we did not compare the outcome between endoscopic and microscopic
7
transsphenoidal surgery. However, several series of the microsurgical approach have reported
8
remission rates of 67-95% for microadenomas and 47-68% for macroadenomas (overall, 42-72%). 3-7
9
There is still no evidence that the endoscopic approach is superior to the microscopic approach in
10
terms of efficacy or safety.2,9-11 In subgroup analysis in our study, the remission rate of noninvasive
11
macroadenomas was similar to that of microadenomas. A recent meta-analysis also reported that the
12
endoscopic group achieved remission in patients with noninvasive macroadenomas at the high rate of
13
83.3% (80.6-87.1), which was significantly higher than that in the microscopic group (66.9% [60.2%-
14
73.6%], P<.001).11 Thus, for noninvasive macroadenomas, endoscopic surgery may be superior to
15
microscopic surgery. However, another systemic review suggested that for small intrasellar adenomas
16
can be removed in experienced surgeons by either the endoscopic or microscopic surgery, but for
17
larger adenomas with extrasellar extension, the endoscopic surgery may have better outcomes and less
18
complications.24
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A number of studies have investigated the predictive markers for postsurgical remission,9,17,23
20
although the most important determinant for surgical outcome is the experience and skill of the
21
neurosurgeon.25 Larger tumor size and cavernous sinus invasion were the most important parameters
22
to determine the surgical outcome in our study. Sarkar et al. suggested that adenomas < 20 mm in size
23
elevated the remission rate.10 Similarly, we demonstrated that the remission rate of adenomas < 30
24
mm in size was similar to that of microadenomas. Absence of cavernous invasion (Knosp score of 0-2)
25
increased the probability for remission (OR=6.8, P <.001),9 which was comparable to the predictive
26
power of cavernous sinus invasion in our study (OR=8.75). Although the endoscope offers a more
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panoramic view and enhances the visualization of the lateral extent of large tumors,8 the endoscopic
2
view did not change the intrinsic tumor behavior and overcome the unresectability of invasiveness.
3
The surgical outcome for invasive pituitary tumors was similar in both endoscopic and microscopic
4
surgeries.5,26,27 In previous studies, preoperative GH levels may have also predicted biochemical remission.9,10 On
6
the other hand, Shirvani et al. reported that neither preoperative GH nor IGF-1 predicted surgical
7
outcomes.27 We confirmed the predictive value of preoperative GH levels for remission, but failed to
8
find the cut-off value. Moreover, in multivariate analyses, cavernous sinus invasion and immediate
9
postoperative GH levels were more significant for predicting surgical outcomes than preoperative GH
10
levels. Unlike GH levels, we were not able to demonstrate the predictive power of preoperative IGF-1
11
levels.
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Immediate postoperative GH levels were useful as an early marker for predicting remission in the
13
present study. Other researchers have also mentioned that immediate postoperative GH levels might
14
be the predictor for remission, but the cut-off values are controversial. Hazer et al. suggested that the
15
cut-off value of postoperative GH levels in predicting remission was 2.33 ng/mL on the first day.23
16
Instead, Starke et al. showed that immediate postoperative GH levels less than 1.15 ng/mL provided
17
the best predictor of surgical remission (OR=7.7, P<.001; sensitivity of 73%, specificity of 85%).9
18
However, Jane et al. reported that a cut-off value of 2.5 ng/ml was the best predictor of remission.17 In
19
our ROC analysis using the Youden index, the optimal cut-off value of immediate postoperative GH
20
level as a predictor was 2.5 ng/mL. Therefore, despite the different cut-off values, measurements of
21
GH levels at postoperative day 1 or day 2 were fundamental to assessing surgical outcome.
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We reaffirmed the importance of successful pseudocapsule resection. Previous literature also
23
demonstrated the value of pseudocapsule resection in tumor recurrence and biochemical remission in
24
pituitary adenoma surgery.28,29 However, the pseudocapsules were not always formed in all cases and
25
there were still concerns regarding cerebrospinal fluid leak and hypopituitarism..
26
Regarding endocrinological outcomes, previous studies have indicated a range of novel, post-
11
ACCEPTED MANUSCRIPT operative anterior pituitary deficiency rates, between 4.1 and 21.3%.5,9,10,17 Our data showed that
2
hypopituitarism worsened in 16/134 (11.9%) patients, which is similar to findings from other studies.
3
Similar to the study performed by Jane et al.,17 32.1% of patients with hypogonadism recovered,
4
although novel, post-operative hypogonadism occurred in 11.9% of patients. Postoperative
5
complications were similar to those reported in previous studies. The incidence of transient diabetes
6
insipidus appeared to be higher than expected, and desmopressin use was a criterion to define
7
transient diabetes insipidus. However, diabetes insipidus persisted in only 2 patients (1.5%), which
8
was lower than the results of previous studies (around 5%).9,10,17
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Our study had several limitations worth mentioning. The surgical outcome was short-term, and
10
long-term data such as recurrence or delayed remission were not shown. Given that no patients had
11
pre-operative radiation or medical therapy, the selection bias may exist. Several surgeons performed
12
the endoscopic surgery, and there may be inter-individual variation according to surgical skill and
13
experience. The discrepancy between preoperative GH and IGF-1 levels as predictors for remission
14
was clearly unexplainable. GH levels represent the tumor size and characteristics, whereas IGF-1
15
levels are affected by several extrinsic factors such as gender, nutrition, and diabetes.30 As the
16
biochemical remission criteria, we did not follow the guideline published in 2010. The 2014
17
Endocrine Society Guideline admitted that many GH assays do not have sufficient accuracy at GH
18
levels < 1.0 µg/L. In addition, GH assays in our institutes did not achieve satisfactory accuracy at low
19
GH level. Therefore, we adhere to the cut-off value with a nadir GH < 1.0 µg/L for remission.
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We conducted a study with the second largest sample size regarding endoscopic surgical outcome
23
in acromegaly, and the first study in Korea. Endoscopic transsphenoidal surgery for acromegaly
24
presented high remission rates and a low incidence of endocrine deficits and complications. Absence
25
of cavernous sinus invasion and immediate postoperative GH levels < 2.5 ng/mL may predict
26
biochemical remission after endoscopic surgery.
12
ACCEPTED MANUSCRIPT 1 2 3
Disclosure: All authors state that they have no conflicts of interest.
4 5
Acknowledgments
6
supported by a grant from the Korea Health Technology R&D Project through the Korea Health
7
Industry Development Institute (KHIDI), funded by the Ministry of Health & Welfare, Republic of
8
Korea (grant number: HI16C-1111-020016 to Kim YH).
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We thank all colleagues who contributed to the study. This research was
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acromegaly complications. Pituitary. 2013;16(3):294-302. 2.
5 6
practice guideline. J Clin Endocrinol Metab. 2014;99(11):3933-3951. 3.
7 8
Kim MS, Jang HD, Kim OL. Surgical results of growth hormone-secreting pituitary adenoma. J Korean Neurosurg Soc. 2009;45(5):271-274.
4.
9 10
Katznelson L, Laws ER, Jr., Melmed S, et al. Acromegaly: an endocrine society clinical
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Melmed S, Casanueva FF, Klibanski A, et al. A consensus on the diagnosis and treatment of
Ludecke DK, Abe T. Transsphenoidal microsurgery for newly diagnosed acromegaly: a personal view after more than 1,000 operations. Neuroendocrinology. 2006;83(3-4):230-239.
5.
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Beauregard C, Truong U, Hardy J, Serri O. Long-term outcome and mortality after transsphenoidal adenomectomy for acromegaly. Clin Endocrinol (Oxf). 2003;58(1):86-91.
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Kreutzer J, Vance ML, Lopes MB, Laws ER, Jr. Surgical management of GH-secreting
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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
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Sarkar S, Rajaratnam S, Chacko G, Chacko AG. Endocrinological outcomes following
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Phan K, Xu J, Reddy R, Kalakoti P, Nanda A, Fairhall J. Endoscopic endonasal versus
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systematic review and meta-analysis. World Neurosurg. 2016.
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Micko AS, Wohrer A, Wolfsberger S, Knosp E. Invasion of the cavernous sinus space in pituitary adenomas: endoscopic verification and its correlation with an MRI-based
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Ku CR, Kim EH, Oh MC, Lee EJ, Kim SH. Surgical and endocrinological outcomes in the treatment of growth hormone-secreting pituitary adenomas according to the shift of surgical
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Hwang JM, Kim YH, Kim JW, Kim DG, Jung HW, Chung YS. Feasibility of endoscopic endonasal approach for recurrent pituitary adenomas after microscopic trans-sphenoidal
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approach. J Korean Neurosurg Soc. 2013;54(4):317-322.
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Hong SD, Nam DH, Kong DS, Kim HY, Chung SK, Dhong HJ. Endoscopic Modified Transseptal Transsphenoidal Approach for Maximal Preservation of Sinonasal Quality of Life
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Youden WJ. Index for rating diagnostic tests. Cancer. 1950;3(1):32-35.
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Jane JA, Jr., Starke RM, Elzoghby MA, et al. Endoscopic transsphenoidal surgery for acromegaly: remission using modern criteria, complications, and predictors of outcome. J
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Clin Endocrinol Metab. 2011;96(9):2732-2740. 18.
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pituitary adenomas: early surgical results in 200 patients and comparison with previous
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Dehdashti AR, Ganna A, Karabatsou K, Gentili F. Pure endoscopic endonasal approach for
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Gondim JA, Almeida JP, de Albuquerque LA, Gomes E, Schops M, Ferraz T. Pure endoscopic
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Hazer DB, Isik S, Berker D, et al. Treatment of acromegaly by endoscopic transsphenoidal surgery: surgical experience in 214 cases and cure rates according to current consensus
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Singh H, Essayed WI, Cohen-Gadol A, Zada G, Schwartz TH. Resection of pituitary tumors:
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McLaughlin N, Laws ER, Oyesiku NM, Katznelson L, Kelly DF. Pituitary centers of excellence. Neurosurgery. 2012;71(5):916-924; discussion 924-916.
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Petrossians P, Borges-Martins L, Espinoza C, et al. Gross total resection or debulking of pituitary adenomas improves hormonal control of acromegaly by somatostatin analogs. Eur J
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Endocrinol. 2005;152(1):61-66. 27.
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pituitary adenomas in 130 patients. World Neurosurg. 2014;81(1):125-130. 28.
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Kim EH, Ku CR, Lee EJ, Kim SH. Extracapsular en bloc resection in pituitary adenoma surgery. Pituitary. 2015;18(3):397-404.
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Xie T, Liu T, Zhang X, et al. Time to Revive the Value of the Pseudocapsule in Endoscopic Endonasal Transsphenoidal Surgery for Growth Hormone Adenomas. World Neurosurg.
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Shirvani M, Motiei-Langroudi R. Transsphenoidal surgery for growth hormone-secreting
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Zeinalizadeh M, Habibi Z, Fernandez-Miranda JC, Gardner PA, Hodak SP, Challinor SM.
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ACCEPTED MANUSCRIPT Fig. 1. Remission rates according to centers, tumor size, and cavernous sinus invasion
2
* P <0.05
3
Fig. 2. Endocrinological outcomes of endoscopic transsphenoidal surgery
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ACCEPTED MANUSCRIPT Table 1. Baseline characteristics of acromegalic patients Total
Variables
SMC
SNUH
(n=60)
(n=74)
p Value
46.1 ± 13.5
45.1 ± 13.3
46.9 ± 13.8
0.426
Male
60 (44.8%)
27 (45.0%)
33 (44.6%)
0.963
Maximal diameter of tumor (mm)
20.1 ± 10.4
20.0 ± 10.6
20.1 ± 10.3
0.132
Macroadenoma (≥10 mm)
119 (88.8%)
52 (86.7%)
67 (90.5%)
0.479
Cavernous sinus invasion
47 (35.1%)
16 (26.7%)
31 (41.9%)
0.066
Visual deficit
18 (13.4%)
6 (10.0%)
12 (16.2%)
0.396
GH (ng/mL)
34.9 ± 48.1
28.6 ± 42.8
40.1 ± 51.9
0.172
Nadir GH during OGTT
28.5 ± 14.5
23.8 ± 42.4
32.6 ± 49.0
0.304
IGF-1 (ng/mL)
796 ± 344
656 ± 195
908 ± 395
<0.001
IGF-I (% of ULN)
263 ± 228
209 ± 70
307 ± 155
<0.001
Prolactin (ng/mL)
23.5 ± 59.7
18.0 ± 36.7
0.241
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Age (years)
30.2 ± 79.0
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Data are presented as mean ± standard deviation or n (%). SMC = Samsung medical center; SNUH = Seoul national university hospital; OGTT = oral glucose tolerance test; ULN = upper limit of normal.
ACCEPTED MANUSCRIPT Table 2. Comparison of parameters between remission and non-remission group Remission
Non-remission
(n=99)
(n=35)
Age (years)
47.0 ± 12.5
43.5 ± 15.9
0.194
Male
55 (55.6%)
19 (54.3%)
0.897
Maximal diameter of tumor (mm)
18.1 ± 8.9
25.7 ± 12.2
0.001
Macroadenoma (≥10 mm)
86 (86.9%)
33 (94.3%)
0.006
20-30 mm
19 (19.2%)
≥30 mm
12 (12.1%)
Cavernous sinus invasion
22 (22.2%)
Pseudocapsule resection
91 (92.9%)
Nadir GH during OGTT (ng/mL) Preoperative IGF-1 (ng/mL) Preoperative IGF-I (% of ULN) Prolactin (ng/mL)
13 (37.1%)
<0.001
7 (7.1%)
<0.001
10 (28.6%)
0.027
26.1 ± 32.3
59.6 ± 71.9
<0.001
20.6 ± 26.2
53.4 ± 77.2
<0.001
774.0 ± 357.8
860.5 ± 298.9
0.209
252.9 ± 132.4
294.1 ± 132.9
0.121
21.1 ± 56.6
30.1 ± 68.2
0.449
20 (20.2%)
11 (31.4%)
0.176
TE D
Preoperative ACTH deficiency
8 (22.9%)
25 (71.4%)
8 (8.1%)
Preoperative GH (ng/mL)
12 (34.3%)
M AN U
Visual deficit
RI PT
55 (55.6%)
SC
10-19 mm
p Value
Preoperative TSH deficiency
19 (19.2%)
8 (27.9%)
0.642
Preoperative FSH/LH deficiency
45 (45.5%)
16 (45.7%)
0.979
1.9 ± 2.9
11.6 ± 19.5
<0.001
33 (33.3%)
13 (37.1%)
0.683
Immediate postoperative GH (ng/mL)
EP
Postoperative diabetes insipidus
AC C
Data are presented as mean ± standard deviation or n (%). SMC = Samsung medical center; SNUH = Seoul national university hospital; OGTT = oral glucose tolerance test; ULN = upper limit of normal.
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Table 3. Multivariate analysis for predictors for biochemical remission Unadjusted ORs
Adjusted ORs
0.55 (0.37-0.81)
1.29 (0.70-2.36)
Absence of cavernous sinus invasion
8.75 (3.65-20.9)
5.14 (1.52-17.3)
Preoperative GH (ng/mL) (per 5 ng/dL increase)
0.93 (0.89-0.98)
0.97 (0.91-1.02)
Immediate postoperative GH (ng/mL)< 2.5 ng/dL
14.9 (5.70-38.7)
9.60 (3.41-26.9)
Pseudocapsule resection
52.0 (16.0-169.1)
38.9 (9.1-166.6)
RI PT
Tumor size (per 10 mm increase)
AC C
EP
TE D
M AN U
SC
Data are shown as odds ratios (95% confidence interval). ORs = odds ratios.
ACCEPTED MANUSCRIPT in more than 30 Remission criteria nadir GH <1.0 nadir GH <1.0 nadir GH <1.0 nadir GH <1.0 nadir GH <1.0 nadir GH <0.4 nadir GH <0.4 nadir GH <0.4 nadir GH <0.4 nadir GH <1.0 nadir GH <0.4
AC C
EP
TE D
M AN U
SC
RI PT
Table 4. Literature review of biochemical remission after endoscopic surgery acromegalic patients Number of Macro Micro Reference Year n macro Overall adenoma adenoma adenoma Cappabianca et al. 2002 36 30 64% 60% 83% Kabil et al. 2005 48 35 85% 80% 100% Frank et al. 2006 83 59 70% 65% 83% Dehdashi et al. 2008 34 26 71% 65% 83% Gondim et al. 2010 67 53 75% 72% 86% Jane et al. 2011 60 46 70% 61% 10% Starke et al. 2013 72 59 71% 66% 88% Hazer et al 2013 214 163 63% 63% 63% Sarkar et al. 2014 66 34 29% 44% 13% 73% 72% 87% Current study 2017 134 119 48% 45% 67%
AC C
EP
TE D
M AN U
SC
RI PT
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AC C
EP
TE D
M AN U
SC
RI PT
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ACCEPTED MANUSCRIPT Highlights
AC C
EP
TE D
M AN U
SC
RI PT
The main contribution of our study was the initial surgical outcomes and complications of endoscopic pituitary surgery in the second largest data set of acromegaly patients from two referral centers. In addition, we elucidated that low preoperative GH levels, tumor size < 3 cm, an absence of cavernous sinus invasion, and immediate postoperative GH levels < 2.5 ng/mL predicted biochemical remission.
ACCEPTED MANUSCRIPT Abbreviations list GH: Growth hormone IGF-1: Insulin-like growth factor-1 SNUH : Seoul National University Hospital
RI PT
SMC: Samsung Medical Center ETS : Transsphenoidal surgery MRI : Magnetic resonance imaging
SC
CVs : Coefficients of variations LH : Luteinizing hormone
E2: Estradiol TSH: Thyroid-stimulating hormone ACTH: Adrenocorticotropic hormone RIA: Radioimmunoassay
AC C
EP
TE D
IRMA: Immunoradiometric assay
M AN U
FSH : follicle-stimulating hormone