Gross Total Resection in Low-Grade and Pretreated High-Grade Invasive Growth Hormone Pituitary Adenomas Promises Favorable Outcomes

Gross Total Resection in Low-Grade and Pretreated High-Grade Invasive Growth Hormone Pituitary Adenomas Promises Favorable Outcomes | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Gross Total Resection in Low-Grade and Pretreated High-Grade Invasive Growth Hormone Pituitary Adenomas Promises Favorable Outcomes Ting-Wei Chang, Chun-Chia Tseng, Yu-Chi Wang, Yin-Cheng Huang, and 3 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-6370980/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted 9 You are reading this latest preprint version Abstract Introduction: Growth hormone (GH)-secreting pituitary tumors produce systemic comorbidities, thus achieving gross total resection (GTR) and biochemical remission are imperative. The aim of this study was to identify predictors affecting resection status and biochemical remission. Methods: We retrospectively reviewed 54 GH adenoma patients receiving endoscopic endonasal transsphenoidal approach (EETSA). Medical records and magnetic resonance imaging were reviewed for tumor size, volume, resection status, invasion status, and Knosp and Hardy-Wilson grades. We also classified invasion status into high- and low-grade groups. Biochemical remission was defined as an insulin-like growth factor 1 value within sex- and age-adjusted reference or a random GH level < 1.0 ng/mL. Results: The degrees of horizontal and vertical invasion based on preoperative Knosp and Hardy-Wilson grade were highly associated with intraoperative resection status (p=0.015, 0.014 and 0.017 respectively). We also found more significant differences between resection status and higher-grade invasion (p=0.006, 0.006 and 0.001, respectively). Knosp, Hardy-Wilson grades and resection status were significantly associated with biochemical remission (p=0.0007, 0.0428, 0.0006 and 0.0012, respectively). Although there was no difference between micro- or macroadenoma, tumor size and volume were statistically significant associated with outcomes (p=0.024, 0.0032, respectively). Similarly, more significant differences between biochemical remission and higher-grade invasion were found (p=0.00005, 0.009 and 0.00001, respectively). Conclusions: EETSA remains the best treatment option for GH adenomas. Biochemical remission was highly associated with invasion status and the possibility of achieving GTR. Earlier diagnosis and more aggressive resection for low-grade and pretreated high-grade tumors are the key factors associated with favorable outcomes. GH pituitary adenoma endoscopic endonasal transsphenoidal approach Knosp and Hardy-Wilson grade resection status biochemical remission pre-operative treatment Figures Figure 1 Figure 2 Introduction Acromegaly is a condition caused by the overproduction of growth hormone (GH) due to pituitary tumors, and the subsequent production of insulin-like growth factor 1 (IGF-1). The severe systemic comorbidities of acromegaly including cardiovascular disease, diabetes mellitus, and musculoskeletal disease make controlling acromegaly necessary. The extent of associated complications and mortality risk are related to the length of exposure to excess GH and IGF-1, and thus early diagnosis and treatment are imperative [ 1 ]. Achieving biochemical remission remains the most important goal when treating patients with GH-secreting pituitary tumors. Surgery is the first-line treatment modality, and an endoscopic endonasal transsphenoidal approach (EETSA) is the most appropriate [ 2 , 3 ]. An important factor to predict the outcome after surgery is postoperative remission, and several predictors of postoperative biochemical remission have been identified, including preoperative human growth hormone and IGF-1 levels, tumor size, tumor volume, Hardy-Wilson classification, Knosp classification, sphenoid sinus invasion and prior surgery [ 3 – 9 ]. Most of these factors are related to the difficulty in achieving gross total resection (GTR) and biochemical remission [ 2 , 4 , 10 – 17 ]. However, very few studies have comprehensively discussed the factors influencing outcomes in patients with GH adenomas. Therefore, we retrospectively reviewed our 16-year experience in treating patients with GH adenomas who received EETSA as primary treatment. The aim of this study was to identify the pre- and postoperative factors affecting GTR and biochemical remission in our patients, and to compare our results with other studies. In addition, in some cases, preoperative medications may be a more feasible approach. Materials and Methods We retrospectively reviewed the medical records of patients with GH-secreting pituitary tumors at Linkou Chang Gung Memorial Hospital from October 2004 to December 2020. This study was performed in line with the principles of the Declaration of Helsinki. Approval was granted by the Ethics Committee of the Institutional Review Board (IRB) of Chang Gung Memorial Hospital (IRB No. 202401326B0). Informed consent was obtained from all individual participants included in the study. During this period, 54 patients received EETSA for pituitary tumor removal. Of these patients, 50 had sufficient medical records including pre- and postoperative magnetic resonance imaging (MRI), and data on GH and IGF-1 levels. Two patients did not have postoperative MRI scans, and two patients were lost to follow-up from our outpatient department. Pre- and postoperative MRI scans were reviewed by a neurosurgeon and neuroradiologist for general items including tumor size, tumor volume and resection status, and some specific characteristics including cavernous sinus invasion, parasellar invasion, suprasellar invasion, infrasellar invasion, Knosp classification, and Hardy-Wilson classification. We used Knosp classification for evaluating the degree of cavernous sinus invasion, and Hardy-Wilson classification for the degree of infrasellar, suprasellar and parasellar invasion [ 18 , 19 ]. In addition, we also divided the tumors into two groups on the basis of the level of cavernous sinus invasion. A less invasive tumor was defined as Knosp grade < 2, and a more invasive tumor as Knosp grade 3 and 4 [ 12 ]. Tumors classified below Hardy-Wilson grade 2 were defined as less infrasellar or sphenoidal sinus invasion, and those with Hardy-Wilson grade 3 or higher were defined as more infrasellar or sphenoidal sinus invasion [ 6 ]. The level of suprasellar invasion was based on Hardy-Wilson grade 0 ~ C. Tumors classified below Hardy-Wilson grade C were considered less parasellar invasion, and grade D and E tumors were considered to have more parasellar invasion ability [ 6 ]. Tumor size was defined by measuring the maximal horizontal length of the tumor in MRI coronal view. Tumors were classified as microadenoma if the size was < 1 cm, and macroadenoma if the size was ≥ 1 cm. Tumor volume was calculated as “ABC/2”, where A represents the longest tumor length, B represents the longest perpendicular line to A, and C represents the tumor height. Biochemical remission was determined according to the current consensus guidelines as an IGF-1 value within sex- and age-adjusted reference or random GH level < 1.0 ng/mL [ 20 , 21 ]. We used MedCalc version 19.7 (MedCalc Software Ltd., Ostend, Belgium) for data analysis. Fisher’s exact test was used for comparing categorical variables, the chi-square test was used for comparing ordinal variables, and the Mann-Whitney test was used for comparing continuous variables. A p value ≤ 0.05 was considered to indicate a statistically significant difference. Results As shown in Table 1 , the overall rate of GTR in the patients receiving surgery was Table 1 Characteristics of the Study Patients Variable Value Demographics Male 23 (46%) Age (years) 44.4 ± 14.2 Tumor Characteristics Macroadenoma 40 (80%) Tumor Size (cm) 1.6 ± 0.7 Tumor Volume (cm 3 ) 2.1 ± 2.4 Knosp Grade 0 3 (6%) 1 18 (36%) 2 15 (30%) 3 12 (24%) 4 2 (4%) Hardy-Wilson Grade 1 9 (18%) 2 19 (38%) 3 14 (28%) 4 18 (36%) Hardy-Wilson Grade 0 18 (38%) A 8 (16%) B 6 (12%) C 3 (6%) D 7 (14%) E 8 (16%) Post OP Characteristics Gross Total Resection 39(78%) Post-OP hGH 1.6 ± 3.1 Post-OP IGF-1 279 ± 191.9 Biochemical Remission 27 (54%) Follow-up period (months) 80.7 ± 46.9 hGH, human growth hormone; IGF-1, insulin-like growth factor 1; Post-OP, postoperative Values are given as frequency (percentage) for categorical variables or mean ± standard deviation for continuous variables. 78% (39 of 50 patients), and 27 patients (54%) achieved biochemical remission. We then compared the patients according to the status of resection (GTR or subtotal resection), and found no significant differences in tumor characteristics including micro- or macroadenoma, tumor size and tumor volume between the two groups (p > 0.99, p = 0.09 and 0.06 respectively) (Table 2 ). In addition, the possibility of GTR decreased with increasing Knosp grade (p = 0.015), and Hardy-Wilson grade was also significantly associated with GTR status (p = 0.014 and 0.017 respectively). We then further divided the patients into two groups according to the degree of invasiveness by Hardy-Wilson and Knosp grade, and found that the GTR rate for both classification systems reached statistical significance (p = 0.006, 0.006 and 0.001, respectively) (Table 2 − 1). Table 2 Statistical Analysis of the Patients with or without Gross Total Resection Values Variable GTR ( n = 39) STR ( n = 11) P value Demographics Male 16(41.03%) 7(63.64%) 0.30 Age (years) 45.3 ± 14.5 41.4 ± 12.5 0.41 Tumor Characteristics Macroadenoma 31(79.49%) 9(81.82%) 1 Tumor Size (cm) 1.4 ± 0.5 2.1 ± 1.1 0.09 Tumor Volume (cm 3 ) 1.7 ± 1.8 3.5 ± 3.6 0.06 Knosp Grade 0.015 0 3 0 1 17 1 2 12 3 3 7 5 4 0 2 Hardy-Wilson Grade 0.014 1 7 2 2 19 0 3 9 5 4 4 4 Hardy-Wilson Grade 0.017 0 16 2 A 8 0 B 5 1 C 3 0 D 4 3 E 3 5 GTR, gross total resection; STR, subtotal resection; hGH, human growth hormone; IGF-1, insulin-like growth factor 1 Values are given as frequency (percentage) for categorical variables or mean ± standard deviation for continuous variables. Table 2 − 1. Statistical Analysis of the Patients with or without Gross Total Resection According to the Degree of Invasiveness Values Variable GTR ( n = 39) STR ( n = 11) P value Knosp Grade 0.006 0 ~ 2 32 4 3 ~ 4 7 7 Hardy-Wilson Grade 0.006 0 ~ 2 26 2 3 ~ 4 13 9 Hardy-Wilson Grade 0.001 0 ~ C 32 7 D ~ E 3 8 GTR, gross total resection; STR, subtotal resection In analysis of the patients with and without biochemical remission, the patients who achieved biochemical remission had a smaller tumor size (p = 0.024) and volume (p = 0.0032) (Table 3 ). We also found that the rate of achieving biochemical remission decreased with higher invasiveness according to Knosp and Hardy-Wilson grade (p = 0.0007, 0.0428 and 0.0006, respectively). However, there were no significant differences between the patients with or without supra-, intra- or infrasellar invasion (p = 0.57, 0.08 and 0.37, respectively). Biochemical remission was also related to resection status (p = 0.0012), and achieving GTR was also highly related to invasion status. The rate of biochemical remission also reached a statistical difference in these two classification systems. We further divided the patients into two groups by the degree of invasiveness in the different grading systems, and found that the rate of achieving biochemical remission was significantly associated with both grading systems (p = 0.00005, 0.009 and 0.00001, respectively) (Table 3 − 1). Table 3 Statistical Analysis of the Patients with or without Biochemical Remission Values Variable Remission ( n = 27) Non-remission ( n = 23) P value Demographics Male 13 (48.15%) 10 (43.48%) 0.78 Age (years) 44.3 ± 12.8 44.6 ± 15.6 0.88 Tumor Characteristics Macroadenoma 20 (74.07%) 20(86.96%) 0.78 Tumor Size 1.3 ± 0.5 cm 1.8 ± 0.8 cm 0.024 Tumor Volume 1.4 ± 1.5 cm 3 3 ± 2.9 cm 3 0.0032 Suprasellar invasion 12 (44.44%) 13 (56.52%) 0.57 Pure intrasellar lesion 14 (51.85%) 6 (26.09%) 0.08 Infrasellar invasion 7 (25.93%) 9 (39.13%) 0.37 Knosp Grade 0.0007 0 3 0 1 14 4 2 9 6 3 1 11 4 0 2 Hardy-Wilson Grade 0.0428 1 7 2 2 13 6 3 4 10 4 3 5 Hardy-Wilson Grade 0.0006 0 14 4 A 7 1 B 3 3 C 2 1 D 0 7 E 1 7 Gross Total Resection 26(96.3%) 13(56.52%) 0.0012 Pre-OP hGH 14.3 ± 15.1 32.4 ± 37.7 0.19 Pre-OP IGF-1 603.7 ± 235.8 688.9 ± 196.4 0.12 hGH, human growth hormone; IGF-1, insulin-like growth factor 1 Values are given as frequency (percentage) for categorical variables or mean ± standard deviation for continuous variables. Table 3 − 1. Statistical Analysis of the Patients with or without Biochemical Remission According to the Degree of Invasiveness Values Variable Remission ( n = 27) Non-remission ( n = 23) P value Knosp Grade 0.00005 0 ~ 2 26 10 3 ~ 4 1 13 Hardy-Wilson Grade 0.009 0 ~ 2 20 8 3 ~ 4 7 15 Hardy-Wilson Grade 0.00001 0 ~ C 26 9 D ~ E 1 14 Discussion Acromegaly is a disease which manifests as progressive bone and cartilage growth as well as systemic complications including cardiovascular, metabolic, and respiratory issues. The first-line therapy for acromegaly is surgical resection, and surgical resection alone leads to disease control in approximately 90% of microadenoma cases and 40–60% of macroadenoma cases [ 3 ]. Postoperative biochemical remission is highly related to the preoperative condition and intraoperative resection status [ 3 – 5 , 7 , 22 , 23 ]. The importance of biochemical remission cannot be overemphasized, because it ameliorates the systemic effects of elevated GH, IGF-1, and the resultant mortality/morbidity [ 24 ]. Classification of parasellar invasion Knosp grade and Hardy-Wilson classification based on preoperative MRI are used to determine cavernous sinus and parasellar invasion [ 8 , 9 , 18 , 19 , 25 ]. Detailed descriptions of Knosp and Hardy grades are shown in Figs. 1 and 2 . A higher grade of tumor invasion is associated with greater difficulty in achieving GTR, particularly pituitary functioning tumors in which biochemical remission is even more critical than non-functioning tumors. Factors influencing intraoperative resection status It is known that cells secreting GH reside in the inferior and lateral aspects of the pituitary gland. Consequently, tumors tend to grow in an inferior and lateral direction. Our results are similar to previous studies in which GTR was associated with achieving biochemical remission [ 4 , 11 , 12 ]. Therefore, achieving GTR is an important predictive factor for disease control. On the other hand, the most crucial determinant in resection is horizontal and vertical invasion. In this study, intraoperative resection status was highly associated with preoperative Knosp and Hardy-Wilson grades (p = 0.015, 0.014 and 0.017, respectively) (Table 2 ). These results show that the surgical difficulty increased when the tumor extended beyond the sellar region in a horizontal or vertical direction. However, our data showed that tumor size and volume were not significantly associated with achieving GTR (p = 0.09 and 0.06, respectively), in contrast to the results reported by Zeng et al [ 12 ]. The main reason for this difference may be due to the mean size of macroadenoma in our study of around 1.76 cm, which may indicate a lack of higher-grade invasiveness, and subsequently that the possibility of achieving GTR was similar to the microadenoma patients. This finding also strengthens the importance of making an earlier diagnosis in GH adenoma patients, as the smaller tumor size would increase the possibility of achieving GTR and subsequent biochemical remission. Furthermore, the p -value for tumor volume (p = 0.06) in the view of GTR was closer to 0.05 than tumor size (p = 0.09), which may suggest that more precise volumetric measurement is important when defining the mass effect of a tumor, especially in irregularly shaped or residual tumors [ 26 , 27 ]. We also found stronger associations between higher Knosp and Hardy grades and a lower probability of achieving GTR (p = 0.006, 0.006, and 0.001, respectively) (Table 2 − 1). These results further highlight the importance of carefully interpretating preoperative MRI and the degree of peripheral invasion, especially in those with higher invasion classification. Factors influencing biochemical remission Unlike intraoperative resection status, we found that tumor size and volume were positively correlated with postoperative biochemical remission (p = 0.024 and 0.0032, respectively) (Table 3 ), which is similar to the results of other studies [ 4 , 5 , 11 , 22 ]. In addition, preoperative Knosp and Hardy-Wilson classification (p = 0.007, 0.0428, and 0.0006, respectively) and the resultant intraoperative resection status (p = 0.0012) were also significantly associated with postoperative biochemical remission as mentioned above. Interestingly, suprasellar, pure intrasellar and infrasellar invasion were not risk factors for biochemical remission (p = 0.57, 0.08 and 0.37, respectively). This result further supports that the grading of classification is far more important than the presence or absence of surrounding invasion status. The abovementioned suprasellar, pure intrasellar and infrasellar factors describe vertical tumor invasion status, which is not thought to be as critical as horizontal invasion. Although intrasellar tumors were easier to resect, the surgical techniques were similar to those with lower grade Knosp grade. In addition, for patients with infrasellar invasion toward the sphenoid floor or clivus, complete resection of tumors infiltrating into bone was challenging. In addition, GTR may be feasible for lower grade suprasellar invasion, but it remains challenging for higher grade suprasellar invasion, as demonstrated in Table 3 − 1. Furthermore, although tumor size and volume were predictive factors of biochemical remission, the lower preoperative GH and IGF-1 levels were not correlated with postoperative biochemical remission (p = 0.19 and 0.12, respectively). Tumors with a smaller size and volume are thought to harbor fewer secreting tumor cells; however, not every tumor cell produces an equivalent amount of GH and the resultant systemic effects. We found stronger associations between higher Knosp and Hardy-Wilson grades and a lower probability of postoperative biochemical remission (p = 0.00005, 0.009, and 0.00001, respectively) (Table 3 − 1). These results further support the importance of carefully interpreting preoperative MRI and the degree of peripheral invasion, especially in those with higher invasion classification. Regardless of postoperative biochemical remission or intraoperative resection status, we found that the most pivotal predictive factor was preoperative grading of invasion status, especially in those with a higher grade. Careful interpretation of preoperative MRI and removing as much of the tumor as possible are the key factors associated with favorable outcomes. Association of tumor size and volume with resection status and biochemical remission Many studies have reported an association between tumor size and biochemical remission rate, and some studies have mentioned that patients who achieve remission have a smaller tumor size [ 3 , 6 , 11 ]. In addition, some studies have reported that patients with microadenoma have a higher remission rate [ 6 , 12 ]. In our study, the patients with microadenoma (< 1 cm) did not have a significantly higher remission rate compared to those with macroadenoma. However, the patients who achieved remission did have a smaller tumor size (< 1.3 cm, p = 0.024), which is similar to the study by Samuel et al [ 3 ]. A possible explanation for this finding is that our patients had smaller macroadenomas (mean size 1.76 ± 0.67 cm). As a result, we suggest that the crucial cut-off value of tumor size to achieve GTR should be ≥ 1.3 cm, or the average width of the sellar region. Hence, the 1 cm definition for the classification of micro- and macroadenomas may not be necessary, especially in GH-secreting or other functioning tumors necessitating surgical resection. Furthermore, in tumors that did not invade the cavernous sinus or extend into the supra- or infrasellar region, the tumor size and volume were determining predictors; in contrast, in tumors that extended beyond the sellar region, the determining predictor of biochemical remission was the presence or absence of higher-grade invasion. Association of tumor invasion grading with resection status and biochemical remission The Hardy-Wilson and Knosp grading systems are widely used to classify the level of tumor invasion, and they are also key indicators of whether GTR can be achieved. A higher level of tumor invasion is considered to impede complete surgical resection, and therefore biochemical remission. Although some studies have reported that a higher grade was associated with a lower rate of biochemical remission, the results have been inconsistent [ 2 , 3 , 7 , 22 ]. Whether Hardy-Wilson grade can predict biochemical remission remains controversial. Mohammad et al reported that biochemical remission was independent of Hardy-Wilson grade [ 4 ], whereas Campbell et al and Yildirim et al found that remission was related to Hardy-Wilson grade [ 6 , 22 ]. In addition, Shin et al and Yildirim et al found that Hardy-Wilson grade was a predictor of biochemical remission [ 3 , 6 ]. In our study, we comprehensively reviewed all classifications, and found that the probability of achieving GTR and rate of biochemical remission decreased with higher Hardy-Wilson grade. In addition, we also found that the rates of achieving GTR and biochemical remission were related to cavernous sinus invasion. Furthermore, when considering the level of suprasellar extension only, there was no statistical significance among Hardy-Wilson grade 0 ~ C. This may imply that with mature endoscopic endonasal surgery, GTR can also be achieved even when the tumor extends into the suprasellar space. In addition, although we used an EETSA, which is via the infrasellar space, sphenoid sinus or clivus invasion may imply a higher degree of tumor invasion, and consequently greater difficulty in curing the disease [ 6 ]. However, cavernous sinus invasion is still associated with the greatest difficulty in achieving complete tumor removal and ideal hormone control because of the vital structures inside. Clinical implications of the treatment of GH adenomas based on invasiveness status Our results showed that GH adenomas with high-grade invasiveness hindered complete resection, and that achieving GTR always increased the risk of unnecessary vascular and neurological injuries. However, several previous studies reported that somatostatin receptor ligand (SRL) treatment effectively normalized GH and IGF-1, improved clinical symptoms and quality of life, and reduced tumor volume in 62.9 ~ 81% patients [ 28 – 31 ]. Most importantly, pretreatment with SRLs before surgery has been demonstrated to improve surgical cure rates in patients with GH-secreting pituitary macroadenomas [ 32 ]. Furthermore, T2 hypointense adenomas have been shown to respond more dramatically to SRL treatment [ 33 – 36 ]. As a result, in higher grade GH adenomas, preoperative medications may not only reduce the tumor size but also lower the invasiveness, thereby facilitating surgical procedures and promising similar outcomes to lower grade tumors. To sum up, for pure intrasellar tumors or those with lower invasiveness, aggressive GTR should be attempted during surgery. However, for high-grade invasive tumors, preoperative SRL treatment may be a feasible approach to achieve GTR and biochemical remission. Conclusions Pituitary GH adenomas exert systemic effects, and EETSA remains the best treatment for biochemical remission. GTR was associated with biochemical remission and was influenced by invasion status, especially in those with higher grade invasion. Biochemical remission was highly associated with invasion status and resection status rather than tumor size and volume. Earlier diagnosis and more aggressive resection for low-grade and pretreated high-grade tumors are the key factors associated with favorable outcomes. Abbreviations GH growth hormone IGF-1 insulin-like growth factor 1 EETSA endoscopic endonasal transsphenoidal approach GTR gross total resection MRI magnetic resonance imaging SRL somatostatin receptor ligand Declarations Consent for publication Informed consent was obtained from all individual participants included in the study. Authors' contributions Ting-Wei Chang and Chun-Chia Tseng wrote the main manuscript text, Yin-Cheng Huang, Peng-Wei Hsu, Chi-Cheng Chuang and Cheng-Chi Lee collected the data, Ting-Wei Chang and Yu-Chi Wang did the analysis and prepared the tables and figures, Chi-Cheng Chuang, and Cheng-Chi Lee supervised the manuscript. Competing Interests The authors have no relevant financial or non-financial interests to disclose. Acknowledgements We acknowledged Chang Gung Memorial Hospital and Chang Gung University to support the research and we received a grant from Chang Gung Memorial Hospital. Funding This research was funded by a grant from Chang Gung Memorial Hospital (CMRPG1L0051, CMRPG1L0052, CMRPG1N0071, CMRPG1N0072, Cheng Chi Lee), and the funder had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Ethics Approval This study was performed in line with the principles of the Declaration of Helsinki. Approval was granted by the Ethics Committee of the Institutional Review Board (IRB) of Chang Gung Memorial Hospital (IRB No. 202401326B0). Informed consent was obtained from all individual participants included in the study. The authors affirm that human research participants provided informed consent for publication of their data in the manuscript. Data Availability The data that support the findings of this study are not openly available due to reasons of sensitivity and are available from the corresponding author upon reasonable request. Clinical Trial Number : not applicable References Abreu A, et al. Challenges in the diagnosis and management of acromegaly: a focus on comorbidities. Pituitary. 2016;19(4):448–57. Araujo-Castro M, et al. Predictive model of surgical remission in acromegaly: age, presurgical GH levels and Knosp grade as the best predictors of surgical remission. J Endocrinol Invest. 2021;44(1):183–93. Shin SS, et al. Endoscopic endonasal approach for growth hormone secreting pituitary adenomas: outcomes in 53 patients using 2010 consensus criteria for remission. Pituitary. 2013;16(4):435–44. Taghvaei M, et al. Endoscopic Endonasal Approach to the Growth Hormone-Secreting Pituitary Adenomas: Endocrinologic Outcome in 68 Patients. World Neurosurg. 2018;117:e259–68. Hofstetter CP, et al. Endoscopic endonasal transsphenoidal surgery for growth hormone-secreting pituitary adenomas. Neurosurg Focus. 2010;29(4):E6. Yildirim AE, et al. Endoscopic endonasal transsphenoidal treatment for acromegaly: 2010 consensus criteria for remission and predictors of outcomes. Turk Neurosurg. 2014;24(6):906–12. Jane JA Jr., et al. Endoscopic transsphenoidal surgery for acromegaly: remission using modern criteria, complications, and predictors of outcome. J Clin Endocrinol Metab. 2011;96(9):2732–40. Davies BM, et al. Assessing size of pituitary adenomas: a comparison of qualitative and quantitative methods on MR. Acta Neurochir (Wien). 2016;158(4):677–83. Chatzellis E, et al. Aggressive pituitary tumors. Neuroendocrinology. 2015;101(2):87–104. Cardinal T, et al. Postoperative GH and Degree of Reduction in IGF-1 Predicts Postoperative Hormonal Remission in Acromegaly. Front Endocrinol (Lausanne). 2021;12:743052. Cardinal T, et al. Impact of tumor characteristics and pre- and postoperative hormone levels on hormonal remission following endoscopic transsphenoidal surgery in patients with acromegaly. Neurosurg Focus. 2020;48(6):E10. Zheng Y, Wang CD, Mai Y, Zhu RK. ZF, Surgical management of growth hormone-secreting pituitary adenomas: A retrospective analysis of 33 patients. Medicine, 2020. 2020;99:19(e19855). Shen SC, et al. Long-Term Effects of Intracapsular Debulking and Adjuvant Somatostatin Analogs for Growth Hormone-Secreting Pituitary Macroadenoma: 10 Years of Experience in a Single Institute. World Neurosurg. 2019;126:e41–7. Almeida JP, et al. Reoperation for growth hormone-secreting pituitary adenomas: report on an endonasal endoscopic series with a systematic review and meta-analysis of the literature. J Neurosurg. 2018;129(2):404–16. Yano S, et al. Intraoperative Scoring System to Predict Postoperative Remission in Endoscopic Endonasal Transsphenoidal Surgery for Growth Hormone-Secreting Pituitary Adenomas. World Neurosurg. 2017;105:375–85. Briceno V, et al. Efficacy of transsphenoidal surgery in achieving biochemical cure of growth hormone-secreting pituitary adenomas among patients with cavernous sinus invasion: a systematic review and meta-analysis. Neurol Res. 2017;39(5):387–98. Babu H, et al. Long-Term Endocrine Outcomes Following Endoscopic Endonasal Transsphenoidal Surgery for Acromegaly and Associated Prognostic Factors. Neurosurgery. 2017;81(2):357–66. Knosp E et al. Pituitary adenomas with invasion of the cavernous sinus space: a magnetic resonance imaging classification compared with surgical findings. Neurosurgery, 1993. 33(4): pp. 610-7; discussion 617-8. Hardy J. Transphenoidal microsurgery of the normal and pathological pituitary. Clin Neurosurg. 1969;16:185–217. Giustina A, et al. A consensus on criteria for cure of acromegaly. J Clin Endocrinol Metab. 2010;95(7):3141–8. Giustina A et al. Consensus on criteria for acromegaly diagnosis and remission. Pituitary, 2023. Campbell PG, et al. Outcomes after a purely endoscopic transsphenoidal resection of growth hormone-secreting pituitary adenomas. Neurosurg Focus. 2010;29(4):E5. Shirvani M, Motiei-Langroudi R. Transsphenoidal surgery for growth hormone-secreting pituitary adenomas in 130 patients. World Neurosurg. 2014;81(1):125–30. Holdaway IM, Rajasoorya RC, Gamble GD. Factors influencing mortality in acromegaly. J Clin Endocrinol Metab. 2004;89(2):667–74. Hardy J, Vezina JL. Transsphenoidal neurosurgery of intracranial neoplasm. Adv Neurol. 1976;15:261–73. Lee CC, et al. Prediction of Long-term Post-operative Testosterone Replacement Requirement Based on the Pre-operative Tumor Volume and Testosterone Level in Pituitary Macroadenoma. Sci Rep. 2015;5:16194. Chuang CC, et al. Different Volumetric Measurement Methods for Pituitary Adenomas and Their Crucial Clinical Significance. Sci Rep. 2017;7:40792. Caron PJ, et al. Tumor shrinkage with lanreotide Autogel 120 mg as primary therapy in acromegaly: results of a prospective multicenter clinical trial. J Clin Endocrinol Metab. 2014;99(4):1282–90. Caron PJ, et al. Effects of lanreotide Autogel primary therapy on symptoms and quality-of-life in acromegaly: data from the PRIMARYS study. Pituitary. 2016;19(2):149–57. Caron PJ, et al. Glucose and lipid levels with lanreotide autogel 120 mg in treatment-naive patients with acromegaly: data from the PRIMARYS study. Clin Endocrinol (Oxf). 2017;86(4):541–51. Colao A, Auriemma RS, Pivonello R. The effects of somatostatin analogue therapy on pituitary tumor volume in patients with acromegaly. Pituitary. 2016;19(2):210–21. Mao ZG, et al. Preoperative lanreotide treatment in acromegalic patients with macroadenomas increases short-term postoperative cure rates: a prospective, randomised trial. Eur J Endocrinol. 2010;162(4):661–6. Hagiwara A, et al. Comparison of growth hormone-producing and non-growth hormone-producing pituitary adenomas: imaging characteristics and pathologic correlation. Radiology. 2003;228(2):533–8. Heck A, et al. Intensity of pituitary adenoma on T2-weighted magnetic resonance imaging predicts the response to octreotide treatment in newly diagnosed acromegaly. Clin Endocrinol (Oxf). 2012;77(1):72–8. Potorac I, Beckers A, Bonneville JF. T2-weighted MRI signal intensity as a predictor of hormonal and tumoral responses to somatostatin receptor ligands in acromegaly: a perspective. Pituitary. 2017;20(1):116–20. Potorac I, et al. Pituitary MRI characteristics in 297 acromegaly patients based on T2-weighted sequences. Endocr Relat Cancer. 2015;22(2):169–77. Additional Declarations No competing interests reported. Cite Share Download PDF Status: Under Review Version 1 posted Editorial decision: Revision requested 27 May, 2025 Reviews received at journal 26 May, 2025 Reviews received at journal 20 May, 2025 Reviewers agreed at journal 19 May, 2025 Reviewers agreed at journal 14 May, 2025 Reviewers invited by journal 14 May, 2025 Editor assigned by journal 28 Apr, 2025 Submission checks completed at journal 28 Apr, 2025 First submitted to journal 03 Apr, 2025 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-6370980","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":457886757,"identity":"c7ec1324-859b-4c57-9b21-1dabd27bd48c","order_by":0,"name":"Ting-Wei Chang","email":"","orcid":"","institution":"Chang Gung Memorial Hospital at Linkou, Chang Gung University","correspondingAuthor":false,"prefix":"","firstName":"Ting-Wei","middleName":"","lastName":"Chang","suffix":""},{"id":457886758,"identity":"a8608eba-0655-4950-b68f-8f35113fef24","order_by":1,"name":"Chun-Chia Tseng","email":"","orcid":"","institution":"Chang Gung Memorial Hospital at Linkou, Chang Gung University","correspondingAuthor":false,"prefix":"","firstName":"Chun-Chia","middleName":"","lastName":"Tseng","suffix":""},{"id":457886759,"identity":"45fc3760-fc23-41f7-a62b-d850c7f2562e","order_by":2,"name":"Yu-Chi Wang","email":"","orcid":"","institution":"Chang Gung Memorial Hospital at Linkou, Chang Gung University","correspondingAuthor":false,"prefix":"","firstName":"Yu-Chi","middleName":"","lastName":"Wang","suffix":""},{"id":457886760,"identity":"8e77da0b-034d-4466-92ed-b1520ccc89ab","order_by":3,"name":"Yin-Cheng Huang","email":"","orcid":"","institution":"Chang Gung Memorial Hospital at Linkou, Chang Gung University","correspondingAuthor":false,"prefix":"","firstName":"Yin-Cheng","middleName":"","lastName":"Huang","suffix":""},{"id":457886761,"identity":"18a07138-ed32-4c60-9a88-135356506e61","order_by":4,"name":"Peng-Wei Hsu","email":"","orcid":"","institution":"Chang Gung Memorial Hospital at Linkou, Chang Gung University","correspondingAuthor":false,"prefix":"","firstName":"Peng-Wei","middleName":"","lastName":"Hsu","suffix":""},{"id":457886762,"identity":"4ff34aaf-a4c8-4ca0-a790-3d41db33735c","order_by":5,"name":"Chi-Cheng Chuang","email":"","orcid":"","institution":"Chang Gung Memorial Hospital at Linkou, Chang Gung University","correspondingAuthor":false,"prefix":"","firstName":"Chi-Cheng","middleName":"","lastName":"Chuang","suffix":""},{"id":457886763,"identity":"5c1105c9-1ecd-444f-ac6b-f0802dadef06","order_by":6,"name":"Cheng-Chi Lee","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAAv0lEQVRIiWNgGAWjYNCCChs5EHXgAfFazqQZg7UkEK2Dse1QYgOIQZQWgxvZiY95zhxInx92+CHQFjs53QaCWnI3G86ouJO78XaaAVBLsrHZAcJatkl8OPMsd+PsBJCWA4nbiNCy/Udi2+F0w9npH4jWso3hY9vhBHnpHCJtkTzzdrPkjDNphhukcwoOJBgQ4Re+47kbP/NU2MjLz07f/OFDhZ0cQS0KMAUGYIYBAeUgIN+AzhgFo2AUjIJRgA4AB2NPXQaoZKkAAAAASUVORK5CYII=","orcid":"","institution":"Chang Gung Memorial Hospital at Linkou, Chang Gung University","correspondingAuthor":true,"prefix":"","firstName":"Cheng-Chi","middleName":"","lastName":"Lee","suffix":""}],"badges":[],"createdAt":"2025-04-03 16:23:23","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-6370980/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-6370980/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":83125599,"identity":"76e6663a-80fe-4b2c-8e3e-fd85e633dc7b","added_by":"auto","created_at":"2025-05-20 09:39:13","extension":"jpeg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":246473,"visible":true,"origin":"","legend":"\u003cp\u003eKnosp grade. This system grades the parasellar extension of a tumor towards the cavernous sinus in relation to the intracavernous carotid artery [8, 18]\u003c/p\u003e","description":"","filename":"floatimage1.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-6370980/v1/cda9415fe48223ed650d2879.jpeg"},{"id":83125626,"identity":"ef3bb860-08e5-4936-9c46-1013858fda7f","added_by":"auto","created_at":"2025-05-20 09:39:14","extension":"jpeg","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":1044164,"visible":true,"origin":"","legend":"\u003cp\u003eHardy-Wilson classification of pituitary tumors. Upper panel shows the classification of downward sphenoid bone invasion (grade 0: intact with normal contour; grade I: intact with bulging floor; grade II: intact with enlarged fossa; grade III: localized sellar destruction; grade IV: diffuse sellar destruction). Only grade III and IV tumors are considered invasive or high grade. Lower panel describes classification of upward suprasellar extension [grade A: only intrasellar location; grade B: recess of the third ventricle; grade C: whole anterior third ventricle; grade D: intracranial extradural; grade E: extracranial extradural] [9]\u003c/p\u003e","description":"","filename":"floatimage2.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-6370980/v1/07eb7fa328dce6a207696a3e.jpeg"},{"id":83125745,"identity":"42a56932-5cc9-4b65-8d35-b77b480e170e","added_by":"auto","created_at":"2025-05-20 09:39:37","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":2196178,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-6370980/v1/31b89be7-5634-45e3-a16a-a52d6d014f75.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Gross Total Resection in Low-Grade and Pretreated High-Grade Invasive Growth Hormone Pituitary Adenomas Promises Favorable Outcomes","fulltext":[{"header":"Introduction","content":"\u003cp\u003eAcromegaly is a condition caused by the overproduction of growth hormone (GH) due to pituitary tumors, and the subsequent production of insulin-like growth factor 1 (IGF-1). The severe systemic comorbidities of acromegaly including cardiovascular disease, diabetes mellitus, and musculoskeletal disease make controlling acromegaly necessary. The extent of associated complications and mortality risk are related to the length of exposure to excess GH and IGF-1, and thus early diagnosis and treatment are imperative [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. Achieving biochemical remission remains the most important goal when treating patients with GH-secreting pituitary tumors. Surgery is the first-line treatment modality, and an endoscopic endonasal transsphenoidal approach (EETSA) is the most appropriate [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e, \u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]. An important factor to predict the outcome after surgery is postoperative remission, and several predictors of postoperative biochemical remission have been identified, including preoperative human growth hormone and IGF-1 levels, tumor size, tumor volume, Hardy-Wilson classification, Knosp classification, sphenoid sinus invasion and prior surgery [\u003cspan additionalcitationids=\"CR4 CR5 CR6 CR7 CR8\" citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e]. Most of these factors are related to the difficulty in achieving gross total resection (GTR) and biochemical remission [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e, \u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e, \u003cspan additionalcitationids=\"CR11 CR12 CR13 CR14 CR15 CR16\" citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e]. However, very few studies have comprehensively discussed the factors influencing outcomes in patients with GH adenomas. Therefore, we retrospectively reviewed our 16-year experience in treating patients with GH adenomas who received EETSA as primary treatment. The aim of this study was to identify the pre- and postoperative factors affecting GTR and biochemical remission in our patients, and to compare our results with other studies. In addition, in some cases, preoperative medications may be a more feasible approach.\u003c/p\u003e"},{"header":"Materials and Methods","content":"\u003cp\u003eWe retrospectively reviewed the medical records of patients with GH-secreting pituitary tumors at Linkou Chang Gung Memorial Hospital from October 2004 to December 2020. This study was performed in line with the principles of the Declaration of Helsinki. Approval was granted by the Ethics Committee of the Institutional Review Board (IRB) of Chang Gung Memorial Hospital (IRB No. 202401326B0). Informed consent was obtained from all individual participants included in the study. During this period, 54 patients received EETSA for pituitary tumor removal. Of these patients, 50 had sufficient medical records including pre- and postoperative magnetic resonance imaging (MRI), and data on GH and IGF-1 levels. Two patients did not have postoperative MRI scans, and two patients were lost to follow-up from our outpatient department.\u003c/p\u003e \u003cp\u003ePre- and postoperative MRI scans were reviewed by a neurosurgeon and neuroradiologist for general items including tumor size, tumor volume and resection status, and some specific characteristics including cavernous sinus invasion, parasellar invasion, suprasellar invasion, infrasellar invasion, Knosp classification, and Hardy-Wilson classification. We used Knosp classification for evaluating the degree of cavernous sinus invasion, and Hardy-Wilson classification for the degree of infrasellar, suprasellar and parasellar invasion [\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e, \u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e]. In addition, we also divided the tumors into two groups on the basis of the level of cavernous sinus invasion. A less invasive tumor was defined as Knosp grade\u0026thinsp;\u0026lt;\u0026thinsp;2, and a more invasive tumor as Knosp grade 3 and 4 [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e]. Tumors classified below Hardy-Wilson grade 2 were defined as less infrasellar or sphenoidal sinus invasion, and those with Hardy-Wilson grade 3 or higher were defined as more infrasellar or sphenoidal sinus invasion [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]. The level of suprasellar invasion was based on Hardy-Wilson grade 0\u0026thinsp;~\u0026thinsp;C. Tumors classified below Hardy-Wilson grade C were considered less parasellar invasion, and grade D and E tumors were considered to have more parasellar invasion ability [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]. Tumor size was defined by measuring the maximal horizontal length of the tumor in MRI coronal view. Tumors were classified as microadenoma if the size was \u0026lt;\u0026thinsp;1 cm, and macroadenoma if the size was \u0026ge; 1 cm. Tumor volume was calculated as \u0026ldquo;ABC/2\u0026rdquo;, where A represents the longest tumor length, B represents the longest perpendicular line to A, and C represents the tumor height. Biochemical remission was determined according to the current consensus guidelines as an IGF-1 value within sex- and age-adjusted reference or random GH level\u0026thinsp;\u0026lt;\u0026thinsp;1.0 ng/mL [\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e, \u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eWe used MedCalc version 19.7 (MedCalc Software Ltd., Ostend, Belgium) for data analysis. Fisher\u0026rsquo;s exact test was used for comparing categorical variables, the chi-square test was used for comparing ordinal variables, and the Mann-Whitney test was used for comparing continuous variables. A \u003cem\u003ep\u003c/em\u003e value \u0026le; 0.05 was considered to indicate a statistically significant difference.\u003c/p\u003e"},{"header":"Results","content":"\u003cp\u003eAs shown in Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e, the overall rate of GTR in the patients receiving surgery was\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eCharacteristics of the Study Patients\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"2\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eVariable\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eValue\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDemographics\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMale\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e23 (46%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAge (years)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e44.4\u0026thinsp;\u0026plusmn;\u0026thinsp;14.2\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTumor Characteristics\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMacroadenoma\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e40 (80%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTumor Size (cm)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1.6\u0026thinsp;\u0026plusmn;\u0026thinsp;0.7\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTumor Volume (cm\u003csup\u003e3\u003c/sup\u003e)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2.1\u0026thinsp;\u0026plusmn;\u0026thinsp;2.4\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eKnosp Grade\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e3 (6%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e18 (36%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e15 (30%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e12 (24%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2 (4%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHardy-Wilson Grade\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e9 (18%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e19 (38%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e14 (28%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e18 (36%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHardy-Wilson Grade\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e18 (38%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eA\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e8 (16%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eB\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e6 (12%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eC\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e3 (6%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eD\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e7 (14%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eE\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e8 (16%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePost OP Characteristics\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eGross Total Resection\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e39(78%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePost-OP hGH\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1.6\u0026thinsp;\u0026plusmn;\u0026thinsp;3.1\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePost-OP IGF-1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e279\u0026thinsp;\u0026plusmn;\u0026thinsp;191.9\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBiochemical Remission\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e27 (54%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eFollow-up period (months)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e80.7\u0026thinsp;\u0026plusmn;\u0026thinsp;46.9\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"2\"\u003ehGH, human growth hormone; IGF-1, insulin-like growth factor 1; Post-OP, postoperative\u003c/td\u003e\u003c/tr\u003e \u003ctr\u003e\u003ctd colspan=\"2\"\u003eValues are given as frequency (percentage) for categorical variables or mean\u0026thinsp;\u0026plusmn;\u0026thinsp;standard deviation for continuous variables.\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003e78% (39 of 50 patients), and 27 patients (54%) achieved biochemical remission. We then compared the patients according to the status of resection (GTR or subtotal resection), and found no significant differences in tumor characteristics including micro- or macroadenoma, tumor size and tumor volume between the two groups (p\u0026thinsp;\u0026gt;\u0026thinsp;0.99, p\u0026thinsp;=\u0026thinsp;0.09 and 0.06 respectively) (Table\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e2\u003c/span\u003e). In addition, the possibility of GTR decreased with increasing Knosp grade (p\u0026thinsp;=\u0026thinsp;0.015), and Hardy-Wilson grade was also significantly associated with GTR status (p\u0026thinsp;=\u0026thinsp;0.014 and 0.017 respectively). We then further divided the patients into two groups according to the degree of invasiveness by Hardy-Wilson and Knosp grade, and found that the GTR rate for both classification systems reached statistical significance (p\u0026thinsp;=\u0026thinsp;0.006, 0.006 and 0.001, respectively) (Table\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e2\u003c/span\u003e\u0026thinsp;\u0026minus;\u0026thinsp;1).\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eStatistical Analysis of the Patients with or without Gross Total Resection\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"7\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c7\" colnum=\"7\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colspan=\"6\" nameend=\"c7\" namest=\"c2\"\u003e \u003cp\u003eValues\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eVariable\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"3\" nameend=\"c4\" namest=\"c2\"\u003e \u003cp\u003eGTR\u003c/p\u003e \u003cp\u003e(\u003cem\u003en\u003c/em\u003e\u0026thinsp;=\u0026thinsp;39)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eSTR\u003c/p\u003e \u003cp\u003e(\u003cem\u003en\u003c/em\u003e\u0026thinsp;=\u0026thinsp;11)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c7\" namest=\"c6\"\u003e \u003cp\u003e\u003cem\u003eP\u003c/em\u003e value\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003eDemographics\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c5\" namest=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c7\" namest=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMale\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e \u003cp\u003e16(41.03%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"3\" nameend=\"c6\" namest=\"c4\"\u003e \u003cp\u003e7(63.64%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.30\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAge (years)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e \u003cp\u003e45.3\u0026thinsp;\u0026plusmn;\u0026thinsp;14.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"3\" nameend=\"c6\" namest=\"c4\"\u003e \u003cp\u003e41.4\u0026thinsp;\u0026plusmn;\u0026thinsp;12.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.41\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTumor Characteristics\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colspan=\"3\" nameend=\"c6\" namest=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMacroadenoma\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e \u003cp\u003e31(79.49%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"3\" nameend=\"c6\" namest=\"c4\"\u003e \u003cp\u003e9(81.82%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTumor Size (cm)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e \u003cp\u003e1.4\u0026thinsp;\u0026plusmn;\u0026thinsp;0.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"3\" nameend=\"c6\" namest=\"c4\"\u003e \u003cp\u003e2.1\u0026thinsp;\u0026plusmn;\u0026thinsp;1.1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.09\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTumor Volume (cm\u003csup\u003e3\u003c/sup\u003e)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e \u003cp\u003e1.7\u0026thinsp;\u0026plusmn;\u0026thinsp;1.8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"3\" nameend=\"c6\" namest=\"c4\"\u003e \u003cp\u003e3.5\u0026thinsp;\u0026plusmn;\u0026thinsp;3.6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.06\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eKnosp Grade\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colspan=\"3\" nameend=\"c6\" namest=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.015\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"3\" nameend=\"c6\" namest=\"c4\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e \u003cp\u003e17\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"3\" nameend=\"c6\" namest=\"c4\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e \u003cp\u003e12\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"3\" nameend=\"c6\" namest=\"c4\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e \u003cp\u003e7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"3\" nameend=\"c6\" namest=\"c4\"\u003e \u003cp\u003e5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"3\" nameend=\"c6\" namest=\"c4\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHardy-Wilson Grade\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colspan=\"3\" nameend=\"c6\" namest=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.014\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e \u003cp\u003e7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"3\" nameend=\"c6\" namest=\"c4\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e \u003cp\u003e19\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"3\" nameend=\"c6\" namest=\"c4\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e \u003cp\u003e9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"3\" nameend=\"c6\" namest=\"c4\"\u003e \u003cp\u003e5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e \u003cp\u003e4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"3\" nameend=\"c6\" namest=\"c4\"\u003e \u003cp\u003e4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHardy-Wilson Grade\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colspan=\"3\" nameend=\"c6\" namest=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.017\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e \u003cp\u003e16\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"3\" nameend=\"c6\" namest=\"c4\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eA\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e \u003cp\u003e8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"3\" nameend=\"c6\" namest=\"c4\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eB\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e \u003cp\u003e5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"3\" nameend=\"c6\" namest=\"c4\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eC\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"3\" nameend=\"c6\" namest=\"c4\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eD\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e \u003cp\u003e4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"3\" nameend=\"c6\" namest=\"c4\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eE\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"3\" nameend=\"c6\" namest=\"c4\"\u003e \u003cp\u003e5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"7\"\u003eGTR, gross total resection; STR, subtotal resection; hGH, human growth hormone; IGF-1, insulin-like growth factor 1\u003c/td\u003e\u003c/tr\u003e \u003ctr\u003e\u003ctd colspan=\"7\"\u003eValues are given as frequency (percentage) for categorical variables or mean\u0026thinsp;\u0026plusmn;\u0026thinsp;standard deviation for continuous variables.\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab3\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003e\u0026thinsp;\u003cb\u003e\u0026minus;\u0026thinsp;1.\u003c/b\u003e Statistical Analysis of the Patients with or without Gross Total Resection According to the Degree of Invasiveness\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"6\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colspan=\"5\" nameend=\"c6\" namest=\"c2\"\u003e \u003cp\u003eValues\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eVariable\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e \u003cp\u003eGTR\u003c/p\u003e \u003cp\u003e(\u003cem\u003en\u003c/em\u003e\u0026thinsp;=\u0026thinsp;39)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eSTR\u003c/p\u003e \u003cp\u003e(\u003cem\u003en\u003c/em\u003e\u0026thinsp;=\u0026thinsp;11)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c6\" namest=\"c5\"\u003e \u003cp\u003e\u003cem\u003eP\u003c/em\u003e value\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eKnosp Grade\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colspan=\"3\" nameend=\"c5\" namest=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.006\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e0\u0026thinsp;~\u0026thinsp;2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e32\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"3\" nameend=\"c5\" namest=\"c3\"\u003e \u003cp\u003e4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e3\u0026thinsp;~\u0026thinsp;4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"3\" nameend=\"c5\" namest=\"c3\"\u003e \u003cp\u003e7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHardy-Wilson Grade\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colspan=\"3\" nameend=\"c5\" namest=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.006\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e0\u0026thinsp;~\u0026thinsp;2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e26\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"3\" nameend=\"c5\" namest=\"c3\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e3\u0026thinsp;~\u0026thinsp;4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e13\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"3\" nameend=\"c5\" namest=\"c3\"\u003e \u003cp\u003e9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHardy-Wilson Grade\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colspan=\"3\" nameend=\"c5\" namest=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e0\u0026thinsp;~\u0026thinsp;C\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e32\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"3\" nameend=\"c5\" namest=\"c3\"\u003e \u003cp\u003e7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eD\u0026thinsp;~\u0026thinsp;E\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"3\" nameend=\"c5\" namest=\"c3\"\u003e \u003cp\u003e8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"6\"\u003eGTR, gross total resection; STR, subtotal resection\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eIn analysis of the patients with and without biochemical remission, the patients who achieved biochemical remission had a smaller tumor size (p\u0026thinsp;=\u0026thinsp;0.024) and volume (p\u0026thinsp;=\u0026thinsp;0.0032) (Table\u0026nbsp;\u003cspan refid=\"Tab5\" class=\"InternalRef\"\u003e3\u003c/span\u003e). We also found that the rate of achieving biochemical remission decreased with higher invasiveness according to Knosp and Hardy-Wilson grade (p\u0026thinsp;=\u0026thinsp;0.0007, 0.0428 and 0.0006, respectively). However, there were no significant differences between the patients with or without supra-, intra- or infrasellar invasion (p\u0026thinsp;=\u0026thinsp;0.57, 0.08 and 0.37, respectively). Biochemical remission was also related to resection status (p\u0026thinsp;=\u0026thinsp;0.0012), and achieving GTR was also highly related to invasion status. The rate of biochemical remission also reached a statistical difference in these two classification systems. We further divided the patients into two groups by the degree of invasiveness in the different grading systems, and found that the rate of achieving biochemical remission was significantly associated with both grading systems (p\u0026thinsp;=\u0026thinsp;0.00005, 0.009 and 0.00001, respectively) (Table\u0026nbsp;\u003cspan refid=\"Tab5\" class=\"InternalRef\"\u003e3\u003c/span\u003e\u0026thinsp;\u0026minus;\u0026thinsp;1).\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab4\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 3\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eStatistical Analysis of the Patients with or without Biochemical Remission\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"7\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c7\" colnum=\"7\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colspan=\"6\" nameend=\"c7\" namest=\"c2\"\u003e \u003cp\u003eValues\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eVariable\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"3\" nameend=\"c4\" namest=\"c2\"\u003e \u003cp\u003eRemission\u003c/p\u003e \u003cp\u003e(\u003cem\u003en\u003c/em\u003e\u0026thinsp;=\u0026thinsp;27)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eNon-remission\u003c/p\u003e \u003cp\u003e(\u003cem\u003en\u003c/em\u003e\u0026thinsp;=\u0026thinsp;23)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c7\" namest=\"c6\"\u003e \u003cp\u003e\u003cem\u003eP\u003c/em\u003e value\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003eDemographics\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c5\" namest=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c7\" namest=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMale\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e \u003cp\u003e13 (48.15%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"3\" nameend=\"c6\" namest=\"c4\"\u003e \u003cp\u003e10 (43.48%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.78\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAge (years)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e \u003cp\u003e44.3\u0026thinsp;\u0026plusmn;\u0026thinsp;12.8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"3\" nameend=\"c6\" namest=\"c4\"\u003e \u003cp\u003e44.6\u0026thinsp;\u0026plusmn;\u0026thinsp;15.6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.88\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTumor Characteristics\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colspan=\"3\" nameend=\"c6\" namest=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMacroadenoma\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e \u003cp\u003e20 (74.07%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"3\" nameend=\"c6\" namest=\"c4\"\u003e \u003cp\u003e20(86.96%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.78\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTumor Size\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e \u003cp\u003e1.3\u0026thinsp;\u0026plusmn;\u0026thinsp;0.5 cm\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"3\" nameend=\"c6\" namest=\"c4\"\u003e \u003cp\u003e1.8\u0026thinsp;\u0026plusmn;\u0026thinsp;0.8 cm\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.024\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTumor Volume\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e \u003cp\u003e1.4\u0026thinsp;\u0026plusmn;\u0026thinsp;1.5 cm\u003csup\u003e3\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"3\" nameend=\"c6\" namest=\"c4\"\u003e \u003cp\u003e3\u0026thinsp;\u0026plusmn;\u0026thinsp;2.9 cm\u003csup\u003e3\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.0032\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSuprasellar invasion\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e \u003cp\u003e12 (44.44%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"3\" nameend=\"c6\" namest=\"c4\"\u003e \u003cp\u003e13 (56.52%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.57\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePure intrasellar lesion\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e \u003cp\u003e14 (51.85%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"3\" nameend=\"c6\" namest=\"c4\"\u003e \u003cp\u003e6 (26.09%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.08\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eInfrasellar invasion\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e \u003cp\u003e7 (25.93%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"3\" nameend=\"c6\" namest=\"c4\"\u003e \u003cp\u003e9 (39.13%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.37\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eKnosp Grade\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colspan=\"3\" nameend=\"c6\" namest=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.0007\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"3\" nameend=\"c6\" namest=\"c4\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e \u003cp\u003e14\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"3\" nameend=\"c6\" namest=\"c4\"\u003e \u003cp\u003e4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e \u003cp\u003e9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"3\" nameend=\"c6\" namest=\"c4\"\u003e \u003cp\u003e6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"3\" nameend=\"c6\" namest=\"c4\"\u003e \u003cp\u003e11\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"3\" nameend=\"c6\" namest=\"c4\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHardy-Wilson Grade\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colspan=\"3\" nameend=\"c6\" namest=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.0428\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e \u003cp\u003e7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"3\" nameend=\"c6\" namest=\"c4\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e \u003cp\u003e13\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"3\" nameend=\"c6\" namest=\"c4\"\u003e \u003cp\u003e6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e \u003cp\u003e4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"3\" nameend=\"c6\" namest=\"c4\"\u003e \u003cp\u003e10\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"3\" nameend=\"c6\" namest=\"c4\"\u003e \u003cp\u003e5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHardy-Wilson Grade\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colspan=\"3\" nameend=\"c6\" namest=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.0006\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e \u003cp\u003e14\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"3\" nameend=\"c6\" namest=\"c4\"\u003e \u003cp\u003e4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eA\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e \u003cp\u003e7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"3\" nameend=\"c6\" namest=\"c4\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eB\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"3\" nameend=\"c6\" namest=\"c4\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eC\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"3\" nameend=\"c6\" namest=\"c4\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eD\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"3\" nameend=\"c6\" namest=\"c4\"\u003e \u003cp\u003e7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eE\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"3\" nameend=\"c6\" namest=\"c4\"\u003e \u003cp\u003e7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eGross Total Resection\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e \u003cp\u003e26(96.3%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"3\" nameend=\"c6\" namest=\"c4\"\u003e \u003cp\u003e13(56.52%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.0012\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePre-OP hGH\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e \u003cp\u003e14.3\u0026thinsp;\u0026plusmn;\u0026thinsp;15.1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"3\" nameend=\"c6\" namest=\"c4\"\u003e \u003cp\u003e32.4\u0026thinsp;\u0026plusmn;\u0026thinsp;37.7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.19\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePre-OP IGF-1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e \u003cp\u003e603.7\u0026thinsp;\u0026plusmn;\u0026thinsp;235.8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"3\" nameend=\"c6\" namest=\"c4\"\u003e \u003cp\u003e688.9\u0026thinsp;\u0026plusmn;\u0026thinsp;196.4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.12\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"7\"\u003ehGH, human growth hormone; IGF-1, insulin-like growth factor 1\u003c/td\u003e\u003c/tr\u003e \u003ctr\u003e\u003ctd colspan=\"7\"\u003eValues are given as frequency (percentage) for categorical variables or mean\u0026thinsp;\u0026plusmn;\u0026thinsp;standard deviation for continuous variables.\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab5\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 3\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003e\u0026thinsp;\u003cb\u003e\u0026minus;\u0026thinsp;1.\u003c/b\u003e Statistical Analysis of the Patients with or without Biochemical Remission According to the Degree of Invasiveness\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"6\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colspan=\"5\" nameend=\"c6\" namest=\"c2\"\u003e \u003cp\u003eValues\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eVariable\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e \u003cp\u003eRemission\u003c/p\u003e \u003cp\u003e(\u003cem\u003en\u003c/em\u003e\u0026thinsp;=\u0026thinsp;27)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eNon-remission\u003c/p\u003e \u003cp\u003e(\u003cem\u003en\u003c/em\u003e\u0026thinsp;=\u0026thinsp;23)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c6\" namest=\"c5\"\u003e \u003cp\u003e\u003cem\u003eP\u003c/em\u003e value\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eKnosp Grade\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colspan=\"3\" nameend=\"c5\" namest=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.00005\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e0\u0026thinsp;~\u0026thinsp;2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e26\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"3\" nameend=\"c5\" namest=\"c3\"\u003e \u003cp\u003e10\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e3\u0026thinsp;~\u0026thinsp;4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"3\" nameend=\"c5\" namest=\"c3\"\u003e \u003cp\u003e13\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHardy-Wilson Grade\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colspan=\"3\" nameend=\"c5\" namest=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.009\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e0\u0026thinsp;~\u0026thinsp;2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e20\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"3\" nameend=\"c5\" namest=\"c3\"\u003e \u003cp\u003e8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e3\u0026thinsp;~\u0026thinsp;4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"3\" nameend=\"c5\" namest=\"c3\"\u003e \u003cp\u003e15\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHardy-Wilson Grade\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colspan=\"3\" nameend=\"c5\" namest=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.00001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e0\u0026thinsp;~\u0026thinsp;C\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e26\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"3\" nameend=\"c5\" namest=\"c3\"\u003e \u003cp\u003e9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eD\u0026thinsp;~\u0026thinsp;E\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"3\" nameend=\"c5\" namest=\"c3\"\u003e \u003cp\u003e14\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eAcromegaly is a disease which manifests as progressive bone and cartilage growth as well as systemic complications including cardiovascular, metabolic, and respiratory issues. The first-line therapy for acromegaly is surgical resection, and surgical resection alone leads to disease control in approximately 90% of microadenoma cases and 40\u0026ndash;60% of macroadenoma cases [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]. Postoperative biochemical remission is highly related to the preoperative condition and intraoperative resection status [\u003cspan additionalcitationids=\"CR4\" citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e, \u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e, \u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e, \u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e]. The importance of biochemical remission cannot be overemphasized, because it ameliorates the systemic effects of elevated GH, IGF-1, and the resultant mortality/morbidity [\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e].\u003c/p\u003e\n\u003ch3\u003eClassification of parasellar invasion\u003c/h3\u003e\n\u003cp\u003eKnosp grade and Hardy-Wilson classification based on preoperative MRI are used to determine cavernous sinus and parasellar invasion [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e, \u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e, \u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e, \u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e, \u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e]. Detailed descriptions of Knosp and Hardy grades are shown in Figs.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e1\u003c/span\u003e and \u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e2\u003c/span\u003e. A higher grade of tumor invasion is associated with greater difficulty in achieving GTR, particularly pituitary functioning tumors in which biochemical remission is even more critical than non-functioning tumors.\u003c/p\u003e\n\u003ch3\u003eFactors influencing intraoperative resection status\u003c/h3\u003e\n\u003cp\u003eIt is known that cells secreting GH reside in the inferior and lateral aspects of the pituitary gland. Consequently, tumors tend to grow in an inferior and lateral direction. Our results are similar to previous studies in which GTR was associated with achieving biochemical remission [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e, \u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e, \u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e]. Therefore, achieving GTR is an important predictive factor for disease control. On the other hand, the most crucial determinant in resection is horizontal and vertical invasion. In this study, intraoperative resection status was highly associated with preoperative Knosp and Hardy-Wilson grades (p\u0026thinsp;=\u0026thinsp;0.015, 0.014 and 0.017, respectively) (Table\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e2\u003c/span\u003e). These results show that the surgical difficulty increased when the tumor extended beyond the sellar region in a horizontal or vertical direction. However, our data showed that tumor size and volume were not significantly associated with achieving GTR (p\u0026thinsp;=\u0026thinsp;0.09 and 0.06, respectively), in contrast to the results reported by Zeng et al [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e]. The main reason for this difference may be due to the mean size of macroadenoma in our study of around 1.76 cm, which may indicate a lack of higher-grade invasiveness, and subsequently that the possibility of achieving GTR was similar to the microadenoma patients. This finding also strengthens the importance of making an earlier diagnosis in GH adenoma patients, as the smaller tumor size would increase the possibility of achieving GTR and subsequent biochemical remission. Furthermore, the \u003cem\u003ep\u003c/em\u003e-value for tumor volume (p\u0026thinsp;=\u0026thinsp;0.06) in the view of GTR was closer to 0.05 than tumor size (p\u0026thinsp;=\u0026thinsp;0.09), which may suggest that more precise volumetric measurement is important when defining the mass effect of a tumor, especially in irregularly shaped or residual tumors [\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e, \u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e]. We also found stronger associations between higher Knosp and Hardy grades and a lower probability of achieving GTR (p\u0026thinsp;=\u0026thinsp;0.006, 0.006, and 0.001, respectively) (Table\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e2\u003c/span\u003e\u0026thinsp;\u0026minus;\u0026thinsp;1). These results further highlight the importance of carefully interpretating preoperative MRI and the degree of peripheral invasion, especially in those with higher invasion classification.\u003c/p\u003e\n\u003ch3\u003eFactors influencing biochemical remission\u003c/h3\u003e\n\u003cp\u003eUnlike intraoperative resection status, we found that tumor size and volume were positively correlated with postoperative biochemical remission (p\u0026thinsp;=\u0026thinsp;0.024 and 0.0032, respectively) (Table\u0026nbsp;\u003cspan refid=\"Tab5\" class=\"InternalRef\"\u003e3\u003c/span\u003e), which is similar to the results of other studies [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e, \u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e, \u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e, \u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e]. In addition, preoperative Knosp and Hardy-Wilson classification (p\u0026thinsp;=\u0026thinsp;0.007, 0.0428, and 0.0006, respectively) and the resultant intraoperative resection status (p\u0026thinsp;=\u0026thinsp;0.0012) were also significantly associated with postoperative biochemical remission as mentioned above. Interestingly, suprasellar, pure intrasellar and infrasellar invasion were not risk factors for biochemical remission (p\u0026thinsp;=\u0026thinsp;0.57, 0.08 and 0.37, respectively). This result further supports that the grading of classification is far more important than the presence or absence of surrounding invasion status. The abovementioned suprasellar, pure intrasellar and infrasellar factors describe vertical tumor invasion status, which is not thought to be as critical as horizontal invasion. Although intrasellar tumors were easier to resect, the surgical techniques were similar to those with lower grade Knosp grade. In addition, for patients with infrasellar invasion toward the sphenoid floor or clivus, complete resection of tumors infiltrating into bone was challenging. In addition, GTR may be feasible for lower grade suprasellar invasion, but it remains challenging for higher grade suprasellar invasion, as demonstrated in Table\u0026nbsp;\u003cspan refid=\"Tab5\" class=\"InternalRef\"\u003e3\u003c/span\u003e\u0026thinsp;\u0026minus;\u0026thinsp;1. Furthermore, although tumor size and volume were predictive factors of biochemical remission, the lower preoperative GH and IGF-1 levels were not correlated with postoperative biochemical remission (p\u0026thinsp;=\u0026thinsp;0.19 and 0.12, respectively). Tumors with a smaller size and volume are thought to harbor fewer secreting tumor cells; however, not every tumor cell produces an equivalent amount of GH and the resultant systemic effects. We found stronger associations between higher Knosp and Hardy-Wilson grades and a lower probability of postoperative biochemical remission (p\u0026thinsp;=\u0026thinsp;0.00005, 0.009, and 0.00001, respectively) (Table\u0026nbsp;\u003cspan refid=\"Tab5\" class=\"InternalRef\"\u003e3\u003c/span\u003e\u0026thinsp;\u0026minus;\u0026thinsp;1). These results further support the importance of carefully interpreting preoperative MRI and the degree of peripheral invasion, especially in those with higher invasion classification. Regardless of postoperative biochemical remission or intraoperative resection status, we found that the most pivotal predictive factor was preoperative grading of invasion status, especially in those with a higher grade. Careful interpretation of preoperative MRI and removing as much of the tumor as possible are the key factors associated with favorable outcomes.\u003c/p\u003e \u003cdiv id=\"Sec8\" class=\"Section2\"\u003e \u003ch2\u003eAssociation of tumor size and volume with resection status and biochemical remission\u003c/h2\u003e \u003cp\u003eMany studies have reported an association between tumor size and biochemical remission rate, and some studies have mentioned that patients who achieve remission have a smaller tumor size [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e, \u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e, \u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e]. In addition, some studies have reported that patients with microadenoma have a higher remission rate [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e, \u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e]. In our study, the patients with microadenoma (\u0026lt;\u0026thinsp;1 cm) did not have a significantly higher remission rate compared to those with macroadenoma. However, the patients who achieved remission did have a smaller tumor size (\u0026lt;\u0026thinsp;1.3 cm, p\u0026thinsp;=\u0026thinsp;0.024), which is similar to the study by Samuel et al [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]. A possible explanation for this finding is that our patients had smaller macroadenomas (mean size 1.76\u0026thinsp;\u0026plusmn;\u0026thinsp;0.67 cm). As a result, we suggest that the crucial cut-off value of tumor size to achieve GTR should be \u0026ge; 1.3 cm, or the average width of the sellar region. Hence, the 1 cm definition for the classification of micro- and macroadenomas may not be necessary, especially in GH-secreting or other functioning tumors necessitating surgical resection. Furthermore, in tumors that did not invade the cavernous sinus or extend into the supra- or infrasellar region, the tumor size and volume were determining predictors; in contrast, in tumors that extended beyond the sellar region, the determining predictor of biochemical remission was the presence or absence of higher-grade invasion.\u003c/p\u003e \u003c/div\u003e\n\u003ch3\u003eAssociation of tumor invasion grading with resection status and biochemical remission\u003c/h3\u003e\n\u003cp\u003eThe Hardy-Wilson and Knosp grading systems are widely used to classify the level of tumor invasion, and they are also key indicators of whether GTR can be achieved. A higher level of tumor invasion is considered to impede complete surgical resection, and therefore biochemical remission. Although some studies have reported that a higher grade was associated with a lower rate of biochemical remission, the results have been inconsistent [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e, \u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e, \u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e, \u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e]. Whether Hardy-Wilson grade can predict biochemical remission remains controversial. Mohammad et al reported that biochemical remission was independent of Hardy-Wilson grade [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e], whereas Campbell et al and Yildirim et al found that remission was related to Hardy-Wilson grade [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e, \u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e]. In addition, Shin et al and Yildirim et al found that Hardy-Wilson grade was a predictor of biochemical remission [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e, \u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]. In our study, we comprehensively reviewed all classifications, and found that the probability of achieving GTR and rate of biochemical remission decreased with higher Hardy-Wilson grade. In addition, we also found that the rates of achieving GTR and biochemical remission were related to cavernous sinus invasion. Furthermore, when considering the level of suprasellar extension only, there was no statistical significance among Hardy-Wilson grade 0\u0026thinsp;~\u0026thinsp;C. This may imply that with mature endoscopic endonasal surgery, GTR can also be achieved even when the tumor extends into the suprasellar space. In addition, although we used an EETSA, which is via the infrasellar space, sphenoid sinus or clivus invasion may imply a higher degree of tumor invasion, and consequently greater difficulty in curing the disease [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]. However, cavernous sinus invasion is still associated with the greatest difficulty in achieving complete tumor removal and ideal hormone control because of the vital structures inside.\u003c/p\u003e\n\u003ch3\u003eClinical implications of the treatment of GH adenomas based on invasiveness status\u003c/h3\u003e\n\u003cp\u003eOur results showed that GH adenomas with high-grade invasiveness hindered complete resection, and that achieving GTR always increased the risk of unnecessary vascular and neurological injuries. However, several previous studies reported that somatostatin receptor ligand (SRL) treatment effectively normalized GH and IGF-1, improved clinical symptoms and quality of life, and reduced tumor volume in 62.9\u0026thinsp;~\u0026thinsp;81% patients [\u003cspan additionalcitationids=\"CR29 CR30\" citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e]. Most importantly, pretreatment with SRLs before surgery has been demonstrated to improve surgical cure rates in patients with GH-secreting pituitary macroadenomas [\u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e]. Furthermore, T2 hypointense adenomas have been shown to respond more dramatically to SRL treatment [\u003cspan additionalcitationids=\"CR34 CR35\" citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e36\u003c/span\u003e]. As a result, in higher grade GH adenomas, preoperative medications may not only reduce the tumor size but also lower the invasiveness, thereby facilitating surgical procedures and promising similar outcomes to lower grade tumors. To sum up, for pure intrasellar tumors or those with lower invasiveness, aggressive GTR should be attempted during surgery. However, for high-grade invasive tumors, preoperative SRL treatment may be a feasible approach to achieve GTR and biochemical remission.\u003c/p\u003e"},{"header":"Conclusions","content":"\u003cp\u003ePituitary GH adenomas exert systemic effects, and EETSA remains the best treatment for biochemical remission. GTR was associated with biochemical remission and was influenced by invasion status, especially in those with higher grade invasion. Biochemical remission was highly associated with invasion status and resection status rather than tumor size and volume. Earlier diagnosis and more aggressive resection for low-grade and pretreated high-grade tumors are the key factors associated with favorable outcomes.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cp\u003eGH growth hormone\u003c/p\u003e\n\u003cp\u003eIGF-1 insulin-like growth factor 1\u003c/p\u003e\n\u003cp\u003eEETSA\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;endoscopic endonasal transsphenoidal approach\u003c/p\u003e\n\u003cp\u003eGTR\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;gross total resection\u003c/p\u003e\n\u003cp\u003eMRI\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;\u0026nbsp;magnetic resonance imaging\u003c/p\u003e\n\u003cp\u003eSRL \u0026nbsp; \u0026nbsp; \u0026nbsp; somatostatin receptor ligand\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eConsent for publication\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eInformed consent was obtained from all individual participants included in the study.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthors\u0026apos; contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eTing-Wei Chang and Chun-Chia Tseng wrote the main manuscript text, Yin-Cheng Huang, Peng-Wei Hsu, Chi-Cheng Chuang and Cheng-Chi Lee\u003csup\u003e\u0026nbsp;\u003c/sup\u003ecollected the data, Ting-Wei Chang and Yu-Chi Wang did the analysis and prepared the tables and figures, Chi-Cheng Chuang, and Cheng-Chi Lee supervised the manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting Interests\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors have no relevant financial or non-financial interests to disclose.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgements\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWe acknowledged Chang Gung Memorial Hospital and Chang Gung University to support the research and we received a grant from Chang Gung Memorial Hospital.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis research was funded by a grant from Chang Gung Memorial Hospital (CMRPG1L0051, CMRPG1L0052, CMRPG1N0071, CMRPG1N0072, Cheng Chi Lee), and the funder had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthics Approval\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis study was performed in line with the principles of the Declaration of Helsinki. Approval was granted by the Ethics Committee of the Institutional Review Board (IRB) of Chang Gung Memorial Hospital (IRB No. 202401326B0). Informed consent was obtained from all individual participants included in the study. The authors affirm that human research participants provided informed consent for publication of their data in the manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eData Availability\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe data that support the findings of this study are not openly available due to reasons of sensitivity and are available from the corresponding author upon reasonable request.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eClinical Trial Number\u003c/strong\u003e: not applicable\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eAbreu A, et al. Challenges in the diagnosis and management of acromegaly: a focus on comorbidities. Pituitary. 2016;19(4):448\u0026ndash;57.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eAraujo-Castro M, et al. Predictive model of surgical remission in acromegaly: age, presurgical GH levels and Knosp grade as the best predictors of surgical remission. J Endocrinol Invest. 2021;44(1):183\u0026ndash;93.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eShin SS, et al. Endoscopic endonasal approach for growth hormone secreting pituitary adenomas: outcomes in 53 patients using 2010 consensus criteria for remission. Pituitary. 2013;16(4):435\u0026ndash;44.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eTaghvaei M, et al. Endoscopic Endonasal Approach to the Growth Hormone-Secreting Pituitary Adenomas: Endocrinologic Outcome in 68 Patients. World Neurosurg. 2018;117:e259\u0026ndash;68.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eHofstetter CP, et al. Endoscopic endonasal transsphenoidal surgery for growth hormone-secreting pituitary adenomas. Neurosurg Focus. 2010;29(4):E6.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eYildirim AE, et al. Endoscopic endonasal transsphenoidal treatment for acromegaly: 2010 consensus criteria for remission and predictors of outcomes. Turk Neurosurg. 2014;24(6):906\u0026ndash;12.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eJane JA Jr., et al. Endoscopic transsphenoidal surgery for acromegaly: remission using modern criteria, complications, and predictors of outcome. J Clin Endocrinol Metab. 2011;96(9):2732\u0026ndash;40.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eDavies BM, et al. Assessing size of pituitary adenomas: a comparison of qualitative and quantitative methods on MR. Acta Neurochir (Wien). 2016;158(4):677\u0026ndash;83.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eChatzellis E, et al. Aggressive pituitary tumors. Neuroendocrinology. 2015;101(2):87\u0026ndash;104.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eCardinal T, et al. Postoperative GH and Degree of Reduction in IGF-1 Predicts Postoperative Hormonal Remission in Acromegaly. Front Endocrinol (Lausanne). 2021;12:743052.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eCardinal T, et al. Impact of tumor characteristics and pre- and postoperative hormone levels on hormonal remission following endoscopic transsphenoidal surgery in patients with acromegaly. Neurosurg Focus. 2020;48(6):E10.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eZheng Y, Wang CD, Mai Y, Zhu RK. ZF, \u003cem\u003eSurgical management of growth hormone-secreting pituitary adenomas: A retrospective analysis of 33 patients.\u003c/em\u003e Medicine, 2020. 2020;99:19(e19855).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eShen SC, et al. Long-Term Effects of Intracapsular Debulking and Adjuvant Somatostatin Analogs for Growth Hormone-Secreting Pituitary Macroadenoma: 10 Years of Experience in a Single Institute. World Neurosurg. 2019;126:e41\u0026ndash;7.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eAlmeida JP, et al. Reoperation for growth hormone-secreting pituitary adenomas: report on an endonasal endoscopic series with a systematic review and meta-analysis of the literature. J Neurosurg. 2018;129(2):404\u0026ndash;16.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eYano S, et al. Intraoperative Scoring System to Predict Postoperative Remission in Endoscopic Endonasal Transsphenoidal Surgery for Growth Hormone-Secreting Pituitary Adenomas. World Neurosurg. 2017;105:375\u0026ndash;85.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBriceno V, et al. Efficacy of transsphenoidal surgery in achieving biochemical cure of growth hormone-secreting pituitary adenomas among patients with cavernous sinus invasion: a systematic review and meta-analysis. Neurol Res. 2017;39(5):387\u0026ndash;98.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBabu H, et al. Long-Term Endocrine Outcomes Following Endoscopic Endonasal Transsphenoidal Surgery for Acromegaly and Associated Prognostic Factors. Neurosurgery. 2017;81(2):357\u0026ndash;66.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKnosp E et al. \u003cem\u003ePituitary adenomas with invasion of the cavernous sinus space: a magnetic resonance imaging classification compared with surgical findings.\u003c/em\u003e Neurosurgery, 1993. 33(4): pp. 610-7; discussion 617-8.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eHardy J. Transphenoidal microsurgery of the normal and pathological pituitary. Clin Neurosurg. 1969;16:185\u0026ndash;217.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eGiustina A, et al. A consensus on criteria for cure of acromegaly. J Clin Endocrinol Metab. 2010;95(7):3141\u0026ndash;8.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eGiustina A et al. Consensus on criteria for acromegaly diagnosis and remission. Pituitary, 2023.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eCampbell PG, et al. Outcomes after a purely endoscopic transsphenoidal resection of growth hormone-secreting pituitary adenomas. Neurosurg Focus. 2010;29(4):E5.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eShirvani M, Motiei-Langroudi R. Transsphenoidal surgery for growth hormone-secreting pituitary adenomas in 130 patients. World Neurosurg. 2014;81(1):125\u0026ndash;30.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eHoldaway IM, Rajasoorya RC, Gamble GD. Factors influencing mortality in acromegaly. J Clin Endocrinol Metab. 2004;89(2):667\u0026ndash;74.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eHardy J, Vezina JL. Transsphenoidal neurosurgery of intracranial neoplasm. Adv Neurol. 1976;15:261\u0026ndash;73.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLee CC, et al. Prediction of Long-term Post-operative Testosterone Replacement Requirement Based on the Pre-operative Tumor Volume and Testosterone Level in Pituitary Macroadenoma. Sci Rep. 2015;5:16194.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eChuang CC, et al. Different Volumetric Measurement Methods for Pituitary Adenomas and Their Crucial Clinical Significance. Sci Rep. 2017;7:40792.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eCaron PJ, et al. Tumor shrinkage with lanreotide Autogel 120 mg as primary therapy in acromegaly: results of a prospective multicenter clinical trial. J Clin Endocrinol Metab. 2014;99(4):1282\u0026ndash;90.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eCaron PJ, et al. Effects of lanreotide Autogel primary therapy on symptoms and quality-of-life in acromegaly: data from the PRIMARYS study. Pituitary. 2016;19(2):149\u0026ndash;57.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eCaron PJ, et al. Glucose and lipid levels with lanreotide autogel 120 mg in treatment-naive patients with acromegaly: data from the PRIMARYS study. Clin Endocrinol (Oxf). 2017;86(4):541\u0026ndash;51.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eColao A, Auriemma RS, Pivonello R. The effects of somatostatin analogue therapy on pituitary tumor volume in patients with acromegaly. Pituitary. 2016;19(2):210\u0026ndash;21.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMao ZG, et al. Preoperative lanreotide treatment in acromegalic patients with macroadenomas increases short-term postoperative cure rates: a prospective, randomised trial. Eur J Endocrinol. 2010;162(4):661\u0026ndash;6.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eHagiwara A, et al. Comparison of growth hormone-producing and non-growth hormone-producing pituitary adenomas: imaging characteristics and pathologic correlation. Radiology. 2003;228(2):533\u0026ndash;8.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eHeck A, et al. Intensity of pituitary adenoma on T2-weighted magnetic resonance imaging predicts the response to octreotide treatment in newly diagnosed acromegaly. Clin Endocrinol (Oxf). 2012;77(1):72\u0026ndash;8.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003ePotorac I, Beckers A, Bonneville JF. T2-weighted MRI signal intensity as a predictor of hormonal and tumoral responses to somatostatin receptor ligands in acromegaly: a perspective. Pituitary. 2017;20(1):116\u0026ndash;20.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003ePotorac I, et al. Pituitary MRI characteristics in 297 acromegaly patients based on T2-weighted sequences. Endocr Relat Cancer. 2015;22(2):169\u0026ndash;77.\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"discover-oncology","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"dion","sideBox":"Learn more about [Discover Oncology](https://www.springer.com/12672)","snPcode":"","submissionUrl":"","title":"Discover Oncology","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"Discover Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"GH pituitary adenoma, endoscopic endonasal transsphenoidal approach, Knosp and Hardy-Wilson grade, resection status, biochemical remission, pre-operative treatment","lastPublishedDoi":"10.21203/rs.3.rs-6370980/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-6370980/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eIntroduction: \u003c/strong\u003eGrowth hormone (GH)-secreting pituitary tumors produce systemic comorbidities, thus achieving gross total resection (GTR) and biochemical remission are imperative. The aim of this study was to identify predictors affecting resection status and biochemical remission.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMethods: \u003c/strong\u003eWe retrospectively reviewed 54 GH adenoma patients receiving endoscopic endonasal transsphenoidal approach (EETSA). Medical records and magnetic resonance imaging were reviewed for tumor size, volume, resection status, invasion status, and Knosp and Hardy-Wilson grades. We also classified invasion status into high- and low-grade groups. Biochemical remission was defined as an insulin-like growth factor 1 value within sex- and age-adjusted reference or a random GH level \u0026lt; 1.0 ng/mL.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eResults: \u003c/strong\u003eThe degrees of horizontal and vertical invasion based on preoperative Knosp and Hardy-Wilson grade were highly associated with intraoperative resection status (p=0.015, 0.014 and 0.017 respectively). We also found more significant differences between resection status and higher-grade invasion (p=0.006, 0.006 and 0.001, respectively). Knosp, Hardy-Wilson grades and resection status were significantly associated with biochemical remission (p=0.0007, 0.0428, 0.0006 and 0.0012, respectively). Although there was no difference between micro- or macroadenoma, tumor size and volume were statistically significant associated with outcomes (p=0.024, 0.0032, respectively). Similarly, more significant differences between biochemical remission and higher-grade invasion were found (p=0.00005, 0.009 and 0.00001, respectively).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConclusions: \u003c/strong\u003eEETSA remains the best treatment option for GH adenomas. Biochemical remission was highly associated with invasion status and the possibility of achieving GTR. Earlier diagnosis and more aggressive resection for low-grade and pretreated high-grade tumors are the key factors associated with favorable outcomes.\u003c/p\u003e","manuscriptTitle":"Gross Total Resection in Low-Grade and Pretreated High-Grade Invasive Growth Hormone Pituitary Adenomas Promises Favorable Outcomes","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-05-20 09:38:17","doi":"10.21203/rs.3.rs-6370980/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2025-05-27T04:26:31+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-05-26T17:30:36+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-05-20T08:07:48+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"113241909138531492413852269249585608368","date":"2025-05-19T19:19:58+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"166328859597554417273624437692627106789","date":"2025-05-15T02:38:35+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2025-05-15T02:22:42+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2025-04-28T07:08:51+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2025-04-28T07:03:12+00:00","index":"","fulltext":""},{"type":"submitted","content":"Discover Oncology","date":"2025-04-03T16:16:32+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"discover-oncology","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"dion","sideBox":"Learn more about [Discover Oncology](https://www.springer.com/12672)","snPcode":"","submissionUrl":"","title":"Discover Oncology","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"Discover Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"f299b13f-da45-446a-bfb6-f994801d2bc7","owner":[],"postedDate":"May 20th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"under-review","subjectAreas":[],"tags":[],"updatedAt":"2025-07-28T06:53:10+00:00","versionOfRecord":[],"versionCreatedAt":"2025-05-20 09:38:17","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-6370980","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-6370980","identity":"rs-6370980","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}