18F-fluoro-ethyl-tyrosine PET co-registered with MRI in patients with persisting acromegaly

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Bakker, Marco J.T. Verstegen, Diandra C. Manole, and 11 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-3799944/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 30 May, 2024 Read the published version in Clinical Endocrinology → Version 1 posted You are reading this latest preprint version Abstract Purpose To report our experience with 18 F-fluoro-ethyl-tyrosine (FET) positron emission tomography-computed tomography (PET-CT) co-registered with MRI (FET-PET/MRI CR ) in the care trajectory for complex acromegaly patients. Methods In 10 patients with insufficiently controlled acromegaly referred to our team to evaluate surgical options, FET-PET/MRI CR was used to support decision-making if MRI alone and multidisciplinary team evaluation did not provide sufficient clarity to proceed to surgery. Results FET-PET/MRI CR showed suspicious (para)sellar tracer uptake in all patients. In 5 patients FET-PET/MRI CR was fully concordant with conventional MRI, and in 1 patient partially concordant. FET-PET/MRI CR identified new suspicious foci in 4 other patients. Surgical re-exploration was performed in 9 patients (aimed at total resection ( 6 ), debulking ( 2 ), diagnosis ( 1 )), and 1 patient underwent radiation therapy. In 7 of 9 (78%) operated patients FET-PET/MRI CR findings were confirmed intraoperatively, and in 6 patients (67%) also histologically. IGF-1 decreased significantly in 8 patients (89%). All patients showed clinical improvement. Complete biochemical remission was achieved in 3 patients (50% of procedures in which total resection was anticipated feasible). Biochemistry improved in 5 and was unchanged in 1 patient. No permanent complications occurred. Outcome categorized by integrated outcome quadrants (IOQs) defined by preoperative intended effect versus permanent complications at 6 months was IOQ-1 (goal achieved without complications) in 6 (67%) and IOQ-3 (goal not achieved, no complications) in 3 patients. Conclusion In complex acromegaly cases FET-PET/MRI CR can provide additional information to aid decision-making by the multidisciplinary pituitary team, especially when (further) surgery is being considered. acromegaly functional imaging Positron Emission Tomography 18F-fluoro-ethyl-tyrosine surgical decision making transsphenoidal surgery Figures Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Figure 6 Figure 7 Introduction Acromegaly is a rare chronic disorder with increased morbidity and mortality and decreased quality of life when not treated adequately.( 1 – 6 ) Current guidelines recommend surgery as a first line treatment.( 7 ) Surgical remission rates range from 80–90% for microadenomas, and 50–75% for macroadenomas, while invasive adenomas may not be amenable for total resection ( 7 – 10 ). Patients who do not achieve disease control after first-line surgery need additional (multimodality) treatment with either revision surgery, medication, and/or radiotherapy.( 7 ) Although life-long medical treatment is possible, drugs are expensive, may have side effects, and can be associated with lower quality of life scores than surgical remission.( 11 , 12 ) Radiotherapy has the obvious disadvantage of a delayed biochemical effect and a high risk of pituitary insufficiency.( 13 ) In contrast, where total resection is considered feasible, repeat surgery in a pituitary tumor center of excellence may represent the most cost-effective route to achieving long term, drug-free remission. However, reported outcomes of revision surgery, which is usually only performed in patients with a clear non-invasive residual adenoma on conventional magnetic resonance imaging (MRI), are highly variable with success rates ranging from 27–60%.( 8 , 10 , 14 ) There is therefore an unmet need to better select candidates for reoperation, and to more accurately predict its chances and risks, so surgical and non-surgical treatment modalities can be weighed. Identification of small residual or recurrent adenoma is notoriously difficult on conventional MRI, due to postoperative tissue remodeling, small size, and/or proximity to the cavernous sinus. Improved tumor localization is essential to predict likely surgical outcomes (i.e. both remission and complication rates). In recent years, functional imaging has been introduced as adjunct tool to enable more accurate localization of functioning adenomas, using the carbon-11 labeled amino acid (AA) 11 C-methionine (MET) as radiotracer.( 15 – 18 ) A clear added value of MET-PET/MRI CR for treatment decision making in patients with Cushing’s disease and persistent or recurrent acromegaly has been shown.( 15 , 17 , 18 ) Recently, our team and the Cambridge group showed added value of MET-PET/MRI CR in the surgical management of prolactinoma.( 19 , 20 ) An important drawback of MET is its short half-life (20 min), limiting its use to institutions with an onsite cyclotron. The F-18 labeled AA radiotracer 18 F-fluoro-ethyl-tyrosine (FET) shares the same uptake mechanism via the L-type amino acid transporter 1 (LAT1),( 21 ) but has logistic advantages over MET related to its longer half-life (110 min), enabling transportation and more flexibility in planning. FET has proven utility in diagnosing primary brain tumors, but not yet in pituitary adenomas. Comparative clinical studies have shown a strong correlation between FET and MET uptake in brain tumors (e.g. gliomas, metastases),( 22 – 24 ) indicating that the utility of MET might be extrapolated to FET for patients with pituitary adenomas. We evaluated 10 patients with persistent or recurrent acromegaly with inadequate disease control who underwent FET-PET/MRI CR . The aim of this study is to report our experience with FET-PET/MRI CR and to describe its role in clinical decision making and treatment outcome. Subjects and Methods Study center The Leiden University Medical Centre (LUMC) is a tertiary referral Endo-ERN center for pituitary and complex endoscopic skull base surgery, performing over 150 surgeries per annum. A dedicated multidisciplinary team (MDT) with 3 endocrinologists, 3 neurosurgeons, 1 ENT-surgeon, 2 neuroradiologists, 1 nuclear medicine physician/nuclear radiologist, 1 ophthalmologist, a radiation oncologist, and two nurse specialist case managers, meets every second week. All patients are cared for in a predefined pituitary care pathway as described previously, and comprehensive outcomes are collected prospectively. The need for ethical approval for care outcome evaluation of pituitary surgery care path was waived by the Scientific Committee (G19.011).( 25 ) Care path protocol including functional imaging In 2018 we started collaboration with Cambridge with a view to implementing functional imaging in our pituitary care path. The first patients underwent their MET-PET imaging in Cambridge in 2017–2018. From 2019, functional imaging with MET was performed in the Netherlands. Due to logistic issues, we switched to FET-PET in 2020 after obtaining approval from the Dutch Health and Youth Inspectorate for clinical implementation of FET-PET in patients with complex pituitary disease. Apart from substituting FET-PET for MET-PET, the clinical protocol for this diagnostic care path was not changed. The care path is considered in patients with persistent or recurrent acromegaly following primary surgery, and in whom dedicated MRI is inconclusive, either with the aim of achieving total resection or in other complex cases (e.g. medically treated) with a need to revisit surgical options. In brief, the clinical case together with all available imaging is discussed in the MDT, especially the treatment naive MRI scans which are often very informative. If MRI clearly localizes the site(s) of residual/recurrent disease and total resection is considered feasible or, on the contrary, if there is clear evidence of invasion, no functional imaging is needed. In case of an unclear lesion on MRI and a strong wish to proceed to surgery when feasible, functional imaging is recommended. This can be because of uncertainty regarding multifocality, or a suspected lesion in an unfavorable anatomy or situation, e.g. due to multiple reoperations. The indication and the individualized clinical question for functional imaging is approved by the MDT. After acquisition of the FET-PET/MRI CR , a thorough evaluation of all available images is undertaken in a second MDT, which includes a nuclear medicine physician with expertise in molecular pituitary imaging. All clinical data, including pituitary function and previous surgical and pathology reports are reviewed in conjunction with the combined images. The neurosurgeon and the endocrinologist reappraise all available data in the outpatient clinic and finally decide on the treatment plan, together with the patient. We prospectively record details of the surgical plan. Surgery is typically performed by two pituitary neurosurgeons, ( 26 ) fully informed about the functional imaging results and MDT discussions. They record the surgical findings in a standard surgical report, which also acknowledges the judgment of the neurosurgeon about the chances of success. In the postoperative phase, we evaluate biochemistry and the pathology report. At 6 months, cases are discussed with the team to evaluate the case including the added value of functional imaging to improve the quality of the pituitary surgery care path. Subjects We included all consecutive patients (n = 10) with acromegaly who had active disease and passed the previously mentioned steps to proceed to functional imaging with FET-PET/CT co-registered with MRI (FET-PET/MRI CR ) between December 2020 and October 2022. Active disease was defined as persistent symptomatology and lack of biochemical control, with increased IGF1 values (SD > + 2) despite pharmacological treatment or at a median evaluation at 6 months after previous surgery. Patient trajectories Based on the clinical situation and the radiological characteristics, we identified typical diagnostic dilemmas that directed to functional imaging, and patients were classified accordingly in two slightly different care trajectories (Fig. 1 ): Care trajectory 1: FET-PET/MRI CR to optimize outcome of revision surgery following unexpectedly unsuccessful primary surgery (5 subjects) : This group had unexpected persisting disease and a difficult to interpret postoperative MRI. To evaluate remission chances of revision surgery, FET-PET/MRI CR was used to differentiate between residual adenoma and postoperative changes. Care trajectory 2: FET-PET/MRI CR to revisit (surgical) treatment options because of non-control or intolerance of medical treatment (5 subjects) : In this group, typically there was a need to reconsider surgical options because of insufficient biochemical and clinical control under maximal tolerated medical therapy, but no (clear) remnant adenoma, or multiple possible foci, on MRI after shrinkage and/or previous surgery. Either the first surgery and imaging were long ago or tumors at diagnosis were not as clear as in group 1. For the patients that were operated previously, the remission chance of prior surgery(s) was retrospectively estimated as possible or unlikely. To revisit (surgical) treatment options FET-PET/MRI CR was performed. Since these care trajectories have differences in characteristics, medical need, a priori probabilities and outcomes, we describe the groups separately in addition to describing the total cohort. We report on the decision-making process and outcomes. Imaging details MRI All MR imaging acquired at our institution was performed on an Achieva 3.0 T TXMR system (Philips Healthcare, Best, The Netherlands) using a commercial 32-channel head coil, according to our local MR pituitary protocol as previously described.( 19 ) Briefly, the protocol consisted of coronal and sagittal T1-weighted turbo spin echo images (T1w TSE, with a slice thickness of 3 mm), and coronal T2 weighted TSE (T2w, slice thickness 3 mm) imaging of the sella region before intravenous (i.v.) contrast administration, dynamic coronal T1 weighted fast field echo (T1w FFE, slice thickness 1.5 mm) imaging of the sella during i.v. administration, coronal and sagittal T1w TSE imaging of the sella after i.v. contrast administration. When appropriate, an additional post-contrast axial 3D T1w FFE of the whole brain was acquired (resolution 1 x 1 mm, 1 mm slice thickness) in the same frame of reference as the pituitary sequences. PET-CT acquisition with 18 F-FET (FET-PET/CT) All PET acquisitions were performed according to the European Association of Nuclear Medicine (EANM) guidelines for brain tumor imaging using labelled amino acid analogues.( 27 ) Patients were instructed to fast for at least 6 hours prior to the PET acquisition. O-(2-[18F]-fluoroethyl)-L-tyrosine ( 18 F-FET), was synthesized in compliance with good manufacturing practice at the Radionuclide Centre of the Amsterdam University Medical Centre (Amsterdam UMC) location VU University Medical Centre (VUMC), Amsterdam, the Netherlands. PET-CT scans were acquired at our own institution using a hybrid PET/CT system (Vereos, Philips Healthcare, Best, The Netherlands). A standard dose of 200 MBq 18 F-FET was injected intravenously. After injection of the radiopharmaceutical a low-dose CT of the head (220 mAs, 140 kV, 0.5 s rotation, 0.984 mm pitch, 1 mm slice thickness) was acquired, followed by dynamic PET acquisition of the brain up to 50 minutes after injection (start approx. 5 minutes after injection, 5-min acquisition frames). The scan was performed after withdrawal of somatostatin receptor ligands (SRL), typically for 3 months or more, however in cases with clearly active disease shorter withdrawal (minimum of 1 month) was allowed. Pegvisomant, acting peripherally, does not affect the scan result and can be continued. Image processing and co-registration with MRI (FET-PET/MRI CR ) : Summation images (10–30 min and 20–40 min after injection) were used for co-registration with MRI, clinical reading, and calculation of semiquantitative uptake parameters. Co-registration with MRI was performed in our hospital using IntelliSpace Portal version 10 (ISP, Philips Healthcare) as described earlier.( 19 ) Tyrosine uptake maps were individually thresholded to the corresponding background (cerebellar) uptake. Maximal adenoma-to-background ratio (TBR max ) was calculated as a ratio in relation to the cerebellum (used as reference brain tissue): max standardized uptake value (SUV max ) adenoma / mean standardized uptake value (SUV mean ) cerebellum. All MRI images were independently reviewed by experienced neuroradiologists on dedicated PACS workstations using Sectra IDS7 software (Sectra Imtec AB, Linköping, Sweden) without knowledge of the PET findings. The absence or presence of cavernous sinus invasion was defined according to modified Knosp criteria.( 28 ) The co-registered images were qualitatively and semi-quantitatively reviewed by an experienced nuclear medicine physician and discussed by the multidisciplinary team as described above. Study parameters and outcomes Clinical characteristics Data on patient characteristics (e.g. age, sex), disease characteristics (e.g. clinical symptoms, nadir GH and IGF-1 levels, duration of disease, previous treatments), and tumor characteristics (e.g. size and invasion) at different time points (at diagnosis, before FET-PET/MRI CR , after FET-PET/MRI CR guided TSS) were extracted from the electronic patient records. To correlate the TBR max with disease activity, the last IGF-1 value before FET-PET/MRI CR measured at least 6 months after previous surgery and before starting pegvisomant was used. Pre-operative assessment The intended effect of surgery was either 1) biochemical remission (total resection), 2) debulking to achieve clinically significant tumor reduction for medication reduction, radiation field reduction and/or symptom relief, or 3) primarily obtaining tissue for diagnosis. A priori estimation of chances for achieving the intended effect and complications: before and after FET-PET/MRI CR an estimate was made of the chance of achieving the intended effect and risks by the neurosurgeon and endocrinologist. The estimated chance of was divided into 5 classes: very unlikely (~ 0 to ~ 20%), unlikely (~ 21 to ~ 40%), possibly (~ 41 to ~ 60%), likely (~ 61 to ~ 80%), and very likely ( > ~ 81%). The estimated chance of long-term risks, mainly determined by the risk of permanent pituitary deficiencies, was divided into 3 classes: low ( ~ 5%). Post-operative assessment Patients were scored based on intended effect achieved or not, e.g. biochemical remission/total resection or debulking/partial resection. Biochemical remission was defined as adequate suppression of GH after glucose load (< 0.4 ug/l) and/or normalization of the IGF-1 level ( < + 2 SD) at 6 months postoperatively without the need for adjunctive medical therapy. Additionally, clinical improvement was recorded, defined as improved GH/IGF-1 levels with or without lower doses of medication and clinical improvement of the patient (e.g. less symptoms, or less severe symptoms). Discrepancies in biochemical values were evaluated by the endocrine team, and included repeat measurements, and clinical symptomatology. Complications were defined as 1) all clinically relevant, including transient, complications (e.g. cerebrospinal fluid (CSF) leakage, reoperation because of bleeding, CSF leakage or epistaxis, re-admission for hyponatremia (due to SIADH) or other causes (e.g. meningitis, transient pituitary insufficiency including AVP deficiency (AVPD)), and as 2) permanent complications at 6 months excluding the transient ones (e.g. persistent AVPD and/or anterior pituitary hormone deficiency, persistent nerve damage). Furthermore, we used integrated outcome squares, an outcome integration model developed in our team. This method enables integrating intended and adverse effects, ranging from good to poor reflected by four integrated outcome quadrants (IOQ's). Here the IOQ is composed by preoperative goal (total resection or debulking) versus permanent complication: IOQ-1 = good outcome (intended effect achieved, without permanent complications), IOQ-2 = intermediate outcome (intended effect achieved, with permanent complications), IOQ-3 = intermediate outcome (intended effect not achieved, without permanent complications), IOQ-4 = poor outcome (intended effect not achieved, with permanent complications).( 8 ) Statistics We report descriptive statistics. Data are presented as median (minimum-maximum). Correlation between TBR max and IGF-1 levels were analyzed using Spearman correlation. Results Clinical characteristics (Table 1 ) Table 1 Patients’ characteristics Number of patients Age in yr (range) Sex (M:F) Duration of disease in yr (range) IGF1 SD at diagnosis Glucose mediated GH nadir at diagnosis Last IGF1 SD before FET-PET/MRI CR IGF1 SD before FETPET guided surgery (range) Macro: Microadenoma Prior surgery Prior medication (n) Duration in mo (range) All 10 52 (23–60) 4:6 2.6 (1.3–21) + 10.0 SD (3.7–14.5) # 8.4 (0.5–24) ^ + 3.7 (3.0-4.8) ### + 3.7 (3.0-4.8)* 7:2 (+ 1 no substrate) 9 10 12 (6-252) Group 1 5 40 (23–54) 2:3 1.8 (1.3–3.1) + 10.2 SD (7.2–14.5) ## 8.4 (3.3–58) ^^ + 3.5 (3.0-4.4) + 3.5 (3.0-4.4) 4:1 5 5 6 (3–13) Group 2 5 57 (35–60) 2:3 3.3 (1.5–21) + 4.5 SD (3.7–10) ### 11.4 (0.5–24) ^^^ + 3.8 (3.6–3.8) ### + 4.2 (3.6–4.8)* 3:1 (+ 1 no substrate) 4 5 40 (6-252) Median (range) F: female, GH: growth hormone, M: male, mo: months, n: number, SD: standard deviation, yr: years # 3 missing (S1, S5, S9). ## 1 missing (S9). ### 2 missing (S1, S5). ^ 2 missing (S1, S6). ^^ 1 missing (S6). ^^^ 1 missing (S1). * without S7 (not operated). Ten patients (4 males and 6 females) with a median age of 52 years (range 23–60 years) were included in this study (Table 1 ). They were diagnosed with acromegaly with a median of 2.6 years prior to FET-PET/MRI CR (range 1.3–22 years). At diagnosis, 1 patient had no visible lesion, 2 patients had a microadenoma, and 7 patients had a macroadenoma on MRI scan. Recent MRI before FET-PET/MRI CR showed a suspected remnant adenoma in 6 subjects albeit difficult to delineate and discriminate from postoperative changes (3, 4, 6 (group 1); 1, 5, 8 (group 2)), while in 4 cases (2, 9 (group 1); 7, 10 (group 2)) no clear (remnant) lesion was identified. Seven patients were on pegvisomant monotherapy at the time of FET-PET/MRI CR , 1 patient had combination therapy with pegvisomant and SRL, where SRL was withdrawn prior to the scan until his IGF-1 was considered high enough (+ 3.6 SD, case 1), and 2 patients were without medication at the time of FET-PET/MRI CR (9 and 10). The median last IGF-1 SD value before FET-PET/MRI CR was + 3.7 (3.0-4.4). FET-PET/MRI CR showed suspicious tracer uptake in all 10 patients. In 5 patients (50%) FET-PET/MRI CR findings were completely concordant with conventional MRI (cases 1, 3, 4, 6, 8), and in 1 patient (case 5) partially concordant. In 4 subjects ( 2 , 7 , 9 and 10 ), FET-PET/MRI CR identified new foci of suspicious uptake, not corresponding to conventional MRI. There was no correlation between the TBR max and the last IGF-1 value before FET-PET/MRI CR (R 2 = 0.121, p = 0.399). In 7 of 9 (78%) operated patients FET-PET/MRI CR findings were confirmed intraoperatively, and in 6 of 9 (67%) patients also histologically. IGF-1 decreased significantly in 8 of 9 (89%) operated patients (Fig. 2 ). Performance of FET-PET/MRI CR in the predetermined care trajectories See Tables 2 and 3 , and Online Resource 1 for all case descriptions. Table 2 Overall outcomes and per group. Surgery Goal of surgery Intraoperative positive findings Confirmative histology Complications Clinical improvement Biochemical remission Postoperative IGF-1 (x ULN) Further treatment IOQ FETPET helpful? All 9 of 10 6 remission 2 debulking 1 diagnosis 7 yes 1 no 1 ? 7 positive* 1 uncertain 1 negative 2 SIADH 1 CSF leak 9 yes # 3 complete 5 improved # 1 unchanged 1.3 (0.7–1.9) # 6 no 2 med 1 med + RTP 6 IOQ-1 3 IOQ-3 9 yes 1 no Group 1 5 of 5 5 remission 4 yes 1 no 4 positive 1 negative 1 SIADH 5 yes 3 complete 1 improved 1 unchanged 0.8 (0.7–1.8) 4 no 1 med 3 IOQ-1 2 IOQ-3 4 yes 1 no Group 2 4 of 5 1 remission 2 debulking 1 diagnosis 3 yes* 1 uncertain 3 positive* 1 uncertain 1 SIADH 1 CSF leak 4 yes # 4 improved # 1.3 (1.3–1.9) # 2 no 1 med 1 med + RTP 3 IOQ-1 1 IOQ-3 5 yes Median (range) CSF: cerebrospinal fluid, IOQ: integrated outcome squares, Med: medication, SIADH: syndrome of inappropriate ADH, RTP: radiotherapy, ULN: upper limit of normal. * 1 positive histology of FET-negative lesion (case 5) # Subject 8: clinically and biochemically (IGF-1 1.3x ULN) improved with postoperatively Pegvisomant 30mg 5 times weekly, as compared to severe headache and IGF-1 1.9 x ULN preoperatively with the same dose of Pegvisomant. Care trajectory 1: FET-PET/MRI CR to optimize outcome of revision surgery following unexpectedly unsuccessful prior surgery. Before FET-PET/MRI CR . Five patients with inconclusive findings on postoperative conventional MRI were included in this group (subject 2, 3, 4, 6, 9) (median duration of disease 1.8 years (range 1.8–3.1 years)). Four patients had a macroadenoma at the time of primary diagnosis ( 2 , 3 , 6 , 9 ), and the other patient (subject 4) had a large microadenoma with close relation to the cavernous sinus without invasion. All had undergone surgery once or twice, 4 patients in our center and 1 patient (case 9) in another academic center (first surgery for cases 2 and 3, and second surgery for cases 4, 6 and 9), with a retrospectively likely estimated chance of remission. Thus, postoperative persistent disease was unexpected and not well understood based on the preoperative radiological characteristics in these 5 patients. All subjects had been treated shortly with medication, predominantly pegvisomant to not affect tumor volume and functional imaging (median duration 6 months (range 3–16 months) as a bridging therapy until there was a clear indication to proceed with revision surgery in case a lesion could be identified. FET-PET/MRI CR ( Figs. 3 and 4 ). The median last IGF-1 SD value before FET-PET/MRI CR was + 3.5 (3.0-4.4). FET-PET/MRI CR revealed suspicious uptake in the sellar region for all 5 patients, corresponding to the possible lesion on conventional MRI in 3 patients ( 3 , 4 , 6 ), and non-corresponding in 2 patients (case 2 and 9) without a clear substrate on MRI. FET-PET/MRI CR guided treatment decision. Revision surgery was chosen as treatment for all 5 patients with intended biochemical remission, with a possibly estimated probability and low (4 patients: 3, 4, 6, 9) or moderate (1 patient: case 2) estimated risk for complications. Outcome after FET-PET/MRI CR guided surgery. Suggestive adenoma was found during surgery in 4 cases ( 3 , 4 , 6 , 9 ), all with positive histology. In these 4 cases, findings were consistent with functional imaging. In the other case (case 2), the area with increased tracer uptake was inspected during surgery and after considering it safe, was resected, with negative histology. Thus, in 4 of 5 (80%) operated patients FET-PET/MRI CR findings were intraoperatively and histologically confirmed. One patient had a transient complication: SIADH (case 4: moderate estimated risk). No permanent complications occurred. All patients showed clinical improvement. Complete biochemical remission was achieved in 3 patients ( 3 , 4 , 9 ) (60%) (Fig. 2 ). Biochemistry improved in subject 6. In subject 2 IGF-1 did not clearly improve or normalize, but his symptoms (severe headache) did, and postoperative MRI showed that the suspected lesion was removed, and he has an ongoing normal glucose suppression of serum GH. One patient restarted with medication during postoperative follow up for elevated IGF-1 in the context of normal glucose-mediated GH suppression (case 6). Based on the preoperative goal, an IOQ-1 (goal set preoperatively achieved without permanent complications) was achieved in 3/5 (60%) patients (cases 3, 4, 9) and an IOQ-3 (goal not achieved, no permanent complications) in 2/5 patients (cases 2, 6) at 6 months postoperatively. Care trajectory 2: FET-PET/MRI CR to revisit treatment options because of non-control or drug intolerance Before FET-PET/MRI CR . This group is represented by 5 patients. All had persistent uncontrolled disease at inclusion in this study and were under maximal tolerable doses of chronic medication (SRL and pegvisomant) (median duration of disease 3.3 years (range 1.5–21 years); median duration of medication 40 months (range 6-252 months; case 7 = 6 months, other cases ≥ 31 months)), and with clinical high need for alternative treatment. Four patients had been operated before, 2 of which more than once. Conventional MRI just before FET-PET/MRI CR was difficult to interpret due to postoperative changes (case 1), the absence of a clear (remnant) adenoma (cases 7, 10) or possible multifocality (cases 5, 8), but none had evidence of a tumor without the prospect of total resection at any stage during treatment. In detail, for case 1, with an initial macroadenoma without cavernous sinus invasion, a possible remnant was described on MRI, but was difficult to interpret due to an unavailable baseline MRI and postoperative changes after 3 surgeries. Case 5 had multiple possible remnant lesions of an initial macroadenoma with cavernous sinus invasion (Knosp 3A) after surgery and long-term medical treatment. Case 7 had postoperative changes and no certain remnant of an original macroadenoma. She was retrospectively estimated as unlikely remission chance at prior surgery given cavernous sinus invasion (Knosp 3A with a small remnant between the limbs of the carotid siphon). In case 8, MRI before FET-PET/MRI CR showed two possible small foci – one on the left side of the sella, which was described at diagnosis and was targeted during first surgery elsewhere (retrospectively highly suggestive for a Rathke’s cleft cyst (RCC)) and a second one on the right side of the sella. Imaging interpretation was further complicated because of a suboptimal baseline (preoperative) MRI-scan. Case 10 was not operated before due to lack of a visible lesion on baseline MRI and was therefore treated with primary medical treatment. FET-PET/MRI CR ( Figs. 5 and 6 ). The median last IGF-1 SD value before FET-PET/MRI CR was + 3.8 (3.7–3.8) (case 1 and 5 excluded due to no known values without use of pegvisomant). Case 1 also used SRL, all other cases had used SRL (case 5 both first and second generation SRL) in the past which was stopped because of side effects. FET-PET/MRI CR showed increased tracer uptake in all 5 patients: fully concordant with MRI in 2 patients ( 1 , 8 ), partially concordant in 1 patient (case 5: 2 of 5 possible lesions positive), and 2 were discordant (case 7: positive lesion on the right not visible on MRI; 10: no lesion on MRI, positive on FET-PET/MRI CR ). FET-PET/MRI CR guided treatment decision. Surgical re-exploration was performed in 4 patients ( 1 , 5 , 8 , 10 ), and 1 patient underwent radiation therapy (case 7). Regarding case 7, FET uptake was diffusely increased in the right cavernous sinus reconfirming the impossibility for surgical cure. For the 4 surgical patients, the goal of surgery varied between: achieving biochemical remission (case 8), debulking for medication reduction, radiation field reduction and/or symptom relief (cases 1, 5), and obtaining tissue for diagnosis (case 10), all estimated as possibly. The risk of complications was estimated as low (case 10), moderate (cases 1, 5), and high (case 8). Outcome after FET-PET/MRI CR guided surgery. Suggestive (remnant) adenoma was found during surgery in 3 cases ( 1 , 8 , 10 ), 2 of them with positive histology ( 8 , 10 ) and 1 with uncertain histology (case 1). In these 3 cases, findings were consistent with functional imaging. In the other operated patient (case 5), a FET-PET/MRI CR negative lesion was histologically positive. Thus, 3 of 4 (75%) operated patients had confirmative histology (one patient (case 5) with non-concordant FET-PET/MRI CR ). Subject 1: debulking was performed as expected with clinical and biochemical improvement such that he could lower his medication immediately post-surgery, which was considered of added value, and then underwent radiotherapy 6 months later as anticipated. Subject 5: debulking was performed as expected, with clinical and biochemical improvement (glucose-mediated GH nadir normalized (0.37 mcg/L); IGF-1 + 2.8 SD (1.4x ULN)) and because of no symptomatology he is still followed without treatment (last follow up almost 2 years postoperative). Subject 8 was a case with preoperative normal glucose-mediated GH suppression but elevated IGF-1 and severe symptoms, irresponsive to medical treatment. Medical treatment failed to normalize IGF-1 and previous surgery had negative pathology. A good outcome of surgery was the histological confirmation of acromegaly. Postoperative IGF-I improved but did not normalize, and because her symptoms (severe headache) were not reduced, we restarted on pegvisomant without awaiting the time needed for interpretable IGF-1. Now she has normalized at a lower dose of pegvisomant than preoperatively (210 vs 150 mg/wk) in combination with a low-carbohydrate diet. In subject 10 there was a need for surgical exploration to confirm acromegaly because of an uncertain diagnosis, inconclusive small lesion on MRI, and side effects on both SRL and pegvisomant. Surgical findings and histology were positive, confirming the diagnosis of acromegaly. She experienced clinical improvement, and biochemistry normalized, and she is now followed without need for medication. Two patients had transient complications: SIADH (case 8 (high estimated risk)) and CSF leakage needing a re-operation (case 5 (low estimated risk)). No permanent complications occurred. Thus, complete biochemical remission was not achieved in any of the patients (as was anticipated in 3 of the 4 operated patients). However, biochemistry improved in all 4 subjects ( 1 , 5 , 8 , 10 ) (Fig. 2 ) and 3 out of 4 showed clinical improvement. (Additional) added value was confirmation of the histological diagnosis of acromegaly in subjects 8 and 10 (primary intended effect) with preoperative diagnostic uncertainty due to discrepant values (normal GH nadir after glucose loading, increased IGF-1). Based on the preoperative goal, an IOQ-1 (goal set preoperatively achieved without permanent complications) was achieved in 3 patients ( 1 , 5 , 10 ) (75%) and an IOQ-3 (goal not achieved, no permanent complications) in 1 patient (case 8) at 6 months postoperatively. Discussion This is the first case series reporting on the use of FET-PET/MRI CR in the care trajectory of patients with persistent acromegaly. The reported findings illustrate how 18 F-FET can provide added value in selected complex cases, informing the preoperative decision-making process in a multidisciplinary setting of a center of expertise. Functional imaging with 11 C-methionine co-registered with MRI has proven added value for localizing tumor remnants in functioning pituitary adenomas.( 15 – 18 ) ( 19 , 20 ) Due to logistical challenges in securing a reliable source of 11 C-methionine, we initiated the use of 18 F-fluoro-ethyl-tyrosine ( 18 F-FET) in September 2020, an AA analogue with a longer half-life and thus more suitable for clinical application in our institution. 18 F-FET has not yet proven clinical efficacy in pituitary adenomas except for a retrospective case series of FET-PET/MRI CR in Cushing’s disease.( 29 ) However, a key rationale for its use is the fact that FET and MET share the same uptake mechanism and a close correlation has been found between FET and MET uptake in primary brain tumors (e.g. gliomas and metastases),( 22 – 24 ). Although FET and MET share the same molecular mechanism to enter the cell (via the L-type amino acid transporter 1 (LAT1)),( 21 ) in contrast to MET, FET is neither metabolized nor incorporated into proteins. Here, we report our first results and our learning curve, building on our previous experience with MET-PET/MRI CR . We incorporated FET-PET/MRI CR in the clinical decision-making process in the same way as MET-PET/MRI CR , in a dedicated care path with repeat MDT discussions, as described in the Methods. We advocate for restrictive use because of costs and time-consuming interpretation. Therefore, only cases in which the team agrees on its added value, with a clearly formulated clinical question, were referred for FET-PET/MRI CR . Evaluation of all available imaging was thoroughly discussed, to prevent information loss between MD partners and the surgeons performing the intervention. We believe that, irrespective of the type of functional imaging used, this setup is crucial for the potential impact of functional imaging. In our practice, two typical patient journeys are considered for functional imaging as highlighted in this case series. The first group typically had a non-invasive (Knosp < 2) clear adenoma at preoperative imaging such that not obtaining remission at first surgery was unexpected. Due to postoperative tissue remodeling, the postoperative MRI is usually more difficult to interpret. Therefore, many cases will not be offered revision surgery as was the case in our team prior to the introduction of functional imaging. Nowadays, with the implementation of functional imaging in selected cases, we try to understand the lack of success, and use this new modality to set optimal conditions for a reintervention, which seems to be a successful strategy based on the findings of this study. Clinical questions in these cases were assessment of extension and invasion, confirmation of the primary culprit lesion, discrimination between postoperative changes and tumor remnants. In those postoperative patients, FET-PET/MRI CR highlighted all tumors, in 80% FET-PET/MRI CR findings were intraoperatively and histologically confirmed, and 60% resulted in total resection without complications. The other group is more heterogenous as they were treated longer ago, had lower quality baseline imaging and / or a trajectory of medical treatment with shrinkage that may further complicate imaging interpretation. This group had a high need for alternative treatment. Four patients in this group were already operated (more than) once. Post medication changes (e.g. due to direct anti-tumor effects of somatostatin analogs, dopamine agonists or pasireotide (case 5))( 30 ), may have resulted in scattered small remnants, or even absence of a clear remnant. Initial images prior to any intervention, were typically of limited quality, and added to the uncertainty about the location and extent of the original tumor. Nevertheless, FET-PET/MRI CR was positive in all cases, with complete concordance with MRI in 2 cases, partial in 1 case and no (negative MRI) concordance in 2 cases. In 75% of cases, FET-PET/MRI CR findings were intraoperatively and histologically confirmed. In one patient, FET-PET/MRI CR supported our decision to refrain from further surgery. In another patient, FET-PET/MRI CR assisted in surgical mapping of multiple possible foci. In this patient, a FET-negative lesion was found to be histologically positive, with no clear explanation. Additional added value was confirmation of the diagnosis of acromegaly in 2 subjects with difficult preoperative biochemistry. In 3 of the 4 operated patients after FET-PET/MRI CR the intended outcome (IOQ-1) was achieved, and no permanent complications occurred. It is important to note that FET and MET have distinct metabolic fates, resulting in differences in uptake pattern and distribution over time. FET is an AA analogue which is neither metabolized nor incorporated into proteins, in contrast to MET, which is an essential AA. The L-type AA system is a reversible transport system, and it seems that efflux of nonmetabolized FET occurs from the adenoma tissue, leading to washout of the tracer over time and pooling of FET in the direction of and into the cavernous sinus (Fig. 4 ). Because metabolism is increased in a functional adenoma, the AA transport is expected to be increased as well, resulting in higher tracer uptake at the site of the adenoma. Appropriate timing of PET acquisition after tracer injection is crucial. We have observed that appreciation of the ‘normal’ biodistribution of FET in the sellar region and its washout is crucial for the interpretation of FET-PET/MRI CR images (unpublished clinical observation). Unfortunately, reference data regarding normal appearances of tracer uptake in the cavernous sinus region and pituitary tissue in healthy controls is currently lacking, and the time course for FET uptake over time and wash-out characteristics of the tracer from (different types of) pituitary adenomas is not known. This should be considered for further development of the technique. Another challenge of our approach to only use FET-PET/MRI CR as a ‘last resort scan’ is that we lack reference in case of obvious tumors. When taking these uncertainties into account, we hypothesize that in the situation that both tracers are available MET may be preferred for clinical questions regarding (remnant) lesions close to or in the cavernous sinus. Interestingly, the uptake of FET is lower in the normal pituitary gland compared to MET. Hence, for small, not highly metabolically active (remnant) lesions in the pituitary gland, FET might be advantageous over MET. A current challenge with MET-PET/MRI CR is that these small lesions are not easily visible due to lack of contrast with normal gland uptake. There were also similarities with MET-PET/MRI CR . Both are not useful in cystic lesions due to no or low tracer uptake (i). For both techniques crucial steps are (ii) awareness for technical issues such as co-registration mismatch, (iii) adequate withdrawal of tumor directed drugs, (iv) availability and quality of pituitary MRI at diagnosis (i.e. pre-treatment) is essential for optimal interpretation of the functional scan, (v) implementation and use of this technique requires an MDT setting for dedicated evaluation of added value. Regarding the activity of the adenoma, it is recommended to withdraw somatostatin analogues at least three months prior to functional imaging,( 16 ) to ensure activity of the lesion. However, in our patients with small remnants, poor quality of life and a high need for an alternative treatment, the time interval for which SRL withdrawal was considered acceptable was limited and therefore, if needed, pegvisomant was used to bridge the period to scan. Therefore, IGF-1 levels at the time of FET-PET/MRI CR were typically only modestly increased, which is an extra challenge for the performance of functional imaging. The fact that TBR max did not correlate to IGF-1 levels in our study population may be related to this selected case mix with small remnants and little IGF-I variation. Previous studies on MET report a clear correlation between metabolic activity and serum hormone level (prolactin and growth hormone) and further investigation is needed to assess whether the different metabolic fate of FET compared to MET is another explanation for this lack of correlation when using FET.( 31 – 33 ) A further limitation is that we could not compare FET-PET/MRI CR to MET-PET/MRI CR in the same patient. As already mentioned, FET-PET/MRI CR was introduced because of logistical problems. However, as next step it would be worthwhile to investigate which tracer is best applied in which clinical situation. In conclusion (Fig. 7 ), functional imaging with FET-PET/MRI CR has clear added value in the clinical decision-making process of patients with acromegaly with persisting disease due to small remnants, particularly when MET is not available or in cases with intrasellar disease. We describe our approach where functional imaging is restricted to complex cases. FET-PET/MRI CR images differ from MET-PET/MRI CR images concerning radiotracer uptake pattern in the sellar and cavernous sinus region, which is clinically relevant for (remnant) lesions in (close relation to) the cavernous sinus. Interpretation of FET-PET/MRI CR images is challenging due to the physiological uptake of FET in the adjacent cavernous sinus and its wash out over time from both adenoma tissue and surrounding normal tissue, warranting appropriate timing of PET acquisition. A learning curve of interpretation of physiological distribution of the tracer in the sellar region and surroundings is therefore required. Also, more knowledge needs to be acquired concerning the uptake mechanisms of tyrosine by functional adenoma tissues, as not only cystic lesions are thought to be FET-negative, but apparently also some solid lesions, as was the case in one of the patients (case 5) in this study. Furthermore, a FET-PET/MRI CR guided surgical procedure can be safely performed after (multiple) previous surgeries by an experienced surgical team. This makes revisiting surgical options for a group of currently medically treated patients that do not clearly have an inoperable remnant worthwhile. Declarations Disclosures: none of the authors report any disclosures Acknowledgements : Mark Gurnell is supported by the NIHR Cambridge Biomedical Research Centre (NIHR203312*). The authors thank Anneke M.G. Slats-Steenvoorden (Leiden University Medical Center, Leiden, the Netherlands) for her assistance, all patients, and their referring physicians for their trust in the Leiden Pituitary Center. Author contributions: L.B., M.V., N.B., W.F., I.G. and L.P. contributed to conception and design of the study, the acquisition, analysis, and interpretation of data, and reviewed/edited the manuscript. M.G., I.P. D.M., and T.D. contributed to analysis and interpretation of data, and reviewed/edited the manuscript. L.B., M.V., and D.M. wrote the main manuscript text. I.G., L.P., H.L., B.V. and M.K. interpreted the imaging data. L.P and H.L. prepared figures 3-6. L.B. and N.B. prepared figures 1, 2, and 7. All authors reviewed and approved the final manuscript. Funding No funding was received for conducting this study. Conflicts of interest/Competing interests The authors have no conflicts of interest to declare that are relevant to the content of this article. Availability of data and material Data is provided within the manuscript or supplementary information files Ethics approval Data of patients were obtained after a waiver of the medical ethical review was received from our institutional medical ethical review board (G19.011). Consent to participate A declaration of non-objection was obtained for review of patients’ charts. 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O-(2-[18F]fluoroethyl)-L-tyrosine and L-[methyl-11C]methionine uptake in brain tumours: initial results of a comparative study. Eur J Nucl Med. 2000;27(5):542-9. Lobatto DJ, Zamanipoor Najafabadi AH, de Vries F, Andela CD, van den Hout WB, Pereira AM, et al. Toward Value Based Health Care in pituitary surgery: application of a comprehensive outcome set in perioperative care. Eur J Endocrinol. 2019;181(4):375-87. van Furth WR, de Vries F, Lobatto DJ, Kleijwegt MC, Schutte PJ, Pereira AM, et al. Endoscopic Surgery for Pituitary Tumors. Endocrinol Metab Clin North Am. 2020;49(3):487-503. Vander Borght T, Asenbaum S, Bartenstein P, Halldin C, Kapucu O, Van Laere K, et al. EANM procedure guidelines for brain tumour imaging using labelled amino acid analogues. Eur J Nucl Med Mol Imaging. 2006;33(11):1374-80. Micko AS, Wohrer A, Wolfsberger S, Knosp E. Invasion of the cavernous sinus space in pituitary adenomas: endoscopic verification and its correlation with an MRI-based classification. J Neurosurg. 2015;122(4):803-11. Berkmann S, Roethlisberger M, Mueller B, Christ-Crain M, Mariani L, Nitzsche E, et al. Selective resection of cushing microadenoma guided by preoperative hybrid 18-fluoroethyl-L-tyrosine and 11-C-methionine PET/MRI. Pituitary. 2021;24(6):878-86. Coopmans EC, van der Lely AJ, Schneiders JJ, Neggers S. Potential antitumour activity of pasireotide on pituitary tumours in acromegaly. Lancet Diabetes Endocrinol. 2019;7(6):425-6. Bergstrom M, Muhr C, Lundberg PO, Langstrom B. PET as a tool in the clinical evaluation of pituitary adenomas. J Nucl Med. 1991;32(4):610-5. Muhr C. Positron emission tomography in acromegaly and other pituitary adenoma patients. Neuroendocrinology. 2006;83(3-4):205-10. Tang BN, Levivier M, Heureux M, Wikler D, Massager N, Devriendt D, et al. 11C-methionine PET for the diagnosis and management of recurrent pituitary adenomas. Eur J Nucl Med Mol Imaging. 2006;33(2):169-78. Table 3 Table 3 is available in the Supplementary Files section. Additional Declarations No competing interests reported. Supplementary Files ESM1.pdf table3.docx Cite Share Download PDF Status: Published Journal Publication published 30 May, 2024 Read the published version in Clinical Endocrinology → Version 1 posted 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-3799944","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":264113426,"identity":"30836cdb-6d1d-488c-90cd-bdae80c1d370","order_by":0,"name":"Leontine E.H. 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Biermasz","email":"","orcid":"","institution":"Leiden University Medical Center","correspondingAuthor":false,"prefix":"","firstName":"Nienke","middleName":"R.","lastName":"Biermasz","suffix":""},{"id":264113444,"identity":"27544191-3097-4359-a2c3-ce170206cbdc","order_by":13,"name":"Lenka M. Pereira Arias-Bouda","email":"","orcid":"","institution":"Leiden University Medical Center","correspondingAuthor":false,"prefix":"","firstName":"Lenka","middleName":"M. Pereira","lastName":"Arias-Bouda","suffix":""}],"badges":[],"createdAt":"2023-12-24 10:29:12","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-3799944/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-3799944/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1111/cen.15079","type":"published","date":"2024-05-31T00:00:00+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":49075796,"identity":"2d923bef-2ac2-49a0-863a-160b52cc88d8","added_by":"auto","created_at":"2024-01-02 18:34:58","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":181839,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003ePatient care trajectories.\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eMDT: multidisciplinary team, PTCOE: Pituitary Tumor Center of Excellence.\u003c/p\u003e","description":"","filename":"Fig1.png","url":"https://assets-eu.researchsquare.com/files/rs-3799944/v1/a4aceda89ca24ba392039e7c.png"},{"id":49075791,"identity":"aa90380c-624c-48b0-b18b-081b481a73aa","added_by":"auto","created_at":"2024-01-02 18:34:58","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":98068,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eIGF-1 standard deviation before and after FET-PET/MRI\u003c/strong\u003e\u003csup\u003e\u003cstrong\u003eCR\u003c/strong\u003e\u003c/sup\u003e\u003cstrong\u003e guided transsphenoidal surgery.\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eBlack solid line: group 1, grey striped line: group 2.\u003cbr\u003e\n# Subject 8: postoperative value (+2.5, 1.3 x ULN) is with Pegvisomant 30mg 5 times weekly, as compared to +3.7 (1.9 x ULN) preoperatively with the same dose of Pegvisomant.\u003cbr\u003e\nSD: standard deviation, TSS: Transsphenoidal surgery, ULN: upper limit of normal.\u003c/p\u003e","description":"","filename":"Fig2.png","url":"https://assets-eu.researchsquare.com/files/rs-3799944/v1/d51a1cba23799acae408a5af.png"},{"id":49075793,"identity":"dcfb09f9-48be-4057-8885-9517d961a2c0","added_by":"auto","created_at":"2024-01-02 18:34:58","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":4569167,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eImaging in cases 2, 3, 4 and 9 (Care trajectory 1: FET-PET/MRI\u003c/strong\u003e\u003csup\u003e\u003cstrong\u003eCR\u003c/strong\u003e\u003c/sup\u003e\u003cstrong\u003e to optimize outcome of revision surgery of unexpectedly unsuccessful prior surgery).\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCase 2\u003c/strong\u003e: a, b: MRI at baseline (sagittal (a) and coronal (b) views, T\u003csub\u003e1w\u003c/sub\u003e\u0026nbsp; post-contrast) with a small macroadenoma ventrally in the left sella with close relationship to the cavernous sinus. c, d: MRI after first surgery, before FET-PET/MRI\u003csup\u003eCR\u003c/sup\u003e (coronal (c) and axial (d) views, T\u003csub\u003e1w\u003c/sub\u003e post-contrast) with no clear remnant. e, f: FET-PET/MRI\u003csup\u003eCR\u003c/sup\u003e fusion (coronal (e) and axial (f) views) with asymmetrical tracer accumulation in the sella with higher uptake medial to the left carotid artery (red arrows).\u003cbr\u003e\n\u003cstrong\u003eCase 3\u003c/strong\u003e: a, b: MRI at baseline (sagittal (a) and coronal (b) views, T\u003csub\u003e1w\u003c/sub\u003e post-contrast) with a macroadenoma with suprasellar extension but no cavernous sinus invasion. c, d, e: MRI after 1 surgery, before FET-PET/MRI\u003csup\u003eCR\u003c/sup\u003e (coronal (c), axial (d) and sagittal (e) views, T\u003csub\u003e1w\u003c/sub\u003e post-contrast) with a suspected residual adenoma in the right sella floor with probable extension into the sphenoid sinus (red arrows), which is difficult to distinguish from postoperative changes. f, g, h: FET-PET/MRI\u003csup\u003eCR\u003c/sup\u003e fusion (coronal (f), axial (g) and sagittal (h) views) with a suspected residual adenoma on the sella floor extending into the sphenoid sinus (red arrows).\u003cbr\u003e\n\u003cstrong\u003eCase 4\u003c/strong\u003e: a, b, c: MRI at baseline (sagittal (a), coronal (b) and axial (c) views, T\u003csub\u003e1w\u003c/sub\u003e post-contrast) showing a microadenoma on the left with close relationship to the cavernous sinus but without clear invasion. d, e: MRI after 2 surgeries and somatostatin receptor ligand (SRL), before FET-PET/MRI\u003csup\u003eCR\u003c/sup\u003e (coronal T\u003csub\u003e1w\u003c/sub\u003e post-contrast (d) and coronal T\u003csub\u003e2w\u003c/sub\u003e (e)) with a suspected small residual adenoma in the left sella (red arrows). f, g: FET-PET/MRI\u003csup\u003eCR\u003c/sup\u003e fusion (coronal (f) and axial (g) views) with increased uptake in the left sella at the site of the suspected lesion (red arrows).\u003cbr\u003e\n\u003cstrong\u003eCase 9\u003c/strong\u003e: a, b, c: MRI at baseline (coronal T\u003csub\u003e1w\u003c/sub\u003e post-contrast (a) view) and after 5 months treatment with SRL (sagittal (b) and coronal (c) views T\u003csub\u003e1w\u003c/sub\u003e post-contrast) with a macroadenoma without cavernous sinus invasion. d, e: MRI after 2 surgeries and SRL, before FET-PET/MRI\u003csup\u003eCR\u003c/sup\u003e (coronal (d) and axial (e) views, T\u003csub\u003e1w\u003c/sub\u003e post-contrast) with no clear remnant; possible small lesion on the right side (red arrow), tissue caudally more extending to the left is suggested to be post-operative changes (white arrow). f, g: FET-PET/MRI\u003csup\u003eCR\u003c/sup\u003e fusion (coronal (f) and axial (g) view) with increased uptake on the left and right cranially of the resection cavity (red arrows). No uptake in the area on the sella floor (white arrow).\u003c/p\u003e","description":"","filename":"Fig3.png","url":"https://assets-eu.researchsquare.com/files/rs-3799944/v1/eec23546420adf03df832796.png"},{"id":49076602,"identity":"b7892ba8-6a25-4f7a-b51d-69d6959f1d3b","added_by":"auto","created_at":"2024-01-02 18:42:58","extension":"png","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":3238343,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eImaging in case 6 (Care trajectory 1), who had both a MET-PET/MRI\u003c/strong\u003e\u003csup\u003e\u003cstrong\u003eCR\u003c/strong\u003e\u003c/sup\u003e\u003cstrong\u003e and FET-PET/MRI\u003c/strong\u003e\u003csup\u003e\u003cstrong\u003eCR\u003c/strong\u003e\u003c/sup\u003e\u003cstrong\u003e.\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e- Top left: MRI at baseline (sagittal (a) and coronal (b) views, T\u003csub\u003e1w\u003c/sub\u003e post-contrast) with a macroadenoma in the sella left without cavernous sinus invasion.\u003cbr\u003e\n- Bottom left: MET-PET/MRI\u003csup\u003eCR\u003c/sup\u003e: c, d, e: MRI after first surgery, before MET-PET (coronal T\u003csub\u003e1w\u003c/sub\u003e post-contrast (c), coronal T\u003csub\u003e2w\u003c/sub\u003e (d) and axial T\u003csub\u003e1w\u003c/sub\u003e post-contrast (e) views) with a suspected remnant lesion ventrolaterally on the left (red arrows). f, g: MET-PET/MRI\u003csup\u003eCR\u003c/sup\u003e (coronal (f) and axial (g) view) with increased uptake left anterolateral in the sella (red arrows).\u0026nbsp;\u0026nbsp;\u003cbr\u003e\n- Bottom right: FET-PET/MRI\u003csup\u003eCR\u003c/sup\u003e: h, i: MRI after 2 surgeries, before FET-PET/MRI\u003csup\u003eCR\u003c/sup\u003e (coronal (h) and axial (i) views, T\u003csub\u003e1w\u003c/sub\u003e post-contrast) with a suspected residue on the sellar floor from the midline to left laterally without cavernous sinus invasion (red arrows). j, k: FET-PET/MRI\u003csup\u003eCR\u003c/sup\u003e fusion (coronal (j) and axial (k) view) with increased uptake left anterolateral in the sella concordant with MRI and previous MET-PET findings (red arrows).\u003c/p\u003e","description":"","filename":"Fig4.png","url":"https://assets-eu.researchsquare.com/files/rs-3799944/v1/fd91a61655db5d1af64ffc1f.png"},{"id":49075799,"identity":"29f85129-3ca7-4d7e-a4cb-c029b3f6c220","added_by":"auto","created_at":"2024-01-02 18:34:59","extension":"png","order_by":5,"title":"Figure 5","display":"","copyAsset":false,"role":"figure","size":4639250,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eCase 1\u003c/strong\u003e: No baseline MRI. a, b: MRI after 3 surgeries and long-term somatostatin receptor ligand (SRL), before FET-PET/MRI\u003csup\u003eCR\u003c/sup\u003e (coronal (a) and axial (b) views, T1w post-contrast) with a possible residue in the right sellar region with uncertain cavernous sinus invasion (red arrows). c, d: FET-PET/MRI\u003csup\u003eCR\u003c/sup\u003e fusion (coronal (c) and axial (d) views) demonstrating increased activity in this region (red arrows).\u003cbr\u003e\n\u003cstrong\u003eCase 7\u003c/strong\u003e: a, b: MRI at baseline (coronal (a) and sagittal (b) views, T1w post-contrast) with a macroadenoma on the right side with cavernous sinus invasion (Knosp 3A, with retrospectively suggestive extension lateral to the carotid artery). c, d: MRI after 1 surgery and SRL, before FET-PET/MRI\u003csup\u003eCR\u003c/sup\u003e (coronal (c) and sagittal (d) views, T1w post-contrast) with postoperative changes but no clear residue. E, f: FET-PET/MRI\u003csup\u003eCR\u003c/sup\u003e fusion (coronal (e) and sagittal (f) view) with increased uptake right lateral to the carotid artery in the residue (red arrows). The area outlined in red is the carotid artery.\u003cstrong\u003e\u0026nbsp;\u003cbr\u003e\nCase 8:\u003c/strong\u003e a, b: MRI at baseline (suboptimal quality) (coronal T2w (a) and T1w post-contrast (b) view) with a 7 mm cystic intrasellar lesion on the left suspected for Rathke's cleft cyst (RCC) (white arrows). c, d: MRI after first surgery, before FET-PET/MRI\u003csup\u003eCR\u003c/sup\u003e (coronal (c) and axial (d) views, T1w post-contrast) with a suspected lesion on the right side of the sella (red arrows), possibly extending over the midline to the left, without cavernous sinus invasion (Knosp 1); a small remnant of the cystic lesion targeted during first TSS suspected for a RCC is still visible (white arrows). e, f: FET-PET/MRI\u003csup\u003eCR\u003c/sup\u003e fusion (coronal (e) and axial (f) views) with increased uptake in the suspected lesion on the right (red arrows).\u003cbr\u003e\n\u003cstrong\u003eCase 10\u003c/strong\u003e: a, b: MRI at baseline (coronal (a) and sagittal (b) views, T1w post-contrast) with no clear lesion. c, d: MRI after SRL, before FET-PET/MRI\u003csup\u003eCR\u003c/sup\u003e (coronal (c) and sagittal (d) views, T1w post-contrast) with no clear lesion; 2 small, low suspicious areas (red and white arrow). e, f: FET-PET/MRI\u003csup\u003eCR\u003c/sup\u003e fusion (coronal (e) and sagittal (f) views) with asymmetrical increased uptake on the right side of the sella corresponding to the small area on the right side (red arrows).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eImaging in cases 1, 7, 8 and 10 (Care trajectory 2: FET-PET/MRI\u003c/strong\u003e\u003csup\u003e\u003cstrong\u003eCR\u003c/strong\u003e\u003c/sup\u003e\u003cstrong\u003e to revisit treatment options because of non-control or drug intolerance).\u003c/strong\u003e\u003c/p\u003e","description":"","filename":"Fig5.png","url":"https://assets-eu.researchsquare.com/files/rs-3799944/v1/32863f6d250882a617738d03.png"},{"id":49075798,"identity":"0dee7613-c749-49a8-aa9d-c4da52c3badf","added_by":"auto","created_at":"2024-01-02 18:34:58","extension":"png","order_by":6,"title":"Figure 6","display":"","copyAsset":false,"role":"figure","size":2494399,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eImaging in case 5 (Care trajectory 2).\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e- a, b, c: MRI at baseline (sagittal (a) and coronal (b) views, T\u003csub\u003e1w\u003c/sub\u003e post-contrast, and coronal T\u003csub\u003e2w\u003c/sub\u003e view (c)) with a macroadenoma, extending supra- and parasellar with left cavernous sinus extension (Knosp 3A).\u003cbr\u003e\n- d, e, f, g: MRI after 1 surgery and long-term treatment (SRL, including pasireotide), before FET-PET/MRI\u003csup\u003eCR\u003c/sup\u003e (coronal (d, e, g) and axial (f) views, T\u003csub\u003e1w\u003c/sub\u003e post-contrast) with possible lesions: d) ventrolateral on the left, just below the carotid artery (white arrow), e+f) at the curvature of the carotid syphon on the left side (red arrow) and left paramedial in the sella (more suspected for resection cavity or fat graft) (white arrow), g) caudal to chiasm near the stalk (white arrow).\u003cbr\u003e\n- h, i, k: FET-PET/MRI\u003csup\u003eCR\u003c/sup\u003e fusion (coronal (h, k) and axial (i) views) with: h and i) increased uptake craniolateral in the cavernous sinus (red arrow) and no uptake in the left paramedial sella lesion (white arrow), corresponding to e+f, k), and no uptake in the lesion caudal to the chiasm near the stalk (corresponding to g) (white arrow).\u003c/p\u003e","description":"","filename":"Fig6.png","url":"https://assets-eu.researchsquare.com/files/rs-3799944/v1/5515792bc63fbd0a8a4f549f.png"},{"id":49076838,"identity":"61b69666-a09e-4f4b-8a53-b53fcb4d65ec","added_by":"auto","created_at":"2024-01-02 18:50:58","extension":"png","order_by":7,"title":"Figure 7","display":"","copyAsset":false,"role":"figure","size":166721,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eProposal for implementation of functional imaging in the clinical decision-making process of acromegaly patients with persisting disease.\u003c/strong\u003e\u003c/p\u003e","description":"","filename":"Fig7.png","url":"https://assets-eu.researchsquare.com/files/rs-3799944/v1/29beaf346f6d89ad1ef47e97.png"},{"id":58523533,"identity":"720d8c18-975e-4195-8f70-57dba365b9ff","added_by":"auto","created_at":"2024-06-17 19:37:25","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":28817705,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-3799944/v1/31ad5dd5-2f0e-46d4-a6e9-18bfccf7e6d6.pdf"},{"id":49075794,"identity":"c47c7b91-4996-4c57-b5a1-dfbb3cd2a8fe","added_by":"auto","created_at":"2024-01-02 18:34:58","extension":"pdf","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":193903,"visible":true,"origin":"","legend":"","description":"","filename":"ESM1.pdf","url":"https://assets-eu.researchsquare.com/files/rs-3799944/v1/7e6ffaeeaea56309aa9d40b7.pdf"},{"id":49076837,"identity":"29b772de-2516-4118-95c9-aec50966ecf9","added_by":"auto","created_at":"2024-01-02 18:50:58","extension":"docx","order_by":2,"title":"","display":"","copyAsset":false,"role":"supplement","size":25438,"visible":true,"origin":"","legend":"","description":"","filename":"table3.docx","url":"https://assets-eu.researchsquare.com/files/rs-3799944/v1/b33f829507f9f5dfc3520b72.docx"}],"financialInterests":"No competing interests reported.","formattedTitle":"18F-fluoro-ethyl-tyrosine PET co-registered with MRI in patients with persisting acromegaly","fulltext":[{"header":"Introduction","content":"\u003cp\u003eAcromegaly is a rare chronic disorder with increased morbidity and mortality and decreased quality of life when not treated adequately.(\u003cspan additionalcitationids=\"CR2 CR3 CR4 CR5\" citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e–\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e) Current guidelines recommend surgery as a first line treatment.(\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e) Surgical remission rates range from 80–90% for microadenomas, and 50–75% for macroadenomas, while invasive adenomas may not be amenable for total resection (\u003cspan additionalcitationids=\"CR8 CR9\" citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e–\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e). Patients who do not achieve disease control after first-line surgery need additional (multimodality) treatment with either revision surgery, medication, and/or radiotherapy.(\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e) Although life-long medical treatment is possible, drugs are expensive, may have side effects, and can be associated with lower quality of life scores than surgical remission.(\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e, \u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e) Radiotherapy has the obvious disadvantage of a delayed biochemical effect and a high risk of pituitary insufficiency.(\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e) In contrast, where total resection is considered feasible, repeat surgery in a pituitary tumor center of excellence may represent the most cost-effective route to achieving long term, drug-free remission. However, reported outcomes of revision surgery, which is usually only performed in patients with a clear non-invasive residual adenoma on conventional magnetic resonance imaging (MRI), are highly variable with success rates ranging from 27–60%.(\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e, \u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e, \u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e) There is therefore an unmet need to better select candidates for reoperation, and to more accurately predict its chances and risks, so surgical and non-surgical treatment modalities can be weighed.\u003c/p\u003e \u003cp\u003eIdentification of small residual or recurrent adenoma is notoriously difficult on conventional MRI, due to postoperative tissue remodeling, small size, and/or proximity to the cavernous sinus. Improved tumor localization is essential to predict likely surgical outcomes (i.e. both remission and complication rates). In recent years, functional imaging has been introduced as adjunct tool to enable more accurate localization of functioning adenomas, using the carbon-11 labeled amino acid (AA) \u003csup\u003e11\u003c/sup\u003eC-methionine (MET) as radiotracer.(\u003cspan additionalcitationids=\"CR16 CR17\" citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e–\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e) A clear added value of MET-PET/MRI\u003csup\u003eCR\u003c/sup\u003e for treatment decision making in patients with Cushing’s disease and persistent or recurrent acromegaly has been shown.(\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e, \u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e, \u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e) Recently, our team and the Cambridge group showed added value of MET-PET/MRI\u003csup\u003eCR\u003c/sup\u003e in the surgical management of prolactinoma.(\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e, \u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e)\u003c/p\u003e \u003cp\u003eAn important drawback of MET is its short half-life (20 min), limiting its use to institutions with an onsite cyclotron. The F-18 labeled AA radiotracer \u003csup\u003e18\u003c/sup\u003eF-fluoro-ethyl-tyrosine (FET) shares the same uptake mechanism via the L-type amino acid transporter 1 (LAT1),(\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e) but has logistic advantages over MET related to its longer half-life (110 min), enabling transportation and more flexibility in planning. FET has proven utility in diagnosing primary brain tumors, but not yet in pituitary adenomas. Comparative clinical studies have shown a strong correlation between FET and MET uptake in brain tumors (e.g. gliomas, metastases),(\u003cspan additionalcitationids=\"CR23\" citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e–\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e) indicating that the utility of MET might be extrapolated to FET for patients with pituitary adenomas.\u003c/p\u003e \u003cp\u003eWe evaluated 10 patients with persistent or recurrent acromegaly with inadequate disease control who underwent FET-PET/MRI\u003csup\u003eCR\u003c/sup\u003e. The aim of this study is to report our experience with FET-PET/MRI\u003csup\u003eCR\u003c/sup\u003e and to describe its role in clinical decision making and treatment outcome.\u003c/p\u003e "},{"header":"Subjects and Methods","content":"\u003cp\u003eStudy center\u003c/p\u003e\u003cp\u003eThe Leiden University Medical Centre (LUMC) is a tertiary referral Endo-ERN center for pituitary and complex endoscopic skull base surgery, performing over 150 surgeries per annum. A dedicated multidisciplinary team (MDT) with 3 endocrinologists, 3 neurosurgeons, 1 ENT-surgeon, 2 neuroradiologists, 1 nuclear medicine physician/nuclear radiologist, 1 ophthalmologist, a radiation oncologist, and two nurse specialist case managers, meets every second week. All patients are cared for in a predefined pituitary care pathway as described previously, and comprehensive outcomes are collected prospectively. The need for ethical approval for care outcome evaluation of pituitary surgery care path was waived by the Scientific Committee (G19.011).(\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e)\u003c/p\u003e\u003cp\u003eCare path protocol including functional imaging\u003c/p\u003e\u003cp\u003e In 2018 we started collaboration with Cambridge with a view to implementing functional imaging in our pituitary care path. The first patients underwent their MET-PET imaging in Cambridge in 2017–2018. From 2019, functional imaging with MET was performed in the Netherlands. Due to logistic issues, we switched to FET-PET in 2020 after obtaining approval from the Dutch Health and Youth Inspectorate for clinical implementation of FET-PET in patients with complex pituitary disease. Apart from substituting FET-PET for MET-PET, the clinical protocol for this diagnostic care path was not changed. The care path is considered in patients with persistent or recurrent acromegaly following primary surgery, and in whom dedicated MRI is inconclusive, either with the aim of achieving total resection or in other complex cases (e.g. medically treated) with a need to revisit surgical options.\u003c/p\u003e\u003cp\u003eIn brief, the clinical case together with all available imaging is discussed in the MDT, especially the treatment naive MRI scans which are often very informative. If MRI clearly localizes the site(s) of residual/recurrent disease and total resection is considered feasible or, on the contrary, if there is clear evidence of invasion, no functional imaging is needed. In case of an unclear lesion on MRI and a strong wish to proceed to surgery when feasible, functional imaging is recommended. This can be because of uncertainty regarding multifocality, or a suspected lesion in an unfavorable anatomy or situation, e.g. due to multiple reoperations. The indication and the individualized clinical question for functional imaging is approved by the MDT. After acquisition of the FET-PET/MRI\u003csup\u003eCR\u003c/sup\u003e, a thorough evaluation of all available images is undertaken in a second MDT, which includes a nuclear medicine physician with expertise in molecular pituitary imaging. All clinical data, including pituitary function and previous surgical and pathology reports are reviewed in conjunction with the combined images. The neurosurgeon and the endocrinologist reappraise all available data in the outpatient clinic and finally decide on the treatment plan, together with the patient. We prospectively record details of the surgical plan. Surgery is typically performed by two pituitary neurosurgeons, (\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e) fully informed about the functional imaging results and MDT discussions. They record the surgical findings in a standard surgical report, which also acknowledges the judgment of the neurosurgeon about the chances of success. In the postoperative phase, we evaluate biochemistry and the pathology report. At 6 months, cases are discussed with the team to evaluate the case including the added value of functional imaging to improve the quality of the pituitary surgery care path.\u003c/p\u003e\u003cp\u003eSubjects\u003c/p\u003e\u003cp\u003eWe included all consecutive patients (n = 10) with acromegaly who had active disease and passed the previously mentioned steps to proceed to functional imaging with FET-PET/CT co-registered with MRI (FET-PET/MRI\u003csup\u003eCR\u003c/sup\u003e) between December 2020 and October 2022. Active disease was defined as persistent symptomatology and lack of biochemical control, with increased IGF1 values (SD \u0026gt; + 2) despite pharmacological treatment or at a median evaluation at 6 months after previous surgery.\u003c/p\u003e\u003cp\u003ePatient trajectories\u003c/p\u003e\u003cp\u003eBased on the clinical situation and the radiological characteristics, we identified typical diagnostic dilemmas that directed to functional imaging, and patients were classified accordingly in two slightly different care trajectories (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e):\u003c/p\u003e\u003cp\u003e \u003cb\u003eCare trajectory 1: FET-PET/MRI\u003c/b\u003e \u003csup\u003e \u003cb\u003eCR\u003c/b\u003e \u003c/sup\u003e \u003cb\u003eto optimize outcome of revision surgery following unexpectedly unsuccessful primary surgery (5 subjects)\u003c/b\u003e: This group had unexpected persisting disease and a difficult to interpret postoperative MRI. To evaluate remission chances of revision surgery, FET-PET/MRI\u003csup\u003eCR\u003c/sup\u003e was used to differentiate between residual adenoma and postoperative changes.\u003c/p\u003e\u003cp\u003e \u003cb\u003eCare trajectory 2: FET-PET/MRI\u003c/b\u003e \u003csup\u003e \u003cb\u003eCR\u003c/b\u003e \u003c/sup\u003e \u003cb\u003eto revisit (surgical) treatment options because of non-control or intolerance of medical treatment (5 subjects)\u003c/b\u003e: In this group, typically there was a need to reconsider surgical options because of insufficient biochemical and clinical control under maximal tolerated medical therapy, but no (clear) remnant adenoma, or multiple possible foci, on MRI after shrinkage and/or previous surgery. Either the first surgery and imaging were long ago or tumors at diagnosis were not as clear as in group 1. For the patients that were operated previously, the remission chance of prior surgery(s) was retrospectively estimated as possible or unlikely. To revisit (surgical) treatment options FET-PET/MRI\u003csup\u003eCR\u003c/sup\u003e was performed.\u003c/p\u003e\u003cp\u003eSince these care trajectories have differences in characteristics, medical need, \u003cem\u003ea priori\u003c/em\u003e probabilities and outcomes, we describe the groups separately in addition to describing the total cohort. We report on the decision-making process and outcomes.\u003c/p\u003e\u003cp\u003eImaging details\u003c/p\u003e\u003cp\u003e \u003cstrong\u003eMRI\u003c/strong\u003e \u003c/p\u003e\u003cp\u003e All MR imaging acquired at our institution was performed on an Achieva 3.0 T TXMR system (Philips Healthcare, Best, The Netherlands) using a commercial 32-channel head coil, according to our local MR pituitary protocol as previously described.(\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e) Briefly, the protocol consisted of coronal and sagittal T1-weighted turbo spin echo images (T1w TSE, with a slice thickness of 3 mm), and coronal T2 weighted TSE (T2w, slice thickness 3 mm) imaging of the sella region before intravenous (i.v.) contrast administration, dynamic coronal T1 weighted fast field echo (T1w FFE, slice thickness 1.5 mm) imaging of the sella during i.v. administration, coronal and sagittal T1w TSE imaging of the sella after i.v. contrast administration. When appropriate, an additional post-contrast axial 3D T1w FFE of the whole brain was acquired (resolution 1 x 1 mm, 1 mm slice thickness) in the same frame of reference as the pituitary sequences.\u003c/p\u003e\u003cp\u003e \u003cstrong\u003ePET-CT acquisition with \u003csup\u003e18\u003c/sup\u003eF-FET (FET-PET/CT)\u003c/strong\u003e \u003c/p\u003e\u003cp\u003e All PET acquisitions were performed according to the European Association of Nuclear Medicine (EANM) guidelines for brain tumor imaging using labelled amino acid analogues.(\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e) Patients were instructed to fast for at least 6 hours prior to the PET acquisition. O-(2-[18F]-fluoroethyl)-L-tyrosine (\u003csup\u003e18\u003c/sup\u003eF-FET), was synthesized in compliance with good manufacturing practice at the Radionuclide Centre of the Amsterdam University Medical Centre (Amsterdam UMC) location VU University Medical Centre (VUMC), Amsterdam, the Netherlands. PET-CT scans were acquired at our own institution using a hybrid PET/CT system (Vereos, Philips Healthcare, Best, The Netherlands). A standard dose of 200 MBq \u003csup\u003e18\u003c/sup\u003eF-FET was injected intravenously. After injection of the radiopharmaceutical a low-dose CT of the head (220 mAs, 140 kV, 0.5 s rotation, 0.984 mm pitch, 1 mm slice thickness) was acquired, followed by dynamic PET acquisition of the brain up to 50 minutes after injection (start approx. 5 minutes after injection, 5-min acquisition frames).\u003c/p\u003e\u003cp\u003eThe scan was performed after withdrawal of somatostatin receptor ligands (SRL), typically for 3 months or more, however in cases with clearly active disease shorter withdrawal (minimum of 1 month) was allowed. Pegvisomant, acting peripherally, does not affect the scan result and can be continued.\u003c/p\u003e\u003cp\u003e \u003cb\u003eImage processing and co-registration with MRI (FET-PET/MRI\u003c/b\u003e \u003csup\u003e \u003cb\u003eCR\u003c/b\u003e \u003c/sup\u003e \u003cb\u003e)\u003c/b\u003e: Summation images (10–30 min and 20–40 min after injection) were used for co-registration with MRI, clinical reading, and calculation of semiquantitative uptake parameters. Co-registration with MRI was performed in our hospital using IntelliSpace Portal version 10 (ISP, Philips Healthcare) as described earlier.(\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e) Tyrosine uptake maps were individually thresholded to the corresponding background (cerebellar) uptake. Maximal adenoma-to-background ratio (TBR\u003csub\u003emax\u003c/sub\u003e) was calculated as a ratio in relation to the cerebellum (used as reference brain tissue): max standardized uptake value (SUV\u003csub\u003emax\u003c/sub\u003e) adenoma / mean standardized uptake value (SUV\u003csub\u003emean\u003c/sub\u003e) cerebellum.\u003c/p\u003e\u003cp\u003eAll MRI images were independently reviewed by experienced neuroradiologists on dedicated PACS workstations using Sectra IDS7 software (Sectra Imtec AB, Linköping, Sweden) without knowledge of the PET findings. The absence or presence of cavernous sinus invasion was defined according to modified Knosp criteria.(\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e) The co-registered images were qualitatively and semi-quantitatively reviewed by an experienced nuclear medicine physician and discussed by the multidisciplinary team as described above.\u003c/p\u003e\u003cp\u003eStudy parameters and outcomes\u003c/p\u003e\u003ch2\u003eClinical characteristics\u003c/h2\u003e\u003cp\u003eData on patient characteristics (e.g. age, sex), disease characteristics (e.g. clinical symptoms, nadir GH and IGF-1 levels, duration of disease, previous treatments), and tumor characteristics (e.g. size and invasion) at different time points (at diagnosis, before FET-PET/MRI\u003csup\u003eCR\u003c/sup\u003e, after FET-PET/MRI\u003csup\u003eCR\u003c/sup\u003e guided TSS) were extracted from the electronic patient records. To correlate the TBR\u003csub\u003emax\u003c/sub\u003e with disease activity, the last IGF-1 value before FET-PET/MRI\u003csup\u003eCR\u003c/sup\u003e measured at least 6 months after previous surgery and before starting pegvisomant was used.\u003c/p\u003e\u003ch2\u003ePre-operative assessment\u003c/h2\u003e\u003cp\u003eThe intended effect of surgery was either 1) biochemical remission (total resection), 2) debulking to achieve clinically significant tumor reduction for medication reduction, radiation field reduction and/or symptom relief, or 3) primarily obtaining tissue for diagnosis.\u003c/p\u003e\u003cp\u003eA priori estimation of chances for achieving the intended effect and complications: before and after FET-PET/MRI\u003csup\u003eCR\u003c/sup\u003e an estimate was made of the chance of achieving the intended effect and risks by the neurosurgeon and endocrinologist. The estimated chance of was divided into 5 classes: very unlikely (~ 0 to ~ 20%), unlikely (~ 21 to ~ 40%), possibly (~ 41 to ~ 60%), likely (~ 61 to ~ 80%), and very likely ( \u0026gt; ~ 81%). The estimated chance of long-term risks, mainly determined by the risk of permanent pituitary deficiencies, was divided into 3 classes: low ( \u0026lt; ~ 2%), moderate (~ 2 to ~ 5%), and high ( \u0026gt; ~ 5%).\u003c/p\u003e\u003ch2\u003ePost-operative assessment\u003c/h2\u003e\u003cp\u003ePatients were scored based on intended effect achieved or not, e.g. biochemical remission/total resection or debulking/partial resection. Biochemical remission was defined as adequate suppression of GH after glucose load (\u0026lt; 0.4 ug/l) and/or normalization of the IGF-1 level ( \u0026lt; + 2 SD) at 6 months postoperatively without the need for adjunctive medical therapy. Additionally, clinical improvement was recorded, defined as improved GH/IGF-1 levels with or without lower doses of medication and clinical improvement of the patient (e.g. less symptoms, or less severe symptoms). Discrepancies in biochemical values were evaluated by the endocrine team, and included repeat measurements, and clinical symptomatology.\u003c/p\u003e\u003cp\u003eComplications were defined as 1) all clinically relevant, including transient, complications (e.g. cerebrospinal fluid (CSF) leakage, reoperation because of bleeding, CSF leakage or epistaxis, re-admission for hyponatremia (due to SIADH) or other causes (e.g. meningitis, transient pituitary insufficiency including AVP deficiency (AVPD)), and as 2) permanent complications at 6 months excluding the transient ones (e.g. persistent AVPD and/or anterior pituitary hormone deficiency, persistent nerve damage).\u003c/p\u003e\u003cp\u003eFurthermore, we used integrated outcome squares, an outcome integration model developed in our team. This method enables integrating intended and adverse effects, ranging from good to poor reflected by four integrated outcome quadrants (IOQ's). Here the IOQ is composed by preoperative goal (total resection or debulking) versus permanent complication: IOQ-1 = good outcome (intended effect achieved, without permanent complications), IOQ-2 = intermediate outcome (intended effect achieved, with permanent complications), IOQ-3 = intermediate outcome (intended effect not achieved, without permanent complications), IOQ-4 = poor outcome (intended effect not achieved, with permanent complications).(\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e)\u003c/p\u003e\u003cp\u003eStatistics\u003c/p\u003e\u003cp\u003eWe report descriptive statistics. Data are presented as median (minimum-maximum). Correlation between TBR\u003csub\u003emax\u003c/sub\u003e and IGF-1 levels were analyzed using Spearman correlation.\u003c/p\u003e"},{"header":"Results","content":"\u003cp\u003eClinical characteristics (Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e)\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\u003ePatients\u0026rsquo; characteristics\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"12\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" 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=\"char\" char=\".\" 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=\"char\" char=\".\" class=\"colspec\" colname=\"c7\" colnum=\"7\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c8\" colnum=\"8\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c9\" colnum=\"9\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c10\" colnum=\"10\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c11\" colnum=\"11\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c12\" colnum=\"12\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eNumber of patients\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eAge in yr (range)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eSex (M:F)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003eDuration of disease in yr (range)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c6\"\u003e \u003cp\u003eIGF1 SD at diagnosis\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c7\"\u003e \u003cp\u003eGlucose mediated GH nadir at diagnosis\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c8\"\u003e \u003cp\u003eLast IGF1 SD before FET-PET/MRI\u003csup\u003eCR\u003c/sup\u003e\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c9\"\u003e \u003cp\u003eIGF1 SD before FETPET guided surgery (range)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c10\"\u003e \u003cp\u003eMacro:\u003c/p\u003e \u003cp\u003eMicroadenoma\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c11\"\u003e \u003cp\u003ePrior surgery\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c12\"\u003e \u003cp\u003ePrior medication (n)\u003c/p\u003e \u003cp\u003eDuration in mo (range)\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eAll\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e10\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e52 (23\u0026ndash;60)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e4:6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e2.6 (1.3\u0026ndash;21)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e+\u0026thinsp;10.0 SD (3.7\u0026ndash;14.5)\u003csup\u003e#\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e8.4 (0.5\u0026ndash;24)\u003csup\u003e^\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e+\u0026thinsp;3.7 (3.0-4.8)\u003csup\u003e###\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e+\u0026thinsp;3.7 (3.0-4.8)*\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e7:2 (+\u0026thinsp;1 no substrate)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c11\"\u003e \u003cp\u003e9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c12\"\u003e \u003cp\u003e10\u003c/p\u003e \u003cp\u003e12 (6-252)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eGroup 1\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e40 (23\u0026ndash;54)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e2:3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e1.8 (1.3\u0026ndash;3.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e+\u0026thinsp;10.2 SD (7.2\u0026ndash;14.5)\u003csup\u003e##\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e8.4 (3.3\u0026ndash;58)\u003csup\u003e^^\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e+\u0026thinsp;3.5 (3.0-4.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e+\u0026thinsp;3.5 (3.0-4.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e4:1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c11\"\u003e \u003cp\u003e5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c12\"\u003e \u003cp\u003e5\u003c/p\u003e \u003cp\u003e6 (3\u0026ndash;13)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eGroup 2\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e57 (35\u0026ndash;60)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e2:3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e3.3 (1.5\u0026ndash;21)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e+\u0026thinsp;4.5 SD (3.7\u0026ndash;10)\u003csup\u003e###\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e11.4 (0.5\u0026ndash;24)\u003csup\u003e^^^\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e+\u0026thinsp;3.8 (3.6\u0026ndash;3.8)\u003csup\u003e###\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e+\u0026thinsp;4.2 (3.6\u0026ndash;4.8)*\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e3:1 (+\u0026thinsp;1 no substrate)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c11\"\u003e \u003cp\u003e4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c12\"\u003e \u003cp\u003e5\u003c/p\u003e \u003cp\u003e40 (6-252)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"12\"\u003eMedian (range)\u003c/td\u003e\u003c/tr\u003e \u003ctr\u003e\u003ctd colspan=\"12\"\u003eF: female, GH: growth hormone, M: male, mo: months, n: number, SD: standard deviation, yr: years\u003c/td\u003e\u003c/tr\u003e \u003ctr\u003e\u003ctd colspan=\"12\"\u003e# 3 missing (S1, S5, S9). ## 1 missing (S9). ### 2 missing (S1, S5).\u003c/td\u003e\u003c/tr\u003e \u003ctr\u003e\u003ctd colspan=\"12\"\u003e^ 2 missing (S1, S6). ^^ 1 missing (S6). ^^^ 1 missing (S1).\u003c/td\u003e\u003c/tr\u003e \u003ctr\u003e\u003ctd colspan=\"12\"\u003e* without S7 (not operated).\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eTen patients (4 males and 6 females) with a median age of 52 years (range 23\u0026ndash;60 years) were included in this study (Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). They were diagnosed with acromegaly with a median of 2.6 years prior to FET-PET/MRI\u003csup\u003eCR\u003c/sup\u003e (range 1.3\u0026ndash;22 years). At diagnosis, 1 patient had no visible lesion, 2 patients had a microadenoma, and 7 patients had a macroadenoma on MRI scan. Recent MRI before FET-PET/MRI\u003csup\u003eCR\u003c/sup\u003e showed a suspected remnant adenoma in 6 subjects albeit difficult to delineate and discriminate from postoperative changes (3, 4, 6 (group 1); 1, 5, 8 (group 2)), while in 4 cases (2, 9 (group 1); 7, 10 (group 2)) no clear (remnant) lesion was identified.\u003c/p\u003e \u003cp\u003eSeven patients were on pegvisomant monotherapy at the time of FET-PET/MRI\u003csup\u003eCR\u003c/sup\u003e, 1 patient had combination therapy with pegvisomant and SRL, where SRL was withdrawn prior to the scan until his IGF-1 was considered high enough (+\u0026thinsp;3.6 SD, case 1), and 2 patients were without medication at the time of FET-PET/MRI\u003csup\u003eCR\u003c/sup\u003e (9 and 10). The median last IGF-1 SD value before FET-PET/MRI\u003csup\u003eCR\u003c/sup\u003e was +\u0026thinsp;3.7 (3.0-4.4).\u003c/p\u003e \u003cp\u003eFET-PET/MRI\u003csup\u003eCR\u003c/sup\u003e showed suspicious tracer uptake in all 10 patients. In 5 patients (50%) FET-PET/MRI\u003csup\u003eCR\u003c/sup\u003e findings were completely concordant with conventional MRI (cases 1, 3, 4, 6, 8), and in 1 patient (case 5) partially concordant. In 4 subjects (\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e, \u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e, \u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e and \u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e), FET-PET/MRI\u003csup\u003eCR\u003c/sup\u003e identified new foci of suspicious uptake, not corresponding to conventional MRI. There was no correlation between the TBR\u003csub\u003emax\u003c/sub\u003e and the last IGF-1 value before FET-PET/MRI\u003csup\u003eCR\u003c/sup\u003e (R\u003csup\u003e2\u003c/sup\u003e\u0026thinsp;=\u0026thinsp;0.121, p\u0026thinsp;=\u0026thinsp;0.399).\u003c/p\u003e \u003cp\u003eIn 7 of 9 (78%) operated patients FET-PET/MRI\u003csup\u003eCR\u003c/sup\u003e findings were confirmed intraoperatively, and in 6 of 9 (67%) patients also histologically. IGF-1 decreased significantly in 8 of 9 (89%) operated patients (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003ePerformance of FET-PET/MRI\u003csup\u003eCR\u003c/sup\u003e in the predetermined care trajectories\u003c/p\u003e \u003cp\u003eSee Tables\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e and \u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e, and Online Resource 1 for all case descriptions.\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\u003eOverall outcomes and per group.\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"12\"\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 \u003cdiv align=\"left\" class=\"colspec\" colname=\"c8\" colnum=\"8\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c9\" colnum=\"9\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c10\" colnum=\"10\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c11\" colnum=\"11\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c12\" colnum=\"12\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eSurgery\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eGoal of surgery\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eIntraoperative positive findings\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003eConfirmative histology\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c6\"\u003e \u003cp\u003eComplications\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c7\"\u003e \u003cp\u003eClinical improvement\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c8\"\u003e \u003cp\u003eBiochemical remission\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c9\"\u003e \u003cp\u003ePostoperative \u003c/p\u003e \u003cp\u003eIGF-1 (x ULN)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c10\"\u003e \u003cp\u003eFurther treatment\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c11\"\u003e \u003cp\u003eIOQ\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c12\"\u003e \u003cp\u003eFETPET helpful?\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eAll\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e9 of 10\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e6 remission\u003c/p\u003e \u003cp\u003e2 debulking\u003c/p\u003e \u003cp\u003e1 diagnosis\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e7 yes\u003c/p\u003e \u003cp\u003e1 no\u003c/p\u003e \u003cp\u003e1 ?\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e7 positive*\u003c/p\u003e \u003cp\u003e1 uncertain\u003c/p\u003e \u003cp\u003e1 negative\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e2 SIADH\u003c/p\u003e \u003cp\u003e1 CSF leak\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e9 yes\u003csup\u003e#\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e3 complete\u003c/p\u003e \u003cp\u003e5 improved\u003csup\u003e#\u003c/sup\u003e\u003c/p\u003e \u003cp\u003e1 unchanged\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e \u003cp\u003e1.3 (0.7\u0026ndash;1.9)\u003csup\u003e#\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e6 no\u003c/p\u003e \u003cp\u003e2 med\u003c/p\u003e \u003cp\u003e1 med\u0026thinsp;+\u0026thinsp;RTP\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003e6 IOQ-1\u003c/p\u003e \u003cp\u003e3 IOQ-3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e \u003cp\u003e9 yes\u003c/p\u003e \u003cp\u003e1 no\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eGroup 1\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e5 of 5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e5 remission\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e4 yes\u003c/p\u003e \u003cp\u003e1 no\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e4 positive\u003c/p\u003e \u003cp\u003e1 negative\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e1 SIADH\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e5 yes\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e3 complete\u003c/p\u003e \u003cp\u003e1 improved\u003c/p\u003e \u003cp\u003e1 unchanged\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e \u003cp\u003e0.8 (0.7\u0026ndash;1.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e4 no\u003c/p\u003e \u003cp\u003e1 med\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003e3 IOQ-1\u003c/p\u003e \u003cp\u003e2 IOQ-3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e \u003cp\u003e4 yes\u003c/p\u003e \u003cp\u003e1 no\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eGroup 2\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e4 of 5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1 remission\u003c/p\u003e \u003cp\u003e2 debulking\u003c/p\u003e \u003cp\u003e1 diagnosis\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e3 yes*\u003c/p\u003e \u003cp\u003e1 uncertain\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e3 positive*\u003c/p\u003e \u003cp\u003e1 uncertain\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e1 SIADH\u003c/p\u003e \u003cp\u003e1 CSF leak\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e4 yes\u003csup\u003e#\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e4 improved\u003csup\u003e#\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e \u003cp\u003e1.3 (1.3\u0026ndash;1.9)\u003csup\u003e#\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e2 no\u003c/p\u003e \u003cp\u003e1 med\u003c/p\u003e \u003cp\u003e1 med\u0026thinsp;+\u0026thinsp;RTP\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003e3 IOQ-1\u003c/p\u003e \u003cp\u003e1 IOQ-3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e \u003cp\u003e5 yes\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"12\"\u003eMedian (range)\u003c/td\u003e\u003c/tr\u003e \u003ctr\u003e\u003ctd colspan=\"12\"\u003eCSF: cerebrospinal fluid, IOQ: integrated outcome squares, Med: medication, SIADH: syndrome of inappropriate ADH, RTP: radiotherapy, ULN: upper limit of normal.\u003c/td\u003e\u003c/tr\u003e \u003ctr\u003e\u003ctd colspan=\"12\"\u003e* 1 positive histology of FET-negative lesion (case 5)\u003c/td\u003e\u003c/tr\u003e \u003ctr\u003e\u003ctd colspan=\"12\"\u003e# Subject 8: clinically and biochemically (IGF-1 1.3x ULN) improved with postoperatively Pegvisomant 30mg 5 times weekly, as compared to severe headache and IGF-1 1.9 x ULN preoperatively with the same dose of Pegvisomant.\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003e \u003cem\u003eCare trajectory 1: FET-PET/MRI\u003c/em\u003e \u003csup\u003e \u003cem\u003eCR\u003c/em\u003e \u003c/sup\u003e \u003cem\u003eto optimize outcome of revision surgery following unexpectedly unsuccessful prior surgery.\u003c/em\u003e\u003c/p\u003e \u003cp\u003e \u003cb\u003eBefore FET-PET/MRI\u003c/b\u003e \u003csup\u003e \u003cb\u003eCR\u003c/b\u003e \u003c/sup\u003e. Five patients with inconclusive findings on postoperative conventional MRI were included in this group (subject 2, 3, 4, 6, 9) (median duration of disease 1.8 years (range 1.8\u0026ndash;3.1 years)). Four patients had a macroadenoma at the time of primary diagnosis (\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e, \u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e, \u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e, \u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e), and the other patient (subject 4) had a large microadenoma with close relation to the cavernous sinus without invasion. All had undergone surgery once or twice, 4 patients in our center and 1 patient (case 9) in another academic center (first surgery for cases 2 and 3, and second surgery for cases 4, 6 and 9), with a retrospectively likely estimated chance of remission. Thus, postoperative persistent disease was unexpected and not well understood based on the preoperative radiological characteristics in these 5 patients. All subjects had been treated shortly with medication, predominantly pegvisomant to not affect tumor volume and functional imaging (median duration 6 months (range 3\u0026ndash;16 months) as a bridging therapy until there was a clear indication to proceed with revision surgery in case a lesion could be identified.\u003c/p\u003e \u003cp\u003e \u003cb\u003eFET-PET/MRI\u003c/b\u003e \u003csup\u003e \u003cb\u003eCR\u003c/b\u003e \u003c/sup\u003e \u003cb\u003e(\u003c/b\u003eFigs.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003e and \u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e4\u003c/span\u003e\u003cb\u003e).\u003c/b\u003e The median last IGF-1 SD value before FET-PET/MRI\u003csup\u003eCR\u003c/sup\u003e was +\u0026thinsp;3.5 (3.0-4.4). FET-PET/MRI\u003csup\u003eCR\u003c/sup\u003e revealed suspicious uptake in the sellar region for all 5 patients, corresponding to the possible lesion on conventional MRI in 3 patients (\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e, \u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e, \u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e), and non-corresponding in 2 patients (case 2 and 9) without a clear substrate on MRI.\u003c/p\u003e\u003cp\u003e \u003cb\u003eFET-PET/MRI\u003c/b\u003e \u003csup\u003e \u003cb\u003eCR\u003c/b\u003e \u003c/sup\u003e \u003cb\u003eguided treatment decision.\u003c/b\u003e Revision surgery was chosen as treatment for all 5 patients with intended biochemical remission, with a possibly estimated probability and low (4 patients: 3, 4, 6, 9) or moderate (1 patient: case 2) estimated risk for complications.\u003c/p\u003e \u003cp\u003e \u003cb\u003eOutcome after FET-PET/MRI\u003c/b\u003e \u003csup\u003e \u003cb\u003eCR\u003c/b\u003e \u003c/sup\u003e \u003cb\u003eguided surgery.\u003c/b\u003e Suggestive adenoma was found during surgery in 4 cases (\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e, \u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e, \u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e, \u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e), all with positive histology. In these 4 cases, findings were consistent with functional imaging. In the other case (case 2), the area with increased tracer uptake was inspected during surgery and after considering it safe, was resected, with negative histology. Thus, in 4 of 5 (80%) operated patients FET-PET/MRI\u003csup\u003eCR\u003c/sup\u003e findings were intraoperatively and histologically confirmed. One patient had a transient complication: SIADH (case 4: moderate estimated risk). No permanent complications occurred.\u003c/p\u003e \u003cp\u003eAll patients showed clinical improvement. Complete biochemical remission was achieved in 3 patients (\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e, \u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e, \u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e) (60%) (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e). Biochemistry improved in subject 6. In subject 2 IGF-1 did not clearly improve or normalize, but his symptoms (severe headache) did, and postoperative MRI showed that the suspected lesion was removed, and he has an ongoing normal glucose suppression of serum GH. One patient restarted with medication during postoperative follow up for elevated IGF-1 in the context of normal glucose-mediated GH suppression (case 6).\u003c/p\u003e \u003cp\u003eBased on the preoperative goal, an IOQ-1 (goal set preoperatively achieved without permanent complications) was achieved in 3/5 (60%) patients (cases 3, 4, 9) and an IOQ-3 (goal not achieved, no permanent complications) in 2/5 patients (cases 2, 6) at 6 months postoperatively.\u003c/p\u003e \u003cdiv id=\"Sec6\" class=\"Section2\"\u003e \u003ch2\u003eCare trajectory 2: FET-PET/MRI\u003csup\u003eCR\u003c/sup\u003e to revisit treatment options because of non-control or drug intolerance\u003c/h2\u003e \u003cp\u003e \u003cb\u003eBefore FET-PET/MRI\u003c/b\u003e \u003csup\u003e \u003cb\u003eCR\u003c/b\u003e \u003c/sup\u003e. This group is represented by 5 patients. All had persistent uncontrolled disease at inclusion in this study and were under maximal tolerable doses of chronic medication (SRL and pegvisomant) (median duration of disease 3.3 years (range 1.5\u0026ndash;21 years); median duration of medication 40 months (range 6-252 months; case 7\u0026thinsp;=\u0026thinsp;6 months, other cases\u0026thinsp;\u0026ge;\u0026thinsp;31 months)), and with clinical high need for alternative treatment. Four patients had been operated before, 2 of which more than once. Conventional MRI just before FET-PET/MRI\u003csup\u003eCR\u003c/sup\u003e was difficult to interpret due to postoperative changes (case 1), the absence of a clear (remnant) adenoma (cases 7, 10) or possible multifocality (cases 5, 8), but none had evidence of a tumor without the prospect of total resection at any stage during treatment.\u003c/p\u003e \u003cp\u003eIn detail, for case 1, with an initial macroadenoma without cavernous sinus invasion, a possible remnant was described on MRI, but was difficult to interpret due to an unavailable baseline MRI and postoperative changes after 3 surgeries. Case 5 had multiple possible remnant lesions of an initial macroadenoma with cavernous sinus invasion (Knosp 3A) after surgery and long-term medical treatment. Case 7 had postoperative changes and no certain remnant of an original macroadenoma. She was retrospectively estimated as unlikely remission chance at prior surgery given cavernous sinus invasion (Knosp 3A with a small remnant between the limbs of the carotid siphon). In case 8, MRI before FET-PET/MRI\u003csup\u003eCR\u003c/sup\u003e showed two possible small foci \u0026ndash; one on the left side of the sella, which was described at diagnosis and was targeted during first surgery elsewhere (retrospectively highly suggestive for a Rathke\u0026rsquo;s cleft cyst (RCC)) and a second one on the right side of the sella. Imaging interpretation was further complicated because of a suboptimal baseline (preoperative) MRI-scan. Case 10 was not operated before due to lack of a visible lesion on baseline MRI and was therefore treated with primary medical treatment.\u003c/p\u003e \u003cp\u003e \u003cb\u003eFET-PET/MRI\u003c/b\u003e \u003csup\u003e \u003cb\u003eCR\u003c/b\u003e \u003c/sup\u003e \u003cb\u003e(\u003c/b\u003eFigs.\u0026nbsp;\u003cspan refid=\"Fig5\" class=\"InternalRef\"\u003e5\u003c/span\u003e and \u003cspan refid=\"Fig6\" class=\"InternalRef\"\u003e6\u003c/span\u003e\u003cb\u003e).\u003c/b\u003e The median last IGF-1 SD value before FET-PET/MRI\u003csup\u003eCR\u003c/sup\u003e was +\u0026thinsp;3.8 (3.7\u0026ndash;3.8) (case 1 and 5 excluded due to no known values without use of pegvisomant). Case 1 also used SRL, all other cases had used SRL (case 5 both first and second generation SRL) in the past which was stopped because of side effects. FET-PET/MRI\u003csup\u003eCR\u003c/sup\u003e showed increased tracer uptake in all 5 patients: fully concordant with MRI in 2 patients (\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e), partially concordant in 1 patient (case 5: 2 of 5 possible lesions positive), and 2 were discordant (case 7: positive lesion on the right not visible on MRI; 10: no lesion on MRI, positive on FET-PET/MRI\u003csup\u003eCR\u003c/sup\u003e).\u003c/p\u003e \u003cp\u003e \u003cb\u003eFET-PET/MRI\u003c/b\u003e \u003csup\u003e \u003cb\u003eCR\u003c/b\u003e \u003c/sup\u003e \u003cb\u003eguided treatment decision.\u003c/b\u003e Surgical re-exploration was performed in 4 patients (\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e, \u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e, \u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e), and 1 patient underwent radiation therapy (case 7). Regarding case 7, FET uptake was diffusely increased in the right cavernous sinus reconfirming the impossibility for surgical cure. For the 4 surgical patients, the goal of surgery varied between: achieving biochemical remission (case 8), debulking for medication reduction, radiation field reduction and/or symptom relief (cases 1, 5), and obtaining tissue for diagnosis (case 10), all estimated as possibly. The risk of complications was estimated as low (case 10), moderate (cases 1, 5), and high (case 8).\u003c/p\u003e \u003cp\u003e \u003cb\u003eOutcome after FET-PET/MRI\u003c/b\u003e \u003csup\u003e \u003cb\u003eCR\u003c/b\u003e \u003c/sup\u003e \u003cb\u003eguided surgery.\u003c/b\u003e Suggestive (remnant) adenoma was found during surgery in 3 cases (\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e, \u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e), 2 of them with positive histology (\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e, \u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e) and 1 with uncertain histology (case 1). In these 3 cases, findings were consistent with functional imaging. In the other operated patient (case 5), a FET-PET/MRI\u003csup\u003eCR\u003c/sup\u003e negative lesion was histologically positive. Thus, 3 of 4 (75%) operated patients had confirmative histology (one patient (case 5) with non-concordant FET-PET/MRI\u003csup\u003eCR\u003c/sup\u003e).\u003c/p\u003e \u003cp\u003eSubject 1: debulking was performed as expected with clinical and biochemical improvement such that he could lower his medication immediately post-surgery, which was considered of added value, and then underwent radiotherapy 6 months later as anticipated. Subject 5: debulking was performed as expected, with clinical and biochemical improvement (glucose-mediated GH nadir normalized (0.37 mcg/L); IGF-1\u0026thinsp;+\u0026thinsp;2.8 SD (1.4x ULN)) and because of no symptomatology he is still followed without treatment (last follow up almost 2 years postoperative). Subject 8 was a case with preoperative normal glucose-mediated GH suppression but elevated IGF-1 and severe symptoms, irresponsive to medical treatment. Medical treatment failed to normalize IGF-1 and previous surgery had negative pathology. A good outcome of surgery was the histological confirmation of acromegaly. Postoperative IGF-I improved but did not normalize, and because her symptoms (severe headache) were not reduced, we restarted on pegvisomant without awaiting the time needed for interpretable IGF-1. Now she has normalized at a lower dose of pegvisomant than preoperatively (210 vs 150 mg/wk) in combination with a low-carbohydrate diet. In subject 10 there was a need for surgical exploration to confirm acromegaly because of an uncertain diagnosis, inconclusive small lesion on MRI, and side effects on both SRL and pegvisomant. Surgical findings and histology were positive, confirming the diagnosis of acromegaly. She experienced clinical improvement, and biochemistry normalized, and she is now followed without need for medication.\u003c/p\u003e \u003cp\u003eTwo patients had transient complications: SIADH (case 8 (high estimated risk)) and CSF leakage needing a re-operation (case 5 (low estimated risk)). No permanent complications occurred.\u003c/p\u003e \u003cp\u003eThus, complete biochemical remission was not achieved in any of the patients (as was anticipated in 3 of the 4 operated patients). However, biochemistry improved in all 4 subjects (\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e, \u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e, \u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e) (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e) and 3 out of 4 showed clinical improvement. (Additional) added value was confirmation of the histological diagnosis of acromegaly in subjects 8 and 10 (primary intended effect) with preoperative diagnostic uncertainty due to discrepant values (normal GH nadir after glucose loading, increased IGF-1). Based on the preoperative goal, an IOQ-1 (goal set preoperatively achieved without permanent complications) was achieved in 3 patients (\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e, \u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e) (75%) and an IOQ-3 (goal not achieved, no permanent complications) in 1 patient (case 8) at 6 months postoperatively.\u003c/p\u003e \u003c/div\u003e"},{"header":"Discussion","content":"\u003cp\u003eThis is the first case series reporting on the use of FET-PET/MRI\u003csup\u003eCR\u003c/sup\u003e in the care trajectory of patients with persistent acromegaly. The reported findings illustrate how \u003csup\u003e18\u003c/sup\u003eF-FET can provide added value in selected complex cases, informing the preoperative decision-making process in a multidisciplinary setting of a center of expertise.\u003c/p\u003e \u003cp\u003eFunctional imaging with \u003csup\u003e11\u003c/sup\u003eC-methionine co-registered with MRI has proven added value for localizing tumor remnants in functioning pituitary adenomas.(\u003cspan additionalcitationids=\"CR16 CR17\" citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e) (\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e, \u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e) Due to logistical challenges in securing a reliable source of \u003csup\u003e11\u003c/sup\u003eC-methionine, we initiated the use of \u003csup\u003e18\u003c/sup\u003eF-fluoro-ethyl-tyrosine (\u003csup\u003e18\u003c/sup\u003eF-FET) in September 2020, an AA analogue with a longer half-life and thus more suitable for clinical application in our institution. \u003csup\u003e18\u003c/sup\u003eF-FET has not yet proven clinical efficacy in pituitary adenomas except for a retrospective case series of FET-PET/MRI\u003csup\u003eCR\u003c/sup\u003e in Cushing\u0026rsquo;s disease.(\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e) However, a key rationale for its use is the fact that FET and MET share the same uptake mechanism and a close correlation has been found between FET and MET uptake in primary brain tumors (e.g. gliomas and metastases),(\u003cspan additionalcitationids=\"CR23\" citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e). Although FET and MET share the same molecular mechanism to enter the cell (via the L-type amino acid transporter 1 (LAT1)),(\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e) in contrast to MET, FET is neither metabolized nor incorporated into proteins.\u003c/p\u003e \u003cp\u003eHere, we report our first results and our learning curve, building on our previous experience with MET-PET/MRI\u003csup\u003eCR\u003c/sup\u003e. We incorporated FET-PET/MRI\u003csup\u003eCR\u003c/sup\u003e in the clinical decision-making process in the same way as MET-PET/MRI\u003csup\u003eCR\u003c/sup\u003e, in a dedicated care path with repeat MDT discussions, as described in the Methods. We advocate for restrictive use because of costs and time-consuming interpretation. Therefore, only cases in which the team agrees on its added value, with a clearly formulated clinical question, were referred for FET-PET/MRI\u003csup\u003eCR\u003c/sup\u003e. Evaluation of all available imaging was thoroughly discussed, to prevent information loss between MD partners and the surgeons performing the intervention. We believe that, irrespective of the type of functional imaging used, this setup is crucial for the potential impact of functional imaging.\u003c/p\u003e \u003cp\u003eIn our practice, two typical patient journeys are considered for functional imaging as highlighted in this case series. The first group typically had a non-invasive (Knosp\u0026thinsp;\u0026lt;\u0026thinsp;2) clear adenoma at preoperative imaging such that not obtaining remission at first surgery was unexpected. Due to postoperative tissue remodeling, the postoperative MRI is usually more difficult to interpret. Therefore, many cases will not be offered revision surgery as was the case in our team prior to the introduction of functional imaging. Nowadays, with the implementation of functional imaging in selected cases, we try to understand the lack of success, and use this new modality to set optimal conditions for a reintervention, which seems to be a successful strategy based on the findings of this study. Clinical questions in these cases were assessment of extension and invasion, confirmation of the primary culprit lesion, discrimination between postoperative changes and tumor remnants. In those postoperative patients, FET-PET/MRI\u003csup\u003eCR\u003c/sup\u003e highlighted all tumors, in 80% FET-PET/MRI\u003csup\u003eCR\u003c/sup\u003e findings were intraoperatively and histologically confirmed, and 60% resulted in total resection without complications.\u003c/p\u003e \u003cp\u003eThe other group is more heterogenous as they were treated longer ago, had lower quality baseline imaging and / or a trajectory of medical treatment with shrinkage that may further complicate imaging interpretation. This group had a high need for alternative treatment. Four patients in this group were already operated (more than) once. Post medication changes (e.g. due to direct anti-tumor effects of somatostatin analogs, dopamine agonists or pasireotide (case 5))(\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e), may have resulted in scattered small remnants, or even absence of a clear remnant. Initial images prior to any intervention, were typically of limited quality, and added to the uncertainty about the location and extent of the original tumor. Nevertheless, FET-PET/MRI\u003csup\u003eCR\u003c/sup\u003e was positive in all cases, with complete concordance with MRI in 2 cases, partial in 1 case and no (negative MRI) concordance in 2 cases. In 75% of cases, FET-PET/MRI\u003csup\u003eCR\u003c/sup\u003e findings were intraoperatively and histologically confirmed. In one patient, FET-PET/MRI\u003csup\u003eCR\u003c/sup\u003e supported our decision to refrain from further surgery. In another patient, FET-PET/MRI\u003csup\u003eCR\u003c/sup\u003e assisted in surgical mapping of multiple possible foci. In this patient, a FET-negative lesion was found to be histologically positive, with no clear explanation. Additional added value was confirmation of the diagnosis of acromegaly in 2 subjects with difficult preoperative biochemistry. In 3 of the 4 operated patients after FET-PET/MRI\u003csup\u003eCR\u003c/sup\u003e the intended outcome (IOQ-1) was achieved, and no permanent complications occurred.\u003c/p\u003e \u003cp\u003eIt is important to note that FET and MET have distinct metabolic fates, resulting in differences in uptake pattern and distribution over time. FET is an AA analogue which is neither metabolized nor incorporated into proteins, in contrast to MET, which is an essential AA. The L-type AA system is a reversible transport system, and it seems that efflux of nonmetabolized FET occurs from the adenoma tissue, leading to washout of the tracer over time and pooling of FET in the direction of and into the cavernous sinus (Fig.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e4\u003c/span\u003e). Because metabolism is increased in a functional adenoma, the AA transport is expected to be increased as well, resulting in higher tracer uptake at the site of the adenoma. Appropriate timing of PET acquisition after tracer injection is crucial. We have observed that appreciation of the \u0026lsquo;normal\u0026rsquo; biodistribution of FET in the sellar region and its washout is crucial for the interpretation of FET-PET/MRI\u003csup\u003eCR\u003c/sup\u003e images (unpublished clinical observation). Unfortunately, reference data regarding normal appearances of tracer uptake in the cavernous sinus region and pituitary tissue in healthy controls is currently lacking, and the time course for FET uptake over time and wash-out characteristics of the tracer from (different types of) pituitary adenomas is not known. This should be considered for further development of the technique. Another challenge of our approach to only use FET-PET/MRI\u003csup\u003eCR\u003c/sup\u003e as a \u0026lsquo;last resort scan\u0026rsquo; is that we lack reference in case of obvious tumors. When taking these uncertainties into account, we hypothesize that in the situation that both tracers are available MET may be preferred for clinical questions regarding (remnant) lesions close to or in the cavernous sinus. Interestingly, the uptake of FET is lower in the normal pituitary gland compared to MET. Hence, for small, not highly metabolically active (remnant) lesions in the pituitary gland, FET might be advantageous over MET. A current challenge with MET-PET/MRI\u003csup\u003eCR\u003c/sup\u003e is that these small lesions are not easily visible due to lack of contrast with normal gland uptake.\u003c/p\u003e \u003cp\u003eThere were also similarities with MET-PET/MRI\u003csup\u003eCR\u003c/sup\u003e. Both are not useful in cystic lesions due to no or low tracer uptake (i). For both techniques crucial steps are (ii) awareness for technical issues such as co-registration mismatch, (iii) adequate withdrawal of tumor directed drugs, (iv) availability and quality of pituitary MRI at diagnosis (i.e. pre-treatment) is essential for optimal interpretation of the functional scan, (v) implementation and use of this technique requires an MDT setting for dedicated evaluation of added value. Regarding the activity of the adenoma, it is recommended to withdraw somatostatin analogues at least three months prior to functional imaging,(\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e) to ensure activity of the lesion. However, in our patients with small remnants, poor quality of life and a high need for an alternative treatment, the time interval for which SRL withdrawal was considered acceptable was limited and therefore, if needed, pegvisomant was used to bridge the period to scan. Therefore, IGF-1 levels at the time of FET-PET/MRI\u003csup\u003eCR\u003c/sup\u003e were typically only modestly increased, which is an extra challenge for the performance of functional imaging. The fact that TBR\u003csub\u003emax\u003c/sub\u003e did not correlate to IGF-1 levels in our study population may be related to this selected case mix with small remnants and little IGF-I variation. Previous studies on MET report a clear correlation between metabolic activity and serum hormone level (prolactin and growth hormone) and further investigation is needed to assess whether the different metabolic fate of FET compared to MET is another explanation for this lack of correlation when using FET.(\u003cspan additionalcitationids=\"CR32\" citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e)\u003c/p\u003e \u003cp\u003eA further limitation is that we could not compare FET-PET/MRI\u003csup\u003eCR\u003c/sup\u003e to MET-PET/MRI\u003csup\u003eCR\u003c/sup\u003e in the same patient. As already mentioned, FET-PET/MRI\u003csup\u003eCR\u003c/sup\u003e was introduced because of logistical problems. However, as next step it would be worthwhile to investigate which tracer is best applied in which clinical situation.\u003c/p\u003e \u003cp\u003eIn conclusion (Fig.\u0026nbsp;\u003cspan refid=\"Fig7\" class=\"InternalRef\"\u003e7\u003c/span\u003e), functional imaging with FET-PET/MRI\u003csup\u003eCR\u003c/sup\u003e has clear added value in the clinical decision-making process of patients with acromegaly with persisting disease due to small remnants, particularly when MET is not available or in cases with intrasellar disease. We describe our approach where functional imaging is restricted to complex cases. FET-PET/MRI\u003csup\u003eCR\u003c/sup\u003e images differ from MET-PET/MRI\u003csup\u003eCR\u003c/sup\u003e images concerning radiotracer uptake pattern in the sellar and cavernous sinus region, which is clinically relevant for (remnant) lesions in (close relation to) the cavernous sinus. Interpretation of FET-PET/MRI\u003csup\u003eCR\u003c/sup\u003e images is challenging due to the physiological uptake of FET in the adjacent cavernous sinus and its wash out over time from both adenoma tissue and surrounding normal tissue, warranting appropriate timing of PET acquisition. A learning curve of interpretation of physiological distribution of the tracer in the sellar region and surroundings is therefore required. Also, more knowledge needs to be acquired concerning the uptake mechanisms of tyrosine by functional adenoma tissues, as not only cystic lesions are thought to be FET-negative, but apparently also some solid lesions, as was the case in one of the patients (case 5) in this study. Furthermore, a FET-PET/MRI\u003csup\u003eCR\u003c/sup\u003e guided surgical procedure can be safely performed after (multiple) previous surgeries by an experienced surgical team. This makes revisiting surgical options for a group of currently medically treated patients that do not clearly have an inoperable remnant worthwhile.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eDisclosures:\u003c/strong\u003e none of the authors report any disclosures\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgements\u003c/strong\u003e:\u0026nbsp;Mark Gurnell is supported by the NIHR Cambridge Biomedical Research Centre (NIHR203312*).\u003c/p\u003e\u003cp\u003eThe authors thank Anneke M.G. Slats-Steenvoorden (Leiden University Medical Center, Leiden, the Netherlands) for her assistance, all patients, and their referring physicians for their trust in the Leiden Pituitary Center.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthor contributions:\u0026nbsp;\u003c/strong\u003eL.B., M.V., N.B., W.F., I.G. and L.P. contributed to conception and design of the study, the acquisition, analysis, and interpretation of data, and reviewed/edited the manuscript. M.G., I.P. D.M., and T.D. contributed to analysis and interpretation of data, and reviewed/edited the manuscript. L.B., M.V., and D.M. wrote the main manuscript text. I.G., L.P., H.L., B.V. and M.K. interpreted the imaging data. L.P and H.L. prepared figures 3-6. L.B. and N.B. prepared figures 1, 2, and 7. All authors reviewed and approved the final manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eNo funding was received for conducting this study.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConflicts of interest/Competing interests\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors have no conflicts of interest to declare that are relevant to the content of this article.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAvailability of data and material\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eData is provided within the manuscript or supplementary information files\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthics approval\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eData of patients were obtained after a waiver of the medical ethical review was received from our institutional medical ethical review board (G19.011).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent to participate\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eA declaration of non-objection was obtained for review of patients\u0026rsquo; charts.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for publication\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eA declaration of non-objection was obtained.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eLavrentaki A, Paluzzi A, Wass JA, Karavitaki N. 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Endocr Relat Cancer. 2016;23(6):469-80.\u003c/li\u003e\n\u003cli\u003eGiustina A, Barkhoudarian G, Beckers A, Ben-Shlomo A, Biermasz N, Biller B, et al. Multidisciplinary management of acromegaly: A consensus. Rev Endocr Metab Disord. 2020;21(4):667-78.\u003c/li\u003e\n\u003cli\u003ede Vries F, Lobatto DJ, Verstegen MJT, Schutte PJ, Notting IC, Kruit MC, et al. Outcome Squares Integrating Efficacy and Safety, as Applied to Functioning Pituitary Adenoma Surgery. J Clin Endocrinol Metab. 2021;106(9):e3300-e11.\u003c/li\u003e\n\u003cli\u003eMortini P, Barzaghi LR, Albano L, Panni P, Losa M. Microsurgical therapy of pituitary adenomas. Endocrine. 2018;59(1):72-81.\u003c/li\u003e\n\u003cli\u003eNomikos P, Buchfelder M, Fahlbusch R. The outcome of surgery in 668 patients with acromegaly using current criteria of biochemical \u0026apos;cure\u0026apos;. Eur J Endocrinol. 2005;152(3):379-87.\u003c/li\u003e\n\u003cli\u003eBiermasz NR, van Thiel SW, Pereira AM, Hoftijzer HC, van Hemert AM, Smit JW, et al. Decreased quality of life in patients with acromegaly despite long-term cure of growth hormone excess. J Clin Endocrinol Metab. 2004;89(11):5369-76.\u003c/li\u003e\n\u003cli\u003eFleseriu M, Molitch M, Dreval A, Biermasz NR, Gordon MB, Crosby RD, et al. Disease and Treatment-Related Burden in Patients With Acromegaly Who Are Biochemically Controlled on Injectable Somatostatin Receptor Ligands. Front Endocrinol (Lausanne). 2021;12:627711.\u003c/li\u003e\n\u003cli\u003eHannon MJ, Barkan AL, Drake WM. The Role of Radiotherapy in Acromegaly. Neuroendocrinology. 2016;103(1):42-9.\u003c/li\u003e\n\u003cli\u003eGong X, Zhuo Y, Yuan H, Yang K, Li C, Feng S, et al. Outcome of Endoscopic Transsphenoidal Surgery for Recurrent or Residual Pituitary Adenomas and Comparison to Non-Recurrent or Residual Cohort by Propensity Score Analysis. Front Endocrinol (Lausanne). 2022;13:837025.\u003c/li\u003e\n\u003cli\u003eBashari WA, Senanayake R, Koulouri O, Gillett D, MacFarlane J, Powlson AS, et al. PET-guided repeat transsphenoidal surgery for previously deemed unresectable lateral disease in acromegaly. Neurosurg Focus. 2020;48(6):E8.\u003c/li\u003e\n\u003cli\u003eKoulouri O, Hoole AC, English P, Allinson K, Antoun N, Cheow H, et al. Localisation of an occult thyrotropinoma with (11)C-methionine PET-CT before and after somatostatin analogue therapy. Lancet Diabetes Endocrinol. 2016;4(12):1050.\u003c/li\u003e\n\u003cli\u003eKoulouri O, Kandasamy N, Hoole AC, Gillett D, Heard S, Powlson AS, et al. Successful treatment of residual pituitary adenoma in persistent acromegaly following localisation by 11C-methionine PET co-registered with MRI. Eur J Endocrinol. 2016;175(5):485-98.\u003c/li\u003e\n\u003cli\u003eKoulouri O, Steuwe A, Gillett D, Hoole AC, Powlson AS, Donnelly NA, et al. A role for 11C-methionine PET imaging in ACTH-dependent Cushing\u0026apos;s syndrome. Eur J Endocrinol. 2015;173(4):M107-20.\u003c/li\u003e\n\u003cli\u003eBakker LEH, Verstegen MJT, Ghariq E, Verbist BM, Schutte PJ, Bashari WA, et al. Implementation of functional imaging using (11)C-methionine PET-CT co-registered with MRI for advanced surgical planning and decision making in prolactinoma surgery. Pituitary. 2022;25(4):587-601.\u003c/li\u003e\n\u003cli\u003eBashari WA, van der Meulen M, MacFarlane J, Gillett D, Senanayake R, Serban L, et al. (11)C-methionine PET aids localization of microprolactinomas in patients with intolerance or resistance to dopamine agonist therapy. Pituitary. 2022;25(4):573-86.\u003c/li\u003e\n\u003cli\u003eSun A, Liu X, Tang G. Carbon-11 and Fluorine-18 Labeled Amino Acid Tracers for Positron Emission Tomography Imaging of Tumors. Front Chem. 2017;5:124.\u003c/li\u003e\n\u003cli\u003eGrosu AL, Astner ST, Riedel E, Nieder C, Wiedenmann N, Heinemann F, et al. An interindividual comparison of O-(2-[18F]fluoroethyl)-L-tyrosine (FET)- and L-[methyl-11C]methionine (MET)-PET in patients with brain gliomas and metastases. Int J Radiat Oncol Biol Phys. 2011;81(4):1049-58.\u003c/li\u003e\n\u003cli\u003eVerburg N, Koopman T, Yaqub M, Hoekstra OS, Lammertsma AA, Schwarte LA, et al. Direct comparison of [(11)C] choline and [(18)F] FET PET to detect glioma infiltration: a diagnostic accuracy study in eight patients. EJNMMI Res. 2019;9(1):57.\u003c/li\u003e\n\u003cli\u003eWeber WA, Wester HJ, Grosu AL, Herz M, Dzewas B, Feldmann HJ, et al. O-(2-[18F]fluoroethyl)-L-tyrosine and L-[methyl-11C]methionine uptake in brain tumours: initial results of a comparative study. Eur J Nucl Med. 2000;27(5):542-9.\u003c/li\u003e\n\u003cli\u003eLobatto DJ, Zamanipoor Najafabadi AH, de Vries F, Andela CD, van den Hout WB, Pereira AM, et al. Toward Value Based Health Care in pituitary surgery: application of a comprehensive outcome set in perioperative care. Eur J Endocrinol. 2019;181(4):375-87.\u003c/li\u003e\n\u003cli\u003evan Furth WR, de Vries F, Lobatto DJ, Kleijwegt MC, Schutte PJ, Pereira AM, et al. Endoscopic Surgery for Pituitary Tumors. Endocrinol Metab Clin North Am. 2020;49(3):487-503.\u003c/li\u003e\n\u003cli\u003eVander Borght T, Asenbaum S, Bartenstein P, Halldin C, Kapucu O, Van Laere K, et al. EANM procedure guidelines for brain tumour imaging using labelled amino acid analogues. Eur J Nucl Med Mol Imaging. 2006;33(11):1374-80.\u003c/li\u003e\n\u003cli\u003eMicko AS, Wohrer A, Wolfsberger S, Knosp E. Invasion of the cavernous sinus space in pituitary adenomas: endoscopic verification and its correlation with an MRI-based classification. J Neurosurg. 2015;122(4):803-11.\u003c/li\u003e\n\u003cli\u003eBerkmann S, Roethlisberger M, Mueller B, Christ-Crain M, Mariani L, Nitzsche E, et al. Selective resection of cushing microadenoma guided by preoperative hybrid 18-fluoroethyl-L-tyrosine and 11-C-methionine PET/MRI. Pituitary. 2021;24(6):878-86.\u003c/li\u003e\n\u003cli\u003eCoopmans EC, van der Lely AJ, Schneiders JJ, Neggers S. Potential antitumour activity of pasireotide on pituitary tumours in acromegaly. Lancet Diabetes Endocrinol. 2019;7(6):425-6.\u003c/li\u003e\n\u003cli\u003eBergstrom M, Muhr C, Lundberg PO, Langstrom B. PET as a tool in the clinical evaluation of pituitary adenomas. J Nucl Med. 1991;32(4):610-5.\u003c/li\u003e\n\u003cli\u003eMuhr C. Positron emission tomography in acromegaly and other pituitary adenoma patients. Neuroendocrinology. 2006;83(3-4):205-10.\u003c/li\u003e\n\u003cli\u003eTang BN, Levivier M, Heureux M, Wikler D, Massager N, Devriendt D, et al. 11C-methionine PET for the diagnosis and management of recurrent pituitary adenomas. Eur J Nucl Med Mol Imaging. 2006;33(2):169-78.\u003c/li\u003e\n\u003c/ol\u003e"},{"header":"Table 3","content":"\u003cp\u003eTable 3 is available in the Supplementary Files section.\u003c/p\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":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"acromegaly, functional imaging, Positron Emission Tomography, 18F-fluoro-ethyl-tyrosine, surgical decision making, transsphenoidal surgery","lastPublishedDoi":"10.21203/rs.3.rs-3799944/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-3799944/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003ePurpose\u003c/h2\u003e \u003cp\u003eTo report our experience with \u003csup\u003e18\u003c/sup\u003eF-fluoro-ethyl-tyrosine (FET) positron emission tomography-computed tomography (PET-CT) co-registered with MRI (FET-PET/MRI\u003csup\u003eCR\u003c/sup\u003e) in the care trajectory for complex acromegaly patients.\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e \u003cp\u003eIn 10 patients with insufficiently controlled acromegaly referred to our team to evaluate surgical options, FET-PET/MRI\u003csup\u003eCR\u003c/sup\u003e was used to support decision-making if MRI alone and multidisciplinary team evaluation did not provide sufficient clarity to proceed to surgery.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e \u003cp\u003eFET-PET/MRI\u003csup\u003eCR\u003c/sup\u003e showed suspicious (para)sellar tracer uptake in all patients. In 5 patients FET-PET/MRI\u003csup\u003eCR\u003c/sup\u003e was fully concordant with conventional MRI, and in 1 patient partially concordant. FET-PET/MRI\u003csup\u003eCR\u003c/sup\u003e identified new suspicious foci in 4 other patients. Surgical re-exploration was performed in 9 patients (aimed at total resection (\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e), debulking (\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e), diagnosis (\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e)), and 1 patient underwent radiation therapy. In 7 of 9 (78%) operated patients FET-PET/MRI\u003csup\u003eCR\u003c/sup\u003e findings were confirmed intraoperatively, and in 6 patients (67%) also histologically. IGF-1 decreased significantly in 8 patients (89%). All patients showed clinical improvement. Complete biochemical remission was achieved in 3 patients (50% of procedures in which total resection was anticipated feasible). Biochemistry improved in 5 and was unchanged in 1 patient. No permanent complications occurred. Outcome categorized by integrated outcome quadrants (IOQs) defined by preoperative intended effect versus permanent complications at 6 months was IOQ-1 (goal achieved without complications) in 6 (67%) and IOQ-3 (goal not achieved, no complications) in 3 patients.\u003c/p\u003e\u003ch2\u003eConclusion\u003c/h2\u003e \u003cp\u003eIn complex acromegaly cases FET-PET/MRI\u003csup\u003eCR\u003c/sup\u003e can provide additional information to aid decision-making by the multidisciplinary pituitary team, especially when (further) surgery is being considered.\u003c/p\u003e","manuscriptTitle":"18F-fluoro-ethyl-tyrosine PET co-registered with MRI in patients with persisting acromegaly","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-01-02 18:34:53","doi":"10.21203/rs.3.rs-3799944/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"6f9942d2-3fa6-4084-8ef3-19d5707075c9","owner":[],"postedDate":"January 2nd, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[],"tags":[],"updatedAt":"2024-06-17T19:37:04+00:00","versionOfRecord":{"articleIdentity":"rs-3799944","link":"https://doi.org/10.1111/cen.15079","journal":{"identity":"clinical-endocrinology","isVorOnly":true,"title":"Clinical Endocrinology"},"publishedOn":"2024-05-31 00:00:00","publishedOnDateReadable":"May 31st, 2024"},"versionCreatedAt":"2024-01-02 18:34:53","video":"","vorDoi":"10.1111/cen.15079","vorDoiUrl":"https://doi.org/10.1111/cen.15079","workflowStages":[]},"version":"v1","identity":"rs-3799944","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-3799944","identity":"rs-3799944","version":["v1"]},"buildId":"qtupq5eGEP_6zYnWcrvyt","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}