Clinical Features and Remission Rates in Cushing’s Disease: A Comparison of MRI-Detectable and MRI-Undetectable Pituitary Adenomas

Abstract

We aimed to characterize the clinical features and remission rates of patients with Cushing’s Disease (CD) without magnetic resonance imaging (MRI) detectable pituitary adenoma compared to CD patients with MRI-detectable pituitary adenoma.All patients with adrenocorticotropic hormone (ACTH)-dependent Cushing’s syndrome (CS) without MRI-detectable pituitary adenoma underwent high-dose dexamethasone suppression test, corticotropin-releasing hormone stimulation test, and/or bilateral inferior petrosal sinus sampling (BIPSS). The diagnosis of CD in patients without MRI-detectable adenoma was confirmed when the results of dynamic testing and sampling concordantly indicated ACTH-producing adenoma.These patients were included in MRI-undetectable group. Patients with ACTH-dependent CS had pituitary adenoma≥6 mm and those with pituitary adenoma<6 mm but BIPSS findings indicative of CD were included in MRI-detectable adenoma group. The study included 60 patients without MRI-detectable adenoma and 74 patients with MRI-detectable adenoma. At presentation, patients without MRI-detectable adenoma were older [47 years (30.25–58) vs. 40.5 years (29–49), p=0.036]. Hypertension (65% vs. 47.3%), diabetes mellitus (58.3% vs. 39.2%), and cardiovascular disease (13.3% vs. 2.7%) were more common in patients without MRI-detectable adenoma (p=0.040, p=0.027, p=0.020; respectively). The transsphenoidal surgery as initial treatment was higher in the patients with MRI-detectable adenoma group (97.3% vs. 80%, p=0.001). Third-month remission (60.4% vs. 63.8%, p=0.700) after surgery, and remission rates in the last visit (65.3% vs. 79.7%, p=0.077) were similar between the two groups. Inconclusion, the absence of an MRI-detectable adenoma underscores the necessity for comprehensive management.

Keywords

Cushing’s disease - management - pituitary adenoma - sella imaging - transsphenoidal surgery

Introduction

Cushing’s syndrome (CS) is a rare condition characterized by exposure to cortisol excess [1] [2] [3]. The most common cause of endogenous hypercortisolism is Cushing’s Disease (CD) [2] [4]. CD is almost invariably associated with increased morbidity and mortality, underscoring the importance of prompt diagnosis and treatment [2] [4]. Nevertheless, challenges in diagnosis of CD pave the way for treatment dilemmas, increasing the burden of disease in the long-term [5] [6].

Clinical and laboratory findings offer initial clues to the presence of CS and imaging studies play a pivotal role in the differential diagnosis [4]. The primary radiological method for diagnosis of patients suspected of CD is sella magnetic resonance imaging (MRI) [4]. Sella MRI provides valuable information for the diagnosis and management of CD, guiding further therapeutic interventions [4]. It is noteworthy that adrenocorticotropic hormone (ACTH)-secreting tumors are detected by 1.5 Tesla sella MRI only in half of the cases [7] [8] [9] [10]. Management of CD patients without MRI-detectable adenoma can be burdensome [10] [11]. The presence of CD patients without MRI-detectable adenoma may lead to reluctance in pursuing target-specific treatments like transsphenoidal surgery (TSS), opening the door to less effective medical treatments or more morbid procedures like bilateral adrenalectomy [10] [12]. Therefore, it is important to be well aware of the clinical features and treatment responses of CD patients without MRI-detectable adenoma.

In this study, we aimed to assess the baseline characteristics and long-term outcomes of CD patients without MRI-detectable adenoma compared to those with MRI-detectable adenoma. We also sought to investigate whether absence of MRI-detectable pituitary adenoma confers increased risk of adverse outcomes.

Materials and Methods

Setting and design

This multicenter retrospective study was conducted in Endocrinology and Metabolism Departments of Istanbul University-Cerrahpasa Faculty of Medicine, Istanbul University Faculty of Medicine, Ege University Faculty of Medicine, and Erciyes University Faculty of Medicine.

Ethical Approval

The study protocol was approved by the Ethics Committee of Istanbul University-Cerrahpasa, Cerrahpasa Faculty of Medicine (83045809–804.01–814029/18/10/2023). The study was conducted according to the principles of the Declaration of Helsinki.

Patients and data collection

Patients diagnosed with CD from 2000 to 2023 without missing follow-up data were consecutively included in the study. The inclusion criteria were presence of i) diagnosis of CD, ii) age>18 years, and iii) duration of follow-up at least 6 months. CD was defined by either histopathological confirmation of an ACTH-producing adenoma or when the results of bilateral inferior petrosal sinus sampling (BIPSS) were consistent with CD in patients with ACTH-dependent CD or when the patient underwent remission after TSS [3] [4]. Patients with ectopic CS and ACTH-independent CS were excluded.

Demographic, clinical, radiological and biochemical data were obtained from the patients’ charts.

Endocrinological definitions and follow-up protocols

The diagnosis, management, and follow-up of CD was dictated by internationally agreed guidelines [3] [13] [14] [15]. Time to diagnosis was defined as the interval between the onset of symptoms and definitive diagnosis, including clinical evaluation and biochemical tests.

Hypercortisolism was diagnosed in the presence of at least two of the following tests: elevated late-night salivary cortisol, elevated 24-hour urinary free cortisol (UFC) levels, and lack of cortisol suppression after 1 mg of dexamethasone suppression test (DST) in patients with clinical findings of CS [3]. The lack of cortisol suppression after a 1 mg DST is defined as serum cortisol levels>1.8 μg/dl [3]. ACTH-dependent hypercortisolism was defined as basal ACTH plasma levels>20 pg/ml on at least two occasions in patients with clinical and biochemical hypercortisolism [16]. ACTH levels were assayed via electrochemiluminescence immunoassay method.

All the patients diagnosed with ACTH-dependent CS underwent sella MRI. The presence of≥6 mm pituitary adenoma on sella MRI was considered as CD [9] [17]. The diagnosis of CD in patients with pituitary adenoma<6 mm was confirmed through high-dose dexamethasone suppression test (HDDST), corticotropin-releasing hormone (CRH) stimulation test, and/or BIPSS [3] [9] [17]. These patients with MRI-detectable pituitary adenoma were included in patients with MRI-detectable group. All the patients with ACTH-dependent CS without MRI-detectable pituitary adenoma underwent HDDST, CRH stimulation test, and/or BIPSS [3] [9] [17]. These patients were assigned to patients without MRI-detectable group when the results of dynamic testing and sampling concordantly indicated ACTH producing adenoma. A suppression of>50% in basal cortisol levels following the HDDST and an increase of at least 50% in ACTH and at least 20% in basal cortisol levels following CRH stimulation test were considered indicative of CD [3] [9] [17]. The inclusion process is summarized in [Fig. 1].

Fig. 1 Flowchart of diagnostic process. ACTH: Adrenocorticotropic hormone; BIPSS: Bilateral inferior petrosal sinus sampling; CRH: Corticotropin-releasing hormone; CD: Cushing's disease; HDDST: High-dose dexamethasone suppression test; MRI: Magnetic resonance imaging).

The decision of surgical remission was assessed at the 3rd postoperative month. Remission was based on the regression or disappearance of clinical symptoms, along with serum cortisol levels<5 μg/dl, the presence of normal late-night salivary cortisol levels, normal UFC levels, and normal cortisol suppression following 1 mg DST [13] [14] [15].

Sella MRI

Dynamic sella MRI was performed in all patients, using a superconducting 1.5 Tesla (Magnetom Avanto, Siemens) or 3 Tesla scanner (Ingenia; Philips Healthcare, Best, Netherlands). Before gadolinium injection (0.01 mmol/kg gadobutrol, Gadovist; Bayer Schering Pharma, Berlin, Germany), T1-weighted SE and T2-weighted turbo SE images, followed by coronal dynamic acquisition (T1- weighted turbo spin echo) were obtained in the coronal plane using the following protocol: TR/TE, 844/12ms; 176×172 matrix; two excitations; 14×14 cm field of view (FOV); 3 mm in thickness with 0.3 mm intersection gap. Dynamic MRI scan was conducted within 200 seconds following intravenous injection of the contrast agent.

The presence or absence of adenoma on MRI was verified by experienced neuroradiologists (M.B., B.K., O.K.). Following the neuroradiologists’ evaluation, patients with no detectable adenoma on MRI were categorized as patients without MRI-detectable group, while patients with detectable adenoma on MRI were included in the patients with MRI-detectable group.

Bilateral inferior petrosal sinus sampling

After catheter placement, ACTH was measured simultaneously in blood samples taken from each petrosal sinus and from a peripheral vein before and after CRH injection. When CRH was unavailable, desmopressin was used. The pituitary origin of ACTH was established simultaneously by measurement of central to peripheral ACTH gradients calculated as previously suggested by Oldfield et al. [18]. Based on the recommendation of expert groups, BIPSS was performed in patients without MRI-detectable adenoma and patients with MRI-detectable lesions<6 mm [9] [17]. Samples collected in the purple-top (EDTA) tubes after the BIPSS procedure were routinely kept on ice and delivered to the laboratory immediately [18] [19].

Immunohistochemical staining

Immunohistochemical staining for diagnosing CD is performed using specific antibodies to detect ACTH in tissue samples. Tumor specimens are first fixed and then embedded in paraffin. Sections are cut, mounted on slides, and subjected to antigen retrieval to enhance antibody binding. Primary antibodies against ACTH are applied, followed by secondary antibodies conjugated to enzymes or fluorochromes for visualization. This technique assists in confirming the presence of ACTH-producing adenomas [20].

Statistical analysis

Statistical analyses were conducted using SPSS version 20.0. Data were initially assessed for normality using the Kolmogorov–Smirnov test. Continuous variables were expressed as mean±standard deviation (SD) and/or median [interquartile range (IQR)]. The student’s t-test or analysis of variance (ANOVA) was used to compare means between groups with normally distributed data. Medians were compared using the Mann–Whitney U-test or the Kruskal–Wallis test. Correlation coefficients between continuous variables were calculated using Spearman’s rank-order test and Pearson’s correlation test. Frequencies were compared using Pearson’s chi-square test or Fisher’s exact test. The results were tested at the 95% confidence level, and a p-value<0.05 was considered statistically significant. For inferential statistics, multiple regression analysis was employed to evaluate the impact of multiple independent variables on a dependent variable while controlling for potential confounding factors.

Results

General features of study population

One hundred thirty-four patients were included in the study. Of them, 111 were female (82.8%). The mean age was 48.95±13.41 years. The median age at diagnosis was 42.5 (29.75–52) years. The duration of follow-up was 45.5 (15–95.25) months. The median ACTH was 48.05 pg/ml [30.36–75.47], cortisol was 20.17 μg/dl (15.42–25.5), UFC/ULN (upper limits of normal) was 2.5 [1.19–4.29], and late-night salivary/ULN cortisol was 1.75 (0.65–3.26). A 1.5 Tesla dynamic sella MRI was performed on the 92 patients included in the study. Among these patients, 36 (39.1%) had no detectable adenoma on MRI. A 3 Tesla dynamic sella MRI was performed on 42 patients. Among these patients, 24 (57.1%) had no detectable lesion on MRI (39.1% vs. 57.1%, p=0.052).

The most common comorbidity was hypertension (n=74, 55.2%), followed by diabetes mellitus (n=64, 47.8%), osteoporosis (n=36, 26.9%), and cardiovascular disease (n=10, 7.5%).

A total of 120 patients (89.6%) underwent TSS as first-line treatment. Thirteen patients (9.7%) who did not undergo TSS as first-line treatment were followed with medical treatment. One patient (0.7%) initially underwent bilateral adrenalectomy. TSS was successful in 62.5% of patients in achieving remission at 3rd post-operative month.

Comparison of patients with and without MRI-detectable adenoma

The comparison clinical and laboratory parameters of CD patients without MRI-detectable adenoma (n=60) and those with MRI-detectable adenoma (n=74) are presented in [Table 1]. There was a trend for an older age in patients without MRI-detectable adenoma. Likewise, patients without MRI-detectable adenoma were older at the time of diagnosis. ACTH levels were lower in patients without MRI-detectable adenoma. In the patients with MRI-detectable adenoma group, there was no correlation between adenoma size and ACTH levels (r=0.175, p=0.136). 1 mg DST, UFC/ULN, and late-night salivary cortisol/ULN results showed no difference between study groups ([Table 1]). When the comparisons in [Table 1] were made between patients without MRI-detectable adenoma and those patients with MRI-detectable adenoma<6 mm, ACTH levels were lower in patients without MRI-detectable adenoma [38.78 pg/ml (26.43–59.49) vs. 51.55 pg/ml (34.91–90.25), p=0.019]. Additionally, these patients tended to be older compared to those with adenomas<6 mm on MRI at presentation [47 years (30.25–58) vs. 40.5 years (28.75–48.25), p=0.051].

Table 1 Demographic, clinical, and biochemical characteristics of the patients based on their MRI findings.

Characteristics	Patients without MRI-detectable adenoma (n=60)	Patients with MRI-detectable adenoma (n=74)	p
Age (years) (mean±SD)	51.35±13.46	47±13.14	0.062
Gender (F/M)	47/13	64/10	0.213
Age at diagnosis (years) (median, [IQR])	47 [30.25–58]	40.5 [29–49]	0.036
Time to diagnosis (month) (median, [IQR])a	14 [12–36]	12 [8.25–35.25]	0.310
Follow up period: range (month) (median, [IQR])	53 [15.75–95.75]	39 [12.75–93]	0.650
ACTH (pg/ml) (median, [IQR])	38.78 [26.43–59.49]	55.25 [38.38–84.38]	0.001
Basal cortisol (μg/dl) (median, [IQR])	20.95 [16–25.48]	19.8 [14.46–25.63]	0.842
Cortisol nadir after 1 mg DST (μg/dl) (median, [IQR])	10 [4.5–18.49]	9.65 [4.65–19]	0.955
Mean UFC/ULN level (median, [IQR])	2.04 [0.95–4.31]	2.8 [1.4–4.38]	0.258
Late-night salivary cortisol/ULN level (median, [IQR])b	0.76 [0.35–2.95]	1.98 [1.05–3.74]	0.064

ACTH: Adrenocorticotropic hormone; DST: Dexamethasone suppression test; IQR: Interquartile range; F: Female; M: Male; MRI: Magnetic resonance imaging; SD: Standard deviation; UFC: Urinary free cortisol; ULN: Upper limits of normal. ^a Time to diagnosis was defined as the interval between the onset of symptoms and definitive diagnosis, including clinical evaluation and biochemical tests. ^b Late-night salivary cortisol levels were measured in 37 patients (27.6%) among all patients.

Although the time to diagnosis was similar between the two groups, we observed that hypertension, diabetes mellitus, cardiovascular disease, osteoporosis, and proximal myopathy were more common in patients without MRI-detectable adenoma ([Table 2]). In the multiple logistic regression analysis assessing factors associated with the higher frequency of hypertension and diabetes mellitus, age emerged as a significant determinant. However, neither gender nor the presence of an adenoma on sella MRI was associated with the prevalence of these conditions ([Table 3]). Logistic regression analysis was not performed for osteoporosis due to the low prediction percentage.

Table 2 Comparison of signs and complications in patient groups.

	Patients without MRI-detectable adenoma (n=60)	Patients with MRI-detectable adenoma (n=74)	p
Signs, n (%)
Moon face	32 (53.3)	34 (45.9)	0.395
Skin striae	23 (38.3)	27 (36.5)	0.826
Buffalo hump	32 (53.3)	40 (54.1)	0.934
Hypertension	39 (65)	35 (47.3)	0.040
Diabetes mellitus	35 (58.3)	29 (39.2)	0.027
Osteoporosis	28 (46.6)	8 (10.8)	<0.001
Proximal myopathy	24 (40)	15 (20.3)	0.012
Complications, n (%)
Cardiovascular disease	8 (13.3)a	2 (2.7)b	0.020
Cerebrovascular disease	2 (3.3)	0 (0)	0.114
Thromboembolism	4 (6.6)	0 (0)	0.024

MRI: Magnetic resonance imaging. ^a 7 Patients had coronary artery disease and 1 patient had heart failure. ^b 2 Patients had coronary artery disease.

Table 3 Multiple regression analysis of age, gender, and adenoma presence on hypertension and diabetes mellitus.

Hypertension (dependent variable)	95% CI	p
Age	0.894–0.956	<0.001
Gender	0.380–2.320	0.891
Adenoma on sella MRI	0.265–1.261	0.168
Diabetes mellitus (dependent variable)	95% CI	p
Age	0.891–0.953	<0.001
Gender	0.611–3.820	0.365
Adenoma on sella MRI	0.251–1.194	0.130

CI: Confidence interval; MRI: Magnetic resonance imaging.

The proportion of patients undergoing TSS as first-line treatment was significantly higher in the patients with MRI-detectable adenoma group compared to the patients without MRI-detectable adenoma group (97.3% vs. 80%, p=0.001). The 3rd month success rate of TSS showed no difference as presented in [Fig. 2].

Fig. 2 Percentage of patients achieving remission and non-remission at third months postoperatively based on the MRI findings (p=0.700).

Positive ACTH staining of the adenoma was observed in thirty of 48 (62.5%) operated patients without MRI-detectable adenoma and fifty-four of 72 (75%) patients with MRI-detectable adenoma (p=0.143). Postoperative 3rd month remission rates were higher in patients with positive ACTH staining for patients without MRI-detectable adenoma and patients with MRI-detectable adenoma (p=0.018 and p<0.001, respectively). In the patients with MRI-detectable adenoma, only two of 18 (11.1%) patients with negative ACTH staining achieved remission in the 3rd month.

During the post-TSS period, it was observed that 31.2% (15/48) of the patients without MRI-detectable adenoma and 37.5% (27/72) of the patients with MRI-detectable adenoma received cortisol-lowering medical treatment (p=0.482).

During the follow-up period, bilateral adrenalectomy was performed in eight of 60 (13.3%) and in five of 74 (6.8%) patients without MRI-detectable adenoma and patients with MRI-detectable adenoma, respectively (p=0.201). In the group of patients with MRI-detectable adenoma, 1 patient refused the repeat TSS, 2 patients did not go into remission after TSS and no adenoma was detected on imaging post-TSS, and another 2 patients required rapid correction of hypercortisolism due to catastrophic CD. These 5 patients underwent bilateral adrenalectomy.

Remission status at last visit

Excluding bilateral adrenalectomy, remission was achieved in 65.3% (34/52) of patients without MRI-detectable adenoma and 79.7% (55/69) of patients with MRI-detectable adenoma at last disease status (p=0.077).

Results of dynamic testing and BIPSS in patients without MRI-detectable adenoma

All patients without MRI-detectable adenoma underwent BIPSS (n=60). HDDST and CRH stimulation tests were performed in 51 and 15 patients without MRI-detectable adenoma, respectively. The results of BIPSS were consistent with CD in all patients (n=60, 100%). Among the 51 patients who underwent HDDST, 48 (94.1%) had results consistent with CD. The CRH stimulation test confirmed CD in three patients whose HDDST results were not consistent with CD. In 14 out of 15 patients (93.3%) who underwent the CRH stimulation test, the results were consistent with CD. In one patient whose CRH stimulation test results were not consistent with CD, the HDDST result confirmed the diagnosis. Therefore, when one dynamic test yielded discordant or inconclusive results, the clinical diagnosis was confirmed by the other test.

Discussion

In this study, we observed that patients without MRI-detectable adenoma were older at diagnosis and had lower ACTH levels compared to patients with MRI-detectable adenoma. Despite a similar diagnostic delay, conditions such as hypertension, diabetes mellitus, and osteoporosis were more prevalent at diagnosis in patients without MRI-detectable adenoma compared to MRI-detectable patients. Throughout follow-up, patients without MRI-detectable adenoma had more cardiovascular events. Although transsphenoidal surgery was less preferred in the patients without MRI-detectable adenoma group, we found similar remission rates at the 3rd month post-surgery in both groups. Positive ACTH staining post-transsphenoidal surgery emerged as a significant determinant of remission at the 3rd month after surgery in both groups. Throughout the follow-up, we observed a greater tendency towards bilateral adrenalectomy in patients without MRI-detectable adenoma.

The age at diagnosis of CD often ranges from 30 to 50 years [21] [22]. In the present study, the age at diagnosis was similar to the literature. We observed that patients without MRI-detectable adenoma tended to be older than patients with MRI-detectable adenoma at the time of diagnosis. This may be related to physicians referring patients to endocrinologists earlier after adenoma is detected on MRI. Contrary to our study, Tatsi et al. found a younger age at diagnosis in patients without MRI-detectable adenoma in a study they conducted with 186 patients in the pediatric and adolescent age group [23]. This may be relevant to the faster diagnostic approach to signs and symptoms detected in children. Further studies are needed to assess the association of age with other conditions.

In this study, we found that higher ACTH levels in patients with MRI-detectable adenoma. In a study conducted by Sun et al. with a total of 119 patients, there was no difference in ACTH values according to MRI results [24]. Similarly, Sharifi et al. did not observe statistically significant difference between patients without MRI-detectable adenoma and those with MRI-detectable adenoma groups [25]. However, in some previous studies comparing corticotroph macroadenomas and microadenomas, ACTH levels were found to be higher in macroadenomas [26] [27] [28]. This suggests that there may be a possible correlation between tumor visibility and ACTH levels.

Exposure to hypercortisolemia causes conditions such as hypertension, diabetes mellitus and cardiovascular disease, which significantly affect morbidity and mortality [29] [30]. When the literature was reviewed, patients with corticotroph microadenomas or macroadenomas exhibited similar clinical features in terms of hypertension and diabetes mellitus [26] [31] [32]. Interestingly, we observed that hypertension, diabetes mellitus, and cardiovascular disease were more common in patients without MRI-detectable adenoma. This may be related to the fact that these patients were older at the time of diagnosis. In addition, osteoporosis and proximal myopathy were observed more frequently in the patients without MRI-detectable adenoma than in patients with MRI-detectable adenoma.

In this study, we found that TSS was less frequently chosen as a first-line treatment for patients without MRI-detectable adenoma compared to those with MRI-detectable adenoma. Not surprisingly, neurosurgeons may be reluctant to TSS when there is no MRI-detectable pituitary adenoma.

In the present study, remission rates were similar in patients without MRI-detectable adenoma and patients with MRI-detectable adenoma after surgery. Some investigations have found lower remission rates in patients without MRI-detectable adenoma [11] [33] [34]. In these studies, this situation was attributed to a number of methodological factors, particularly the extent of neurosurgery performed in the absence of visible adenoma. However, some other investigations have found no significant difference in remission between patients without MRI-detectable adenoma and patients with MRI-detectable adenoma [25] [35] [36] [37] [38]. While the absence of lesions on MRI may lead to concerns regarding decreased likelihood of success, in practice, comparable success rates are observed. This situation may be attributed to the utility of diagnostic procedures such as BIPSS in patients without MRI-detectable adenoma cases, which may provide information on the source of ACTH hypersecretion. Moreover, the implementation of neuronavigational techniques offers guidance during surgery, potentially contributing to similar success rates in patients without MRI-detectable adenoma undergoing TSS.

The absence of adenoma detected on histopathology is considered a poor prognostic factor in terms of treatment response [39] [40]. Sun et al. observed histologically similar rates of ACTH staining in a study involving 24 patients without MRI-detectable adenoma and 95 patients with MRI-detectable adenoma [24]. Differently, Sharifi et al. demonstrated a statistically significant difference in histopathological results between patients without MRI-detectable adenoma and patients with MRI-detectable adenoma [25]. In our study, we did not find any difference in postoperative ACTH staining based on MRI findings. On the other hand, postoperative remission rates were higher in patients with positive ACTH staining, regardless of MRI findings. This situation indicates that ACTH staining is a strong predictor of treatment efficacy.

We acknowledge that the retrospective design of this study did not allow us to draw firms conclusions and there is inevitable need for future prospective designs on the course of patients without MRI-detectable adenoma compared to MRI-detectable ones. Given the multi-centered nature, another limitation is that MRIs were not performed under the same protocol. Future large-scale studies will yield more robust results on the outcome of patients with CD without MRI-detectable adenoma.

Conclusions

The results of this study indicate that the clinical severity of CD is not diminished in the absence of an MRI-detectable adenoma. Despite this, TSS was less frequently chosen for patients without MRI-detectable adenoma, leading to a higher rate of bilateral adrenalectomy, a curative option with increased morbidity. Importantly, TSS achieved comparable remission rates in patients with and without MRI-detectable adenoma. Taken together, our results emphasize that primary therapy with pituitary surgery is indicated in CD, even in the absence of a visible adenoma, given the comparable remission rate to those with MRI-detectable lesions.

Conflict of Interest

The authors declare that they have no conflict of interest.

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Publication History

Received: 12 October 2024

Accepted after revision: 22 January 2025

Article published online:
06 March 2025