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Abstract Purpose: Transsphenoidal surgery is the first-line treatment for Cushing’s disease (CD), even with negative preoperative magnetic resonance imaging (MRI) results. Some patients with persistent or recurring hypercortisolism have negative MRI findings after the initial surgery. We aimed to analyze the efficacy of repeat surgery in two groups of patients and determine if there is an association between positive MRI findings and early remission. Patients and Methods: Clinical, imaging, and biochemical information of 42 patients who underwent repeat surgery by a single neurosurgeon between 2002 and 2021 was retrospectively analyzed. We compared the endocrinological, histopathological, and surgical outcomes before and after repeat surgery among 14 CD patients with negative MRI findings and 28 patients with positive MRI findings. Results: Immediate remission was achieved in 29 patients (69.0%) who underwent repeat surgery. Among all patients, 28 (66.7%) had MRI findings consistent with solid lesions. There was no significant difference in remission rates between the recurrence and persistence groups (77.8% vs. 57.1%, odds ratio = 2.625, 95% confidence interval = 0.651 to 10.586). Patients in remission after repeat surgery were not associated with positive MRI findings (odds ratio = 3.667, 95% confidence interval = 0.920 to 14.622). Conclusions: In terms of recurrence, repeat surgery in patients with either positive or negative MRI findings showed reasonable remission rates. For persistent disease with positive MRI findings, repeat surgery is still an option; however, more solid evidence is needed to determine if negative MRI findings are predictors for failed reoperations for persistent hypercortisolism. Keywords: Cushing’s disease; MRI; persistence; recurrence; repeat surgery 1. Introduction Transsphenoidal pituitary surgery is the primary treatment choice for patients with Cushing’s Disease (CD), which has a reported remission rate of 70% to 90% [1,2]. However, hypercortisolism persists in some of these surgical patients and recurs in 3–29% of patients, even in those who have benefited from remission for more than a decade [3,4]. In cases in which the primary surgery failed, serval treatments are considered, including reoperation, medication, conventional radiotherapy, radiosurgery, and bilateral adrenalectomy [4]. With remission rates as high as 87% [5], reoperation is a feasible option worth considering. Although some studies have concentrated on the risk factors and long-term outcomes of repeated transsphenoidal surgery [6,7], the necessity of reoperation in patients with varied clinical, imaging, and pathological characteristics has not been adequately discussed. Reoperation is considered when lesions remain visible on magnetic resonance imaging (MRI), given that tumor removal will likely lead to remission, even if it is located in the cavernous sinus [8]. Nevertheless, the incidence of positive MRI findings is typically low in CD patients with either recurrent or persistent disease [5,9,10,11]. Furthermore, MRI has limitations in revealing the accurate structures of the operated area due to distorted anatomy related to the formation of granulation tissue and inflammatory changes after the initial surgery [12]. Unlike the considerable remission rate achieved after the first operation despite negative MRI findings [1], the decision to perform a second operation without visible lesions detected on MRI is challenging for neurosurgeons. These uncertainties emphasize the importance of discussing the risk factors and the necessity of repeat surgery, especially for patients with negative radiological results. Our retrospective study aimed to ascertain the treatment preference for reoperation in patients with persistent and recurrent CD and evaluate the significance of MRI findings for selecting patients that are likely to benefit from reoperation. Furthermore, we aimed to provide a reference for surgeons in making decisions on repeat surgical intervention for patients who are most likely to benefit, thereby improving the remission rates associated with reoperation. 2. Patients and Methods We retrospectively identified patients with CD treated with repeated transsphenoidal surgery between 2002 and 2021 at our institution. Patients with three or more pituitary surgeries were excluded from the present study. The preoperative and postoperative evaluations of the first surgeries are shown in Table 1. All patients fulfilled the following inclusion criteria: persistent hypercortisolism after initial surgery or recurrence after remission with a period of normocortisolism or adrenal insufficiency. Table 1. Preoperative characteristics of the initial surgery. This study included 42 patients aged 44.4 ± 14.6 years at the time of the repeat operation (Table S1). The median interval between the two operations was 43 months (interquartile range [IQR] = 18–90). The median follow-up duration after the second operation was 15.5 months (IQR = 4–59). 2.1. Diagnosis The diagnostic criteria for recurrence in the present study included new onset or recurrence of symptoms, clinical features, serum cortisol level, 24 h urinary-free cortisol (UFC) level, and biochemical tests (low-dose dexamethasone suppression test and high-dose dexamethasone suppression test (HDDST)), which are frequently used to define CD remission, recurrence, and persistence. An algorithm that is currently used in biochemical assessment and management of recurrent and persistent disease is shown in Figure 1. All tests were performed in a College of American Pathologists-accredited laboratory (No. 7217913). Serum cortisol and UFC were examined using an Access Immunoassay System (Beckman Coulter Inc., Fullerton, CA, USA). The normal ranges were 6.7–22.6 µg/dL and 21–111 µg/24 h, respectively. Plasma adrenocorticotropic hormone (ACTH) levels were measured using an ELSA-ACTH immunoradiometric method (Cisbio Bioassays, Codolet, France). The normal range was 12–78 pg/mL. A serum cortisol value of less than 5 μg/dL was considered to indicate remission. Patients who were not considered to be in remission were discharged and routinely evaluated 6 months after surgery for possible delayed remission. Patients were administered oral cortisone and gradually withdrawn to a physiologic replacement dose after 1 month. The yearly follow-up visit included physical examinations and serum cortisol, UFC, and plasma ACTH assessments. MRI was not performed routinely after surgery unless persistent or recurrent hypercortisolism was confirmed biochemically, as postoperative imaging may not be reliably interpreted for hormone-active pituitary adenoma. Figure 1. Algorithm of the biochemical assessment and treatment of persistent and recurrent Cushing’s disease. Contrast-enhanced pituitary MRI at our center was conducted to facilitate diagnosis and surgical planning using a superconducting magnet 1.5/3.0 Tesla scanner (SIGNA; GE Healthcare, Chicago, IL, USA). Before gadolinium injection (0.01 mmol/kg gadopentetate dimeglumine; Magnevist, Berlex Laboratories, Inc., Montville, NJ, USA), T1-weighted spin echo and T2-weighted turbo spin echo images were obtained in the coronal and sagittal planes. Beginning simultaneously with gadolinium injection, coronal and sagittal T1-weighted spin echo images were obtained 2 min after the injection. Imaging studies were independently reviewed by a neuroradiologist, endocrinologist, and the patient’s neurosurgeon. Pituitary imaging prior to the first surgery performed outside of our center was acquired and re-interpreted by the same team. Full agreement was reached on the positive nature of the MRI findings. Otherwise, when MRI findings appeared normal or interpretation was ambiguous, the MRI findings were considered negative. Meanwhile, bilateral inferior petrosal sinus sampling (BIPSS) with or without vasopressin (available after 2015) stimulation was performed in nine patients who experienced recurrence but lacked initially positive ACTH staining on the first histological examination to reconfirm whether the Cushing’s syndrome diagnosis was pituitary-dependent. Two patients were evaluated by BIPSS, although the initial pathology was positive. Regarding persistent disease, among eight patients without positive ACTH staining in their first pathological assessment, five were confirmed by positive BIPSS results and five were confirmed by visible radiological lesions. Only one patient with negative ACTH-staining adenoma underwent repeat surgery with either negative BIPSS results or negative imaging findings. 2.2. Surgical Procedure The same surgeon performed surgery on all patients via the mononostril transsphenoidal approach under a microscope or endoscope (available from December 2015). The initial location prior to the first operation did not guide the resection during repeat surgery. For each patient with positive MRI results, the imaging-identified areas for adenoma were biopsied as frozen sections for the initial pathological evaluation. Subsequent resection with a rim of pituitary tissue around the tumor cavity was conducted to confirm neoplasm-free margins. No further exploration was performed before frozen pathology confirmation was available unless the BIPSS result showed an increased ACTH level on the other side. For invisible tumors on MRI, the dura mater was opened widely to facilitate exploration of the whole gland, starting from the initial location on MRI before the first surgery or the side with the higher ACTH level in the BIPSS, if available. If no obvious tumor was identified on this side by the neurosurgeon intraoperatively, half of the gland was resected using the guidance of BIPSS lateralization. If a tumor was frozen pathologically and identified after half of the gland was removed, the residual gland remained unresected and was only gently explored and sampled in the most suspected area. In some circumstances in which the frozen section was negative, it was subjected to a subtotal adenohypophysectomy of the intermediate lobe and neurohypophysis. If invasive adenoma characteristics were also identified, the involved dura and medial wall of the cavernous sinus were resected or coagulated. A sample was collected for postoperative pathological confirmation, if available. 2.3. Outcome Patients were defined as being in remission with an immediate postoperative serum cortisol nadir <5 μg/dL or 24 h UFC at a normal level [13]. Persistent hypercortisolism was defined as an increased postoperative UFC level, while recurrent hypercortisolism was defined as a reappearance of hypercortisolism after a period of normocortisolism or adrenal insufficiency. 2.4. Statistical Analysis Descriptive statistics are presented as means ± standard deviations when normally distributed or medians and ranges when not normally distributed to describe patient outcome measures and incidence of remission among the study population. Statistical significance was set at a p value < 0.05. Fisher’s exact test was used to compare proportions of categorical measures between groups. All analyses were conducted using Instat (GraphPad Software, San Diego, CA, USA). 3. Results 3.1. Patient Characteristics The basic information and perioperative evaluations of the two operations are shown in Table 1 and Table S1. Among all 27 recurrent cases, the preoperative MRI before the first operation showed a definite pituitary adenoma. The other 12 patients with persistent hypercortisolism had positive MRI findings before the first surgery. The remaining three patients with negative radiographic findings were diagnosed with CD and underwent the first transsphenoidal surgery (TSS) based on their endocrinological results. For patients with confirmed persistent or recurrent CD, the imaging findings prior to the second operation of 14 individuals were negative (no solid evidence of tumors), and 28 clearly had positive results for the presence of a solid lesion. All patients who underwent a second surgery for recurrent or persistent hypercortisolism after the initial surgery were endocrinologically re-evaluated before the repeat surgery. There were 38 cases with positive HDDST results among 42 patients. BIPSS was performed in 18 patients with only one that did not reach the criteria of pituitary origin. 3.2. Outcome In our study, 29 of 42 patients (69.0%, 22 recurrent and 7 persistent cases of CD) were in remission after the repeat operation without additional therapy during follow-up (Table S1). At follow-up, compared with patients with persistent disease, the recurrence group had a higher remission rate, although the difference was not significant (77.8% [21/27] vs. 57.1% [8/15]; p > 0.05; odds ratio = 2.625, 95% confidence interval = 0.651 to 10.586). Negative preoperative MRI findings were not associated with lower odds of immediate remission after repeat surgery (p > 0.05; odds ratio = 3.667, 95% confidence interval = 0.920 to 14.622; Table 2). Table 2. The remission rate of the recurrent and persistent hypercortisolism patients with or without positive MRI findings. 3.3. Association between Outcomes and MRI Findings The remission rates of the persistent and recurrent disease groups with positive and negative MRI findings prior to the second procedure are shown in Table 2. Twenty-nine patients whose MRI findings revealed the existence of pituitary adenomas achieved successful outcomes after reoperation (Representative case, #19, Figure 2). The other seven patients who experienced recurrent or persistent hypercortisolism without clear imaging evidence of tumor appearance also benefited from reoperation (Representative case, #11, Figure 3). Figure 2. Preoperative and postoperative MR images of the two operations (A–D) demonstrate an in situ relapsed intrasellar mass (yellow arrow). Biochemical results obtained before and after the operations (E) show the tumor-related hormone change. KCZ, ketoconazole; MR, magnetic resonance. Figure 3. MR images (A) demonstrated a pituitary microadenoma on the left side (yellow arrow) before the first operation but not at the subsequent follow-ups (B,C). The biochemical results obtained before the second operation (D) revealed hypercortisolism indicating relapse without obvious MRI confirmation. MR, magnetic resonance; MRI, magnetic resonance imaging. 3.4. Pathology Respectively, 15/27 (55.6%) and 7/15 (46.7%) patients with recurrent and persistent hypercortisolism had ACTH-positive staining in the first pathological findings. Among patients who achieved remission after the second operation, 20 of 29 patients had confirmed adenoma with positive ACTH pathological staining, while 3 patients with adenoma were ACTH-negative. There were five patients that did not achieve remission even though they had positive ACTH-staining adenoma in the second pathological examination. Meanwhile, five patients achieved remission, although no adenomas were found in their pathological specimens. Overall, positive pathology after either the initial or repeated surgery was not a significant predictor for remission after the second surgery. 3.5. Complications Four of forty-two patients experienced major postoperative complications and underwent medical or surgical interventions. Most patients recovered well after the second operation, except in one case with persistent hypercortisolism, where a severe intracranial infection led to death. Another three cases with cerebral spinal fluid leakage related to the second operation were successfully surgically repaired afterwards. Hypopituitarism was a common complication in this subgroup of CD. All of the patients in remission after the second TSS underwent glucocorticoid replacement therapy (hydrocortisone or cortisone), adjusted according to the 24 h UFC. A total of 20 patients (20/29, 68.9%) underwent thyroxine replacement therapy. Three patients (3/29, 10.3%) had permanent diabetes insipidus. In the non-remission group, five patients (5/13, 38.5%) experienced hypothyroidism, and two patients (2/13, 15.4%) had permanent diabetes insipidus. 4. Discussion In the present study, we reported outcomes for 42 patients undergoing repeat TSS for recurrent and persistent disease in which an overall remission rate of 69.0% was achieved. Immediate remission rates after reoperation for recurrence have been reported in the literature up to 87% [13,14], which is similar to those of other second-line therapies such as radiation therapy and medical treatment. The CD recurrence rate after the initial TSS is reportedly 10–25% with a follow-up time of 10 years [15,16,17]. Ram et al. reported that surgeons performed a second TSS immediately after the first TSS when the postoperative serum cortisol level did not meet the standard level of remission. With an interval time of 1 to 6 weeks, 71% of patients with persistent disease achieved immediate remission, and 53% (9/17) achieved long-term remission [13]. Another study showed a remission rate of 70% with reoperation performed within 10 days [18]. A second TSS reportedly leads an additional 8% of patients to long-term CD remission [3]. Recurrence groups had slightly higher remission rates, which are insignificant when compared with persistent groups in the present study. Similar findings are demonstrated in the study by Ram et al. implicating that failure of the initial surgery suggested that the patient was more difficult to treat successfully with surgery than most patients with recurrence [13]. Therefore, the selection criteria for potential patients and reoperation strategies require further discussion. 4.1. Surgical Strategy The surgical strategy for the initial CD surgery varies depending on the major concerns of different pituitary surgeons. Some surgeons intend to preserve more normal gland tissue during surgery while others chase higher remission rates. Selective adenectomy is a reasonable choice for visible tumors. Several authors adopted a slightly extended resection with a rim or sometimes 2–3 mm of like-normal tissue around the tumor, which could be considered a partial hypophysectomy [19,20]. A hemi-hypophysectomy is more common in cases in which no tumor was identified during the operation, and the MRI or BIPSS results indicated remarkable lateralization of the tumor origin [21]. Wide exploration of the contralateral side should also be conducted in cases in which BIPSS results are inconsistent with the MRI findings, which may help identify tiny tumors. More extensive procedures, including subtotal or sometimes total pituitary gland resection, have been performed to maximize remission rates up to 75.9–81.8% [20,22], which may be a reasonable recommendation when imaging/intraoperative findings are not definitive, considering the negative impacts on reoperated patients with persistent hypercortisolism rather than hypopituitarism. Interestingly, pathological confirmation rates are fairly low in cases with extended resection even though they show high remission rates. There seems to be a current trend of surgeons performing a partial hypophysectomy, as a total hypophysectomy can lead to hypopituitarism [5,22,23], given that it may not obviously increase remission rates and may decrease quality of life [24]. 4.2. MRI Findings Regarding radiological findings, we emphasize that negative MRI findings do not necessarily indicate the inexistence of pituitary adenomas or negative pathological results. A number of cases in the study by Wagenmakers et al. showed that remission achieved after repeated transsphenoidal surgery was not predictable by positive MRI findings before the first or second operation [10]. Preoperative MRI provides a reference for the diagnosis of pituitary adenomas, although it has a limited predictive function for patient prognosis [9], especially for the repeat operation in which the original anatomical structure was more or less destroyed in the initial surgery. A positive MRI finding before the second operation should promote confidence in surgeons. The remission rate after reoperation with positive MRI findings was reportedly as high as 72.7% [10]. According to our study, the two positive-MRI groups with different initial surgical outcomes showed higher remission rates, albeit insignificantly. Positive MRI findings suggest better endocrinological outcomes may be achieved by a second operation in both recurrent and persistent disease groups compared with patients with negative imaging findings. An excellent remission rate (more than 80%) was achieved in the recurrent group with positive MRI findings, thus encouraging a repeat TSS. An acceptable remission rate (over 60%) close to those of alternative treatment options was observed in the recurrent group with negative MRI findings, as well as the persistent group with positive MRI findings. We noted that one patient with persistent CD and negative MRI findings achieved remission after reoperation. Therefore, whether a second surgical treatment is beneficial for these patients should be carefully considered. Regarding the recurrent or persistent cases of CD, patients underwent an initial surgery, and we regarded the MRI findings as a possible method to assist in decision making. A second operation is considered when visible lesions remain on MRI under the assumption that removal of the residual tumor leads to remission of the disease. Meanwhile, some recurrent and persistent patients with negative MRI findings also benefited from reoperation. Furthermore, MRI has its limitations in revealing the accurate structures of the originally operated area. The distortion and cicatrization from the previous operation and material packing in the sellar region lead to confusion [12,25]. Unlike the considerable remission rate achieved after the initial operation despite negative MRI findings, reoperation without certain lesion detection on MRI is associated with dissatisfactory remission rates [1], similar to the results of our study. Nevertheless, Knappe and Lüdecke [9] presented a different opinion regarding the significance of MRI findings and reported that it was not usually helpful for determining therapeutic strategies due to its low incidence of detecting existing microadenomas (missed diagnosis in 38–70% of cases). However, the BIPSS results in these cases in which MRI revealed no definitive information on tumors are therefore critical for surgeons to ascertain the pituitary origin of the disease, although another study suggested that MRI and BIPSS do not help locate recurrent tumors [10]. MRI may not help identify tumors in the cavernous sinus or other parasellar regions. 4.3. Pathology We compared the pathological results and remission situations of recurrent patients and persistent patients and failed to find any relationship between pathological results and remission expectations. These findings are supported by the findings of Ram et al. [13], in which no tumors were found in 11 of 17 patients during the second procedure, and 6 of 11 patients achieved remission. In a series by Locatelli et al. [11], no tumors were found in 8 of 12 patients during the second operation, and 5 had surgical remissions. Even in cases of remission, the positive rate of pathological exams was not as high as expected. There was no significant difference in remission rates between patients grouped by pathological results or one-to-one correspondence between histopathological confirmation and surgical outcomes [11]. To date, little evidence supports the prediction of reoperation outcomes by either of the two pathology results. 4.4. Other Considerations and Factors In patients with recurrent and persistent hypercortisolism after their first operation, it was difficult to identify solid lesions on MRI compared with the initial preoperative scans. Notably, BIPSS may provide more information, especially for patients who did not undergo this test before the first operation. Moreover, it may help avoid unnecessary repeat TSS in patients with persistent hypercortisolism by revealing false positives for pituitary ACTH overproduction. BIPSS results have the potential to not only confirm the pituitary origin of the condition (despite the fact that the first histological examination did not show ACTH-positive staining) but also to guide exploration and decision making for a hemi-hypophysectomy or accessing the cavernous sinus, especially for patients without obvious tumors identified intraoperatively. Careful dissection is highly recommended on the side of the obviously lateralized BIPSS results, which sometimes also indicate cavernous sinus invasion not shown on MRI and the necessity of opening the medical wall to achieve extended exploration. The predictive value of BIPSS lateralization in repeated surgery requires further investigation, although it is not optimal in native patients with CD [26]. According to a study by Lonser et al. [27], over 20% of CD patients had cavernous sinus invasion that was confirmed histologically. The authors advocated for complete resection, including the invaded sella dura and medial cavernous sinus wall by an experienced surgeon’s hands. Notably, endoscopy with magnification and lighting provides a panoramic view to facilitate extended exploration of the sella, including the cavernous sinus, compared with the microscope-based approach. Micko et al. demonstrated that an endoscope allows for a radical inspection of the entire medial wall of the cavernous sinus [28] and increases the lateral angle of visualizations to facilitate differentiation between tumor tissues and other tissues. These advantages over the microscopic transsphenoidal approach are critical for recurrent and unremitted cases; however, further studies with larger sample sizes are needed to verify this conclusion. 4.5. Other Adjunctive Treatments to Repeat Surgery Previous studies have noted that ketoconazole may contribute to enhanced tumor appearance on MRI to facilitate pituitary resection in some circumstances [29]. Castinetti et al. reported that visible lesions may be identified on MRI in one-third of patients who were administered ketoconazole [30]. In the literature, reoperation for persistent cases without visible lesions on MRI is rarely satisfactory [31], although these patients may benefit from radiosurgery using the entire sellar region as the therapeutic target [32]. The hormonal normalization was achieved after radiosurgery in half of the cases, including those with negative MRI findings [33]. In general, the radiosurgery outcomes and the less commonly used radiotherapy are more favorable, particularly in MRI-negative cases with persistent hypercortisolism compared with repeat surgery, with potentially fewer complications and a shorter length of hospital stay [34,35]. Salvage TSS for refractory CD after radiation therapy has rarely been reported [36] owing to the difficulty of disrupting surgical landmarks, the formation of scar tissue, and the effects of preoperative radiotherapy [34]. Bilateral adrenalectomy is generally considered the ultima ratio in patients who fail to respond to other treatment options. However, patients who undergo bilateral adrenalectomy will require lifelong surveillance of the corticotroph tumor’s progression, which may lead to Nelson’s syndrome, via MRI and ACTH measurements. Most experts agree that selective transsphenoidal adenomectomy should be recommended as the first-line therapy in patients with Nelson’s syndrome before extrasellar expansion of the tumor occurs [37]. 4.6. Limitations Similar to previous studies, our sample size was not large enough to conduct powerful statistical analyses. Some patients lost during follow-up limited the evaluation of long-term outcomes in the current study. We observed a trend in the predictable values of positive preoperative MRI findings, which is not enough evidence to support an apparent relationship. A potential weakness of the present study is that the outcome was only focused on the biochemical benefits of remission after surgical intervention, possibly leading to an underestimation of the risks of hypopituitarism and decreased quality of life. Indeed, larger case series are needed to further investigate the potential predictive factors and best surgical strategy. 5. Conclusions Patients with initial surgical treatment may experience hypercortisolism without positive MRI findings in both recurrent and persistent disease. Our findings suggest that for most patients who experience recurrent or persistent CD, reoperation should be an option even with negative MRI findings. However, further comprehensive investigation on recurrent or persistent CD patients is required. Larger groups of surgically treated CD patients with long follow-up periods should be evaluated to improve reoperation outcomes and determine the appropriate selection criteria for repeat surgery, especially for persistent CD patients. Supplementary Materials The following supporting information can be downloaded at: https://www.mdpi.com/article/10.3390/jcm11226848/s1, Table S1. Preoperative and postoperative evaluation of the repeated surgery of 42 patients. Author Contributions B.W. and Y.S. contributed to the study’s conception and design. S.Z. drafted the manuscript. J.R., Z.Z., H.J., Q.S., T.S. and W.W. contributed to data acquisition, analysis, and interpretation. B.W. and Y.S. critically revised the manuscript for important intellectual content. Y.S. and L.B. accept final responsibility for this article. All authors have read and agreed to the published version of the manuscript. Funding This work was supported in part by the National Natural Science Foundation of China (82000751) and the Shanghai Sailing Program (20YF1438900). Institutional Review Board Statement This study involving human participants was conducted in accordance with the 1964 Helsinki declaration and its later amendments or comparable ethical standards and was approved by the Ruijin Hospital Ethics Committee of Shanghai Jiao Tong University School of Medicine (approval number 2020-64). Informed Consent Statement The need for individual consent was waived by the Ethics Committee owing to the retrospective nature of the study. Data Availability Statement All data generated or analyzed during this study are included in this article. Further enquiries may be directed to the corresponding authors. Conflicts of Interest The authors have no relevant financial or non-financial interests to disclose. 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Corticotroph tumor progression after bilateral adrenalectomy (Nelson’s syndrome): Systematic review and expert consensus recommendations. Eur. J. Endocrinol. 2021, 184, P1–P16. [Google Scholar] [CrossRef] Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations. © 2022 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/). Share and Cite MDPI and ACS Style Wang, B.; Zheng, S.; Ren, J.; Zhong, Z.; Jiang, H.; Sun, Q.; Su, T.; Wang, W.; Sun, Y.; Bian, L. Reoperation for Recurrent and Persistent Cushing’s Disease without Visible MRI Findings. J. Clin. Med. 2022, 11, 6848. https://doi.org/10.3390/jcm11226848 AMA Style Wang B, Zheng S, Ren J, Zhong Z, Jiang H, Sun Q, Su T, Wang W, Sun Y, Bian L. Reoperation for Recurrent and Persistent Cushing’s Disease without Visible MRI Findings. Journal of Clinical Medicine. 2022; 11(22):6848. https://doi.org/10.3390/jcm11226848 Chicago/Turabian Style Wang, Baofeng, Shuying Zheng, Jie Ren, Zhihong Zhong, Hong Jiang, Qingfang Sun, Tingwei Su, Weiqing Wang, Yuhao Sun, and Liuguan Bian. 2022. "Reoperation for Recurrent and Persistent Cushing’s Disease without Visible MRI Findings" Journal of Clinical Medicine 11, no. 22: 6848. https://doi.org/10.3390/jcm11226848 Find Other Styles Note that from the first issue of 2016, MDPI journals use article numbers instead of page numbers. See further details here. Article Metrics Citations No citations were found for this article, but you may check on Google Scholar Article Access Statistics Article access statisticsArticle Views20. Nov21. Nov22. Nov23. Nov24. Nov25. Nov26. Nov27. Nov28. Nov29. Nov30. Nov1. Dec2. Dec3. Dec4. Dec5. Dec6. Dec7. Dec8. Dec9. Dec10. 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Abstract Background. Cushing’s disease (CD) recurrence in pregnancy is thought to be associated with estradiol fluctuations during gestation. CD recurrence in the immediate postpartum period in a patient with a documented dormant disease during pregnancy has never been reported. Case Report. A 30-year-old woman with CD had improvement of her symptoms after transsphenoidal resection (TSA) of her pituitary lesion. She conceived unexpectedly 3 months postsurgery and had no symptoms or biochemical evidence of recurrence during pregnancy. After delivering a healthy boy, she developed CD 4 weeks postpartum and underwent a repeat TSA. Despite repeat TSA, she continued to have elevated cortisol levels that were not well controlled with medical management. She eventually had a bilateral adrenalectomy. Discussion. CD recurrence may be higher in the peripartum period, but the link between pregnancy and CD recurrence and/or persistence is not well studied. Potential mechanisms of CD recurrence in the postpartum period are discussed below. Conclusion. We describe the first report of recurrent CD that was quiescent during pregnancy and diagnosed in the immediate postpartum period. Understanding the risk and mechanisms of CD recurrence in pregnancy allows us to counsel these otherwise healthy, reproductive-age women in the context of additional family planning. 1. Introduction Despite a relatively high prevalence of Cushing’s syndrome (CS) in women of reproductive age, it is rare for pregnancy to occur in patients with active disease [1]. Hypercortisolism leads to infertility through impairment of the hypothalamic gonadal axis. Additionally, while Cushing’s disease (CD) is the leading etiology of CS in nonpregnant adults, it is less common in pregnancy, accounting for only 30–40% of the CS cases in pregnant women [2]. It has been suggested that in CD there is hypersecretion of both cortisol and androgens, impairing fertility to a greater extent, while in CS of an adrenal origin, hypersecretion is almost exclusively of cortisol with minimal androgen production [3]. Regardless of the cause, active CS in pregnancy is associated with a higher maternal and fetal morbidity, hence, prompt diagnosis and treatment are essential. Pregnancy is considered a physiological state of hypercortisolism, and the peripartum period is a common time for women to develop CD [3, 4]. A recent study reported that 27% of reproductive-age women with CD had onset associated with pregnancy [4]. The high rate of pregnancy-associated CD suggests that the stress of pregnancy and peripartum pituitary corticotroph hyperstimulation may promote or accelerate pituitary tumorigenesis [4–6]. During pregnancy, the circulating levels of corticotropin-releasing hormone (CRH) in the plasma increase exponentially as a result of CRH production by the placenta, decidua, and fetal membranes rather than by the hypothalamus. Unbound circulating placental CRH stimulates pituitary ACTH secretion and causes maternal plasma ACTH levels to rise [4]. A review of the literature reveals many studies of CD onset during the peripartum period, but CD recurrence in the peripartum period has only been reported a handful of times [7–10]. Of these, most cases recurred during pregnancy. CD recurrence in the immediate postpartum period has only been reported once [7]. Below, we report for the first time a case of CD recurrence that occurred 4 weeks postpartum, with a documented dormant disease throughout pregnancy. 2. Case Presentation A 30-year-old woman initially presented with prediabetes, weight gain, dorsal hump, abdominal striae, depression, lower extremity weakness, and oligomenorrhea with a recent miscarriage 10 months ago. Diagnostic tests were consistent with CD. Results included the following: three elevated midnight salivary cortisols: 0.33, 1.38, and 1.10 μg/dL (<0.010–0.090); 1 mg dexamethasone suppression test (DST) with cortisol 14 μg/dL (<1.8); elevated 24 hr urine cortisol (UFC) measuring 825 μg/24 hr (6–42); ACTH 35 pg/mL (7.2–63.3). MRI of the pituitary gland revealed a left 4 mm focal lesion (Figure 1(a)). After transsphenoidal resection (TSA), day 1, 2, and 3 morning cortisol values were 18, 5, and 2 μg/dL, respectively. Pathology did not show a definitive pituitary neoplasm. She was rapidly titrated off hydrocortisone (HC) by six weeks postresection. Her symptoms steadily improved, including improved energy levels, improved mood, and resolution of striae. She resumed normal menses and conceived unexpectedly around 3 months post-TSA. Hormonal evaluation completed a few weeks prior to her pregnancy indicated no recurrence: morning ACTH level, 27.8 pg/mL; UFC, 5 μg/24 hr; midnight salivary cortisol, 0.085 and 0.014 μg/dL. Her postop MRI at that time did not show a definitive adenoma (Figure 1(b)). During pregnancy, she had a normal oral glucose tolerance test at 20 weeks and no other sequela of CD. Every 8 weeks, she had 24-hour urine cortisol measurements. Of these, the highest was 93 μg/24 hr at 17 weeks and none were in the range of CD (Table 1). Towards the end of her 2nd trimester, she started to complain of severe fatigue. Given her low 24 hr urine cortisol level of 15 μg/24 hr at 36 weeks gestation, she was started on HC. She underwent a cesarean section at 40 weeks gestation for oligohydramnios and she subsequently delivered a healthy baby boy weighing 7.6 pounds with APGAR scores at 1 and 5 minutes being 9 and 9. HC was discontinued immediately after delivery. Around four weeks postpartum she developed symptoms suggestive for CD. Diagnostic tests showed an elevated midnight salivary cortisol of 0.206 and 0.723 μg/dL, and 24-hour urine cortisol of 400 μg/24 hr. MRI pituitary illustrated a 3 mm adenoma in the left posterior region of the gland, which was thought to represent a recurrent tumor (Figure 1(c)). A discrete lesion was found and resected during repeat TSA. Pathology confirmed corticotroph adenoma with MIB-1 < 3%. On postoperative days 1, 2, and 3, the cortisol levels were 26, 10, and 2.8 μg/dL, respectively. She was tapered off HC within one month. Her symptoms improved only slightly and she continued to report weight gain, muscle weakness, and fatigue. Three months after repeat TSA, biochemical data showed 1 out of 2 midnight salivary cortisols elevated at 0.124 μg/dL and elevated urine cortisol of 76 μg/24 hr. MRI pituitary demonstrated a 3 × 5 mm left enhancement, concerning for residual or enlarged persistent tumor. Subsequent lab work continued to show a biochemical excess of cortisol, and the patient was started on metyrapone but reported no significant improvement of her symptoms and only mild improvement of excess cortisol. After a multidisciplinary discussion, the patient made the decision to pursue bilateral adrenalectomy, as she refused further medical management and opted against radiation given the risk of hypogonadism. (a) (b) (c) (a) (b) (c) Figure 1 (a) Initial: MRI pituitary with and without contrast showing a coronal T1 postcontrast image immediately prior to our patient’s pituitary surgery. The red arrow points to a 3 × 3 × 5 mm hypoenhancing focus representing a pituitary microadenoma. (b) Postsurgical: MRI pituitary with and without contrast showing a coronal T1 postcontrast image obtained three months after transsphenoidal pituitary surgery. The red arrow shows that a hypoenhancing focus is no longer seen and has been resected. (c) Postpartum: MRI pituitary with and without contrast showing a coronal T1 postcontrast image obtained four weeks postpartum. The red arrow points to a 3 mm relatively hypoenhancing lesion representing a recurrent pituitary adenoma. Table 1 24-hour urine-free cortisol measurements collected approximately every 8 weeks throughout our patient’s pregnancy. 3. Discussion The symptoms and signs of Cushing’s syndrome overlap with those seen in normal pregnancy, making diagnosis of Cushing’s disease during pregnancy challenging [1]. Potential mechanisms of gestational hypercortisolemia include increased systemic cortisol resistance during pregnancy, decreased sensitivity of plasma ACTH to negative feedback causing an altered pituitary ACTH setpoint, and noncircadian secretion of placental CRH during pregnancy causing stimulation of the maternal HPA axis [5]. Consequently, both urinary excretion of cortisol and late-night salivary cortisol undergo a gradual increase during normal pregnancy, beginning at the 11th week of gestation [2]. Cushing’s disease is suggested by 24-hour urinary-free cortisol levels greater than 3-fold of the upper limit of normal [2]. It has also been suggested that nocturnal salivary cortisol be used to diagnose Cushing’s disease by using the following specific trimester thresholds: first trimester, 0.25 μg/dL; second trimester, 0.26 μg/dL; third trimester 0.33, μg/dL [11]. By these criteria, our patient had no signs or biochemical evidence of CD during pregnancy but developed CD 4 weeks postpartum. A recent study by Tang et al. proposed that there may be a higher risk of developing CD in the peripartum period, but did not test for CD during pregnancy, and therefore was not able to definitively say exactly when CD onset occurred in relation to pregnancy [4]. Previous literature suggests that there may be a higher risk of ACTH-secreting pituitary adenomas following pregnancy as there is a significant surge of ACTH and cortisol hormones at the time of labor. This increased stimulation of the pituitary corticotrophs in the immediate postpartum period may promote tumorigenesis [6]. It has also been suggested that the hormonal milieu during pregnancy may cause accelerated growth of otherwise dormant or small slow-growing pituitary corticotroph adenomas [4, 5]. However, the underlying mechanisms of CD development in the postpartum period have yet to be clarified. We highlight the need for more research to investigate not only the development, but also the risk of CD recurrence in the postpartum period. Such research would be helpful for family planning. 4. Conclusion Hypothalamic-pituitary-adrenal axis activation during pregnancy and the immediate postpartum period may result in higher rates of CD recurrence in the postpartum period, as seen in our patient. In general, more testing for CS in all reproductive-age females with symptoms suggesting CS, especially during and after childbirth, is necessary. Such testing can also help us determine when CD occurred in relation to pregnancy, so that we can further understand the link between pregnancy and CD occurrence, recurrence, and/or persistence. Learning about the potential mechanisms of CD development and recurrence in pregnancy will help us to counsel these reproductive-age women who desire pregnancy. Abbreviations CD: Cushing’s disease TSA: Transsphenoidal resection DST: Dexamethasone suppression test ACTH: Adrenocorticotropic hormone MRI: Magnetic-resonance imaging HC: Hydrocortisone CTH: Corticotroph-releasing hormone HPA: Hypothalamic-pituitary-adrenal. Data Availability The data used to support the findings of this study are included within the article. Additional Points Note. Peripartum refers to the period immediately before, during, or after pregnancy and postpartum refers to any period after pregnancy up until 1 year postdelivery. Disclosure This case report is a follow up to an abstract that was presented in ENDO 2020 Abstracts. https://doi.org/10.1210/jendso/bvaa046.2128. Conflicts of Interest The authors declare that they have no conflicts of interest. Acknowledgments The authors thank Dr. Puneet Pawha for his help in reviewing MRI images and his suggestions. References J. R. Lindsay and L. K. Nieman, “The hypothalamic-pituitary-adrenal axis in pregnancy: challenges in disease detection and treatment,” Endocrine Reviews, vol. 26, no. 6, pp. 775–799, 2005.View at: Publisher Site | Google Scholar W. Huang, M. E. Molitch, and M. E. 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Researchers published the study covered in this summary on Research Square as a preprint that has not yet been peer reviewed. Key Takeaways Among women who underwent pituitary surgery to treat Cushing disease subsequent pregnancy had no apparent effect on Cushing disease recurrence, in a single-center review of 113 women treated over a 30-year period. Why This Matters No single factor predicts the recurrence of Cushing disease during long-term follow-up of patients who have undergone pituitary surgery. This is the first study to assess the effect of pregnancy on Cushing disease recurrence in a group of reproductive-age women who initially showed post-surgical remission. Study Design Retrospective study of 355 patients with confirmed Cushing disease who were admitted to a single tertiary hospital in Brazil between 1990 and 2020. All patients had transsphenoidal surgery, with a minimum follow-up of 6 months and median follow-up of 83 months. Remission occurred in 246 of these patients. The current analysis focused on 113 of the patients who achieved remission, were women, were 45 years old or younger at time of surgery (median 32 years old), and had information available on their obstetric history. Ninety-one of these women (81%) did not become pregnant after their surgery, and 22 (19%) became pregnant after surgery. Key Results Among the 113 women in the main analysis 43 (38%) had a Cushing disease recurrence, a median of 48 months after their pituitary surgery. Following surgery, 11 women in each of the two subgroups (recurrence, no recurrence) became pregnant. Although the subgroup with recurrence had a higher incidence of pregnancy (11/43; 26%) compared with those with no recurrence (11/70; 16%) Kaplan-Meier analysis showed that survival free of Cushing disease recurrence was similar and not significantly different in the women with a postsurgical pregnancy and those who did not become pregnant (P=.531). The review also showed that, of the women who became pregnant, several obstetrical measures were similar between patients who had a recurrence and those who remained in remission, including number of pregnancies per patient, maternal weight gain, type of delivery (normal or cesarean), delivery time (term or premature), neonatal weight, and neonatal size. The review also showed roughly similar rates of maternal and fetal complications in these two subgroups of women who became pregnant. Limitations The study was retrospective and included a relatively small number of patients. The authors collected information on obstetric history for some patients by telephone or email contacts. Disclosures The study received no commercial funding. None of the authors had disclosures. This is a summary of a preprint research study , " Pregnancy After Pituitary Surgery Does Not Influence the Recurrence of Cushing's Disease, " written by researchers at the Sao Paulo (Brazil) University Faculty of Medicine on Research Square provided to you by Medscape. This study has not yet been peer reviewed. The full text of the study can be found on researchsquare.com.

Neuroendocrine pulmonary tumors in people with Cushing syndrome (CS) are associated with increased nodal metastasis, higher recurrence, and lower disease-free survival compared with quiescent bronchopulmonary tumors, according to results from an observational case series published in JAMA Network Open. Researchers said their study shows these tumors are not biologically aggressive and underlying carcinoid biology may not be as important as symptomatic hormonal physiology. Patients (n=68) with CS who underwent curative-intent pulmonary surgery at the National Cancer Institute (NCI) between 1982 and 2020 were retrospectively reviewed for clinical outcomes on the basis of tumor etiology. Outcomes were compared among groups of patients with adrenocorticotropic hormone-secreting carcinoid tumors who were treated at the National Institutes of Health in 2021 (n=68), Hôpital Européen Georges-Pompidou in 2011 (n=14), the Mayo Clinic in 2005 (n=23), and Massachusetts General Hospital in 1997 (n=7). Patients who underwent surgery at the NCI were aged median 41 years (range, 17-80 years), 42.6% were men, 81.8% were White, and mean follow-up after surgery was 16 months (range, 0.1-341 months). Most patients had T status 1a (55.9%). The pathological stages were IA1 (37.3%), IA2 (23.7%), IA3 (1.7%), IIB (16.9%), IIIA (20.3%), or unknown (13.2%). The patients with typical carcinoid tumors (83.8%) underwent lobectomy (70.2%), wedge (22.8%), segmentectomy (5.3%), and pneumonectomy (1.7%) surgical approaches. Patients with atypical carcinoid tumors (16.2%) underwent lobectomy (72.7%) and wedge (27.3%) approaches. Stratified by surgical approach, lobectomy recipients were younger (P =.01) and more had node-positive atypical carcinoid tumors (P =.01). After surgery, morbidity occurred among 19.1% of patients; overall mortality was 1.5%. Disease-free survival at 5 years following surgery was 73.4% (95% CI, 48.7%-87.6%) and 55.1% (95% CI, 26.3%-76.5%) at 10 years. Disease-free survival was 75.4% (95% CI, 49.2%-89.3%) at 5 years and 50.2% (95% CI, 18.3%-75.7%) at 10 years for typical carcinoid tumors and remained stable at 75.0% among those with atypical carcinoid tumors. Median follow-up after surgery was 16 months (range, 0.1-341 months). At the time of last follow-up, 76.4% of the patient population was alive and tumor free. The overall incidence of persistence/recurrence was 16.2%. Recurrent disease occurred in 7 patients and persistent disease in 4 patients. Only one of this group had an atypical carcinoid tumor. Mean time to recurrence in patients with recurrent disease was 76 months with a median of 55 months. The adrenocorticotropic hormone-secreting carcinoid cohort from multiple institutions was aged median 39 years, 46.4% were men, 72.3% underwent lobectomy or pneumonectomy, 18.7% had morbidity, and 0.9% mortality. The majority of these groups had typical carcinoid tumors (83.9%) with a mean size of 1.1 cm (range, 0.1-10 cm) and 39.4% had lymph node positivity. Recurrence occurred among 12.6% of patients and persistence among 5.4% of patients. Among the recurrence cohort, 85.7% had typical carcinoid tumors. Time to recurrence was >6 years. Disease-free survival was 73% at five years and 55% at 10 years. This study was limited by the small group sizes, however, due to the rarity of this cancer it was not possible to include more individuals. “Ectopic adrenocorticotropic hormone secreting carcinoid tumors with Cushing syndrome appear to be associated with increased metastasis to lymph nodes, higher recurrence (mostly local), and lower overall disease-free survival at 5 and 10 years than quiescent bronchial carcinoid tumors, irrespective of histologic subtype,” the researchers wrote. “Nevertheless, we contend these tumors are not biologically aggressive since these patients have distinct, prolonged survival and delayed time to recurrence.” The researchers also noted that “the current staging system applied to these tumors raises questions about prognostic accuracy. Extrapolation may suggest that the underlying carcinoid biology may not be as important as the symptomatic hormonal physiology.” They suggested future studies may test “whether a lung-sparing surgical approach coupled with routine lymphadenectomy is an optimal intervention in this scenario when normal endocrine functioning is restored and CS sequelae resolve.” Reference Seastedt KP, Alyateem GA, Pittala K, et al. Characterization of outcomes by surgical management of lung neuroendocrine tumors associated with Cushing syndrome. JAMA Netw Open. 2021;4(9):e2124739. doi:10.1001/jamanetworkopen.2021.24739 From https://www.endocrinologyadvisor.com/home/topics/general-endocrinology/cushing-syndrome-and-lungs-and-neuoendocrine-tumors/

Presented by Dr. Magge, Assistant Professor of Neurology at Weill Cornell Medical College and an Assistant Attending Neurologist at New York-Presbyterian Hospital. Dr. Ranakrishna, Chief of Neurological Surgery at NewYork-Presbyterian Brooklyn Methodist Hospital, Associate Professor of Neurological Surgery at Avina and Willis Murphy at Weill Cornell Medicine Click here to attend. Date: Tuesday, October 13, 2020 Time: 10:00 AM Eastern Daylight Time Learning objectives: - the basic characteristics of the different types of pituitary adenomas - the potential predictors of recurrence and aggressiveness in pituitary adenomas - the surgical and radiotherapy options for recurrent pituitary adenomas - the potential medical interventions, including chemotherapy, for recurrent pituitary adenomas

Sponsor: Cedars-Sinai Medical Center Information provided by (Responsible Party): Shlomo Melmed, MD, Cedars-Sinai Medical Center Brief Summary: This phase 2 multicenter, open-label clinical trial will evaluate safety and efficacy of 4 weeks of oral seliciclib in patients with newly diagnosed, persistent, or recurrent Cushing disease. Funding Source - FDA Office of Orphan Products Development (OOPD) Condition or disease Intervention/treatment Phase Cushing Disease Drug: Seliciclib Phase 2 Detailed Description: This phase 2 multicenter, open-label clinical trial will evaluate safety and efficacy of two of three potential doses/schedules of oral seliciclib in patients with newly diagnosed, persistent, or recurrent Cushing disease. Up to 29 subjects will be treated with up to 800 mg/day oral seliciclib for 4 days each week for 4 weeks and enrolled in sequential cohorts based on efficacy outcomes. The study will also evaluate effects of seliciclib on quality of life and clinical signs and symptoms of Cushing disease. Ages Eligible for Study: 18 Years and older (Adult, Older Adult) Sexes Eligible for Study: All Accepts Healthy Volunteers: No Criteria Inclusion criteria: Male and female patients at least 18 years old Patients with confirmed pituitary origin of excess adrenocorticotropic hormone (ACTH) production: Persistent hypercortisolemia established by two consecutive 24 h UFC levels at least 1.5x the upper limit of normal Normal or elevated ACTH levels Pituitary macroadenoma (>1 cm) on MRI or inferior petrosal sinus sampling (IPSS) central to peripheral ACTH gradient >2 at baseline and >3 after corticotropin-releasing hormone (CRH) stimulation Recurrent or persistent Cushing disease defined as pathologically confirmed resected pituitary ACTH-secreting tumor or IPSS central to peripheral ACTH gradient >2 at baseline and >3 after CRH stimulation, and 24 hour UFC above the upper limit of normal reference range beyond post-surgical week 6 Patients on medical treatment for Cushing disease. The following washout periods must be completed before screening assessments are performed: Inhibitors of steroidogenesis (metyrapone, ketoconazole): 2 weeks Somatostatin receptor ligand pasireotide: short-acting, 2 weeks; long-acting, 4 weeks Progesterone receptor antagonist (mifepristone): 2 weeks Dopamine agonists (cabergoline): 4 weeks CYP3A4 strong inducers or inhibitors: varies between drugs; minimum 5-6 times the half-life of drug Exclusion criteria: Patients with compromised visual fields, and not stable for at least 6 months Patients with abutment or compression of the optic chiasm on MRI and normal visual fields Patients with Cushing's syndrome due to non-pituitary ACTH secretion Patients with hypercortisolism secondary to adrenal tumors or nodular (primary) bilateral adrenal hyperplasia Patients who have a known inherited syndrome as the cause for hormone over secretion (i.e., Carney Complex, McCune-Albright syndrome, Multiple endocrine neoplasia (MEN) 1 Patients with a diagnosis of glucocorticoid-remedial aldosteronism (GRA) Patients with cyclic Cushing's syndrome defined by any measurement of UFC over the previous 1 months within normal range Patients with pseudo-Cushing's syndrome, i.e., non-autonomous hypercortisolism due to overactivation of the hypothalamic-pituitary-adrenal (HPA) axis in uncontrolled depression, anxiety, obsessive compulsive disorder, morbid obesity, alcoholism, and uncontrolled diabetes mellitus Patients who have undergone major surgery within 1 month prior to screening Patients with serum K+< 3.5 while on replacement treatment Diabetic patients whose blood glucose is poorly controlled as evidenced by HbA1C >8% Patients who have clinically significant impairment in cardiovascular function or are at risk thereof, as evidenced by congestive heart failure (NYHA Class III or IV), unstable angina, sustained ventricular tachycardia, clinically significant bradycardia, high grade atrioventricular (AV) block, history of acute MI less than one year prior to study entry Patients with liver disease or history of liver disease such as cirrhosis, chronic active hepatitis B and C, or chronic persistent hepatitis, or patients with alanine aminotransferase (ALT) or aspartate aminotransferase (AST) more than 1.5 x ULN, serum total bilirubin more than ULN, serum albumin less than 0.67 x lower limit of normal (LLN) at screening Serum creatinine > 2 x ULN Patients not biochemically euthyroid Patients who have any current or prior medical condition that can interfere with the conduct of the study or the evaluation of its results, such as History of immunocompromise, including a positive HIV test result (ELISA and Western blot). An HIV test will not be required, however, previous medical history will be reviewed Presence of active or suspected acute or chronic uncontrolled infection History of, or current alcohol misuse/abuse in the 12 month period prior to screening Female patients who are pregnant or lactating, or are of childbearing potential and not practicing a medically acceptable method of birth control. If a woman is participating in the trial then one form of contraception is sufficient (pill or diaphragm) and the partner should use a condom. If oral contraception is used in addition to condoms, the patient must have been practicing this method for at least two months prior to screening and must agree to continue the oral contraceptive throughout the course of the study and for 3 months after the study has ended. Male patients who are sexually active are required to use condoms during the study and for three month afterwards as a precautionary measure (available data do not suggest any increased reproductive risk with the study drugs) Patients who have participated in any clinical investigation with an investigational drug within 1 month prior to screening or patients who have previously been treated with seliciclib Patients with any ongoing or likely to require additional concomitant medical treatment to seliciclib for the tumor Patients with concomitant treatment of strong CYP3A4 inducers or inhibitors. Patients who were receiving mitotane and/or long-acting somatostatin receptor ligands octreotide long-acting release (LAR) or lanreotide Patients who have received pituitary irradiation within the last 5 years prior to the baseline visit Patients who have been treated with radionuclide at any time prior to study entry Patients with known hypersensitivity to seliciclib Patients with a history of non-compliance to medical regimens or who are considered potentially unreliable or will be unable to complete the entire study Patients with presence of Hepatitis B surface antigen (HbsAg) Patients with presence of Hepatitis C antibody test (anti-HCV) Read more at https://clinicaltrials.gov/ct2/show/NCT03774446

Wed, Jan 8, 2020, from 4:00 PM - 5:00 PM EST Presented by Paul Gardner, MD Associate Professor of Neurological Surgery Neurosurgical Director, Center for Cranial Base Surgery Executive Vice Chairman for Surgical Services University Pittsburgh Medical Center (UPMC) Learning Objectives: Upon completion of this webinar, participants should be able to: Recognize the role for surgery in treating recurrent adenomas Understand the risk and role of radiosurgery for treatment of recurrent Identify treatment indications for recurrent adenomas. Presenter Bio Paul A. Gardner, MD, is an Associate Professor in the Department of Neurological Surgery at the University of Pittsburgh School of Medicine and Neurosurgical Director of the Center for Cranial Base Surgery as well as Executive Vice Chairman for Surgical Services for the Department of Neurological Surgery at the University of Pittsburgh Medical Center (UPMC). Dr. Gardner joined the faculty of the Department of Neurological Surgery at the University of Pittsburgh School of Medicine in 2008 after completing his residency and fellowship training at the University of Pittsburgh. He completed his undergraduate studies at Florida State University, majoring in biochemistry, and received his Medical Degree from the University of Pittsburgh School of Medicine. Dr. Gardner completed a two-year fellowship in endoscopic endonasal pituitary and endoscopic and open skull base surgery at the University of Pittsburgh Medical Center. His research has focused on evaluating patient outcomes following these surgeries and more recently on molecular phenotyping of rare tumors. He is recognized internationally as a leader in the field of endoscopic endonasal surgery, a minimally invasive surgical approach to the skull base. His other surgical interests include pituitary tumors, open cranial base surgery, and vascular surgery. Register here

Levels of adrenocorticotropic hormone (ACTH) in circulation after pituitary surgery may help predict which Cushing’s disease patients will achieve early remission and which will eventually see the disease return, a study shows. Also, the earlier that patients reached their lowest peak of ACTH levels, the better their long-term outcomes. The study, “Prognostic usefulness of ACTH in the postoperative period of Cushing’s disease,” was published in the journal Endocrine Connections. Removing the pituitary tumor through a minimally invasive surgery called transsphenoidal surgery is still the treatment of choice for Cushing’s disease patients. But not all patients enter remission, and even among those who do, a small proportion will experience disease recurrence. While cortisol levels have been suggested as a main predictor of remission and recurrence, there is no consensus as to which cutoff point should be used after surgery, or the best time for measuring this hormone. Because Cushing’s disease is caused by an ACTH-producing tumor in the pituitary gland, and ACTH has a short half-life (approximately 10 minutes), it is expected that ACTH levels drop markedly within a few hours after surgery. Thus, a group of researchers in Spain aimed to determine whether blood levels of ACTH could be useful for predicting remission of Cushing’s disease both immediately after surgery (defined as less than 72 hours) and in the long term. Researchers analyzed 65 patients with Cushing’s disease who had undergone transsphenoidal surgery (seven required a second intervention) between 2005 and 2016. Remission within three months was seen in 56 of 65 cases; late disease recurrence was seen in 18 of 58 cases. Investigators measured the ACTH nadir concentration (defined as the lowest concentration) and the time taken to reach nadir levels after surgery, as well as the plasma ACTH concentration before hospital discharge. While ACTH levels had no predictive value, the team found that people who went into remission had significantly lower ACTH nadir levels and ACTH levels at discharge. On the other hand, levels of ACHT nadir and at discharge were significantly higher for people who experienced a relapse, compared to those who remained in remission. Using artificial intelligence algorithms, the researchers further found that ACTH nadir, ACTH at discharge, and cortisol nadir values were all of great relevance to predict remission within three months. Analysis indicated that using a cutoff point of 3.3 pmol/L of ACTH after surgery and before discharge gave the best sensitivity and specificity for predicting a patient’s prognosis. Researchers further found that the time patients took to reach their ACTH nadir, regardless of nadir levels, also influenced their outcomes. In fact, patients reaching this nadir in less than than 46 hours more likely achieved early remission. And taking longer than 39 hours to reach the ACTH nadir was significantly more frequent in patients who experienced recurrence. This indicates that the time to ACTH nadir is an important measure for prognosis. “In the immediate postoperative period of patients with [Cushing’s disease], the ACTH concentration is of prognostic utility in relation to late disease remission,” the researchers said. Overall, “we propose an ACTH value <3.3 pmol/L as a good long-term prognostic marker in the postoperative period of CD. Reaching the ACTH nadir in less time is associated to a lesser recurrence rate,” the study concluded. PATRICIA INACIO, PHD EDITOR Patricia holds her Ph.D. in Cell Biology from University Nova de Lisboa, and has served as an author on several research projects and fellowships, as well as major grant applications for European Agencies. She also served as a PhD student research assistant in the Laboratory of Doctor David A. Fidock, Department of Microbiology & Immunology, Columbia University, New York. From https://cushingsdiseasenews.com/2019/08/29/acth-levels-after-surgery-help-predict-remission-recurrence-in-cushings-study-suggests/

A shorter duration of adrenal insufficiency — when the adrenal gland is not working properly — after surgical removal of a pituitary tumor may predict recurrence in Cushing’s disease patients, a new study suggests. The study, “Recovery of the adrenal function after pituitary surgery in patients with Cushing Disease: persistent remission or recurrence?,” was published in the journal Neuroendocrinology. Cushing’s disease is a condition characterized by excess cortisol in circulation due to a tumor in the pituitary gland that produces too much of the adrenocorticotropic hormone (ACTH). This hormone acts on the adrenal glands, telling them to produce cortisol. The first-line treatment for these patients is pituitary surgery to remove the tumor, but while success rates are high, most patients experience adrenal insufficiency and some will see their disease return. Adrenal insufficiency happens when the adrenal glands cannot make enough cortisol — because the source of ACTH was suddenly removed — and may last from months to years. In these cases, patients require replacement hormone therapy until normal ACTH and cortisol production resumes. However, the recovery of adrenal gland function may mean one of two things: either patients have their hypothalamus-pituitary-adrenal axis — a feedback loop that regulates ACTH and cortisol production — functioning normally, or their disease returned. So, a team of researchers in Italy sought to compare the recovery of adrenal gland function in patients with a lasting remission to those whose disease recurred. The study included 61 patients treated and followed at the Ospedale Maggiore Policlinico of Milan between 1990 and 2017. Patients had been followed for a median of six years (minimum three years) and 10 (16.3%) saw their disease return during follow-up. Overall, the median time to recovery of adrenal function was 19 months, but while most patients in remission (67%) had not yet recovered their adrenal function after a median of six years, all patients whose disease recurred experienced adrenal recovery within 22 months. Among those with disease recurrence, the interval from adrenal recovery to recurrence lasted a median of 1.1 years, but in one patient, signs of disease recurrence were not seen for 15.5 years. Statistical analysis revealed that the time needed for adrenal recovery was negatively associated with disease recurrence, suggesting that patients with sorter adrenal insufficiency intervals were at an increased risk for recurrence. “In conclusion, our study shows that the duration of adrenal insufficiency after pituitary surgery in patients with CD is significantly shorter in recurrent CD than in the persistent remission group,” researchers wrote. “The duration of AI may be a useful predictor for CD [Cushing’s disease] recurrence and those patients who show a normal pituitary-adrenal axis within 2 years after surgery should be strictly monitored being more at risk of disease relapse,” they concluded. From https://cushingsdiseasenews.com/2019/01/29/faster-adrenal-recovery-may-predict-recurrence-cushings-disease/

Treatment with fluconazole after cabergoline eased symptoms and normalized cortisol levels in a patient with recurrent Cushing’s disease who failed to respond to ketoconazole, a case study reports. The case report, “Fluconazole as a Safe and Effective Alternative to Ketoconazole in Controlling Hypercortisolism of Recurrent Cushing’s Disease: A Case Report,” was published in the International Journal of Endocrinology Metabolism. Ketoconazole, (brand name Nizoral, among others) is an anti-fungal treatment used off-label for Cushing’s disease to prevent excess cortisol production, a distinct symptom of the disease. However, severe side effects associated with its use often result in treatment discontinuation and have led to its unavailability or restriction in many countries. Consequently, there is a need for alternative medications that help manage disease activity and clinical symptoms without causing adverse reactions, and that could be given to patients who do not respond to ketoconazole treatment. In this case report, researchers in Malaysia reported on a 50-year-old woman who fared well with fluconazole treatment after experiencing severe side effects with ketoconazole. The woman had been in remission for 16 years after a transsphenoidal surgery — a minimally invasive brain surgery to remove a pituitary tumor — but went to the clinic with a three-year history of high blood pressure and gradual weight gain. She also showed classic symptoms of Cushing’s disease: moon face, fragile skin that bruised easily, and purple stretch marks on her thighs. Blood and urine analysis confirmed high cortisol levels, consistent with a relapse of the pituitary tumor. Accordingly, magnetic resonance imaging (MRI) of her brain showed the presence of a small tumor on the right side of the pituitary gland, confirming the diagnosis of recurrent Cushing’s disease. Doctors performed another transsphenoidal surgery to remove the tumor, and a brain MRI then confirmed the success of the surgery. However, her blood and urine cortisol levels remained markedly high, indicating persistent disease activity. The patient refused radiation therapy or adrenal gland removal surgery, and was thus prescribed ketoconazole twice daily for managing the disease. But after one month on ketoconazole, she experienced low cortisol levels. Hydrocortisone — a synthetic cortisol hormone — was administered to maintain steady cortisol levels. However, she developed severe skin itching and peeling, which are known side effects of ketoconazole. She also suffered a brain bleeding episode, for which she had to have a craniotomy to remove the blood clot. Since she experienced adverse effects on ketoconazole, which also hadn’t decreased her disease activity, the doctors switched her to cabergoline. Cabergoline (marketed as Dostinex, among others) is a dopamine receptor agonist that has been shown to be effective in managing Cushing’s disease. But cabergoline treatment also did not lower the disease activity, and her symptoms persisted. The doctors then added fluconazole (marketed as Diflucan, among others), an anti-fungal medication, based on studies that showed promising results in managing Cushing’s syndrome. Three months after the addition of fluconazole to her treatment plan, the patient’s clinical symptoms and cortisol levels had responded favorably. At her next clinical visit 15 months later, her condition remained stable with no adverse events. “This case demonstrates the long-term efficacy of fluconazole in tandem with cabergoline for the control of recurrent Cushing’s disease,” the researchers wrote. The favorable outcome in this case also “supports the notion that fluconazole is a viable substitute for ketoconazole in the medical management of this rare but serious condition,” they concluded. From https://cushingsdiseasenews.com/2018/09/27/fluconazole-safe-effective-alternative-recurrent-cushings-patient-case-report/

Finding may lead to therapies that prevent pituitary tumor recurrence. Read more: https://www.nih.gov/news-events/nih-researchers-find-potential-genetic-cause-cushing-syndrome

Fabiana had transsphenoidal surgery (pituitary) July 30th 2004. She had a recurrence after seven years of being Cushing's free. A second pituitary surgery on 10/26/2011 was unsuccessful. Another Golden Oldie, this bio was last updated 9/12/2015 Fabiana will be our guest in an interview on BlogTalk Radio Wednesday, October 21 at 6:00 PM eastern. The Call-In number for questions or comments is (657) 383-0416. The archived interview will be available after 7:00 PM Eastern through iTunes Podcasts (Cushie Chats) or BlogTalkRadio. While you're waiting, there are currently 88 other past interviews to listen to! ~~~ Well it has taken me a year to write this bio...and just to give some hope to those of you just going thru this process...I have to say that after surgery I have not felt better! I am back to who i always knew I was....the depression and anxiety is gone and I am living life like a 24 year old should! I guess it all started when i was sixteen (hindsight is 20-20 i guess). My periods stopped i was tired all the time and the depression started. We all kind of just chalked it up to being sixteen. But my mom insisted something was not right. we talked with my gyno...who said nothing was wrong, I had a fungus on my head (my hair was getting really thin) and sometimes girls who had normal periods (in my case three years of normal periods) just go awry. My mom wasnt hearing that and demanded a script for an endo. I went....he did blood work...and metioned cushings. But nothing came back definitive...so they put me on birthcontol and gave me some hormones and the chushings was never mentioned again because that all seemed to work. As time went on my depression got worse, the shape of my body started to change-my face and stomach was the most noticeable- and my energy level kept going down. I kept going back to the doctors asking to be tested for mono..or something. I went to a psycologist....but i knew there was no reason for my depression. Two of them told me "i had very good insight" and that I didnt need them. I started getting more anxiety..especially about going out socially. High school ended and my typical optimistic personality started to decline. I put on a good act to my friends but my family was seeing me break down all the time. I went away for college (all the while gaining weight). My sophmore year I had a break down..I called my family crying that i needed help. I couldnt beat my depression. I didnt drink in college because i knew that would mean instant weight gain, i barely went out...i exercised everyday..hard....i joined weight watchers...i stuck with it. I was at 103 lbs....that crept up to 110...that crept up to 117...each time my weight goal would be "ohh if i could just get back to 108..112...115" with each weight gain my original weight goal would get higher and higher. Internally i felt like I was constantly under a black cloud..i knew there was no reason why i shoudl feel this way..i was doing great in school, i had a supportive family, an amazing boyfriend and great friends...why was i depressed? I was becoming emotionally draining to the people closest to me...I would go home a lot on the weekends...i was diagnosed with PMDS....like severe PMS..and was given an antidepresant...i hated it it made me feel like a zombie...i stopped taking it and just made it apoint to work on fighting the depression....and the weight gain. When i was done college i was about 120 lbs. My face was getting rounder and rounder..i was noticing more hair on my face and arms...and a hump between my shoulder blades and the bottom of my neck. My mom saw a tv show about Polycystic ovarian syndrome and felt that maybe that was what was going on with me...i went to my PCP with this and she said it was possible and that i should to talk to my gyno....I am 4'8 and at the time weighing close to 125..i talked to my gyno and she said I was not heavy..that i was just "itailan" ..i told her my periods were getting abnormal again even w/the birthcontrol and that i was so tired all the time and my arms and legs ached. I also told her that i was bruising very easily...and that the weight gain would not stop despite my exercising and following the atikins diet very strickly for over 6 weeks. My boyfriend and I decided to try the diet together..he lost 35 llbs in 6 weeks..i lost NOTHING! I went back to my PCP who ordered an ultra sound of my ovaries.....NOTHING.(i kept thinking i was going crazy and that it was all in my head)....she also decided to do some blood work...and as i was walking out the door she said.."you know what..i am going to give you this 24hr urine test too. Just so that we cover everything". I just kept thinking please let something come back ....please dont let this be all my fault...please dont let this be all in my head.....please dont let me be crazy. When i got the test results back it turned out that the 24hr urine test was the one test i needed to get on the right track to finding what was wrong. My cortisol level was 3x's the normal. I went to an endo...by the time i got to the endocronoligist i was up to 130...i could not work a full day without needing a full day of sleep and my body was aching beyond description. I was crying all the time...in my room...and was becoming more and more of a recluse...i would only hang out with my boyfriend in our houses. I looked my symptoms up on the internet and saw cushings...that was it! I went to the endo and told him..i think it is cushings....he said he had only saw it one other time and that he wanted to do more tests. I got CAT scans, x-rays, MRI's....my adrenals my pituitary my lungs....he did a CRH stimulation test which was getting blood work done every fifteen minutes for 90minutes....it took weeks to get that test scheduled..no one had ever heard of it and therefore did not know how to do it.....finally after 3 months of tests my dr. felt he had enough evidence to diagnos me with cushings disease (tumor on my pituitary) I was diagnosed in March of 2004. By this time i was about 137 lbs i had to work part time (i am an occupational therapist for children..i do home visits....i could not make it thru a whole day) In April i had to change to office work...i could not lift the children and i could barely get up off the floor. I have to say i was one of the lucky people who worked for people who were very supportive and accomidating...my boss was very willing to work with me and willing to hold my job for me. July 30th 2004 i finally had transphenodial surgery to remove my tumor (they went thru my lip and nose because they felt my nose was too small). It is now over 1 year later....i am down to 108 lbs, i have so much energy...no depression....and i dont mind looking at myself in the mirror...i am enjoying my friends and my boyfriend...(who stayed with me thru it all) And my family. I feel healthy mentally, emptionally, and physically. And i just got back into my size 2 jeans!!! It was a crappy time...(as i am sure you all can atest to) but i learned a lot.....most importantly i was bombarded by good wishes and prayers....friends requested masses for me...a nun in brazil prayed for me...people who i never thought i touched their lives...took the time to wish me well...send an email..or call....I got to experience the wonderful loving nature of human beings and i was lucky to be supported by my family (my mom, dad, and two younger brothers) and my boyfriend throughout this entire tough journey. This experience taught me to realize the strength i have as well as to appreciate the good and the bad in life. I was on hydrocortizone for about 8 months...i was lucky that my tumor was in its own little sack so my pituitary gland was not touched. In the end in took about 7 years to diagnose me..i think that if the dr. at 16 would have pursued the cushings idea nothing would have been found because it took so long for my symptoms to really peak...needless to say i love my PCP and my endo ..and that i changed gyno's... I just want to let anyone out there going thru this disease to know..you are not alone....and to take each day is stride...when you need help ask for it....and that this road can lead to a happy ending. God Bless! ps- it is ok to feel bad about what you are going thru...it is a tough thing to endure...and when the docotors tell you there is noting wrong.....follow your gut...and you keep searching for the doctor that will listen... If there is anyone in the philadelphis of south jersey area who needs someone to talk to please feel free to email me... .i will help you out the best i can! Update November 6, 2011 Well- here is an update, after seven years of being Cushings free it has returned. With in those seven years I married my college boyfriend and we now have a son- Nicholas who will be 2 in Decemeber. It has been a blessed and wonderful seven years. However right around when my son was turning 1 I started to notice symptoms again. Increase facial hair, the whole "roundness" of my body, buffalo hump. I decided I was going to work out hard, eat right, and see - I didnt just want to jump to any conclusions. I stuck to it- and nothing.....my hair started thinning again and the acne was coming back and then the missed periods.....so I went to my PCP- told them i needed the 24hr urine and wouldnt you know.....427 cortisol level (on that 0-50 scale)......here we go again. So back to endo- now at Penn Pituitary Center.....it was another journey b/c the tumor wasnt definative on MRI, and it seems to be cycling.....but I was diagnosed with Cushings again- with the option of 2nd pit surgery or BLA.......after some months of trying to make a decision I went with the 50/50 chance of the second pituitary surgery on 10/26/2011. It didnt work- my levels never came down in the hospital and I went home w/ out of range cortisol levels and no need for medication......BLURG......Sooooo on to the next step.....after I recover from this surgery I will most likely have the BLA- with the hopes of not having to deal with Cushings ever again. This time around has been a little more difficult just with being a mom and feeling sick- but I still continue to be amazingly blessed with a supportive family and husband and we are surrounded by love and support and for that I am beyond greatful. I keep all of you in my prayers for relief and health- as I ( we all) know this no easy journey. Many Blessings! Fabiana Update September 12, 2015 So to bring this up to date. My second pituitary surgery in 2011 was unsuccessful. January of 2012 I had both of my adrenal glands removed. Going to adrenal insufficiency was a very difficult transition for me. It took me nearly 2 years before I felt functional. As time went on I felt more human, but I haven't felt healthy since that day. I can and do function, but at a lower expectation of what I used to be capable of....my "new normal". My husband and I decided to try for a second child...my pituitary was damaged from the second surgery and we needed fertility...after 8 months of fertility I got pregnant and we had our second son January of 2015. In April of 2015 we discovered that my ACTH was increasing exponentially. MRI revealed a macroadenoma invading my cavernous sinus. The tumor is sitting on my carotid artery and milimeterrs away from my optic chasim. I was not a candidate for another surgery due to the tumors proximity to.both of those vital structures. So September 1st of this year I started daily radiation treatments. I spent my 34th birthday getting my brain zapped. I am receiving proton beam therapy at the Hospital of the University of Pennsylvania. I am so lucky to live so close to an institute that has some of the rarest treatment options. Again Cushing's is disrupting our life, my husband goes with me every night to radiation while family takes turns watching the kids....I am now on my 18th year of fighting this disease. I never imagined it would get to this point. But here we all are making the best of each day, fighting each day and trying to keep things as "normal" as possible. Blessings to all of you fighting this disease...my new go to saying is" 'effing Cushing's"! For you newbies...Fight, Advocate for yourselves, and find a doc who doesn't dismiss you and hang on to them for dear life. HOME | Sitemap | Adrenal Crisis! | Abbreviations | Glossary | Forums | Donate | Bios | Add Your Bio | Add Your Doctor | CushieWiki