[Diagnostic value of bilateral inferior petrosal sinus sampling in various modifications and methods of radiation and radionuclide imaging in the diagnosis and differential diagnosis of ACTH-dependent endogenous hypercortisolism].

AIM: To analyze the diagnostic performance of bilateral inferior petrosal sinus sampling (BIPSS) with desmopressin as a stimulation agent and prolactin measurements to control catheter position with or without the ACTH/prolactin normalized ratio calculation in the differential diagnosis of ACTH-dependent endogenous hypercortisolism, and the diagnostics performance of ectopic ACTH-syndrome (EAS) visualization. MATERIALS AND METHODS: A single-center diagnostic study with a retrospective analysis of the data was carried out. The study included patients with ACTH-dependent endogenous hypercorticism with no visualization of pituitary adenoma on MRI or adenoma sizes less than 6 mm. All patients underwent BIPSS with and without calculation of the ACTH/prolactin normalized ratio. Visualization of an EAS included pituitary MRI (to exclude EAS), whole-body CT scan with contrast, and somatostatin receptor scintigraphy with 99mTc-Tectrotide and CT (99mTc-Tectrotide SPECT). The final verification was based on immunohistochemical confirmation of the tumor or stable remission of Cushing's disease (CD) after surgical treatment. Statistical data processing was carried out by using IBM SPSS Statistics 23. Confidence intervals were calculated using the JavaStat online calculator. RESULTS: 230 BIPSS were performed in 228 patients (166 women, 62 men), of which 178 patients were verified as CD and 50 cases were EAS of various localization. The effectiveness of catheterization of petrosal sinuses was 96.9%. The sensitivity of BIPSS without ACTH/prolactin ratio calculation (n=70) was 95.9% (95% CI 86.3-98.9), specificity was 92% (95% CI 75.0-97.8), for the BIPSS with additional determination of ACTH/prolactin-normalized ratio (n=51) - 97.3% (95% CI 86.2-99.5) and 93.8% (95% CI 71.7-98.9), respectively. The use of the MRI method for this sample of patients had a sensitivity of 60.2% (95% CI 52.6-67.5), specificity of 59.2% (95% CI 44.2-73.0), the total body CT with contrast has a sensitivity of 74% (95% CI 59.7-85.4), specificity of 100% (95% CI 97.95-100). The diagnostic accuracy for 99mTc-Tectrotide SPECT in NET visualization has a sensitivity of 73.3% (95% CI 44.9-92.2), specificity of 100% (95% CI 95.3-100). CONCLUSION: BIPSS with desmopressin stimulation and prolactin measurements to control catheter position, as well as the additional calculation of the ACTH/prolactin-normalized ratio, is an optimal method for the differential diagnosis of EAS. Patients who are identified an EAS on BIPSS may be further referred for 99mTc-Tectrotide SPECT and CT for tumor visualization.

[A diagnostic maze: Cushing's disease]. / Diagnoselabyrinth: Morbus Cushing.

The case of a 78-year-old female presenting to the authors' department with heart failure with dyspnea at minimal exertion (NYHA III) as well as hypertensive blood pressure and hypokalaemia is reported. Laboratory workup showed hypercortisolism. Further workup, including imaging studies and selective catheterisation of the inferior petrosal sinus, resulted in the diagnosis of Cushing's disease caused by a pituitary microadenoma.

Inferior Petrosal Sinus Sampling Tumor Lateralization and the Surgical Treatment of Cushing Disease: A Meta-Analysis and Systematic Review.

OBJECTIVE: To determine whether accurate inferior petrosal sinus sampling (IPSS) tumor lateralization is associated with improved clinical outcomes following the surgical treatment of Cushing disease. METHODS: The presented study was performed in accordance with Preferred Reporting Items for Systematic Reviews and Meta-analyses guidelines. Data regarding patient demographics, IPSS tumor lateralization, and postoperative endocrinologic outcomes were abstracted and pooled with random effects meta-analysis models. Additional meta-regression models were used to examine the association between the accuracy of IPSS tumor lateralization and postoperative outcomes (recurrence/persistence or remission/cure). Statistical analyses were performed using the Comprehensive Meta-Analysis software (significance of P < 0.05). RESULTS: Seventeen eligible articles were identified, yielding data on 461 patients. Within average follow-up duration (∼59 months), the rate of correct IPSS tumor lateralization was 69% [95% confidence interval: 61%, 76%], and the rate of postoperative remission/cure was 78% [67%, 86%]. Preoperative IPSS tumor lateralization was concordant with magnetic resonance imaging lateralization for 53% of patients [40%, 66%]. There was no significant association between the rate of correct IPSS tumor lateralization and postoperative remission/cure among study-level data (P = 0.735). Additionally, there was no association among subgroup analyses for studies using stimulatory agents during IPSS (corticotropin-releasing hormone or desmopressin, P = 0.635), nor among subgroup analyses for adult (P = 0.363) and pediatric (P = 0.931) patients. CONCLUSIONS: Limited data suggest that the rate of correct IPSS tumor lateralization may not be positively associated with postoperative remission or cure in patients with Cushing disease. These findings bring into question the utility of IPSS tumor lateralization in the context of preoperative planning and surgical approach rather than confirming a pituitary source.

Toward Optimized and Cost-Efficient Protocols for Inferior Petrosal Sinus Sampling in the Diagnosis of Cushing Disease.

BACKGROUND AND OBJECTIVE: Conventional protocols for inferior petrosal sinus sampling (IPSS) during the workup of hypercortisolemia require adrenocorticotrophic hormone (ACTH) measurement at multiple time points with corticotropic-releasing hormone (CRH) used as a stimulator. Modernized evidence-based protocols must also reflect the increased utilization of desmopressin (DDAVP) for ACTH stimulation as the manufacturing shortage of traditionally used CRH continues. We model the diagnostic accuracy and potential economic savings of DDAVP utilization and reduced time point sampling. METHODS: A single-institution, retrospective review of patients undergoing IPSS between 2007 and 2021 was performed. A computational search for the minimal set of time points which preserves conventional diagnostic accuracy was performed by testing all 1 through 5-point combinations generated using a binomial expansion. Economic savings were modeled using a publicly available hospital chargemaster. RESULTS: A total of 50 patients qualified for inclusion, 47 of whom were diagnosed with Cushing disease and 3 with ectopic Cushing syndrome. Single-point diagnostic accuracy for DDAVP-stimulated tests was 71.4%-92.9%, and seven 2-point combinations (5-25 procedural minutes) were found, which preserved conventional diagnostic accuracy. Single-point accuracy for CRH-stimulated tests was 67.9%-89.3%, and two 2-point combinations ( t = -15, t = +2 and t = -15, t = +10) preserved accuracy. For every time point removed, the cost of ACTH laboratory tests was reduced by $507 from $3042 for 6-point IPSS). The shortest and most economical stimulator and time point combination that preserved conventional accuracy was DDAVP sampling at t = 0 and t = +5 or t = +2 and t = +5 minutes, which cost $2028 total compared with the most expensive 6-point IPSS option with CRH ($6392). CONCLUSION: DDAVP is a cost-efficient and effective alternative to CRH during IPSS. Our results encourage prospective evaluation of potentially fewer sampling time points in the interest of time and cost efficiency balanced with preserved accuracy.

Angiographic cross-filling between inferior petrosal sinuses and alteration of adrenocorticotropic hormone sampling results for tumor localization in Cushing disease.

OBJECTIVE: Inferior petrosal sinus (IPS) sampling (IPSS) is a diagnostic procedure used to guide diagnostic localization of imaging-negative adrenocorticotropic hormone (ACTH)-secreting pituitary microadenomas. However, the efficacy of IPSS has been suboptimal at accurately lateralizing the adenoma, reducing surgical cure rates and leading to unintended pituitary dysfunction due to the added exploration. One rationale for the occasional imprecision is the existence of additional petrosal sinus collateral channels that connect the IPS bilaterally, which may lead to false localization results during sampling. The aim of this study was to explore a potential connection between normal anatomical variation in the angioarchitecture of the IPSs and the ACTH results obtained in subsequent IPSS tests. METHODS: A retrospective review was performed on all cases between 1998 and 2013 involving patients at a single institution who underwent IPSS for radiographically equivocal pituitary microadenomas. Cases were reviewed for tumor laterality noted on either operative or pathology reports, as well as the presence of angiographic evidence of cross-filling between the sinuses. In addition, ACTH levels from the right and left IPSs were documented at baseline and at 2, 5, and 10 minutes after corticotropin-releasing hormone (CRH) administration. A ratio of the change in ACTH levels measured at the time of maximal response (10 minutes) versus the levels measured at the initial response (2 minutes) was computed for each patient and compared between patients by their angiographic cross-filling status. RESULTS: There were 41 patients with a histopathologically confirmed right- or left-sided ACTH-secreting pituitary microadenoma who underwent preoperative IPSS. Among these patients, 28 (68%) showed angiographic evidence of cross-filling between the IPSs, and 13 showed no cross-filling. On average, ACTH levels increased by a factor of 3.91 ± 0.77 in the contralateral IPS in patients with angiographic cross-filling, compared with a factor increase of only 1.80 ± 0.27 in patients without cross-filling (p = 0.014). In comparison, ACTH levels increased by a factor of 2.01 ± 0.57 in the ipsilateral IPS in patients with cross-filling, and by 8.78 ± 7.30 in those without cross-filling (p = 0.373). CONCLUSIONS: The presence of angiographic cross-filling, suggestive of a greater degree of vascular channel networking between the right and left IPS, is a significant factor influencing the measured rates of change of ACTH in IPSS and may impact the specificity of this test to accurately determine microadenoma laterality in the preoperative setting.

Detecting the interferences in adrenocorticotropic hormone measurement - three cases reinforcing the efficiency of the complementary clinical and laboratory audit.

Accurate measurement of adrenocorticotropic hormone (ACTH) is crucial in the evaluation of pituitary and adrenal disorders. Although great progress has been achieved in ACTH measurement with immunometric assays, interference may occur and adversely affect the clinical management. The report contributes to compiling the evidence on the clinical challenges with the management of the interferences in the ACTH measurement by presenting three cases: two with clinically overt hypercortisolism and discrepant ACTH concentrations within the reference interval; the third case describes the falsely elevated ACTH in a patient with secondary adrenal insufficiency. In all patients, the results obtained with the two immunometric platforms, chemiluminescence (CLIA) immunoassay (Siemens, Immulite) and electrochemiluminescence (ECLIA) immunoassay (Roche, Cobas), were discordant. Serial dilution of plasma samples revealed nonlinearity. After polyethylene glycol (PEG) precipitation recoveries were less than 22%, 26%, and 3%, respectively, supporting interference. Moreover, a decrease in ACTH concentration after incubation in a heterophile antibody-blocking tube was observed in the second case. In the first case, misinterpretation of ACTH led to inferior petrosal sinus sampling (IPSS), whereas timely detection of assay interference prevented further investigations in other cases. Increasing awareness regarding ACTH interference and comprehensive approach in evaluation could allow timely detection, helping to prevent unnecessary testing and perplexing clinical outcomes.

Non-Invasive Biochemical Testing of ACTH-dependent Cushing's Disease: Do We Still Need Petrosal Sinus Sampling?

Differentiating between a pituitary from an ectopic source of ACTH could be a real one of the major challenges of clinical endocrinology. The Bilateral inferior petrosal sinus sampling (BIPSS) is considered the gold standard for identifying the source of ACTH; however, is not available worldwide. After the SARS-CoV-2 pandemic, algorithms that include biochemical and imaging tests have gained importance as an alternative to BIPSS. This review summarizes the drawbacks in the differential diagnosis of ACTH-dependent Cushing; the evolution of diagnostic tests, and the evidence that exists on their performance. As well as a comparison between the advantages and disadvantages of invasive and non-invasive tests.

Diagnostic challenges in cyclic Cushing's syndrome: a systematic review.

Cyclic Cushing's syndrome is a subentity of Cushing's syndrome in which phases of biochemical hypercortisolism (peaks) are followed by spontaneous periods of physiological or even hypocortisolaemic cortisol secretion (troughs). To identify common features of cyclic Cushing's syndrome, we systematically reviewed single case reports and case series in MEDLINE from database inception to Oct 10, 2022, and identified 707 articles, of which 149 articles were assessed for eligibility and 118 articles (covering 212 cases) were included in the analysis. Pituitary tumours accounted for 67% of cases of cyclic Cushing's syndrome (n=143), ectopic tumours for 17% (n=36), and adrenal tumours for 11% (n=23). Occult tumours accounted for 2% of cases (n=4), and 3% of cases were unclassified (n=6). We compared the clinical symptoms and comorbidities of patients with cyclic Cushing's syndrome with those of patients with non-cyclic Cushing's syndrome and observed no major difference. In adrenocorticotropic hormone (ACTH)-dependent cyclic Cushing's syndrome, bilateral inferior petrosal sinus sampling had a positive (ie, true pituitary) and negative (ie, true ectopic) predictive value of 100% when performed during periods of hypercortisolism, versus a positive predictive value of 73% and a negative predictive value of 86% when performed, irrespective of cortisolaemic status. Overall, 6% of patients (n=12) with cyclic Cushing's syndrome had unnecessary surgery due to misclassification. Remission rates were significantly lower and the time to remission significantly longer in patients with cyclic Cushing's syndrome compared with patients with non-cyclic Cushing's syndrome (p<0·001). Variations in biochemical test results due to unpredictable cycle duration and frequency might cause diagnostic challenges resulting in misdiagnoses and missed diagnoses.

Comparison of the preoperative diagnostic accuracy of BIPSS versus MRI for Cushing disease: a single-centre experience.

BACKGROUND: Cushing disease (CD) arises due to a pituitary corticotroph adenoma, which is the most common cause of Cushing syndrome (CS). Bilateral inferior petrosal sinus sampling (BIPSS) is a safe method for differentiating CD from ectopic adrenocorticotropic hormone (ACTH)-dependent CS. Enhanced high-resolution magnetic resonance imaging (MRI) can localize tiny pituitary lesions. The aim of this study was to compare the preoperative diagnostic accuracy of BIPSS versus MRI for CD in CS patients. We performed a retrospective study of patients who underwent BIPSS and MRI between 2017 and 2021. Low- and high-dose dexamethasone suppression tests were performed. Blood samples were collected simultaneously from the right and left catheter and femoral vein before and after desmopressin stimulation. MRI images were obtained, and endoscopic endonasal transsphenoidal surgery (EETS) was performed in confirmed CD patients. Dominant sides of ACTH secretion during BIPSS and MRI were compared with surgical findings. RESULTS: Twenty-nine patients underwent BIPSS and MRI. CD was diagnosed in 28 patients, 27 of whom received EETS. Localizations of microadenomas by MRI and BIPSS agreed with the EETS findings in 96% and 93% of the cases, respectively. BIPSS and EETS were successfully performed on all patients. CONCLUSION: BIPSS was the most accurate method (gold standard) for establishing a preoperative diagnosis of pituitary-dependent CD and was more sensitive than MRI in diagnosing microadenoma. High-resolution MRI with enhancement had an advantage over BIPSS in microadenoma lateralization diagnostics. The combined use of MRI and BIPSS could improve the preoperative diagnosis accuracy in ACTH-dependent CS patients.

Should We Use Prolactin Adjustment in Bilateral Inferior Petrosal Sinus Sampling to Diagnose Cushing Disease? A Joint Meta-Analysis of Head-to-Head Diagnostic Tests Accuracy Studies.

OBJECTIVE: Previous studies have shown inconsistent results regarding the usefulness of prolactin adjustment in bilateral inferior petrosal sinus sampling (BIPSS) in the differential diagnosis of adrenocorticotropic hormone (ACTH)-dependent Cushing syndrome (CS). This meta-analysis compared the diagnostic accuracy of prolactin adjustment versus no adjustment in BIPSS. METHODS: This study searched the PubMed, Embase, Web of Science, Cochrane library, and WanFang databases for published data as of March 2022 on the use of prolactin adjustment in BIPSS to differentially diagnose ACTH-dependent CS. A Bayesian joint bivariate model was used in the head-to-head comparison of the diagnostic accuracy. RESULTS: This meta-analysis included a total of 10 studies with 300 patients. The combined sensitivity and specificity for BIPSS without prolactin adjustment were 94.47% (95% CI, 88.67%-98.44%) and 91.14% (95% CI, 57.17%-99.80%), respectively. The combined sensitivity and specificity after prolactin adjustment were 99.97% (95% CI, 99.03%-100.00%) and 80.69% (95% CI, 50.27%-97.82%), respectively. After the prolactin adjustment, the sensitivity of BIPSS to diagnose Cushing disease was improved with a statistically significant difference (difference in sensitivity, 5.39%; 95% CI, 1.37%-11.26%), whereas the decrease in specificity was without a statistically significant difference (difference in specificity, -9.20%; 95% CI, -42.02% to 26.61%). CONCLUSION: This meta-analysis indicated that prolactin adjustment in BIPSS might help to recognize Cushing disease among patient with ACTH-dependent CS. However, prolactin adjustment may not help identify ectopic ACTH syndrome in BIPSS.

The lateralization accuracy of inferior petrosal sinus sampling in Cushing's disease: experiences of a tertiary center.

BACKGROUND: The purpose of this study is to determine the accuracy of bilateral inferior petrosal sinus sampling (IPSS) in lateralization and to investigate variables associated with accurate IPSS lateralization prediction. METHODS: Initially, data from 55 patients who underwent IPSS in our institution were reviewed retrospectively. IPSS lateralization and pituitary magnetic resonance imaging (MRI) results of these patients were compared with postoperative follow-up and immunohistochemical data to calculate the positive predictive values (PPVs) for IPSS and MRI. Variables likely to be associated with the accurate prediction of IPSS lateralization were analyzed. RESULTS: Twenty-seven patients (85.2% female, mean age of 38.5 ± 13.1 years) were enrolled in the study. With IPSS, interpetrosal ratios were found to be ≥ 1.4 in 26 (96.2%) cases, and this ratio correctly predicted adenoma localization for 18 patients (PPV: 69.2%). For 16 (59.2%) patients, right lateralization was detected, while left lateralization was detected for 10 (37%) patients. Right-sided IPSS lateralization was associated with enhanced accuracy (p = 0.026). No masses were detected in the MRI images of 10 (37%) patients, while microadenoma of ≤ 6 mm was detected for 17 (63%) patients. MRI results (when positive) correctly identified adenoma localization for 14 of the patients with lateralization accuracy higher than that of IPSS (PPV: 82.3% vs. 69.2%). DISCUSSION: IPSS is a valuable procedure in detecting tumor lateralization, especially in patients with Cushing's disease who have negative pituitary MRI results. However, since lateralization has a limited reliability, the pituitary gland should be comprehensively evaluated by taking into account the MRI findings (if positive) as well as data on the side of IPSS lateralization.

Is Desmopressin Useful in the Evaluation of Cushing Syndrome?

The desmopressin test was first described 30 years ago. Based on the differential secretagogue properties of desmopressin on adrenocorticotropin (ACTH) release between normal and corticotroph tumor cells, this test was intended to facilitate the diagnosis of Cushing syndrome (CS). The distinct expression of the various arginine vasopressin receptors between normal pituitary, corticotroph tumors, or neuroendocrine tumors cells secreting ACTH ectopically suggested that this test could facilitate the etiological diagnosis of ACTH-dependent CS. In this review, we analyze the merits and pitfalls of desmopressin use in the diagnostic procedures of CS. Desmopressin response is not able to completely differentiate the various etiologies of CS; its wider availability has allowed its use for inferior petrosal sinus sampling confirmation of a pituitary source of ACTH excess. In addition, desmopressin can be useful to demonstrate adequate corticotroph tumor resection when its stimulatory effect is lost following pituitary surgery of patients with Cushing disease. Desmopressin response can also be a marker of the risk of longer-term postoperative recurrence. However, this review also highlights the lack of consensual criteria of normal or abnormal response to desmopressin in its various uses and requirement for further research on its usefulness.

Positive predictive value and trends of inferior petrosal sinus sampling (IPSS) in diagnosing cushing disease and ectopic ACTH secretion: A systematic review and meta-analysis.

BACKGROUND: Inferior petrosal sinus sampling (IPSS) offers a means of differentiating between Cushing disease and Cushing syndrome with lower false-positive and false-negative rates relative to traditional techniques. However, consolidated data on efficiency reflecting contemporary use is lacking. We present a comprehensive meta-analysis of IPSS as a means of diagnosing ACTH-cortisol axis derangements via both CRH and desmopressin-stimulated techniques. METHODS: Searches of 7 electronic databases from inception to December 2020 were conducted following PRISMA guidelines. Articles were screened against pre-specified criteria. Outcomes were pooled by random-effects meta-analyses of proportions where possible. We performed a meta-analysis of sixty-eight unique publications, assessing each technique for positive predictive value (PPV), false positive rates, and overall changes in practice patterns over time. RESULTS: A total of 68 studies satisfied all criteria, with 3685 (3471, 94.2% confirmed) and 332 (285, 85.8% confirmed) patients tested for Cushing's disease and syndrome, respectively. Pooled analyses demonstrated an overall PPV of 89.3% (95%CI[83.6%, 94.0%]) in CRH stimulation diagnosis of Cushing disease. In desmopressin stimulation, our analyses demonstrated an overall PPV of 96.5% (95%CI[94.5%, 98.1%]) in diagnosis of Cushing disease. There was a significant decline in the use of CRH-stimulation IPSS in diagnosis of both Cushing disease (p = 0.0055) and Cushing syndrome (p = 0.013). Concurrently, there was a significant increase in the use of desmopressin-stimulation IPSS in diagnosis of both pathologies (p < 0.0001). CONCLUSION: Our findings demonstrate significant changes in practice patterns with respect to IPSS stimulation technique. Our pooled analyses demonstrate improved diagnostic performance in desmopressin stimulation procedures relative to CRH stimulation procedures. Further multi-institutional studies with special attention to acquiring quality data for sensitivity, specificity, and other critical analyses are necessary to truly evaluate this promising technique.

Surgical strategies in the treatment of MR-negative Cushing's Disease: a systematic review and treatment algorithm.

PURPOSE: Several surgical strategies have been proposed to treat MRI-negative Cushing's Disease. These include tumor removal, if identified, and if a tumor is not identified, resection of varying degrees of the pituitary gland, often guided by inferior petrosal sinus sampling (IPSS). The relative risks and benefits of each strategy have never been compared. METHODS: This systematic review of the literature included only studies on the results of surgery for MRI-negative patients with Cushing's Disease in which the surgical strategy was clearly described and associated remission and/or hypopituitarism rates detailed for each strategy. RESULTS: We identified 12 studies that met inclusion criteria for remission rates and 5 studies for hypopituitarism rates. We divided cases into 6 resection strategies. Remission and hypopituitarism rates for each strategy were: (1) tumor identified, resect tumor only (68%, 0%); (2) resect tumor and surrounding capsule (85%, 0%); and if the tumor was not identified (3) resect inferior 1/3 of gland (78%, no data); (4) resect 30-50% of gland based on IPSS (68%, 13%); (5) resect > 50% but < 100% of gland (65%, 9%); (6) resect entire gland (66%, 67%). Strategy 3 only contained 9 patients. CONCLUSION: Remission rates for MRI-negative Cushing's Disease support surgery as a reasonable approach. Results are best if a tumor is found. If a tumor is not identified, one can either remove one-third of the gland guided by IPSS lateralization, or remove both lateral portions along with the inferior portion leaving sufficient central gland to preserve function. Our recommendations are limited by the lack of rigorous and objective data.

Limited Invasive Protocol: Optimizing Diagnostic Modalities in Corticotropin Mediated Cushing Syndrome.

BACKGROUND: To limit the role of bilateral inferior petrosal sinus sampling (BIPSS) in distinguishing between Cushing disease (CD) and ectopic Cushing syndrome (ECS), recent reports have proposed a noninvasive approach based on a combination of biochemical testing and radiological imaging as an alternative to the conventional invasive strategy (CIS). However, this strategy requires further validation. The current study aimed to evaluate 2 limited invasive protocols (LIP-1 and LIP-2) in limiting the role of BIPSS while maintaining a diagnostic accuracy similar to that of CIS. METHODS: This was a single-center study conducted on individuals with corticotropin-dependent Cushing syndrome. The LIPs were based on performing high-dose dexamethasone suppression (>50% cut-off in first [LIP-1] and >80% in second [LIP-2]) and magnetic resonance imaging of the sella in all individuals and selective use of computed tomography of the chest and abdomen before BIPSS. These LIPs were evaluated for limiting the use of BIPSS, their accuracy, and cost in comparison to CIS. RESULTS: Of the 206 individuals, 114 (97 of CD and 21 of ECS) were eligible for the current study. Using LIP-1, LIP-2, and CIS, BIPSS could have been avoided in 62.3%, 35.9%, and 25.4% of individuals, respectively. The positive predictive value for CD using LIP-1 and LIP-2 was 98.9% and 100%, respectively. The cost per patient evaluated using LIP-1, LIP-2, and CIS was $602.21, $966.81, and $1107.78, respectively. CONCLUSION: LIPs represent an equally accurate, less invasive, and more cost-effective alternative to the CIS for distinguishing between CD and ECS.

Diagnostic accuracy of bilateral inferior petrosal sinus sampling using desmopressin or corticotropic- releasing hormone in ACTH-dependent Cushing's syndrome: A systematic review and meta-analysis.

The current gold standard diagnostic method for Cushing disease (CD) is bilateral inferior petrosal sinus sampling (BIPSS) after corticotropin-releasing hormone (CRH) stimulation. Due to shortages of CRH, BIPSS has been performed with desmopressin (DDAVP) instead. The objective of this systematic review and meta-analysis was to estimate the diagnostic accuracy of BIPSS using DDAVP or CRH for the differential diagnosis of Cushing's syndrome (CS). A literature review was done in PubMed, Scopus, EMBASE, and google scholar databases to derive summary estimates of the overall diagnostic sensitivity and accuracy of BIPSS using DDAVP or CRH in Cushing's syndrome. Pooled sensitivity, specificity, diagnostic odds ratio and summary receiver operating characteristic curves (SROC) for differential diagnosis of Cushing's syndrome in the random-effects models, were computed. Overall, 11 different studies with a total of 612 participants, were eligible for the analysis. Five articles with data on BIPSS using DDAVP, 5 papers on BIPSS using CRH, and another one evaluated the results of stimulation using DDAVP, with or without CRH, for differential diagnosis of Cushing's syndrome. The pooled (95% CI) sensitivity and specificity of BIPSS using DDAVP, were 96% (91-98%) and 1.00 (0.00-1.00), respectively. The area under the SROC curve was 0.95. The pooled (95% CI) sensitivity and specificity of BIPSS using CRH, were 98% (92-99%) and 1.00 (0.00-1.00), respectively, and the area under the SROC curve was 0.98. The I2 index (95% CI) was 0% (0-100%) for both BIPSS using DDAVP and using CRH. As a result, DDAVP stimulation is a safe, effective, less expensive, valuable and available alternative to CRH in the setting of BIPSS for all age groups of patients with CS. Registration code in PROSPERO: CRD42021292531.

Does concomitant prolactin measurement increase the accuracy of inferior petrosal sinus sampling?

INTRODUCTION: Prolactin (PRL) measurement during inferior petrosal sinus sampling (IPSS) can be helpful to improve the accuracy. We aimed to evaluate the effect of measuring PRL levels as a predictor for the accuracy of IPSS and evaluate its impact on the lateralization of adenomas. METHODS: In this retrospective cohort study, we reviewed 51 patients who had undergone IPSS for the investigation of ACTH-dependent hypercortisolism. RESULTS: Forty-nine patients had proven Cushing's disease (CD), one had EAS, and the remaining one patient had adrenal adenoma. Forty-seven patients had an above 2 ACTH IPS/P ratio at baseline, and all the post-corticotropin-releasing hormone (CRH) ACTH IPS/P ratios of patients with proven CD were above 3. In these two patients whose ACTH IPS/P ratio at baseline was below 2, PRL IPS/P ratios were above 1.8 in only the dominant side, which was considered secondary to a prolactin intersinus gradient due to the biological effects of the tumor. PRL-adjusted ACTH IPS/P ratios were > 1.3 in all patients with proven CD; it was 0.7 in the patient with EAS. Surgically confirmed positive lateralization was observed in 55.1% of patients with the ACTH gradient, but when PRL-adjusted ACTH IPS/IPS ratios were used in addition to the ACTH gradient, the ratio increased to 67.3%. CONCLUSION: Although PRL-adjusted ACTH IPS/P ratios can be helpful to improve the accuracy of results during IPSS procedures, a prolactin intersinus gradient towards the ACTH-dominant side in patients with CD may invalidate PRL as an indicator of pituitary venous outflow.

Use of magnetic resonance venography for inferior petrosal sinus sampling.

BACKGROUND: Inferior petrosal sinus (IPS) sampling (IPSS) is a transvenous interventional procedure performed to diagnose Cushing's disease. The reported IPSS failure rate is approximately 10% because IPS catheter delivery is conducted blindly and is challenging because of IPS anatomical variations. This study aimed to evaluate the usefulness of preprocedural magnetic resonance venography (MRV) for assessing IPS access routes before IPSS. METHODS: Nineteen consecutive patients who underwent IPSS at a single university hospital in Japan were retrospectively studied. A preprocedural MRV protocol optimized to visualize the IPS before IPSS was established and utilized in the eight most recent cases. An IPSS procedure was considered successful when bilateral IPS catheterization was accomplished. Patient demographics, IPSS success rate, and radiation dose required during IPSS were compared between two groups: MRV group (N = 8) and no-MRV group (N = 11) before IPSS. RESULTS: There were no significant differences in age, sex, and IPSS success rates between the groups. The average radiation dose was 663.6 ± 246.8 (SD) mGy and 981.7 ± 389.5 (SD) mGy in the MRV group and no-MRV group, respectively. Thus, there was a significant reduction in radiation exposure in the MRV group (p = 0.044). Catheterization of the left IPS was unsuccessful in only one patient in the MRV group owing to IPS hypoplasty, as found on the MRV. CONCLUSIONS: Hypoplastic IPSs occur in patients and can complicate IPSS. Preprocedural MRV assessment is useful for understanding venous anatomy and preventing unnecessary intravenous catheter manipulation during IPSS, which involves blind manipulation around the IPS.

Indication to dynamic and invasive testing in Cushing's disease according to different neuroradiological findings.

PURPOSE: Dynamic testing represents the mainstay in the differential diagnosis of ACTH-dependent Cushing's syndrome. However, in case of undetectable or detectable lesion < 6 mm on MRI, bilateral inferior petrosal sinus sampling (BIPSS) is suggested by current guidelines. Aim of this study was to analyze the performance of CRH, desmopressin and high-dose dexamethasone suppression test (HDDST) in the differential diagnosis of ACTH-dependent Cushing's syndrome as well as the impact of invasive and noninvasive tests on surgical outcome in patients affected by Cushing's disease (CD). METHODS: Retrospective analysis on 148 patients with CD and 26 patients with ectopic ACTH syndrome. RESULTS: Among CD patients, negative MRI/lesion < 6 mm was detected in 97 patients (Group A); 29 had a 6-10 mm lesion (Group B) and 22 a macroadenoma (Group C). A positive response to CRH test, HDSST and desmopressin test was recorded in 89.4%, 91·4% and 70.1% of cases, respectively. Concordant positive response to both CRH/HDDST and CRH/desmopressin tests showed a positive predictive value of 100% for the diagnosis of CD. Among Group A patients with concordant CRH test and HDDST, no difference in surgical outcome was found between patients who performed BIPSS and those who did not (66.6% vs 70.4%, p = 0.78). CONCLUSIONS: CRH, desmopressin test and HDDST have high accuracy in the differential diagnosis of ACTH-dependent CS. In patients with microadenoma < 6 mm or non-visible lesion, a concordant positive response to noninvasive tests seems sufficient to diagnose CD, irrespective of MRI finding. In these patients, BIPSS should be reserved to discordant tests.