Targeted analysis of Ubiquitin-Specific Peptidase (USP8) in a population of Iranian people with Cushing's disease and a systematic review of the literature.

OBJECTIVE: Activating mutation in Ubiquitin-specific peptidase (USP8) is identified to enhance cell proliferation and adrenocorticotropic hormone (ACTH) secretion from corticotroph pituitary adenoma. We investigated the USP8 variant status in a population of Iranian people with functional corticotroph pituitary adenoma (FCPA). Moreover, a systematic review was conducted to thoroughly explore the role of USP8 variants and the related pathways in corticotroph adenomas, genotype-phenotype correlation in USP8-mutated individuals with FCPA, and the potential role of USP8 and epidermal growth factor receptor (EGFR) as targeted therapies in PFCAs. METHODS: Genetic analysis of 20 tissue samples from 19 patients with PFCAs was performed using Sanger sequencing. Moreover, a systematic literature review was performed using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. PubMed, Scopus, web of Sciences, and Cochrane databases were searched. The last search was performed on 20 September 2023 for all databases. RESULTS: In our series, we found two somatic mutations including a 7-bp deletion variant: c.2151_2157delCTCCTCC, p. Ser718GlnfsTer3, and a missense variant: c.2159 C > G, p. Pro720Arg (rs672601311) in exon 14. The Systematic review indicated USP8 variant in 35% of corticotroph adenomas, with the highest frequency (25%) in 720 code regions, p. Pro720Arg. Data regarding the impact of USP8 mutational status on clinical characteristics and outcomes in FCPAs are inconsistent. Moreover, Pasireotide as well as inhibitors of EGFR such as Gefitinib and Lapatinib, as well as USP8 inhibitors including -ehtyloxyimino9H-indeno (1, 2-b) pyrazine-2, 3-dicarbonitrile, DUBs-IN-2, and RA-9 indicated promising results in treatment of corticotroph adenomas. CONCLUSION: Although the USP8-EGFR system has been identified as the main trigger and target of corticotroph tumorigenesis, more precise multicenter studies are required to yield more consistent information regarding the phenotype-genotype correlation and to develop effective targeted therapies.

Neuromedin B receptor as a potential therapeutic target for corticotroph adenomas.

PURPOSE: Cushing's disease (CD) results from autonomous adrenocorticotropic hormone (ACTH) secretion by corticotroph adenomas, leading to excessive cortisol production, ultimately affecting morbidity and mortality. Pasireotide is the only FDA approved tumor directed treatment for CD, but it is effective in only about 25% of patients, and is associated with a high rate of hyperglycemia. Neuromedin B (NMB), a member of the bombesin-like peptide family, regulates endocrine secretion and cell proliferation. Here, we assessed NMB and NMB receptor (NMBR) expression in human corticotroph adenomas and the effects of NMBR antagonist PD168368 on murine and human corticotroph tumors. METHODS: To investigate NMB and NMBR expression, real-time qPCR and immunostaining on human pathological specimens of corticotroph, non-functional and somatotroph adenomas were performed. The effects of PD168368 on hormone secretion and cell proliferation were studied in vitro, in vivo and in seven patient-derived corticotroph adenoma cells. NMB and NMBR were expressed in higher extent in human corticotroph adenomas compared with non-functional or somatotroph adenomas. RESULTS: In murine AtT-20 cells, PD168368 reduced proopiomelanocortin (Pomc) mRNA/protein expression and ACTH secretion as well as cell proliferation. In mice with tumor xenografts, tumor growth, ACTH and corticosterone were downregulated by PD168368. In patient-derived adenoma cells, PD168368 reduced POMC mRNA expression in four out of seven cases and ACTH secretion in two out of five cases. A PD168368-mediated cyclin E suppression was also identified in AtT-20 and patient-derived cells. CONCLUSION: NMBR antagonist represents a potential treatment for CD and its effect may be mediated by cyclin E suppression.

Successful management of a patient with active Cushing's disease complicated with coronavirus disease 2019 (COVID-19) pneumonia.

We provide the details of the successful management of a patient with active Cushing's disease complicated with coronavirus disease 2019 (COVID-19) pneumonia. The patient was a 27-year-old Japanese female healthcare worker who was scheduled to undergo pituitary surgery for Cushing's disease. She had been in close contact with an undiagnosed patient infected with COVID-19 and then developed COVID-19 pneumonia. Despite a lack of known risk factors associated with severe COVID-19 infection, the patient's dyspnea worsened and her respiratory condition deteriorated, as indicated by the need for 7 L/min oxygen supply by mask to maintain her oxygen saturation at >90%. Medical treatment was initiated to control hypercortisolism by the 'block and replace' regimen using steroidogenesis inhibitors and hydrocortisone. The COVID-19 pneumonia improved with multi-modal treatment including antiviral therapy. One month later, after a negative severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) test result and with appropriate protection against virus transmission to medical staff in the operating room and daily medical care nurses, trans-sphenoidal surgery was performed by our highly experienced pituitary surgeon. One month after the surgery, the patient's basal ACTH and cortisol levels and urinary free cortisol were all under the detection limit. Surgical remission was expected. Since hypercortisolism due to active Cushing's disease may worsen a COVID-19 infection, multi-disciplinary management that includes appropriate and prompt treatment strategies is mandatory in such cases.

Rapid disease progression in patient with mismatch-repair deficiency pituitary ACTH-secreting adenoma treated with checkpoint inhibitor pembrolizumab.

Secreting pituitary adenomas are tumors for which few treatment options are available, including surgical treatment and management of hormonal imbalance due to altered pituitary secretion. In case of inoperable relapse, radiotherapy or chemotherapeutic treatment can be considered; the effectiveness of these treatments, however, remains limited. In the immunotherapy era, it is necessary to select patients who can benefit from immunotherapeutic treatment. Mismatch repair deficiency is strongly associated with responsiveness to anti-PD-1 in other cancers and can be detected using immunohistochemistry for MLH1, MSH2, MHS6, and PMS2. In this case report, we report a case of rapid disease progression to pembrolizumab in a patient with a MMRd pituitary adrenocorticotropic hormone (ACTH)-secreting adenoma. For the best of our knowledge, we described for the first time, a poor efficacy of pembrolizumab in a patient with ACTH-secreting pituitary adenoma having mismatch repair deficiency probably caused by high levels of cortisol in this patient. Prospective study should be performed to assess the activity of immune checkpoint inhibitor alone or in association with temozolomide in this subsetting of pituitary adenomas.

Long-course temozolomide in aggressive pituitary adenoma: real-life experience in two tertiary care centers and review of the literature.

PURPOSE: Aggressive pituitary adenomas (APAs) and pituitary carcinomas (PCs) are challenging for their invasive nature, resistance to treatment and recurrences. Temozolomide (TMZ) is used with benefit and well-tolerated toxicity profile in APAs and PCs. In most studies patients received ≤ 12 cycles but the best length of treatment is debated since other options after discontinuation are scarce and a second course is mainly unsuccessful. METHODS: We report outcomes of 8 patients with APAs and PCs treated with TMZ for more than 12 continuous cycles with a literature review. Data were retrospectively collected from Padua and Milan University Hospitals. TMZ was used as a single agent (150-200 p.o. mg/m2 daily, 5/28 days) for 14 to 45 cycles. RESULTS: Eight patients (7 M), 7 APAs and 1 PC. Previous treatments included neurosurgery and radiotherapy in all cases except two giant masses (ACTH-silent APA and prolactinoma). No patient had progression disease (PD) during long-term treatment nor toxicities. No one had complete response (CR) but four had partial response (PR). Four ACTH+ tumors maintained stable disease (SD) but the secretion pattern improved in all. After drug withdrawal, three had delayed PD (2 after 18 and one after 29 months, all ACTH+); two are still in SD. CONCLUSIONS: TMZ may be useful and well-tolerated in APAs and PCs as a long-term therapy. PR appears within the first cycles with no escape throughout the treatment; most patients achieve SD. We suggest extended protocols particularly in responsive ACTH+ PAs and PCs, when further therapies may be unsuccessful.

Lapatinib decreases the ACTH production and proliferation of corticotroph tumor cells.

Cushing's disease is almost always caused by hypersecretion of adrenocorticotropic hormone (ACTH) from a pituitary adenoma. A mutation in the deubiquitinase gene USP8 has been found in human ACTH-producing pituitary adenoma cells. This mutational hotspot hyperactivates USP8, rescuing epidermal growth factor receptor (EGFR) from lysosomal degradation and ensuring its sustained signaling in Cushing's disease. An EGFR inhibitor would be an effective anti-tumor agent in EGFR-related tumors. We investigated the effect of a potent dual tyrosine kinase inhibitor, lapatinib, on ACTH production and cell proliferation in AtT-20 mouse corticotroph tumor cells. Lapatinib decreased proopiomelanocortin (Pomc) mRNA levels and ACTH levels in AtT-20 cells and also inhibited cell proliferation, induced apoptosis, and decreased pituitary tumor-transforming gene 1 (Pttg1), a hallmark of pituitary tumors, mRNA levels. KSN/Slc nude mice were subcutaneously inoculated with AtT-20 cells. After 1 week, the mice were randomized either to control or lapatinib groups. The inhibitor decreased the tumor weight of AtT-20 allografts in vivo versus control mice. Lapatinib also significantly decreased Pomc and Pttg1 mRNA levels in the tumor and plasma ACTH and corticosterone levels in vivo. Thus, lapatinib decreases the ACTH production and proliferation of corticotroph tumor cells. An EGFR-targeting therapy could be an important treatment for Cushing's disease.

Clinical outcomes in male patients with lactotroph adenomas who required pituitary surgery: a retrospective single center study.

PURPOSE: Lactotroph adenomas (LA) are the most frequently encountered pituitary tumors. Although more frequently observed in women, LAs in men were recently included in a more aggressive category regardless of histological grading, by the WHO. We aimed to perform a rigorous retrospective review of a single center's pre-operative evaluation, patient characteristics and outcomes of male LAs patients requiring pituitary surgery. METHODS: A retrospective review, over 11 years, of patients who underwent resection of a pituitary adenoma at a single center was conducted. Predictors of persistent disease in male LAs patients along with a comparison to predictors of silent corticotroph adenomas (SCAs) patients who also underwent surgery at the center was also conducted. RESULTS: Thirty-one male patients with LAs were identified. When compared to SCAs patients, LAs male patients were younger (41 vs. 50 years of age, p = 0.01). Men with LAs had more invasive tumors (75% vs. 44.7% p = 0.02). More LAs in men had residual tumor after surgery than patients with SCA (92.6% vs. 42.1%, p < 0.001). Male patients with LAs and patients with SCA had similar rates of requiring additional surgery (28.9% vs. 24.1%, p = NS) and radiation therapy (18.4% vs. 19.4%, p = NS). CONCLUSIONS: High rates of DA resistance, invasive tumors and postoperative residual disease in male patients with LA who required surgery are shown. Surgery improved optic chiasm compression, PRL level and central hypogonadism but, not surprisingly, failed to normalize other pituitary hormones and/or eliminate need for DA therapy.

AT-101 acts as anti-proliferative and hormone suppressive agent in mouse pituitary corticotroph tumor cells.

PURPOSE: Gossypol, a naturally occurring compound in cottonseeds, has anticancer effects against several tumor cell lines. It has been extensively studied in clinical trials and is well tolerated with a favorable safety profile. AT-101, a derivative of R (-)-gossypol, binds to Bcl-2 family proteins and induces apoptosis in vitro. Although transsphenoidal surgical excision of the pituitary corticotroph adenoma is the gold standard of care, it is not successful all the time. Medical therapy for Cushing's disease still remains a challenge for the clinicians. We aimed to investigate the cytotoxic and apoptotic effects of AT-101 in mouse pituitary corticotroph tumor AtT20 cells. METHODS: Cytotoxic effect of AT-101 was assessed by XTT cell viability assay. Apoptosis was shown by measuring DNA fragmentation and Caspase-3/7 activity. Changes in mRNA expressions of apoptosis-related genes were investigated by qPCR array after treatment with AT-101. ACTH was measured by ACTH-EIA Kit. RESULTS: AT-101 induced cytotoxicity and apoptosis in AtT20 cells. mRNA levels of pro-apoptotic genes such as TNFR-SF-10B, Bid, PYCARD, Caspase-8, Caspase-3, and Caspase-7 were induced by 2.0-, 1.5-, 1.7-, 1.5-, 1.6-, and 2-fold, respectively, in AtT20 cells by AT-101 treatment. Moreover, some of the anti-apoptotic genes such as BCL2L10, NAIP1, and PAK-7 were reduced by 2.1-, 2.3-, 4.0-fold, respectively, in AtT20 cells. AT-101 also decreased ACTH secretion significantly. CONCLUSION: AT-101 induces apoptosis in mouse pituitary corticotroph tumor cells.

Temozolomide for aggressive ACTH pituitary tumors: failure of a second course of treatment.

INTRODUCTION: Temozolomide (TMZ) is an oral alkylating agent that has been used over the past 8 years to treat aggressive pituitary tumors resistant to conventional therapy. To date, only 25 patients treated with TMZ for ACTH producing pituitary tumors (14 adenomas and 11 carcinomas) have been reported. MATERIALS AND METHODS: We present a retrospective review of the medical records of three patients with aggressive ACTH producing adenomas treated with TMZ. In the three cases there was evidence of progression to conventional therapy before starting TMZ. We used the conventional scheme for the treatment of gliomas until completing 7, 12 and 6 cycles respectively. Reduction in tumor size was evident after the 3rd, 5th and 4th cycle of TMZ and progression free survival was 25, 19 and more than 12 months in the three patients respectively. Improvement of the ocular and visual symptoms was evident after the 4th cycle of treatment in all cases. Normalization of urinary free cortisol levels was achieved after the 3rd and 9th cycle in the two cases with hypercortisolism. Two of the three patients received a second course of treatment when the disease progressed but it did not stop tumor progression. The principal side effects were G3 neutropenia, G1 and G2 thrombocytopenia, G1 lymphopenia, asthenia and nausea. CONCLUSION: The treatment with TMZ is effective and safe in patients with aggressive corticotrophin tumors resistant to conventional therapy. Nevertheless once the disease progresses, a second course of treatment does not seem to be effective.

Paradoxical and atypical responses to pasireotide in aggressive ACTH-secreting pituitary tumors.

PURPOSE: Pasireotide is the only pituitary targeted medication registered for the treatment of Cushing's disease. Drug efficacy data are largely based on a major prospective study in which the vast majority of patients had microadenomas. The purpose of this study was to summarize results of pasireotide treatment of ACTH secreting macroadenomas from our center. METHODS: Retrospective review of data extracted from clinical files. RESULTS: Three patients presented with large and invasive macroadenomas that required several surgical interventions and radiotherapy treatments. Patient 1 is a 57 year-old male who developed an extreme (27-fold) paradoxical response of urinary free cortisol (UFC) levels as measured 2 weeks after pasireotide institution, which increased further (71-fold) in response to dose increment but decreased to baseline levels after treatment interruption. Patient 2 is a 44 year old woman with a long standing (26 years) ACTH-secreting carcinoma metastatic to bone and after bilateral adrenalectomy. After an initial excellent response to pasireotide treatment, ACTH levels escaped suppression and a further rebound was noted 6 weeks after treatment interruption. Patient 3 is a 53 year old man that after escape from temozolomide therapy was started on pasireotide and rapidly responded by almost normalizing UFC excretion after 4 weeks, but returned to baseline UFC levels after four additional weeks of treatment. CONCLUSIONS: We describe as yet unreported atypical responses to pasireotide treatment in patients with aggressive ACTH-secreting tumors. Increased vigilance is recommended during pasireotide treatment of such patients.

Medical combination therapies in Cushing's disease.

INTRODUCTION: There has been growing interest on medical therapy for the management of Cushing's disease (CD), particularly in cases of persistent or recurrent hypercortisolism. Ketoconazole, an inhibitor of adrenal steroidogenesis, is the most widely used drug, whereas cabergoline and pasireotide are the most promising centrally acting agents. The main purpose of this review article is to highlight the options of medical treatment for CD, with a special emphasis on combination therapies, a topic that has only been addressed by a limited number of studies. CONCLUSIONS: According to the results of these studies, combination therapies involving medications with additive or synergistic effects on ACTH and cortisol secretion seem quite attractive as they yield higher probability of longterm control of the hypercortisolism at lower doses, a lower incidence of side-effects, and possibly a lower rate of treatment escapes. Currently, ketoconazole, cabergoline, and pasireotide are the best drugs to be prescribed in combination.

Pituitary-directed medical therapy in Cushing's disease.

Transsphenoidal surgery remains the first line therapy in Cushing's disease, but a large number of patients will not be cured or disease will recur over time. Repeat pituitary surgery, bilateral adrenalectomy, and radiation have limitations with respect to efficacy and/or side effects. Therefore, there is a clear need for an effective medical treatment. The studies reviewed here suggest a role for pituitary-directed therapies, applying multireceptor ligand somatostatin analogs like pasireotide or second-generation dopamine agonists. Retinoic acid has been also studied in a small prospective study. These compounds target ACTH-secretion at the pituitary level and possibly inhibit corticotrope proliferation. Specific side effects of these compounds need to be considered, especially when used as long-term therapy. These novel approaches could provide options for treatment of patients in whom surgery has failed or is not possible, and while awaiting effects of radiation therapy. Preoperative use to decrease cortisol excess, potentially reducing perioperative complications, needs to be further studied.

Medical therapy for Cushing's disease: adrenal steroidogenesis inhibitors and glucocorticoid receptor blockers.

Morbidity and mortality in Cushing's disease (CD) patients are increased if patients are not appropriately treated. Surgery remains the first line therapy, however the role of medical therapy has become more prominent in patients when biochemical remission is not achieved/or recurs after surgery, while waiting effects of radiation therapy or when surgery is contraindicated. Furthermore, use of preoperative medical therapy has been also recognized. In addition to centrally acting therapies (reviewed elsewhere in this special issue), adrenal steroidogenesis inhibitors, and glucocorticoid receptor antagonists are frequently used. A PubMed search of all original articles or abstracts detailing medical therapy in CD, published within 12 months (2013-2014), were identified and pertinent data extracted. Although not prospectively studied, ketoconazole and metyrapone have been the most frequently used medical therapies. A large retrospective ketoconazole study showed that almost half of patients who continued on ketoconazole therapy achieved biochemical control and clinical improvement; however almost 20% discontinued ketoconazole due to poor tolerability. Notably, hepatotoxicity was usually mild and resolved after drug withdrawal. Etomidate remains the only drug available for intravenous use. A new potent inhibitor of both aldosterone synthase and 11ß-hydroxylase, following the completion of a phase II study LCI699 is being studied in a large phase III with promising results. Mifepristone, a glucocorticoid receptor antagonist, has been approved for hyperglycemia associated with Cushing's syndrome based on the results of a prospective study where it produced in the majority of patients' significant clinical and metabolic improvement. Absence of both a biochemical marker for remission and/or diagnosis of adrenal insufficiency remain, however, a limiting factor. Patient characteristics and preference should guide the choice between different medications in the absence of clinical trials comparing any of these therapies. Despite significant progress, there is still a need for a medical therapy that is more effective and with less adverse effects for patients with CD.

New potential targets for treatment of Cushing's disease: epithelial growth factor receptor and cyclin-dependent kinases.

BACKGROUND: Cushing's disease (CD) is caused by adrenocorticotropic hormone (ACTH)-producing pituitary adenomas (ACTHomas). Drug treatment for CD consists of three strategies: pituitary tumor-targeted therapy, steroidogenesis inhibitors, and glucocorticoid receptor antagonists. All of these strategies are under development, and several new drugs have recently been approved for clinical use or are being tested in clinical trials. Pituitary-targeted drugs are a particularly important method in the treatment of CD. Available pituitary tumor-targeted drugs include a dopamine receptor agonist and a somatostatin analog. Since disrupted cell cycle signaling is clearly associated with pathogenesis of ACTHomas which express active forms of epithelial growth factor receptor (EGFR), cyclins, and the catalytic subunit of cyclin-dependent kinases (CDKs), we focused on these molecules as therapeutic targets for ACTHomas. METHODS: In this review, a literature search were performed using PubMed with following terms; Cushing's disease, EGFR, CDKs, cell cycle, and targeted therapy. CONCLUSION: Accumulating evidence demonstrates that EGFR and cyclin E-CDK2 may be promising targets for treating ACTHomas.

AZA-deoxycytidine stimulates proopiomelanocortin gene expression and ACTH secretion in human pituitary ACTH-secreting tumors.

PURPOSE: It is well known that methylation plays an important role in regulating tissue expression of proopiomelanocortin (POMC) and recent studies have shown that demethylation can occur also in vitro in neuroendocrine tumors. Aim of the present study was to evaluate whether inhibition of methylation modulates POMC expression and ACTH secretion by human corticotrope tumors. METHODS: Twenty two ACTH-secreting pituitary tumors were incubated with 5-AZA-2'-deoxycytidine (AZA), an inhibitor of DNA-methyltransferases, with or without 10 nM corticotropin-releasing hormone (CRH). Both dose response (100 nM-10 µM AZA) and time course (4-96 h) experiments were carried out for measurement of ACTH secretion and POMC gene expression. RESULTS: Incubation with AZA increased constitutive POMC expression and ACTH secretion by human corticotrope adenomas. The effect appeared most notable at 24 and 48 h with 1 µM AZA. Incubation with AZA did not exert an additional stimulatory effect on CRH-stimulated POMC and ACTH. CONCLUSIONS: The present study shows that AZA increases POMC gene expression and ACTH secretion in human pituitary ACTH-secreting tumors. This can be taken to indicate that mechanisms set into motion by AZA play a role in the regulation of ACTH secretion/POMC expression in tumoral corticotropes and paves the way to further studies in Cushing's disease.

Targeting zebrafish and murine pituitary corticotroph tumors with a cyclin-dependent kinase (CDK) inhibitor.

Cushing disease caused by adrenocorticotropin (ACTH)-secreting pituitary adenomas leads to hypercortisolemia predisposing to diabetes, hypertension, osteoporosis, central obesity, cardiovascular morbidity, and increased mortality. There is no effective pituitary targeted pharmacotherapy for Cushing disease. Here, we generated germline transgenic zebrafish with overexpression of pituitary tumor transforming gene (PTTG/securin) targeted to the adenohypophyseal proopiomelanocortin (POMC) lineage, which recapitulated early features pathognomonic of corticotroph adenomas, including corticotroph expansion and partial glucocorticoid resistance. Adult Tg:Pomc-Pttg fish develop neoplastic coticotrophs and pituitary cyclin E up-regulation, as well as metabolic disturbances mimicking hypercortisolism caused by Cushing disease. Early development of corticotroph pathologies in Tg:Pomc-Pttg embryos facilitated drug testing in vivo. We identified a pharmacologic CDK2/cyclin E inhibitor, R-roscovitine (seliciclib; CYC202), which specifically reversed corticotroph expansion in live Tg:Pomc-Pttg embryos. We further validated that orally administered R-roscovitine suppresses ACTH and corticosterone levels, and also restrained tumor growth in a mouse model of ACTH-secreting pituitary adenomas. Molecular analyses in vitro and in vivo showed that R-roscovitine suppresses ACTH expression, induces corticotroph tumor cell senescence and cell cycle exit by up-regulating p27, p21 and p57, and downregulates cyclin E expression. The results suggest that use of selective CDK inhibitors could effectively target corticotroph tumor growth and hormone secretion.

Metformin inhibits cell proliferation and ACTH secretion in AtT20 cells via regulating the MAPK pathway.

We investigated the impact of metformin on ACTH secretion and tumorigenesis in pituitary corticotroph tumors. The mouse pituitary tumor AtT20 cell line was treated with varying concentrations of metformin. Cell viability was assessed using the CCK-8 assay, ACTH secretion was measured using an ELISA kit, changes in the cell cycle were analyzed using flow cytometry, and the expression of related proteins was evaluated using western blotting. RNA sequencing was performed on metformin-treated cells. Additionally, an in vivo BALB/c nude xenograft tumor model was established in nude mice, and immunohistochemical staining was conducted for further verification. Following metformin treatment, cell proliferation was inhibited, ACTH secretion decreased, and G1/S phase arrest occurred. Analysis of differentially expressed genes revealed cancer-related pathways, including the MAPK pathway. Western blotting confirmed a decrease in phosphorylated ERK1/2 and phosphorylated JNK. Combining metformin with the ERK1/2 inhibitor Ulixertinib resulted in a stronger inhibitory effect on cell proliferation and POMC (Precursors of ACTH) expression. In vivo studies confirmed that metformin inhibited tumor growth and reduced ACTH secretion. In conclusion, metformin inhibits tumor progression and ACTH secretion, potentially through suppression of the MAPK pathway in AtT20 cell lines. These findings suggest metformin as a potential drug for the treatment of Cushing's disease.

The therapy of Cushing's disease in adults and children: an update.

Cushing's disease (CD) is a rare endocrine disorder resulting from excessive production of adrenocorticotrophin hormone by a pituitary adenoma. The consequent hypercortisolaemia gives rise to characteristic features of the disease and its morbidities. Treatments aim to restore normal cortisol levels, provide long-term control of the disease and the tumour, and the improvement of patient well-being. The first line of treatment remains transsphenoidal surgery with remission rates of 65-90% in CD secondary to a pituitary microadenoma. Second-line treatment includes repeat surgery, radiotherapy, medical therapy, and bilateral adrenalectomy. The success rate of radiotherapy ranges from 46% to 74% and is probably independent of the mode of delivery of the radiation, but may take several years to become effective. Medical therapy is useful in acutely unwell patients or while awaiting radiotherapy to become effective. The most often-used medical agents include metyrapone and ketoconazole, which inhibit steroidogenesis; less often, centrally-acting drugs or a glucocorticoid receptor blocker are used, but experience with them is more limited. Bilateral adrenalectomy remains an important treatment option to control unresponsive severe hypercortisolism, particularly in patients with severe CD.The management of childhood CD does not differ from adult disease, with transsphenoidal surgery as successful as in adults but radiotherapy is more rapid in onset. Regardless of the age of the patient, Cushing's disease remains a challenge to the physician and requires a multidisciplinary approach to achieve the most desirable outcome.

Pituitary-directed medical therapy with pasireotide for a corticotroph macroadenoma: pituitary volume reduction and literature review.

Hypercortisolism due to an ACTH-secreting pituitary adenoma (Cushing's disease) is a chronic condition associated with high morbidity and mortality if inadequately managed. Pasireotide is a multireceptor-targeted somatostatin analogue and is the only approved medical therapy for Cushing's disease that treats the underlying cause of the disorder. This paper reviews the available literature for medical-therapy-induced adenoma volume reduction in patients with Cushing's disease and reports the experience of a 53-year-old surgically, radiologically and medically naïve (de novo) female with a pituitary macroadenoma who declined surgery. This patient was treated with pasireotide as first-line therapy as part of the largest randomized Phase III study evaluating a medical therapy in patients with Cushing's disease (SOM230B2305 trial). Subcutaneous pasireotide significantly decreased tumor volume, suppressed cortisol secretion, and improved clinical signs and symptoms of Cushing's disease in this patient. Based on this experience, first-line pasireotide has the potential to achieve substantial tumor volume reduction in addition to significant improvements in cortisol levels and signs and symptoms in patients with Cushing's disease for whom surgery is not an option.

Anti-VEGF therapy in pituitary carcinoma.

We report the case of a 44-year-old male patient with an aggressive silent corticotroph cell pituitary adenoma, subtype 2. In that it progressed to carcinoma despite temozolomide administration, anti-VEGF therapy was begun. MRI, PET scan and pathologic analysis were undertaken. After 10 months of anti-VEGF (bevacizumab) treatment no progression of the lesion was noted. The tumor was biopsied and morphological analysis showed severe cell injury, vascular abnormalities and fibrosis. Bevacizumab treatment has continued for additional 16 months to present with stabilization of disease as documented on serial MRI and PET scans. This is the first case of a bevacizumab-treated pituitary carcinoma with long-term, now 26 months, control of disease. The present findings are promising in that anti-angiogenic therapy appears to represent a new option in the treatment of aggressive pituitary tumors.