Emerging therapies for advanced insulinomas and glucagonomas.

Pancreatic neuroendocrine neoplasms (panNENs) are rare relatively malignancies that, despite their frequently slow-growing pattern, have the ability to metastasize. Metastatic and/or advanced insulinomas and glucagonomas are functioning panNENs emerging from the pancreas displaying unique peculiarities, depending on their hormonal syndromes and increased malignant potential. Advanced insulinomas management follows usually the panNENs therapeutic algorithm, but some distinctions are well advised together with aiming to control hypoglycemias that occasionally can be severe and refractory to treatment. When first-generation somatostatin analogues (SSAs) fail to control hypoglycemia syndrome, second-generation SSAs and everolimus have to be considered for exploiting their hyperglycemic effect. There is evidence that everolimus is still effective after rechallenge retaining its hypoglycemic effect independently of its antitumor effect that seems to be mediated by different molecular pathways. Peptide receptor radionuclide therapy (PRRT) constitutes a promising therapeutic option for both its antisecretory and antitumoral action. Similarly, advanced and/or metastatic glucagonomas management also follows the panNENs therapeutic algorithm, but the clinical syndrome has to be addressed by aminoacid infusion and by first-generation SSAs to improve the patient performance status. PRRT seems to be an effective treatment when surgery and SSAs fail. The application of these therapeutic modalities has been shown to be efficacious in controlling the manifestations of the secretory syndrome and prolonging the overall survival of patients suffering from these malignancies.

The Role of Somatostatin Analogues in the Control of Diarrhea and Flushing as Markers of Carcinoid Syndrome: A Systematic Review and Meta-Analysis.

BACKGROUND: Somatostatin analogues (SSAs) are the cornerstone of treatment for carcinoid syndrome (CS)-related symptoms. The aim of this systematic review and meta-analysis is to evaluate the percentage of patients achieving partial (PR) or complete response (CR) with the use of long-acting SSAs in patients with CS. METHODS: A systematic electronic literature search was conducted in PubMed, Cochrane, and Scopus to identify eligible studies. Any clinical trials reporting data on the efficacy of SSAs to alleviate symptoms in adult patients were considered as potentially eligible. RESULTS: A total of 17 studies reported extractable outcomes (PR/CR) for quantitative synthesis. The pooled percentage of patients with PR/CR for diarrhea was estimated to be 0.67 (95% confidence interval (CI): 0.52-0.79, I2 = 83%). Subgroup analyses of specific drugs provided no evidence of a differential response. With regards to flushing, the pooled percentage of patients with PR/CR was estimated to be 0.68 (95% CI: 0.52-0.81, I2 = 86%). Similarly, no evidence of a significant differential response in flushing control was documented. CONCLUSIONS: We estimate there is a 67-68% overall reduction in symptoms of CS associated with SSA treatment. However, significant heterogeneity was detected, possibly revealing differences in the disease course, in management and in outcome definition.

Prognostic Biomarkers in Pituitary Tumours: A Systematic Review.

Pituitary tumours (PTs) are the second most common intracranial tumour. Although the majority show benign behaviour, they may exert aggressive behaviour and can be resistant to treatment. The aim of this review is to report the recently identified biomarkers that might have possible prognostic value. Studies evaluating potentially prognostic biomarkers or a therapeutic target in invasive/recurrent PTs compared with either non-invasive or non-recurrent PTs or normal pituitaries are included in this review. In the 28 included studies, more than 911 PTs were evaluated. A systematic search identified the expression of a number of biomarkers that may be positively correlated with disease recurrence or invasion in PT, grouped according to role: (1) insensitivity to anti-growth signals: minichromosome maintenance protein 7; (2) evasion of the immune system: cyclooxygenase 2, arginase 1, programmed cell death protein 1 (PD-1)/programmed death ligand 2, cluster of differentiation (CD) 80/CD86; (3) sustained angiogenesis: endothelial cell-specific molecule, fibroblast growth factor receptor, matrix metalloproteinase 9, pituitary tumour transforming gene; (4) self-sufficiency in growth signals: epidermal growth factor receptor; and (5) tissue invasion: matrix metalloproteinase 9, fascin protein. Biomarkers with a negative correlation with disease recurrence or invasion include: (1) insensitivity to anti-growth signals: transforming growth factor ß1, Smad proteins; (2) sustained angiogenesis: tissue inhibitor of metalloproteinase 1; (3) tissue invasion: Wnt inhibitory factor 1; and (4) miscellaneous: co-expression of glial fibrillary acidic protein and cytokeratin, and oestrogen receptors α36 and α66. PD-1/programmed cell death ligand 1 showed no clear association with invasion or recurrence, while cyclin A, cytotoxic T lymphocyte-associated protein 4, S100 protein, ephrin receptor, galectin-3 , neural cell adhesion molecule, protein tyrosine phosphatase 4A3 and steroidogenic factor 1 had no association with invasion or recurrence of PT. With the aim to develop a more personalized approach to the treatment of PT, and because of the limited number of molecular targets currently studied in the context of recurrent PT and invasion, a better understanding of the most relevant of these biomarkers by well-d esigned interventional studies will lead to a better understanding of the molecular profile of PT. This should also meet the increased need of treatable molecular targets.

Adrenal insufficiency and pregnancy.

INTRODUCTION: Adrenal insufficiency is a disorder characterized by the failure of adrenocortical function because of distorted function of hypothalamic-pituitary- adrenal (HPA) axis. Pregnancy is a state of a physiological glucocorticoid excess as the HPA axis is functioning at a higher level. PURPOSE OF REVIEW: The aim of the present review was to shed light on current evidence of adrenal insufficiency management during pregnancy, along with maternal and neonatal outcomes. RECENT FINDINGS: A recent multicenter study under the auspices of the European Network for the Study of Adrenal Tumours (ENSAT) presented real-life data of pregnant women with adrenal insufficiency documenting an increased use of hydrocortisone (or mineralocorticoids when needed according to the level of disorder) replacement treatment, increased rates of caesarean section, preterm delivery and adrenal crises along with peripartum and postpartum complications but no maternal or neonatal fatality. These data were in agreement with those obtained from previously published studies. CONCLUSION: The limited published evidence is in line with the present guidelines as real-life data did not document any increased fatality among pregnant women or newborns. Prospective data with prolonged follow-up are needed to shed more light on appropriate dose adjustments to avoid the risks of under-replacement or over-replacement of glucocorticoid and/or mineralocorticoid drugs and their sequelae. SUMMARY: A recent multicenter study by ENSAT presented real-life data of pregnant women with adrenal insufficiency documenting an increased use of hydrocortisone as replacement treatment during pregnancy, along with an increased rate of caesarean section and preterm delivery, adrenal crises, peripartum and postpartum complications but no maternal or neonatal fatality. These data are in agreement with those of a previously published study and also confirm the statements made by the recent guidelines. Prospective data are needed aiming to develop precise therapeutic protocols during each trimester of pregnancy according to the different causes of adrenal insufficiency.

Metastatic medullary thyroid carcinoma: a new way forward.

Medullary thyroid carcinoma (MTC) is a rare malignancy comprising 1-2% of all thyroid cancers in the United States. Approximately 20% of cases are familial, secondary to a germline RET mutation, while the remaining 80% are sporadic and also harbour a somatic RET mutation in more than half of all cases. Up to 15-20% of patients will present with distant metastatic disease, and retrospective series report a 10-year survival of 10-40% from time of first metastasis. Historically, systemic therapies for metastatic MTC have been limited, and cytotoxic chemotherapy has demonstrated poor objective response rates. However, in the last decade, targeted therapies, particularly multitargeted tyrosine kinase inhibitors (TKIs), have demonstrated prolonged progression-free survival in advanced and progressive MTC. Both cabozantinib and vandetanib have been approved as first-line treatment options in many countries; nevertheless, their use is limited by high toxicity rates and dose reductions are often necessary. New generation TKIs, such as selpercatinib or pralsetinib, that exhibit selective activity against RET, have recently been approved as a second-line treatment option, and they exhibit a more favourable side-effect profile. Peptide receptor radionuclide therapy or immune checkpoint inhibitors may also constitute potential therapeutic options in specific clinical settings. In this review, we aim to present all current therapeutic options available for patients with progressive MTC, as well as new or as yet experimental treatments.

Alterations in cortisol and interleukin-6 secretion in patients with COVID-19 suggestive of neuroendocrine-immune adaptations.

PURPOSE: The beneficial effect of glucocorticoids in coronavirus disease (COVID-19) is established, but whether adrenal cortisol secretion is impaired in COVID-19 is not fully elucidated. In this case-control study, we investigated the diurnal free bioavailable salivary cortisol secretion in COVID-19 patients. METHODS: Fifty-two consecutive COVID-19 patients-before dexamethasone treatment in cases required-recruited between April 15 to June 15, 2021, (NCT04988269) at Laikon Athens University-Hospital, and 33 healthy age- and sex-matched controls were included. Diurnal salivary cortisol (8 a.m., 12, 6, and 10 p.m.), plasma adrenocorticotropin (ACTH) and aldosterone, and serum interleukin-6 (IL-6) and C-reactive protein (CRP) levels were assessed. Diurnal salivary dehydroepiandrosterone (DHEA) and IL-6 were also assessed in subgroups of patients. RESULTS: Median CRP and IL-6 measurements were about sixfold higher in patients than controls (both p < 0.001) Morning salivary cortisol levels did not differ between the two groups, but patients exhibited higher median levels of evening and nocturnal salivary cortisol compared to controls [0.391 (0.054, 0663) vs. 0.081 (0.054, 0.243) µg/dl, p < 0.001 and 0.183 (0.090, 0.834) vs. 0.054 (0.054, 0.332) µg/dl, p < 0.001, respectively], resulting in higher time-integrated area under the curve (AUC) (4.81 ± 2.46 vs. 2.75 ± 0.810, respectively, p < 0.001). Circulating ACTH, DHEA, and aldosterone levels were similar in patients and controls. Serum IL-6, but not ACTH levels, was strongly correlated with nocturnal cortisol salivary levels (ρ = 0.555, p < 0.001) in patients. CONCLUSIONS: Increased evening and nocturnal but not morning cortisol secretion may occur in even clinically mild COVID-19. In the context of acute viral infection (COVID-19), IL-6 may partially replace ACTH as a stimulus of the glucocorticoid-secreting adrenal zona-fasciculata without influencing the secretion of DHEA and aldosterone. CLINICAL TRIAL REGISTRATION: https://clinicaltrials.gov/ct2/show/NCT04988269?term=yavropoulou&draw=2&rank=3 (NCT04988269).

Adrenocortical dysfunction in rheumatoid arthritis: Α narrative review and future directions.

BACKGROUND: Iatrogenic adrenal insufficiency (AI) secondary to long-term treatment with exogenous glucocorticoids (GC) is common in patients with systematic rheumatic diseases, including rheumatoid arthritis (RA). Moreover, a proportion of these patients is always in need of even small doses of glucocorticoids to maintain clinical remission, despite concomitant treatment with conventional and biologic disease-modifying drugs. METHODS: We conducted a literature review up to December 2020 on (a) the incidence of AI in both long-term GC-treated and GC-treatment naïve RA patients; (b) the potential effects of increased levels of circulating proinflammatory cytokines, as well as of chronic stress, in adrenocortical function in RA; (c) the circadian cortisol rhythm in RA; and (d) established and evolving methods of assessment of adrenocortical function. RESULTS: Up to 48% of RA patients develop glucocorticoid-induced AI; however, predictors are not established, while adrenocortical dysfunction may also occur in GC-treatment naïve RA patients. Experimental and clinical data have suggested that inadequate production of endogenous cortisol relative to enhanced clinical needs associated with the systemic inflammatory response, coined as the 'disproportion principle', may operate in RA. Although the underlying mechanisms are unknown, both proinflammatory cytokines and chronic stress may contribute the most in the adrenals hyporesponsiveness and the target tissue glucocorticoid resistance that have been described, but not systematically studied. A precise longitudinal assessment of endogenous cortisol production may be needed for optimal RA management. CONCLUSION: Apart from iatrogenic AI, an intrinsically compromised adrenal reserve in RA may have a pathogenetic role and interfere with effective management, thus deserving further research.

Enhanced performance of a modified diagnostic test of primary aldosteronism in patients with adrenal adenomas.

OBJECTIVE: Primary aldosteronism (PA) is the commonest cause of endocrine hypertension ranging from 4.6 to 16.6% according to the diagnostic tests employed. The aim of this study was to compare the traditional saline infusion test (SIT) with the modified post-dexamethasone saline infusion test (DSIT) by applying both tests on the same subjects. METHODS: We studied 68 patients (72% hypertensives) with single adrenal adenoma and 55 normotensive controls with normal adrenal imaging. Serum cortisol, aldosterone, and plasma renin concentration (PRC) were measured and the aldosterone-to-renin ratio (ARR) was calculated. Using the mean ± 2 s.d. values from the controls, we defined the upper normal limits for cortisol, aldosterone, and PRC for both the SIT and DSIT. RESULTS: In the controls, the post-DSIT aldosterone levels and the ARR were approximately two-fold and three-fold lower, respectively, than the corresponding post-SIT values (all P = 0.001) leading to lower cut-offs of aldosterone suppression. Applying these cut-offs to patients with adrenal adenomas, the prevalence of PA was 13.2% following the SIT and 29.4% following the DSIT, respectively. In addition, 54.5% of patients with PA had concomitant autonomous cortisol secretion (ACS). Targeted treatment of PA resulted in resolution of hypertension and restoration of normal secretory aldosterone dynamics. CONCLUSIONS: The DSIT improves the diagnostic accuracy of PA, allowing for the detection of milder forms of PA in patients with adrenal adenomas. This is of particular importance as such patients may be at an increased risk of developing cardiovascular and renal morbidity that could be enhanced in the presence of concomitant ACS.

Adrenocortical Cancer: A 20-Year Experience of a Single Referral Center in Prognosis and Outcomes.

Adrenocortical carcinoma (ACC) is a rare but very aggressive endocrine malignancy with poor survival. Histopathology is important for diagnosis, while in some cases immunohistochemical markers and gene profiling of the resected tumor may be superior to current staging systems to determine prognosis. We aimed to present the 20-year experience at a tertiary hospital in patients with ACCs and correlate the immunohistochemical characteristics of ACCs with the clinical and morphological characteristics of the tumors and the survival of the patients. Forty-five patients with ACC were included in the study. All the resections were R0. The tumor size and weight, the disease stage (ENSAT classification), Weiss score and Helsinki score were examined along with immunohistochemical expression of inhibin-A, melan A, calretinin, Ki67, synaptophysin, p53, vimentin, CKAE1/AE3. The male to female ratio was 1:1.37. The median age at diagnosis was 55.5 years (IQR 19-77). The median size of ACCs was 9 cm (IQR 3.5-22 cm) and the median weight 127 g (IQR 18-1400 g). The median follow up period was 18 months (IQR 1-96). Ki67 varied from<1% to 75% (median: 16.4%). The expression of melan-A and lower expression of Ki-67 (≤4) were independently associated with longer OS time (p=0.01 and p=0.04, respectively). In multivariable analysis, tumor volume>400 cm3 (p=0.046), Weiss score>5 (p=0.007) and overexpression of p53 (p=0.036) were independent risk factors for shorter survival. Adrenocortical carcinoma is a rare and very aggressive endocrine malignancy. The most important factors that determine long-term prognosis of ACC are the disease stage at diagnosis, the Weiss score, and the Ki67 index. Immunohistochemical markers such as melan A could also serve as prognostic factors.

Changing biological behaviour of NETs during the evolution of the disease: progress on progression.

Following improvements in the management and outcome of neuroendocrine neoplasms (NENs) in recent years, we see a subset, particularly of pancreatic NENs, which become more aggressive during the course of the disease. This is reflected by an increase in the Ki-67 labelling index, as a marker of proliferation, which may lead to an occasion of increase in grading, but generally does not appear to be correlated with histologically confirmed dedifferentiation. A systematic review of the literature was performed in PubMed, Cochrane Library, and Embase until May 2020 to identify cases that have behaved in such a manner. We screened 244 articles: only seven studies included cases in their cohort, or in a subset of the cohort studied, with a proven increase in the Ki-67 during follow-up through additional biopsy. In addition to these studies, we have also tried to identify possible pathophysiological mechanisms implicated in advanced NENs, although currently no studies appear to have addressed the mechanisms implicated in the switch to a more aggressive biological phenotype over the course of the disease. Such progression of the disease course may demand a change in the management. Summarising the overall evidence, we suggest that future studies should concentrate on changes in the molecular pathways during disease progression with sequential biopsies in order to shed light on the mechanisms that render a neoplasm more aggressive than its initial phenotype or genotype.

Surgical treatment outcome of primary aldosteronism assessed using new modified diagnostic tests.

PURPOSE: Primary aldosteronism (PA) is the most frequent type of endocrine hypertension. In our previous studies, we introduced two modified diagnostic tests for PA, the post-dexamethasone saline infusion test (DSIT) and the overnight dexamethasone, captopril, and valsartan test (DCVT). In this study, we aimed to validate both tests in respect to the biochemical and clinical response of a cohort of hypertensive patients in pre- and post-surgical setting. METHODS: We retrospectively studied 41 hypertensive patients (16 males), with a median (IQR, range) age of 50 (16, 35-74) years and positive histology for adrenal adenoma. Preoperatively, all patients had a single adenoma on CT and a diagnosis of PA with either DSIT or DCVT. The defined daily dose (DDD) of hypertensive drugs was assessed pre- and postoperatively. DSIT or DCVT and basal ARR were reassessed postoperatively. RESULTS: Two of the 41 patients failed to suppress aldosterone post-surgery, leading to a post-adrenalectomy biochemical cure rate of 95%, while blood pressure was improved in 36 patients, leading to a clinical cure rate of 88% as assessed by the DDD methodology. CONCLUSIONS: The present study was a proof-of-concept process to validate two modified diagnostic tests for PA in clinical practice. These tests, used to diagnose a group of patients with PA, successfully assessed their biochemical cure post-adrenalectomy at rates similar to those reported in the literature.

Immunotherapeutics at the spearhead: current status in targeting neuroendocrine neoplasms.

PURPOSE: Recent advances in the field of immunotherapy have significantly prolonged the survival of patients with aggressive carcinomas, but the role of immunotherapy in neuroendocrine neoplasms (NENs) remains to be elucidated. METHODS AND RESULTS: We report a patient diagnosed with a well-differentiated grade 3 pancreatic NEN (pNEN) and type 3 liver metastases who received compassionate nivolumab as a fifth line treatment and achieved a durable partial response of more than 34 months. We have performed a systematic review to the literature on tumor microenvironment and potential biomarkers in the field of NEN including the tumor mutational burden, the tumor infiltrating lymphocytes, the programmed cell death ligand 1, and the mismatch repair system. The potential role of the immune system modulation together with a critical assessment of the recent phase II clinical studies in NEN including monotherapy with anti-PD-1/PD-L1 monoclonal antibodies, and combination therapies including anti-PD-1 along with anti-CTLA-4 monoclonal antibodies are also provided. CONCLUSION: Immunotherapeutics are gaining a post in the field of NENs in cases progressing during the course of the disease, dictating urgently the identification of biomarkers that will enable selection of NEN patients who may benefit from this treatment.

Distinctive features of pancreatic neuroendocrine neoplasms exhibiting an increment in proliferative activity during the course of the disease.

PURPOSE: Neuroendocrine neoplasms (NENs) differ in their biological behavior and growth potential in a way that can be predicted using histological classification and grading systems. A subset of pancreatic NENs (pNENs) may develop a more aggressive phenotype during the course of the disease, associated with an increase in the Ki-67 proliferation index (PI). The purpose of the study was to present the clinical characteristics of these patients. METHODS: Using re-biopsy of growing lesions, we investigated the increase in Ki-67 PI sufficient to change initial grading (G). RESULTS: Of 264 patients with well differentiated (WD) pNENs who showed progressive disease during follow-up, 15 (6%) exhibited an increase in Ki-67 PI at a median time 36.8 (9.3-255.8) months. All neoplasms had WD-morphology: five had G1 (Ki-67 median value 1%), nine G2 (median value 5%), one G3 (25%) grades. Upon change of Ki-67 PI, 3 patients had G2 (8%) and 12 G3 (57.5%) NENs, while all retained their WD-morphology. At last follow-up, eight patients were alive with a median overall survival (OS) of 52.5 (9.5-264.3) months. Μedian OS was shorter in patients who had a change in Ki-67 PI before 36 months compared to those who had a change of Ki-67 PI at a later stage (27.5 95%CI: 11.88-43.06 vs. 120.87 95%CI: 96.05-145.69; log-rank p = 0.018). CONCLUSIONS: During the course of their disease, 6% patients with progressive pNENs develop an increase in Ki-67 PI resulting in an increase in grading status while maintaining their morphology. This process is associated with worse OS when it occurs at an early stage.

Endocrinological Toxicity Secondary to Treatment of Gastroenteropancreatic Neuroendocrine Neoplasms (GEP-NENs).

Gastroenteropancreatic neuroendocrine neoplasms (GEP-NENs) are increasingly recognized, characterized by prolonged survival even with metastatic disease. Their medical treatment is complex involving various specialties, necessitating awareness of treatment-related adverse effects (AEs). As GEP-NENs express somatostatin receptors (SSTRs), long-acting somatostatin analogs (SSAs) that are used for secretory syndrome and tumor control may lead to altered glucose metabolism. Everolimus and sunitinib are molecular targeted agents that affect glucose and lipid metabolism and may induce hypothyroidism or hypocalcemia, respectively. Chemotherapeutic drugs can affect the reproductive system and water homeostasis, whereas immunotherapeutic agents can cause hypophysitis and thyroiditis or other immune-mediated disorders. Treatment with radiopeptides may temporarily lead to radiation-induced hormone disturbances. As drugs targeting GEP-NENs are increasingly introduced, recognition and management of endocrine-related AEs may improve compliance and the quality of life of these patients.

Anti-Tumor Activity and Safety of Multikinase Inhibitors in Advanced and/or Metastatic Thyroid Cancer: A Systematic Review and Network Meta-Analysis of Randomized Controlled Trials.

Many trials have demonstrated prime antitumor activity of novel, small molecule multikinase inhibitors (MKIs) in advanced and/or metastatic thyroid cancer (TC). In this work, the PubMed, EMBASE, Cochrane Central Register of Controlled Trials, Web of Science, SCOPUS, and clinicaltrials.gov databases were searched. Quality/risk of bias were assessed using GRADE criteria. Randomized clinical trials (RCTs) comparing two or more systemic therapies in patients with advanced and/or metastatic thyroid cancer were assessed. A total of 1347 articles and 548 clinical trials in clinicaltrials.gov were screened. We included seven relevant RCTs comprising 1934 unique patients assigned to different MKIs. Two separate network meta-analyses included four RCTs in radioiodine refractory well-differentiated thyroid cancer (RR-WDTC) and three RCTs in medullary thyroid cancer (MTC), respectively; all with a low risk of bias. We identified three therapies for RR-WDTC: sorafenib [disease control rate (DCR) odds ratio (OR): 0.11 (95% CI: 0.03-0.40); progression-free survival (PFS) hazard ratio (HR): 1.99 (95% CI: 1.62-2.46)], vandetanib [DCR_OR:0.26 (95% CI: 0.06-1.24); PFS_HR: 0.99 (95% CI: 0.82-1.20)] and lenvatinib [DCR_OR: 0.26 (95% CI: 0.05-1.33); PFS_HR: 0.99 (95% CI: 0.81-1.22)]; and the following therapies for MTC: vandetanib 300 mg [objective response rate (ORR)_OR: 3.31 (95% CI: 0.68-16.22); vandetanib 150 mg ORR_OR: 0.60 (95% CI: 0.16-2.33)]; and cabozantinib [ORR_OR: 85.32 (95% CI: 5.22-1395.15)]. Serious side effect (SE) analysis per organ/system demonstrated a varying MKI SE profile across both RR-WDTC and MTC diagnoses, more commonly involving metabolic/nutritional disorders [OR: 2.07 [95% CI: 0.82-5.18)] and gastrointestinal SE [OR: 1.63 (95% CI: 1.0-2.66)]. This network meta-analysis on advanced and/or metastatic TC points towards a higher efficacy of lenvatinib in RR-WDTC. The included MKIs exhibit a varying SE profile across different organs/systems favoring a patient-tailored approach with the anticipated toxicities guiding clinicians' decisions.

Role of Receptor Profiling for Personalized Therapy in a Patient with a Growth Hormone-Secreting Macroadenoma Resistant to First-Generation Somatostatin Analogues.

BACKGROUND: Acromegaly is almost always caused by a pituitary adenoma and is associated with high morbidity and mortality when uncontrolled. Trans-sphenoidal removal of the adenoma is the mainstay of therapy, but fails to control the disease in a significant number of patients who require further treatment. Somatostatin analogues (SSAs) as monotherapy or in combination with growth hormone (GH)-receptor antagonists and/or dopamine agonists are used either alone or in combination following surgical failure to achieve disease control. The use of specific biomarkers may help to individualize the therapeutic plan after surgical failure and direct towards a more personalized approach. METHODS: We report a 41-year-old man with acromegaly and residual disease after repeated surgery that was resistant to first-generation SSAs. RESULTS: Biochemical and tumor control were achieved following the administration of a second-generation SSA, pasireotide, combined with pegvisomant, both at maximal doses and along with cabergoline. Histology specimens showed a sparsely-granulated GH-immunostaining pituitary adenoma with intense positivity for somatostatin receptors 2 and 5 and low levels of E-cadherin. CONCLUSION: Personalized medical therapy guided by currently available biomarkers, such as immunohistochemically-characterized receptor profiling or adhesion molecules, resulted in controlled insulin-like growth factor-1 (IGF-1) and GH levels and symptom alleviation following the combination of three drug-classes.

The Medical Therapy of Craniopharyngiomas: The Way Ahead.

CONTEXT: Craniopharyngiomas, which are categorized as adamantinomatous (ACPs) or papillary (PCPs), have traditionally been treated with surgery and/or radiotherapy, although when the tumors progress or recur, therapeutic possibilities are very limited. Following recent advances in their molecular pathogenesis, new medical therapeutic options have emerged. EVIDENCE ACQUISITION: The search strategy that we selected to identify the appropriate evidence involved the following medical subject headings (MeSH) terms: ("Craniopharyngioma" [MeSH] AND "Craniopharyngioma/drug therapy" [MeSH]) NOT ("review" [Publication Type] OR "review literature as topic" [MeSH Terms] OR "review" [All Fields]) AND ("2009/05/01" [PDat]: "2019/04/28" [PDat]). EVIDENCE SYNTHESIS: Mutations of ß-catenin causing Wnt activation with alterations of the MEK/ERK pathway are encountered in the great majority of patients with ACPs; specific alterations also stratify patients to a more aggressive behavior. In most PCPs there is primary activation of the Ras/Raf/MEK/ERK pathway secondary to BRAF-V600E mutations. BRAF inhibitors, such as dabrafenib or vemurafenib, either alone or in combination with the MEK inhibitors trametinib and cobimetinib, have been administered to patients with PCPs producing clinically useful and, in some cases, sustained responses. In contrast to PCPs, drugs targeting ß-catenin and its downstream MAPK pathway in ACPs have so far only been used in in vitro studies, but there appear to be promising new targets clinically. CONCLUSIONS: The identification of specific genetic alterations in patients with craniopharyngiomas has expanded the therapeutic options, providing evidence for a customized approach using newer molecular agents. More studies including a larger number of carefully selected patients are required to evaluate the response to currently available and evolving agents alone and in combination.