Biomarkers of response to treatment in acromegaly.

INTRODUCTION: Medical treatment of acromegaly is based in a `trial and error` approach. First-generation somatostatin receptor ligands (fg-SRL) are prescribed as first-line medical therapy to the vast majority of patients, despite lack of disease control in approximately 60% of patients. However, other drugs used in acromegaly treatment are available (cabergoline, pasireotide and pegvisomant). AREAS COVERED: In this article, we review and discuss the biomarkers of response to medical treatment in acromegaly. EXPERT OPINION: Biomarkers for fg-SRL that can already be applied in clinical practice are: gender, age, pretreatment GH and IGF-I levels, cytokeratin granulation pattern, and the expression of somatostatin receptor type 2. Using biomarkers of response could guide treatment towards precision medicine with greater efficacy and lower costs.

Long-term Efficacy and Safety of Pasireotide in Patients With Acromegaly: 14 Years of Single-Center Real-World Experience.

CONTEXT: Acromegaly is a rare, chronic, debilitating disorder caused by prolonged hypersecretion of growth hormone (GH) and overproduction of insulin-like growth factor I (IGF-I). Medical therapies, including the somatostatin receptor ligand (SRL) pasireotide, are frequently used to restore biochemical control. OBJECTIVE: As patients often receive therapy over prolonged periods, long-term data from real-life settings are needed. METHODS: A retrospective analysis was performed using a prospectively maintained database of all patients with acromegaly from our primary care center who were enrolled in clinical studies with pasireotide (first visit November 2008). The main outcome measures were safety and biochemical control (age-adjusted IGF-I ≤ upper limit of normal). RESULTS: Patients (n = 50) entered 4 parental studies and 30 continued in the rollover; at data cutoff (June 2022), 27 were still receiving pasireotide. Overall, median (range) exposure was 58 (3-137) months. Normal IGF-I was achieved in 54%, and acromegaly symptoms and quality of life were improved with treatment. No predictors of pasireotide response were identified; however, controlled patients had smaller tumors and lower GH at baseline. Tumor volume reduction occurred in 63% of evaluable patients (n = 10/16). Most patients presented hyperglycemic events, including 63.2% of patients with normal glucose before treatment. Older patients and those with higher IGF-I, glucose, and HbA1c at baseline had higher glucose and HbA1c during pasireotide treatment. CONCLUSION: Pasireotide provided clinical benefit and was well tolerated for more than 11 years of treatment in acromegaly patients, most of whom were resistant to first-generation SRLs.

miR-383-5p, miR-181a-5p, and miR-181b-5p as Predictors of Response to First-Generation Somatostatin Receptor Ligands in Acromegaly.

Acromegaly is a chronic systemic disease caused in the vast majority of cases by growth hormone (GH)-secreting adenoma, with surgery being the first-line treatment. When a cure is not attained with surgery, first-generation somatostatin receptor ligands (fg-SRLs) are the most common medication prescribed. Predictors of response to fg-SRLs have been studied; however, they cannot fully predict the response to fg-SRL. MicroRNAs are small RNAs, the main role of which is messenger RNA (mRNA) post-transcriptional regulation. This study aimed to identify the microRNAs involved in resistance to treatment with fg-SRLs in acromegaly. Ten patients with acromegaly undergoing treatment with fg-SRLs were selected to undergo miRNA sequencing: five controlled and five uncontrolled with treatment. Bioinformatic analysis was performed to detect differentially expressed miRNAs. Then, the same 10 samples were used for validation by qPCR and an additional 22 samples were analyzed, totaling 32 samples. e We found 59 differentially expressed miRNAs in the first analysis. miR-181a-5p and miR-181b-5p were downregulated, and miR-383-5p was upregulated in the uncontrolled group. Receiver operating characteristic (ROC) curve analysis of miR-383-5p showed an NPV of 84.3% and a PPV of 84.5%. In summary, miR-181a-5p, miR-181b-5p, and miR-383-5p are biomarkers of response to fg-SRLs, and they can be used individually or included in prediction models as tools to guide clinical decisions.

Characterization of sporadic somatotropinomas with high GIP receptor expression.

PURPOSE: To analyze the expression of glucose-dependent insulinotropic polypeptide receptor (GIPR) in somatotropinomas specimens and compare clinical, biochemical, radiological, therapeutic, molecular, and pathological data among those who overexpressed (GIPR +) and those who did not overexpress (GIPR - ) GIPR. METHODS: Clinical, biochemical, radiological, molecular, and pathological data were collected. GNAS1 sequencing was performed with the Sanger method. Protein expression of somatostatin receptor subtypes 2 and 5 and CAM 5.2 were analyzed by immunohistochemistry. Quantitative real-time PCR was performed to analyze the mRNA expression of GIPR with the TaqMan® method. Positive expression was considered when the fold change (FC) was above 17.2 (GIPR +). RESULTS: A total of 74 patients (54% female) were included. Eighteen tumors (24%) were GIPR + . Gsp mutation was detected in 30 tumors (40%). GIPR + tumors were more frequently densely granulated adenomas (83% vs 47%, p = 0.028). There was no difference in clinical, biochemical, radiological, therapeutic (surgical cure or response to medical therapy), or other pathological features between GIPR + and GIPR -  tumors. Twenty-eight out of 56 (50%) GIPR -  tumors harbored a gsp mutation, whereas two out of 18 (11%) GIPR + tumors harbored a gsp mutation (p = 0.005). CONCLUSION: We described, for the first time, that GIPR + and gsp mutations are not mutually exclusive, but gsp mutations are less common in GIPR + tumors. GIPR + and GIPR -  tumors have similar clinical, biochemical, radiological, therapeutic, and pathological features, with the exception of a high frequency of densely granulated adenomas among GIPR + tumors.

MicroRNA in Acromegaly: Involvement in the Pathogenesis and in the Response to First-Generation Somatostatin Receptor Ligands.

Acromegaly is a chronic and systemic disease due to excessive growth hormone and insulin-like growth factor type I caused, in the vast majority of cases, by a GH-secreting pituitary adenoma. About 40% of these tumors have somatic mutations in the stimulatory G protein alpha-subunit 1 gene. The pathogenesis of the remaining tumors, however, is still not fully comprehended. Surgery is the first-line therapy for these tumors, and first-generation somatostatin receptor ligands (fg-SRL) are the most prescribed medications in patients who are not cured by surgery. MicroRNAs are small, non-coding RNAs that control the translation of many mRNAs, and are involved in the post-transcriptional regulation of gene expression. Differentially expressed miRNAs can explain differences in the pathogenesis of acromegaly and tumor resistance. In this review, we focus on the most validated miRNAs, which are mainly involved in acromegaly's tumorigenesis and fg-SRL resistance, as well as in circulating miRNAs in acromegaly.

Pituitary MRI Features in Acromegaly Resulting From Ectopic GHRH Secretion From a Neuroendocrine Tumor: Analysis of 30 Cases.

CONTEXT: Ectopic acromegaly is a consequence of rare neuroendocrine tumors (NETs) that secrete GHRH. This abnormal GHRH secretion drives GH and IGF-1 excess, with a clinical presentation similar to classical pituitary acromegaly. Identifying the underlying cause for the GH hypersecretion in the setting of ectopic GHRH excess is, however, essential for proper management both of acromegaly and the NET. Owing to the rarity of NETs, the imaging characteristics of the pituitary in ectopic acromegaly have not been analyzed in depth in a large series. OBJECTIVE: Characterize pituitary magnetic resonance imaging (MRI) features at baseline and after NET treatment in patients with ectopic acromegaly. DESIGN: Multicenter, international, retrospective. SETTING: Tertiary referral pituitary centers. PATIENTS: Thirty ectopic acromegaly patients having GHRH hypersecretion. INTERVENTION: None. MAIN OUTCOME MEASURE: MRI characteristics of pituitary gland, particularly T2-weighted signal. RESULTS: In 30 patients with ectopic GHRH-induced acromegaly, we found that most patients had hyperplastic pituitaries. Hyperplasia was usually moderate but was occasionally subtle, with only small volume increases compared with normal ranges for age and sex. T2-weighted signal was hypointense in most patients, especially in those with hyperplastic pituitaries. After treatment of the NET, pituitary size diminished and T2-weighted signal tended to normalize. CONCLUSIONS: This comprehensive study of pituitary MRI characteristics in ectopic acromegaly underlines the utility of performing T2-weighted sequences in the MRI evaluation of patients with acromegaly as an additional tool that can help to establish the correct diagnosis.

Approach to the Patient: Differential Diagnosis of Cystic Sellar Lesions.

Cystic lesions arising in the sellar region are not uncommon and encompass cystic pituitary adenomas, Rathke cleft cysts, craniopharyngiomas, and arachnoid cysts. Their clinical presentation may be similar, including headache, visual field defects, and anterior pituitary hormone deficits, which makes differential diagnosis challenging. On the other hand, imaging features may indicate certain pathologies. In this approach to the patient, we describe the case of a patient who presented with right temporal hemianopsia and a sellar/suprasellar cystic lesion, which was determined to be Rathke cleft cyst. We discuss the imaging characteristics that may suggest a particular diagnosis between Rathke cleft cyst, cystic pituitary adenoma, craniopharyngioma, and arachnoid cyst and propose a flowchart for aiding in the imaging differential diagnosis.

Pituitary MRI Standard and Advanced Sequences: Role in the Diagnosis and Characterization of Pituitary Adenomas.

Pituitary adenomas (PAs) represent the most frequently found lesions in the sellar region; however, several other lesions may be encountered in this region, such as meningiomas, craniopharyngiomas, and aneurysms. High-quality imaging is fundamental for diagnosis, characterization, and guidance of treatment planning of PAs. Sellar magnetic resonance imaging (MRI) is considered the imaging modality of choice for the evaluation of lesions in the sella turcica. The sellar MRI standard protocol includes coronal and sagittal T1-weighted spin-echo sequencing with and without gadolinium-based contrast agent and coronal T2-weighted (T2w) fast-spin echo sequencing. A systematic MRI approach to the pituitary region generally provides information that includes the size and shape of the PA, the presence of cysts or hemorrhage within the tumor, its relationship with the optic pathways and surrounding structures, potential cavernous sinus invasion, sphenoid sinus pneumatization type, and differential diagnosis with other sellar lesions. The standard protocol is sufficient for the evaluation of most cases; however, some advanced techniques (susceptibility imaging, diffusion-weighted imaging, 3D T2w high-resolution sequences, magnetic resonance elastography, perfusion-weighted imaging) may render additional information, which may be important for some cases. In this "approach to the patient" manuscript, we will discuss the use of standard and advanced MRI sequences in the diagnosis and characterization of PAs, including MRI features associated with treatment response that may aid in presurgical evaluation and planning, and red flags that may point to an alternative diagnosis.

Current opinion on the diagnosis and management of non-functioning pituitary adenomas.

INTRODUCTION: Non-functioning pituitary adenomas (NFPAs) are clinically silent tumors and the second most common pituitary adenoma. Surgery is the mainstay of treatment as there is, as yet, no effective medical treatment. AREAS COVERED: We present current knowledge on the clinical diagnosis, histopathological classification, molecular data, and management strategies in NFPA. EXPERT OPINION: NFPA is a heterogeneous group of tumors, in respect to their origin and clinical course. In recent years, research on pathology and molecular biology have advanced our knowledge of NFPA pathogenesis. NFPA exhibit, in the majority of cases, an indolent behavior, with satisfactory response to treatment. In aggressive cases, multimodal management is needed; however, even this approach may be insufficient, so the development of new treatments is warranted for better management. In this setting, the understanding of the mechanisms involved in the genesis and progression of NFPA is crucial for the identification and development of directed treatments with higher chances of response.

Growth hormone-releasing hormone-secreting pulmonary neuroendocrine tumor associated with pituitary hyperplasia and somatotropinoma.

Acromegaly caused by ectopic growth hormone-releasing hormone (GHRH)-secreting tumor is exceedingly rare. We report a case of acromegaly secondary to GHRH secretion by an incidentally diagnosed pulmonary neuroendocrine tumor (NET) and review 47 similar cases in literature. A 22-year-old male patient presented with symptoms of pituitary apoplexy. Magnetic resonance imaging (MRI) showed apoplexy of a pituitary adenoma. Routinely prior to surgery, a chest radiography was performed which revealed a mass in the left lung. During investigation, the patient was diagnosed with metastatic GHRH-secreting pulmonary NET. In retrospect, it was noted that the patient had pituitary hyperplasia 20 months prior to the MRI which showed the presence of a pituitary adenoma. The histological findings confirmed somatotroph hyperplasia adjacent to somatotropinoma. This case suggests that GHRH secretion can be associated with pituitary hyperplasia, which may be followed by pituitary adenoma formation.

Cyclic ACTH-secreting thymic carcinoid: a case report and review of the literature

SUMMARY Cyclic Cushing's syndrome (CS) due to thymic carcinoid is a rare disorder. We report a case of cyclic CS due to ectopic adrenocorticotropic hormone (ACTH)-secreting atypical thymic carcinoid tumor and reviewed similar cases published in the literature. Our patient had hypercortisolemia lasting approximately one month, followed by normal cortisol secretion, with relapse one year later. Histopathology revealed an atypical ACTH-positive thymic carcinoid. Ectopic CS can be derived from atypical thymic carcinoids, which can be aggressive tumors with early relapse, suggesting that this type of tumor probably needs aggressive treatment.

Cyclic ACTH-secreting thymic carcinoid: a case report and review of the literature.

Cyclic Cushing's syndrome (CS) due to thymic carcinoid is a rare disorder. We report a case of cyclic CS due to ectopic adrenocorticotropic hormone (ACTH)-secreting atypical thymic carcinoid tumor and reviewed similar cases published in the literature. Our patient had hypercortisolemia lasting approximately one month, followed by normal cortisol secretion, with relapse one year later. Histopathology revealed an atypical ACTH-positive thymic carcinoid. Ectopic CS can be derived from atypical thymic carcinoids, which can be aggressive tumors with early relapse, suggesting that this type of tumor probably needs aggressive treatment.

Hydroxychloroquine with azithromycin in patients hospitalized for mild and moderate COVID-19.

OBJECTIVES: To assess the efficacy of hydroxychloroquine in combination with azithromycin in terms of clinical and biochemical outcomes in adult patients with COVID-19 hospitalized for acute respiratory distress syndrome (ARDS), and to describe the occurrence of adverse events. METHOD: Retrospective comparative study, based in a quaternary private hospital in Rio de Janeiro, Brazil, involving 193 adult patients hospitalized for mild and moderate COVID-19 related ARSD, analyzing treatment efficacy based on clinical and biochemical outcomes. RESULTS: The active group comprised 101 (52.3%) patients using hydroxychloroquine associated with azithromycin and the control group 92 (47.7%) patients who did not take these medications. Median age was 59 (47-70) in the active group and 65 (47-77) in the control group (p < 0.05). Patients in the control group had greater extent of pulmonary involvement on baseline chest CT scans (p < 0.05). All other baseline variables (BMI, comorbidities, previous use of medications and biochemical assessments) were similar between groups. In the medication group, 25% (25 out of 101) were admitted to the ICU, compared to 21% (19 out of 92) in the control group (p > 0.05). No difference in mortality, duration of non-invasive oxygen use or duration of hospitalization was seen between groups. The therapeutic regimen was well tolerated, with only eight (7.9%) patients presenting gastrointestinal symptoms and eight (7.9%) patients withdrawn treatment due to QTc prolongation. CONCLUSIONS: Patients treated with hydroxychloroquine combined with azithromycin and the control group had similar clinical outcomes. This therapeutic regimen was considered ineffective in hospitalized patients with mild to moderate COVID-19 related ARDS and was associated with few non-severe adverse events.

Congenital growth hormone deficiency associated with hip dysplasia and Legg-Calve-Perthes disease.

OBJECTIVE: Growth hormone deficiency (GHD) is usually treated with recombinant human GH (rhGH), and this has been rarely associated with hip disorders. We analysed the clinical data of patients with congenital GHD receiving rhGH who had associated hip dysplasia or Legg-Calve-Perthes disease (LCPD), with a view to determining whether the hip dysplasia was associated with the underlying disease or with rhGH treatment. DESIGN: We performed a retrospective analysis of paediatric and adolescent patients seen between 1992-2018 with congenital GHD and hip disorders. Data were collected through a review of the patients' medical records and included demographics, clinical and imaging data, and the time frame between the onset of the symptoms related to the hip disorders and the onset of GH treatment. RESULTS: Of the 13 patients with hip disorders, hip dysplasia was present in ten patients and LCPD in three. Hip dysplasia was diagnosed before rhGH was initiated in 50% of cases. These patients had bilateral hip dysplasia and isolated GHD. LCPD was diagnosed in one patient before rhGH was commenced and did not progress. In two patients, LCPD was diagnosed after rhGH was started and did temporarily progress in one of them, but rhGH was not discontinued because LCPD did not seem to be related to rhGH treatment. CONCLUSIONS: This study suggests that hip dysplasia could be a manifestation of an underlying GHD. Additionally, rhGH treatment may not necessarily be causative of LCPD.

Telomerase expression in clinically non-functioning pituitary adenomas.

PURPOSE: Non-functioning pituitary adenomas (NFPA) are benign tumors, however, some are agressive. We aimed to assess if human telomerase reverse transcriptase (hTERT) is present in NFPA and if it can be used as a marker of aggressiveness and proliferation. METHODS: Consecutive patients operated for NFPA whose fresh frozen tumors were available were included. We analyzed tumor's aggressiveness (based on radiological progression) and proliferation (based on Ki-67), as well as hTERT mRNA by quantitative real-time polymerase chain reaction (RT-qPCR). RESULTS: We included 109 samples from 86 patients followed for a median period of 60 months (5-120 months). Aggressive tumors were present in 66% cases and proliferative tumors in 47.7%. Seven (6.4%) samples expressed hTERT: 3 (42.8%) had aggressive and proliferative tumors, 2 (28.6%) only exhibited aggressiveness and the remaining 2 (28.6%) only proliferation. From the aggressive and proliferative tumors, 14% and 16%, respectively, expressed hTERT. From the non-aggressive and non-proliferative tumors, 9% and 6%, respectively, expressed hTERT. CONCLUSION: hTERT expression is present in a minority of NFPA and does not seem to be related to aggressiveness or proliferation in NFPA.

Growth hormone-releasing hormone-secreting pulmonary neuroendocrine tumor associated with pituitary hyperplasia and somatotropinoma

SUMMARY Acromegaly caused by ectopic growth hormone-releasing hormone (GHRH)-secreting tumor is exceedingly rare. We report a case of acromegaly secondary to GHRH secretion by an incidentally diagnosed pulmonary neuroendocrine tumor (NET) and review 47 similar cases in literature. A 22-year-old male patient presented with symptoms of pituitary apoplexy. Magnetic resonance imaging (MRI) showed apoplexy of a pituitary adenoma. Routinely prior to surgery, a chest radiography was performed which revealed a mass in the left lung. During investigation, the patient was diagnosed with metastatic GHRH-secreting pulmonary NET. In retrospect, it was noted that the patient had pituitary hyperplasia 20 months prior to the MRI which showed the presence of a pituitary adenoma. The histological findings confirmed somatotroph hyperplasia adjacent to somatotropinoma. This case suggests that GHRH secretion can be associated with pituitary hyperplasia, which may be followed by pituitary adenoma formation.

Hydroxychloroquine with azithromycin in patients hospitalized for mild and moderate COVID-19

ABSTRACT Objectives: To assess the efficacy of hydroxychloroquine in combination with azithromycin in terms of clinical and biochemical outcomes in adult patients with COVID-19 hospitalized for acute respiratory distress syndrome (ARDS), and to describe the occurrence of adverse events. Method: Retrospective comparative study, based in a quaternary private hospital in Rio de Janeiro, Brazil, involving 193 adult patients hospitalized for mild and moderate COVID-19 related ARSD, analyzing treatment efficacy based on clinical and biochemical outcomes. Results: The active group comprised 101 (52.3%) patients using hydroxychloroquine associated with azithromycin and the control group 92 (47.7%) patients who did not take these medications. Median age was 59 (47-70) in the active group and 65 (47−77) in the control group (p < 0.05). Patients in the control group had greater extent of pulmonary involvement on baseline chest CT scans (p < 0.05). All other baseline variables (BMI, comorbidities, previous use of medications and biochemical assessments) were similar between groups. In the medication group, 25% (25 out of 101) were admitted to the ICU, compared to 21% (19 out of 92) in the control group (p > 0.05). No difference in mortality, duration of non-invasive oxygen use or duration of hospitalization was seen between groups. The therapeutic regimen was well tolerated, with only eight (7.9%) patients presenting gastrointestinal symptoms and eight (7.9%) patients withdrawn treatment due to QTc prolongation. Conclusions: Patients treated with hydroxychloroquine combined with azithromycin and the control group had similar clinical outcomes. This therapeutic regimen was considered ineffective in hospitalized patients with mild to moderate COVID-19 related ARDS and was associated with few non-severe adverse events.

Acromegaly: Update on Management and Long-Term Morbidities.

Acromegaly is a systemic disease associated with great morbidity and increased mortality if not adequately treated. In the past decades much improvement has been achieved in its treatment and in the knowledge of its comorbidities. We provide an update of acromegaly management with current recommendations. We also address long-term comorbidities emphasizing the changing face of the disease in more recent series, with a decrease of cardiovascular disease severity and an increased awareness of comorbidities like bone disease, manifested mainly as vertebral fractures and the change in the main cause of death (from cardiovascular disease to cancer in more recent series).

Cyclin A in nonfunctioning pituitary adenomas.

PURPOSE: Assess cyclin A in nonfunctioning pituitary adenomas (NFPA) and compare its expression in non-invasive and non-proliferative tumors with invasive and proliferative tumors (12× higher risk of recurrence). METHODS: Quantitative real time polymerase chain reaction to analyze cyclin A using normal pituitary gland as reference. Fold change (FC) > 1 was considered as increased. Tumor invasion was based on Knosp criteria (grades 3-4 considered invasive) and proliferation on the presence of at least two of three criteria: Ki-67 ≥ 3%; mitoses > 2/10; positive p53. Both groups were compared with Mann-Whitney test considering p value < 0.05 as statistically significant. RESULTS: Thirty-one patients with NFPA were included. Tumors were mainly of gonadotrophic origin (74.2%), followed by corticotrophic (19.4%) and lactotrophic (3.2%) origins and null-cell adenomas (3.2%). Median tumor diameter was 3.5 cm (1.8-8.0) and Ki-67 was 3.0% (0.3-11%). Sixteen patients had tumors classified as non-invasive and non-proliferative and 15 as invasive and proliferative. Median FC was 0.31 in all tumors (0.13-1.94). Cyclin A was not related to invasion or proliferation (FC 0.41 in non-invasive and non-proliferative tumors and FC 0.30 in invasive and proliferative tumors; p = 0.968). Four (12.9%) patients had tumors that exhibited increased cyclin A [median FC of 1.04 (1.02-1.94)]-three of gonadotrophic origin and one null-cell adenoma, with two tumors classified as non-invasive and non-proliferative and two tumors classified as invasive and proliferative. Median tumor diameter in these samples was 3.4 cm (2.4-3.6) and Ki-67 was 5.1% (2-11%). CONCLUSIONS: Cyclin A was increased in a minority of NFPA and does not seem to be related to invasion or proliferation.

Collision sellar lesions: coexistence of pituitary adenoma and Rathke cleft cyst-a single-center experience.

PURPOSE: Collision sellar lesions represent the coexistence of distinct histopathological lesions found in the sella turcica. They are uncommon entities and have mainly been reported as pituitary adenoma (PA) associated to Rathke cleft cyst (RCC). Pre- and perioperative diagnosis is difficult, since most of the cases appear clinically, radiologically, and macroscopically as solitary cystic sellar lesion. METHODS: A retrospective study of histological reports from patients operated for PA from 2013 to 2018 in a single neurosurgery reference center was performed. Patients who also exhibited RCC in the histological sections were included. Clinical and biochemical data were collected from medical files. MRI scans and histopathological slides were also reviewed. RESULTS: Among 554 PA, five patients (0.9%) presented the association of PA and RCC. At diagnosis, patients had median age of 60 years (33-78) with, at least, one pituitary dysfunction, and visual field loss and/or headache. There was a female predominance (n = 3). All patients had nonfunctioning PA. MRI studies showed a predominantly cystic lesion and were unable to distinguish both lesions. The definitive diagnosis was made by histopathology. CONCLUSION: The association of PA and RCC is extremely rare. On MRI, they appear as a solid-cystic or cystic sellar tumors. RCC can rupture causing granulomatous reaction with cholesterol crystal formation, which can be mistaken for craniopharyngiomas during surgery. Therefore, collision sellar lesion must be included in the differential diagnosis of cystic sellar lesions. The definitive diagnosis is made by histological study.