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Niliyeh S, Sayarifard F, Moradi A, Setoodeh A, Ebrahimi P. A Rare Case of ACTH-Secreting Pituitary Adenoma in a Pediatric Patient. Diagnosis and Management: Case Report and Literature Review. Clin Case Rep 2025; 13:e70385. [PMID: 40190362 PMCID: PMC11970971 DOI: 10.1002/ccr3.70385] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2024] [Revised: 03/14/2025] [Accepted: 03/23/2025] [Indexed: 04/09/2025] Open
Abstract
Due to its rare incidence, pituitary adenoma requires high vigilance and suspicion. Therefore, physicians should consider this differential diagnosis and perform the necessary workup, such as an overnight or standard dexamethasone suppression test and brain magnetic resonance imaging (MRI), to rule it out if sudden hormonal changes without any other explanation are observed in children.
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Affiliation(s)
- Shadi Niliyeh
- Pediatric Endocrinology, Fellow, Children's Medical Center, School of MedicineTehran University of Medical SciencesTehranIran
| | - Fatemeh Sayarifard
- Pediatric Endocrinology, Fellow, Children's Medical Center, School of MedicineTehran University of Medical SciencesTehranIran
| | - Ali Moradi
- Center for Translational Medicine, Faculty of MedicineSemmelweis UniversityBudapestHungary
| | - Aria Setoodeh
- Growth and Development Research Center, Children's Medical Center, School of MedicineTehran University of Medical SciencesTehranIran
| | - Pouya Ebrahimi
- Cardiology Department, Tehran Heart Center, Cardiovascular Disease Research InstituteTehran University of Medical SciencesTehranIran
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Martin C, Leclercq D, Boch AL, Jublanc C, Kuhn E. Determinants of cerebrospinal fluid leakage in a large cohort of macroprolactinomas. ANNALES D'ENDOCRINOLOGIE 2025; 86:101685. [PMID: 39818291 DOI: 10.1016/j.ando.2025.101685] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/15/2024] [Revised: 12/20/2024] [Accepted: 12/31/2024] [Indexed: 01/18/2025]
Abstract
INTRODUCTION Macroprolactinomas are the most frequent subtype of pituitary adenomas. Their treatment has been improved since the onset of dopamin agonists (DA). Nevertheless, DA can cause a cerebospinal fluid (CSF) leakage by shrinking the tumor and lead to a bacterial meningitis. This complication might have lethal consequences. METHODS We conducted an observational, retrospective study in the Pituitary Unit in Pitié Salpêtrière Hospital. A total of 171 patients with macroprolactinomas (larger diameter greater than 10mm) were included in the study. We compared patients who presented cerebrospinal rhinorrhea and/or meningitis, so-called complicated patients (C group), to patients who presented no complications during their follow-up, so-called uncomplicated patients (UC group): no occurrence of rhinorrhea, meningitis. RESULTS Cerebrospinal fluid (CSF) leakage has been found in 5% of patients in our large cohort of macroprolactinoma. Determinants of CSF leakage seems to be : adenoma size with concomitant supra- and infrasellar extension, very high prolactin level (>1000µg/l), cabergoline treatment. CONCLUSION Cerebrospinal rhinorrhea is a rare complication of macroprolactinomas, but potentially lethal because of meningitis risk. Anti-pneumococcal and anti-haemophilus vaccination appears to be appropriate in these patients at the time of introduction of DA, to prevent meningitis.
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Affiliation(s)
- Coline Martin
- Assistance publique-Hôpitaux de Paris, Pituitary Unit, Pitié-Salpêtrière Hospital, 75013 Paris, France
| | - Delphine Leclercq
- Assistance publique-Hôpitaux de Paris, Neuroradiology Department, Pitié-Salpêtrière Hospital, 75013 Paris, France
| | - Anne-Laure Boch
- Assistance publique-Hôpitaux de Paris, Neurosurgery Department, Pitié-Salpêtrière Hospital, 75013 Paris, France
| | - Christel Jublanc
- Assistance publique-Hôpitaux de Paris, Pituitary Unit, Pitié-Salpêtrière Hospital, 75013 Paris, France
| | - Emmanuelle Kuhn
- Assistance publique-Hôpitaux de Paris, Pituitary Unit, Pitié-Salpêtrière Hospital, 75013 Paris, France.
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Balinisteanu I, Caba L, Florea A, Popescu R, Florea L, Ungureanu MC, Leustean L, Gorduza EV, Preda C. Unlocking the Genetic Secrets of Acromegaly: Exploring the Role of Genetics in a Rare Disorder. Curr Issues Mol Biol 2024; 46:9093-9121. [PMID: 39194755 DOI: 10.3390/cimb46080538] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2024] [Revised: 08/14/2024] [Accepted: 08/18/2024] [Indexed: 08/29/2024] Open
Abstract
Acromegaly is a rare endocrine disorder characterized by the excessive production of growth hormone (GH) in adulthood. Currently, it is understood that certain pituitary neuroendocrine tumors (PitNETs) exhibit a hereditary predisposition. These tumors' genetic patterns fall into two categories: isolated and syndromic tumors. The isolated forms are characterized by molecular defects that predispose exclusively to PitNETs, including familial isolated pituitary adenomas (FIPAs) and sporadic genetic defects not characterized by hereditary predisposition. All the categories involve either germline or somatic mutations, or both, each associated with varying levels of penetrance and different phenotypes. This highlights the importance of genetic testing and the need for a more comprehensive view of the whole disease. Despite the availability of multiple treatment options, diagnosis often occurs after several years, and management is still difficult. Early detection and intervention are crucial for preventing complications and enhancing the quality of life for affected individuals. This review aims to elucidate the molecular, clinical, and histological characteristics of GH-secreting PitNETs, providing insights into their prevalence, treatment nuances, and the benefits of genetic testing for each type of genetic disorder associated with acromegaly.
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Affiliation(s)
- Ioana Balinisteanu
- Endocrinology Department, "Grigore T. Popa" University of Medicine and Pharmacy, 700115 Iasi, Romania
| | - Lavinia Caba
- Medical Genetics Department, "Grigore T. Popa" University of Medicine and Pharmacy, 700115 Iasi, Romania
| | - Andreea Florea
- Medical Genetics Department, "Grigore T. Popa" University of Medicine and Pharmacy, 700115 Iasi, Romania
| | - Roxana Popescu
- Medical Genetics Department, "Grigore T. Popa" University of Medicine and Pharmacy, 700115 Iasi, Romania
| | - Laura Florea
- Nephrology-Internal Medicine Department, "Grigore T. Popa" University of Medicine and Pharmacy, 700115 Iasi, Romania
| | - Maria-Christina Ungureanu
- Endocrinology Department, "Grigore T. Popa" University of Medicine and Pharmacy, 700115 Iasi, Romania
| | - Letitia Leustean
- Endocrinology Department, "Grigore T. Popa" University of Medicine and Pharmacy, 700115 Iasi, Romania
| | - Eusebiu Vlad Gorduza
- Medical Genetics Department, "Grigore T. Popa" University of Medicine and Pharmacy, 700115 Iasi, Romania
| | - Cristina Preda
- Endocrinology Department, "Grigore T. Popa" University of Medicine and Pharmacy, 700115 Iasi, Romania
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Grottoli S, Ghigo E. Pituitary tumor centers of excellence (PTCOE): the next border of acromegaly treatment. Pituitary 2024; 27:314-316. [PMID: 38916827 DOI: 10.1007/s11102-024-01416-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 06/15/2024] [Indexed: 06/26/2024]
Affiliation(s)
- Silvia Grottoli
- Endocrinology, Diabetology and Metabolism, Department of Medical Science, University of Turin, Corso Dogliotti 14, 10126, Torino, Italy.
| | - Ezio Ghigo
- Endocrinology, Diabetology and Metabolism, Department of Medical Science, University of Turin, Corso Dogliotti 14, 10126, Torino, Italy
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Savvidis C, Kallistrou E, Kouroglou E, Dionysopoulou S, Gavriiloglou G, Ragia D, Tsiama V, Proikaki S, Belis K, Ilias I. Circadian rhythm disruption and endocrine-related tumors. World J Clin Oncol 2024; 15:818-834. [PMID: 39071458 PMCID: PMC11271730 DOI: 10.5306/wjco.v15.i7.818] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/30/2023] [Revised: 06/20/2024] [Accepted: 06/27/2024] [Indexed: 07/16/2024] Open
Abstract
This review delved into the intricate relationship between circadian clocks and physiological processes, emphasizing their critical role in maintaining homeostasis. Orchestrated by interlocked clock genes, the circadian timekeeping system regulates fundamental processes like the sleep-wake cycle, energy metabolism, immune function, and cell proliferation. The central oscillator in the hypothalamic suprachiasmatic nucleus synchronizes with light-dark cycles, while peripheral tissue clocks are influenced by cues such as feeding times. Circadian disruption, linked to modern lifestyle factors like night shift work, correlates with adverse health outcomes, including metabolic syndrome, cardiovascular diseases, infections, and cancer. We explored the molecular mechanisms of circadian clock genes and their impact on metabolic disorders and cancer pathogenesis. Specific associations between circadian disruption and endocrine tumors, spanning breast, ovarian, testicular, prostate, thyroid, pituitary, and adrenal gland cancers, are highlighted. Shift work is associated with increased breast cancer risk, with PER genes influencing tumor progression and drug resistance. CLOCK gene expression correlates with cisplatin resistance in ovarian cancer, while factors like aging and intermittent fasting affect prostate cancer. Our review underscored the intricate interplay between circadian rhythms and cancer, involving the regulation of the cell cycle, DNA repair, metabolism, immune function, and the tumor microenvironment. We advocated for integrating biological timing into clinical considerations for personalized healthcare, proposing that understanding these connections could lead to novel therapeutic approaches. Evidence supports circadian rhythm-focused therapies, particularly chronotherapy, for treating endocrine tumors. Our review called for further research to uncover detailed connections between circadian clocks and cancer, providing essential insights for targeted treatments. We emphasized the importance of public health interventions to mitigate lifestyle-related circadian disruptions and underscored the critical role of circadian rhythms in disease mechanisms and therapeutic interventions.
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Affiliation(s)
- Christos Savvidis
- Department of Endocrinology, Hippocration General Hospital, Athens GR-11527, Greece
| | - Efthymia Kallistrou
- Department of Endocrinology, Hippocration General Hospital, Athens GR-11527, Greece
| | - Eleni Kouroglou
- Department of Endocrinology, Hippocration General Hospital, Athens GR-11527, Greece
| | - Sofia Dionysopoulou
- Department of Endocrinology, Hippocration General Hospital, Athens GR-11527, Greece
| | | | - Dimitra Ragia
- Department of Endocrinology, Hippocration General Hospital, Athens GR-11527, Greece
| | - Vasiliki Tsiama
- Department of Endocrinology, Hippocration General Hospital, Athens GR-11527, Greece
| | - Stella Proikaki
- Department of Endocrinology, Hippocration General Hospital, Athens GR-11527, Greece
| | - Konstantinos Belis
- Department of Endocrinology, Hippocration General Hospital, Athens GR-11527, Greece
| | - Ioannis Ilias
- Department of Endocrinology, Hippocration General Hospital, Athens GR-11527, Greece
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Miao X, Fu Z, Luo X, Wang J, Yuan L, Zhao S, Feng Y, Huang S, Xiao S. A study on the correlations of PRL levels with anxiety, depression, sleep, and self-efficacy in patients with prolactinoma. Front Endocrinol (Lausanne) 2024; 15:1369729. [PMID: 38572480 PMCID: PMC10989272 DOI: 10.3389/fendo.2024.1369729] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/12/2024] [Accepted: 02/29/2024] [Indexed: 04/05/2024] Open
Abstract
Purpose The purpose of this study was to explore the factors influencing PRL levels in patients with prolactinoma and to investigate the correlations between anxiety, depression, sleep, self-efficacy, and PRL levels. Methods This retrospective study included 176 patients with prolactinoma who received outpatient treatment at the Affiliated Hospital of Zunyi Medical University from May 2017 to August 2022. The general information questionnaire, Hospital Anxiety and Depression Scale (HADS), Athens Insomnia Scale (AIS), and General Self-Efficacy Scale (GSES) were used for data collection. A generalized estimating equation (GEE) model was used to analyze the factors influencing PRL levels in patients with prolactinoma. GEE single-effect analysis was used to compare PRL levels at different time points between anxiety group and nonanxiety group, between insomnia group and normal group, and between low, medium, and high self-efficacy groups. Results The median baseline PRL level and the PRL levels at 1, 3, 6, and 12 months of follow-up were 268.50 ng/ml, 122.25 ng/ml, 21.20 ng/ml, 19.65 ng/ml, and 16.10 ng/ml, respectively. Among patients with prolactinoma, 59.10% had anxiety (HADS-A score = 7.35 ± 3.34) and 28.98% had depression (HADS-D score = 5.23 ± 3.87), 9.10% had sleep disorders (AIS score = 6.10 ± 4.31) and 54.55% had low self-efficacy (GSES score = 2.13 ± 0.83). Educational level, tumor size, number of visits, sleep quality, anxiety level, and self-efficacy level were found to be factors influencing PRL levels in patients with prolactinoma (P<0.05). Higher PRL levels were observed in the anxiety group compared to the non-anxiety group (P<0.001), in the insomnia group compared to the normal group (P<0.05), and in the low self-efficacy group compared to the medium and high self-efficacy groups (P<0.05). Conclusion PRL levels in patients with prolactinoma are related to education level, tumor size, number of visits, anxiety, self-efficacy, and sleep but not depression. PRL levels were higher in patients with anxiety, low self-efficacy, and sleep disorders.
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Affiliation(s)
- Xiaoju Miao
- Department of Nursing, Affiliated Hospital of Zunyi Medical University, Zunyi, China
- The First Ward of the Neurosurgery Department, Affiliated Hospital of Zunyi Medical University, Zunyi, China
| | - Zhongmin Fu
- Department of Nursing, Affiliated Hospital of Zunyi Medical University, Zunyi, China
- The First Ward of the Neurosurgery Department, Affiliated Hospital of Zunyi Medical University, Zunyi, China
| | - Xian Luo
- Department of Nursing, Affiliated Hospital of Zunyi Medical University, Zunyi, China
- The First Ward of the Neurosurgery Department, Affiliated Hospital of Zunyi Medical University, Zunyi, China
| | - Jun Wang
- Department of Nursing, Affiliated Hospital of Zunyi Medical University, Zunyi, China
- The First Ward of the Neurosurgery Department, Affiliated Hospital of Zunyi Medical University, Zunyi, China
| | - Lili Yuan
- Department of Nursing, Affiliated Hospital of Zunyi Medical University, Zunyi, China
- The First Ward of the Neurosurgery Department, Affiliated Hospital of Zunyi Medical University, Zunyi, China
| | - Shunjun Zhao
- Department of Nursing, Affiliated Hospital of Zunyi Medical University, Zunyi, China
- The First Ward of the Neurosurgery Department, Affiliated Hospital of Zunyi Medical University, Zunyi, China
| | - Yi Feng
- Department of Nursing, Affiliated Hospital of Zunyi Medical University, Zunyi, China
| | - Shiming Huang
- Department of Nursing, Affiliated Hospital of Zunyi Medical University, Zunyi, China
| | - Shunwu Xiao
- The First Ward of the Neurosurgery Department, Affiliated Hospital of Zunyi Medical University, Zunyi, China
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Voznyak O, Zinkevych I, Lytvynenko A, Hryniv N, Ilyuk R, Kobyliak N. Prognostic factors for surgical treatment of prolactin-secreting pituitary adenomas. Front Surg 2024; 11:1283179. [PMID: 38375408 PMCID: PMC10875013 DOI: 10.3389/fsurg.2024.1283179] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2023] [Accepted: 01/19/2024] [Indexed: 02/21/2024] Open
Abstract
Introduction Usually, prolactinomas are treated with dopamine agonists (DA). Surgery is considered an option when the patient cannot bear or does not respond positively to DA therapy. Aim This study aims to determine the early and late outcomes of surgery, with particular emphasis on developing prognostic factors for surgical treatment and analyzing risk factors affecting the recurrence of hyperprolactinemia and prolactinoma. Material and methods This retrospective study was conducted at the Feofaniya Clinical Hospital of the State Administration of Affairs (Kyiv, Ukraine), evaluating 109 patients' records from 2009 to 2019. The main patients' inclusion criteria were: serum prolactin (PRL) level of more than 100 ng/ml, presence of pituitary adenoma (PA) on MRI, histologically approved PA by microscopy. According to the size of the prolactin-secreting PA (PSPAs) the selected 109 patients were divided into two groups: micro- (≤10 mm, n = 75) and macroadenoma group (10-40 mm, n = 34). Results 1 month after the operation, PRL levels decreased by 87% (p < 0.001), 12 months-by 93% (p < 0.001). After receiving surgery and DA therapy for 12 months 77.1% of patients achieved biochemical remission. Out of the total number of patients observed, 15.6% (n = 17) had a Knosp score greater than 3. Additionally, in the macroadenoma group, the percentage of patients with a Knosp score greater than 3 was 41,2%, which was significantly higher as compared to the microadenoma group (4%, p < 0.001). In patients with microadenomas a weak reverse correlation between patients' age (r = -0.258, p < 0.026) and positive with tumor size (r = 0.251, p < 0.030) was revealed. In the macroadenoma group significant association was found only between preoperative serum PRL level and tumor size (r = 0.412, p < 0.016). The preoperative PRL can be used as a diagnostic marker for lack of early biochemical remission in patients with PSPAs with diagnostic accuracy 66.9%. Conclusions This study found that primary transsphenoidal surgery is an effective treatment in reaching PRL level control in patients with both micro- and macroprolactinomas. The correct and thorough selection of candidates for surgery is crucial to achieve postoperative serum PRL normalization in the vast majority of patients.
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Affiliation(s)
- Oleksandr Voznyak
- Centre of Neurosurgery, Clinical Hospital “Feofaniya”, Kyiv, Ukraine
| | | | - Andrii Lytvynenko
- Centre of Neurosurgery, Clinical Hospital “Feofaniya”, Kyiv, Ukraine
| | - Nazarii Hryniv
- Centre of Neurosurgery, Clinical Hospital “Feofaniya”, Kyiv, Ukraine
| | - Roman Ilyuk
- Centre of Neurosurgery, Clinical Hospital “Feofaniya”, Kyiv, Ukraine
| | - Nazarii Kobyliak
- Medical Laboratory CSD, Kyiv, Ukraine
- Endocrinology Department, Bogomolets National Medical University, Kyiv, Ukraine
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Voznyak O, Zinkevych I, Lytvynenko A, Hryniv N, Ilyuk R, Kobyliak N. Gender Differences in Patients with Prolactinoma: Single-center Ukrainian Experience. Rev Recent Clin Trials 2024; 19:204-214. [PMID: 38561622 DOI: 10.2174/0115748871288948240325080936] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2023] [Revised: 02/20/2024] [Accepted: 02/23/2024] [Indexed: 04/04/2024]
Abstract
INTRODUCTION Prolactinomas are the most common type of pituitary gland tumors that secrete overly prolactin. They account for approximately 60% of all hormone-secreting hypophysis tumors. AIM This study aims to analyze gender differences in patients with prolactinomas who were operated on transsphenoidal surgery and conduct a single-center retrospective analysis of patient data. MATERIAL AND METHODS This study evaluated the medical records of 109 patients (61 females and 48 males) from 2009 to 2019 at Feofaniya Clinical Hospital of the State Administration of Affairs in Kyiv, Ukraine. The primary criterion for including patients was a Serum Prolactin (PRL) level of over 100 ng/ml and the presence of a pituitary adenoma (PA) as observed on MRI. Additionally, the histological examination needed to confirm the presence of Prolactin-Secreting Pituitary Adenomas (PSPAs) without plurihormonal activity through both microscopy and immunohistochemical (IHC) staining. RESULTS Significant differences in preoperative PRL levels were not observed. However, males had significantly larger tumor sizes and prevalence of macroadenomas. In male patients, the preoperative PLR levels showed a weak negative correlation with age (r=-0.304, p < 0.036) and a positive correlation with tumor size (r=0.555, p < 0.001) and cavernous sinus invasion (r=0.339, p < 0.018). In females, preoperative PRL was significantly associated only with tumor size and Knosp grade. CONCLUSION Prolactin-Secreting Pituitary Adenomas (PSPAs) are more common in women than men and are characterized by larger and more invasive tumors with high PRL levels at diagnosis. The PRL level and tumor size before surgery can predict early biochemical remission in both males and females with an accuracy of 58.3% and 68.8%, respectively.
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Affiliation(s)
- Oleksandr Voznyak
- Centre of Neurosurgery, Clinical Hospital "Feofaniya", Zabolotny str, 21, Kyiv, 03143, Ukraine
| | - Iaroslav Zinkevych
- Centre of Neurosurgery, Clinical Hospital "Feofaniya", Zabolotny str, 21, Kyiv, 03143, Ukraine
| | - Andrii Lytvynenko
- Centre of Neurosurgery, Clinical Hospital "Feofaniya", Zabolotny str, 21, Kyiv, 03143, Ukraine
| | - Nazarii Hryniv
- Centre of Neurosurgery, Clinical Hospital "Feofaniya", Zabolotny str, 21, Kyiv, 03143, Ukraine
| | - Roman Ilyuk
- Centre of Neurosurgery, Clinical Hospital "Feofaniya", Zabolotny str, 21, Kyiv, 03143, Ukraine
| | - Nazarii Kobyliak
- Medical Laboratory CSD, Kyiv, 02000, Ukraine
- Department of Endocrinology, Bogomolets National Medical University, Kyiv, 01024, Ukraine
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Zhang Y, Li V, Liu J, Zhu H, Lu L, Pan H, Wang R, Deng K, Yao Y. Case report: Identification of potential prognosis-related LAG3 overexpression and DICER1 mutation in pituitary carcinoma: two cases. Front Neurosci 2023; 17:1191596. [PMID: 37901430 PMCID: PMC10600493 DOI: 10.3389/fnins.2023.1191596] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2023] [Accepted: 09/29/2023] [Indexed: 10/31/2023] Open
Abstract
Metastatic PitNETs are a rare life-threatening condition with poor prognosis and documentation. Due to the scarce literature and lack of precise treatment, we hope to better characterise PitNET using the next-generation whole exon sequencing (WES) and RNA sequencing. This case study outlines a 54 years-old man and a 52 years-old woman who were both diagnosed with PitNET and analysis of peripheral blood and tumours were performed by WES and RNA sequencing. Analysis showed that DICER1 mutations in precancerous lesions and LAG3 overexpression were significant in aiding the prognosis and diagnosis of PitNETs. The first case with overexpressed LAG3 and DICER1 mutation died 26 months later, and the second case with LAG3 overexpression achieved partial remission. This study revealed that heightened expression of LAG3 offered promising targets for ICI and mutations in DICER1 could provide markers for effective diagnosis and prognosis.
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Affiliation(s)
- Yi Zhang
- Department of Neurosurgery, Peking Union Medical College Hospital, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, China
| | - Victoria Li
- Faculty of Medicine, Dentistry and Health Sciences, The University of Melbourne, Melbourne, VIC, Australia
| | - Jifang Liu
- Department of Neurosurgery, Peking Union Medical College Hospital, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, China
| | - Huijuan Zhu
- Department of Endocrinology, Peking Union Medical College Hospital, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, China
| | - Lin Lu
- Department of Endocrinology, Peking Union Medical College Hospital, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, China
| | - Hui Pan
- Department of Endocrinology, Peking Union Medical College Hospital, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, China
| | - Renzhi Wang
- Department of Neurosurgery, Peking Union Medical College Hospital, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, China
| | - Kan Deng
- Department of Neurosurgery, Peking Union Medical College Hospital, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, China
| | - Yong Yao
- Department of Neurosurgery, Peking Union Medical College Hospital, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, China
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Kim EH, Kim J, Ku CR, Lee EJ, Kim SH. Surgical Treatment of Prolactinomas: Potential Role as a First-Line Treatment Modality. Yonsei Med J 2023; 64:489-496. [PMID: 37488700 PMCID: PMC10375245 DOI: 10.3349/ymj.2022.0406] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/07/2022] [Revised: 05/01/2023] [Accepted: 06/01/2023] [Indexed: 07/26/2023] Open
Abstract
PURPOSE Treatment with dopamine agonists (DAs) has been the first-line standard treatment for prolactinoma, and surgery has been reserved for drug intolerance and resistance for several decades. We evaluated whether surgery plays a primary role in prolactinoma management. MATERIALS AND METHODS We conducted a retrospective study of 210 prolactinoma patients who had received surgical treatment at our institution. We analyzed the treatment outcomes according to tumor extent, sex, and preoperative DA medication. RESULTS Overall hormonal remission was achieved in 164 patients (78.1%), and complete removal was achieved in 194 patients (92.4%). When the tumors were completely removed, the remission rate increased to 84.5%. Anterior pituitary function was normalized or improved in 94.6% of patients, whereas only 4.1% of patients showed worsening of hormone control. Hormonal remission was higher in patients who had not received DA preoperatively than in those who had received preoperative DA treatment. Smaller tumor size (<1 cm), no invasion into the cavernous sinus, and female sex were predictors of good surgical outcomes. CONCLUSION Although DAs remain the first-line standard treatment for prolactinomas, surgery can be an excellent option and should be considered as an alternative primary treatment modality when patients are predicted to achieve a good surgical outcome.
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Affiliation(s)
- Eui Hyun Kim
- Department of Neurosurgery, Yonsei University College of Medicine, Seoul, Korea
- Pituitary Tumor Center, Severance Hospital, Seoul, Korea
- Yonsei Endocrine Research Institute, Yonsei University College of Medicine, Seoul, Korea
| | - Junhyung Kim
- Department of Neurosurgery, Yonsei University College of Medicine, Seoul, Korea
| | - Cheol Ryong Ku
- Pituitary Tumor Center, Severance Hospital, Seoul, Korea
- Yonsei Endocrine Research Institute, Yonsei University College of Medicine, Seoul, Korea
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea
| | - Eun Jig Lee
- Pituitary Tumor Center, Severance Hospital, Seoul, Korea
- Yonsei Endocrine Research Institute, Yonsei University College of Medicine, Seoul, Korea
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea
| | - Sun Ho Kim
- Department of Neurosurgery, Yonsei University College of Medicine, Seoul, Korea.
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Maia R, Miranda A, Geraldo AF, Sampaio L, Ramaglia A, Tortora D, Severino M, Rossi A. Neuroimaging of pediatric tumors of the sellar region-A review in light of the 2021 WHO classification of tumors of the central nervous system. Front Pediatr 2023; 11:1162654. [PMID: 37416813 PMCID: PMC10320298 DOI: 10.3389/fped.2023.1162654] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/09/2023] [Accepted: 06/07/2023] [Indexed: 07/08/2023] Open
Abstract
Sellar/suprasellar tumors comprise about 10% of all pediatric Central Nervous System (CNS) tumors and include a wide variety of entities, with different cellular origins and distinctive histological and radiological findings, demanding customized neuroimaging protocols for appropriate diagnosis and management. The 5th edition of the World Health Organization (WHO) classification of CNS tumors unprecedently incorporated both histologic and molecular alterations into a common diagnostic framework, with a great impact in tumor classification and grading. Based on the current understanding of the clinical, molecular, and morphological features of CNS neoplasms, there have been additions of new tumor types and modifications of existing ones in the latest WHO tumor classification. In the specific case of sellar/suprasellar tumors, changes include for example separation of adamantinomatous and papillary craniopharyngiomas, now classified as distinct tumor types. Nevertheless, although the current molecular landscape is the fundamental driving force to the new WHO CNS tumor classification, the imaging profile of sellar/suprasellar tumors remains largely unexplored, particularly in the pediatric population. In this review, we aim to provide an essential pathological update to better understand the way sellar/suprasellar tumors are currently classified, with a focus on the pediatric population. Furthermore, we intend to present the neuroimaging features that may assist in the differential diagnosis, surgical planning, adjuvant/neoadjuvant therapy, and follow-up of this group of tumors in children.
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Affiliation(s)
- Rúben Maia
- Department of Neuroradiology, Centro Hospitalar Universitário São João, Porto, Portugal
| | - André Miranda
- Diagnostic Neuroradiology Unit, Imaging Department, Centro Hospitalar Vila Nova de Gaia/Espinho, Vila Nova de Gaia, Portugal
- Life and Health Sciences Research Institute (ICVS), School of Medicine, University of Minho, Braga, Portugal
| | - Ana Filipa Geraldo
- Diagnostic Neuroradiology Unit, Imaging Department, Centro Hospitalar Vila Nova de Gaia/Espinho, Vila Nova de Gaia, Portugal
- Faculty of Medicine, University of Lisbon, Lisbon, Portugal
| | - Luísa Sampaio
- Department of Neuroradiology, Centro Hospitalar Universitário São João, Porto, Portugal
- Faculty of Medicine, University of Porto, Porto, Portugal
| | - Antonia Ramaglia
- Neuroradiology Unit, IRCCS Istituto Giannina Gaslini, Genoa, Italy
| | - Domenico Tortora
- Neuroradiology Unit, IRCCS Istituto Giannina Gaslini, Genoa, Italy
| | | | - Andrea Rossi
- Neuroradiology Unit, IRCCS Istituto Giannina Gaslini, Genoa, Italy
- Department of Health Sciences (DISSAL), University of Genoa, Genoa, Italy
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Vamvoukaki R, Chrysoulaki M, Betsi G, Xekouki P. Pituitary Tumorigenesis-Implications for Management. MEDICINA (KAUNAS, LITHUANIA) 2023; 59:medicina59040812. [PMID: 37109772 PMCID: PMC10145673 DOI: 10.3390/medicina59040812] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/19/2023] [Revised: 04/11/2023] [Accepted: 04/17/2023] [Indexed: 04/29/2023]
Abstract
Pituitary neuroendocrine tumors (PitNETs), the third most common intracranial tumor, are mostly benign. However, some of them may display a more aggressive behavior, invading into the surrounding structures. While they may rarely metastasize, they may resist different treatment modalities. Several major advances in molecular biology in the past few years led to the discovery of the possible mechanisms involved in pituitary tumorigenesis with a possible therapeutic implication. The mutations in the different proteins involved in the Gsa/protein kinase A/c AMP signaling pathway are well-known and are responsible for many PitNETS, such as somatotropinomas and, in the context of syndromes, as the McCune-Albright syndrome, Carney complex, familiar isolated pituitary adenoma (FIPA), and X-linked acrogigantism (XLAG). The other pathways involved are the MAPK/ERK, PI3K/Akt, Wnt, and the most recently studied HIPPO pathways. Moreover, the mutations in several other tumor suppressor genes, such as menin and CDKN1B, are responsible for the MEN1 and MEN4 syndromes and succinate dehydrogenase (SDHx) in the context of the 3PAs syndrome. Furthermore, the pituitary stem cells and miRNAs hold an essential role in pituitary tumorigenesis and may represent new molecular targets for their diagnosis and treatment. This review aims to summarize the different cell signaling pathways and genes involved in pituitary tumorigenesis in an attempt to clarify their implications for diagnosis and management.
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Affiliation(s)
- Rodanthi Vamvoukaki
- Endocrinology and Diabetes Clinic, University Hospital of Heraklion, School of Medicine, University of Crete, 71500 Crete, Greece
| | - Maria Chrysoulaki
- Endocrinology and Diabetes Clinic, University Hospital of Heraklion, School of Medicine, University of Crete, 71500 Crete, Greece
| | - Grigoria Betsi
- Endocrinology and Diabetes Clinic, University Hospital of Heraklion, School of Medicine, University of Crete, 71500 Crete, Greece
| | - Paraskevi Xekouki
- Endocrinology and Diabetes Clinic, University Hospital of Heraklion, School of Medicine, University of Crete, 71500 Crete, Greece
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Miranda ISDM, Valadares LP, Barra GB, Mesquita PG, de Santana LB, de Castro LF, Rita THS, Naves LA. Clinical and molecular features of four Brazilian families with multiple endocrine neoplasia type 1. Front Endocrinol (Lausanne) 2023; 14:1117873. [PMID: 36967793 PMCID: PMC10036827 DOI: 10.3389/fendo.2023.1117873] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/07/2022] [Accepted: 02/20/2023] [Indexed: 03/12/2023] Open
Abstract
Objective Multiple endocrine neoplasia type 1 (MEN1) is an autosomal dominant syndrome characterized by its clinical variability and complexity in diagnosis and treatment. We performed both clinical and molecular descriptions of four families with MEN1 in a follow-up at a tertiary center in Brasília. Methods From a preliminary review of approximately 500 medical records of patients with pituitary neuroendocrine tumor (PitNET) from the database of the Neuroendocrinology Outpatient Clinic of the University Hospital of Brasília, a total of 135 patients met the criteria of at least two affected family members. From this cohort, we have identified 34 families: only four with a phenotype of MEN1 and the other 30 families with the phenotype of familial isolated pituitary adenoma (FIPA). Eleven patients with a clinical diagnosis of MEN1 from these four families were selected. Results Variants in MEN1 gene were identified in all families. One individual from each family underwent genetic testing using targeted high-throughput sequencing (HTS). All patients had primary hyperparathyroidism (PHPT), and the second most common manifestation was PitNET. One individual had well-differentiated liposarcoma, which has been previously reported in a single case of MEN1. Three variants previously described in the database and a novel variant in exon 2 have been found. Conclusions The study allowed the genotypic and phenotypic characterization of families with MEN1 in a follow-up at a tertiary center in Brasília.
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Abstract
Hereditary pituitary tumorigenesis is seen in a relatively small proportion (around 5%) of patients with pituitary neuroendocrine tumors (PitNETs). The aim of the current review is to describe the main clinical and molecular features of such pituitary tumors associated with hereditary or familial characteristics, many of which have now been genetically identified. The genetic patterns of inheritance are classified into isolated familial PitNETs and the syndromic tumors. In general, the established genetic causes of familial tumorigenesis tend to present at a younger age, often pursue a more aggressive course, and are more frequently associated with growth hormone hypersecretion compared to sporadic tumors. The mostly studied molecular pathways implicated are the protein kinase A and phosphatidyl-inositol pathways, which are in the main related to mutations in the syndromes of familial isolated pituitary adenoma (FIPA), Carney complex syndrome, and X-linked acrogigantism. Another well-documented mechanism consists of the regulation of p27 or p21 proteins, with further acceleration of the pituitary cell cycle through the check points G1/S and M/G1, mostly documented in multiple endocrine neoplasia type 4. In conclusion, PitNETs may occur in relation to well-established familial germline mutations which may determine the clinical phenotype and the response to treatment, and may require family screening.
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Affiliation(s)
- Eleni Armeni
- Dept. of Endocrinology, Royal Free Hospital, London, NW3 2QG, UK.
| | - Ashley Grossman
- Dept. of Endocrinology, Royal Free Hospital, London, NW3 2QG, UK
- Centre for Endocrinology, Barts and the London School of Medicine, London, UK
- Green Templeton College, University of Oxford, Oxford, UK
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15
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Agrawal N, Gersey ZC, Abou-Al-Shaar H, Gardner PA, Mantica M, Agnihotri S, Mahmud H, Fazeli PK, Zenonos GA. Major Genetic Motifs in Pituitary Adenomas: A Practical Literature Update. World Neurosurg 2023; 169:43-50. [PMID: 36115566 PMCID: PMC11195535 DOI: 10.1016/j.wneu.2022.09.036] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2022] [Revised: 09/06/2022] [Accepted: 09/07/2022] [Indexed: 01/12/2023]
Abstract
BACKGROUND The literature includes many studies examining the genetic abnormalities that influence pituitary adenomas (PAs). We aimed to state the collective knowledge on the genetic underpinnings of PAs by organizing, summarizing, and consolidating the literature to serve as a comprehensive review for scientists and clinicians of the most up-to-date information underlying the genetic landscape of PAs. METHODS The PubMed and Google Scholar databases were searched using multiple key words and combined Medical Subject Headings terms; only articles published in English between January 2000 and January 2022 were included. Articles in which the focus did not relate to genetics, that included mainly anecdotal evidence, or that were single case studies were eliminated. RESULTS PAs are one of the most common intracranial neoplasms. However, the genetic underpinnings for these tumors are not yet fully elucidated. There are several categories of PAs: clinically significant versus not clinically significant, functional versus nonfunctional, and germline-derived versus sporadic origin. Each of these disease subcategories is characterized by unique genetic aberrations. Recently, more genes and other types of genetic aberrations have been identified as possible causes of PAs, such as copy number variations and altered levels of microRNAs. CONCLUSIONS This review serves to consolidate and summarize the literature discussing the genetic motifs of PAs to help physicians and scientists deliver patient-centered therapies.
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Affiliation(s)
- Nishant Agrawal
- Departments of Neurological Surgery, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, USA; University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA
| | - Zachary C Gersey
- Departments of Neurological Surgery, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, USA
| | - Hussam Abou-Al-Shaar
- Departments of Neurological Surgery, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, USA
| | - Paul A Gardner
- Departments of Neurological Surgery, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, USA
| | - Megan Mantica
- Departments of Neuro-Oncology, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, USA
| | - Sameer Agnihotri
- Departments of Neurological Surgery, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, USA
| | - Hussain Mahmud
- Departments of Endocrinology and Metabolism, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, USA
| | - Pouneh K Fazeli
- Departments of Endocrinology and Metabolism, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, USA
| | - Georgios A Zenonos
- Departments of Neurological Surgery, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, USA.
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Couselo M, Frara S, Giustina A, Casanueva FF. Pituitary tumor centers of excellence for Cushing's disease. Pituitary 2022; 25:772-775. [PMID: 36087228 PMCID: PMC9587956 DOI: 10.1007/s11102-022-01264-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 07/18/2022] [Indexed: 10/29/2022]
Affiliation(s)
- Marcos Couselo
- Santiago de Compostela University, IDIS-Complejo Hospitalario Universitario de Santiago (CHUS), CIBER de Fisiopatologia Obesidad y Nutricion (CIBERobn), Instituto Salud Carlos III, Santiago de Compostela, Spain
| | - Stefano Frara
- Institute of Endocrine and Metabolic Sciences, San Raffaele Vita-Salute University and IRCCS San Raffaele Hospital, Milan, Italy
| | - Andrea Giustina
- Institute of Endocrine and Metabolic Sciences, San Raffaele Vita-Salute University and IRCCS San Raffaele Hospital, Milan, Italy
| | - Felipe F Casanueva
- Santiago de Compostela University, IDIS-Complejo Hospitalario Universitario de Santiago (CHUS), CIBER de Fisiopatologia Obesidad y Nutricion (CIBERobn), Instituto Salud Carlos III, Santiago de Compostela, Spain.
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Liu J, Wang J, Tian W, Xu Y, Li R, Zhao K, You C, Zhu Y, Bartsch JW, Niu H, Zhang H, Shu K, Lei T. PDCD10 promotes the aggressive behaviors of pituitary adenomas by up-regulating CXCR2 and activating downstream AKT/ERK signaling. Aging (Albany NY) 2022; 14:6066-6080. [PMID: 35963638 PMCID: PMC9417224 DOI: 10.18632/aging.204206] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2022] [Accepted: 07/27/2022] [Indexed: 12/05/2022]
Abstract
As the second most common primary intracranial neoplasms, about 40% of pituitary adenomas (PAs) exhibit aggressive behaviors and resulting in poor patient prognosis. The molecular mechanisms underlying the aggressive behaviors of PAs are not yet fully understood. Biochemical studies have reported that programmed cell death 10 (PDCD10) is a component of the striatin-interacting phosphatase and kinase (STRIPAK) complex and plays a dual role in cancers in a tissue- or disease-specific manner. In the present study, we report for the first time that the role of PDCD10 in PAs. Cell proliferation, migration and invasion were either enhanced by overexpressing or inhibited by silencing PDCD10 in PA cells. Moreover, PDCD10 significantly promoted epithelial–mesenchymal transition (EMT) of pituitary adenoma cells. Mechanistically, we showed that the expression of CXCR2, together with phosphorylation levels of AKT and ERK1/2 were regulated by PDCD10. Activation of CXCR2 inversed inactivation of AKT/ERK signal pathways and the tumor-suppressive effects induced by PDCD10 silencing. Finally, the pro-oncogenic effect of PDCD10 was confirmed by in vivo tumor grafting. Taken together, we demonstrate for the first time that PDCD10 can induce aggressive behaviors of PAs by promoting cellular proliferation, migration, invasion and EMT through CXCR2-AKT/ERK signaling axis.
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Affiliation(s)
- Jingdian Liu
- Department of Neurosurgery, Tongji Hospital Affiliated to Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Junwen Wang
- Department of Neurosurgery, Tongji Hospital Affiliated to Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Weidong Tian
- Department of Neurosurgery, The First Affiliated Hospital, School of Medicine, Shihezi University, Shihezi, China
| | - Yu Xu
- Department of Neurosurgery, Tongji Hospital Affiliated to Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Ran Li
- Department of Neurosurgery, Tongji Hospital Affiliated to Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Kai Zhao
- Department of Neurosurgery, Tongji Hospital Affiliated to Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Chao You
- Department of Neurosurgery, Tongji Hospital Affiliated to Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Yuan Zhu
- Department of Neurosurgery, University of Duisburg-Essen, Essen, Germany
| | | | - Hongquan Niu
- Department of Neurosurgery, Tongji Hospital Affiliated to Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Huaqiu Zhang
- Department of Neurosurgery, Tongji Hospital Affiliated to Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Kai Shu
- Department of Neurosurgery, Tongji Hospital Affiliated to Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Ting Lei
- Department of Neurosurgery, Tongji Hospital Affiliated to Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
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18
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Wallace NJ, Devaiah AK. Pituitary Carcinoma Diagnosis and Survival Improvement, with Affordable Care Act Correlation: A SEER Database Study. Skull Base Surg 2022; 83:305-311. [DOI: 10.1055/s-0040-1722747] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2020] [Accepted: 11/01/2020] [Indexed: 10/22/2022]
Abstract
Abstract
Introduction Pituitary carcinomas are challenging tumors to diagnose and treat due to their rarity and limited data surrounding their etiology. Traditionally, these patients have exhibited poor survival. Over the last several decades, our understanding of pituitary carcinomas has dramatically increased, and there have been recent initiatives to improve patient access to health care, including the Affordable Care Act (ACA). This study investigates whether there were any changes in incidence and treatment outcomes of pituitary carcinoma that correlated with these advances.
Methods A retrospective case review was conducted utilizing the Surveillance, Epidemiology, and End Results (SEER) database of the National Cancer Institute. Those with primary site pituitary tumors with noncontiguous metastases were identified from 1975 to 2016. Demographic data, overall, and cause-specific outcomes were obtained. The data were analyzed using SPSS to generate 5-year Kaplan–Meier curves.
Results The incidence of pituitary carcinoma pre- and post-ACA was 0.31 and 2.14 diagnoses/year, respectively. This represents a significant increase (Chi-square, p < 0.00002). In addition, 1-, 2-, and 5-year overall survival of these patients was determined to be 88.2, 74.0, and 66.6% which was significantly improved compared with prior studies. Cause-specific survival of these patients follow similar trends exhibiting 94.1, 79.0, 71.1% after 1, 2, and 5 years, respectively.
Conclusion The survival for pituitary carcinoma has improved significantly which signals a change in how practitioners should counsel their patients. There is a significant surge in the number of cases in the post-ACA timeline, which suggests that improving patient access has played a part in wider recognition and treatment initiation for this disease.
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Affiliation(s)
- Nathan J. Wallace
- Department of Otolaryngology, Boston University School of Medicine, Boston, Massachusetts, United States
| | - Anand K. Devaiah
- Departments of Otolaryngology, Neurological Surgery, and Ophthalmology, Boston University School of Medicine, Boston, Massachusetts, United States
- Division of Biomedical & Health Technology Development & Transfer Domain, Boston University Institute for Health System Innovation & Policy, Boston, Massachusetts, United States
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Koskay G, Opperman P, Mezzacappa FM, Surdell D. Decision-Making and Management in a Patient With Coexistent Colloid Cyst and Pituitary Macroadenoma: A Case Report. Cureus 2022; 14:e22884. [PMID: 35399429 PMCID: PMC8980217 DOI: 10.7759/cureus.22884] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 03/06/2022] [Indexed: 11/06/2022] Open
Abstract
The coexistence of separate and distinct primary intracranial tumors is rare. Specifically, there are no previous reports of a colloid cyst coexisting with a pituitary macroadenoma. We present the case of a 40-year-old male with a colloid cyst associated with mild enlargement of the right lateral ventricle and a coexistent pituitary macroadenoma with compression of the optic apparatus. An endoscopic endonasal transsphenoidal surgery (EETS) for resection of the pituitary mass was performed first due to the patient’s complaints of acute visual changes. He then underwent a right frontal craniotomy for resection of the colloid cyst one month later. The patient recovered without residual deficits in vision, and he did not require ventricular shunting after removal of the colloid cyst. We aimed to discuss our decision-making process and the management of these coexistent lesions.
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Immunotherapy for Neuro-oncology. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2022; 1342:233-258. [PMID: 34972967 DOI: 10.1007/978-3-030-79308-1_7] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Subscribe] [Scholar Register] [Indexed: 10/19/2022]
Abstract
Immunotherapy has changed the landscape of treatment of many solid and hematological malignancies and is at the forefront of cancer breakthroughs. Several circumstances unique to the central nervous system (CNS) such as limited space for an inflammatory response, difficulties with repeated sampling, corticosteroid use for management of cerebral edema, and immunosuppressive mechanisms within the tumor and brain parenchyma have posed challenges in clinical development of immunotherapy for intracranial tumors. Nonetheless, the success of immunotherapy in brain metastases (BMs) from solid cancers such as melanoma and non-small cell lung cancer (NSCLC) proves that the CNS is not an immune-privileged organ and is capable of initiating and regulating immune responses that lead to tumor control. However, the development of immunotherapeutics for the most malignant primary brain tumor, glioblastoma (GBM), has been challenging due to systemic and profound tumor-mediated immunosuppression unique to GBM, intratumoral and intertumoral heterogeneity, and lack of stably expressed clonal antigens. Here, we review recent advances in the field of immunotherapy for neuro-oncology with a focus on BM, GBM, and rare CNS cancers.
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Nys C, Versyck G, Buelens E, Engelborghs K, Cornips E, Van Leeuwen-Wintjens H, Vankelecom H, Weyns F, Peuskens D. Transnasal transsphenoidal pituitary surgery in a large tertiary hospital, a retrospective study. Acta Chir Belg 2021; 123:272-280. [PMID: 34590931 DOI: 10.1080/00015458.2021.1988231] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/20/2022]
Abstract
OBJECTIVES Pituitary adenomas (PAs), although being small tumours, can have quite an impact on patients' lives causing hormonal and visual disturbances, for which surgery must be performed. As a large peripheral hospital with specialists in pituitary surgery, an assessment of the efficacy and safety of transnasal transsphenoidal pituitary surgery was made. METHODS A retrospective analysis of neurosurgical reports as well as pre and postoperative imaging was made to evaluate the presenting symptoms, tumoural variables, peri-operative morbidity, and long-term outcome. RESULTS This cohort included 105 patients who were operated for PAs over a 9-year period, with a slight male predominance. Adenomas had a mean maximum diameter of almost 25 mm, with one-third of tumours presenting with a Knosp-grade 3 or 4. As expected, most patients presented with either visual (32.4%) or hormonal (40.0%) disturbances. After surgery, 85.3% had complete resolution of visual deficits, and 97.1% had normalisation of hormonal hypersecretion. Postoperative hormonal insufficiency requiring substitution was observed in 43.1% and was significantly more frequent in males and in non-functioning pituitary adenomas (NFAs). Postoperative cerebrospinal fluid (CSF) leakage was observed in 2.9%, and merely one patient developed meningitis. Tumour recurrence was significantly more frequent in patients with partial resection as compared to complete resection (25.6 vs. 7.9%). CONCLUSIONS This study demonstrates that transnasal transsphenoidal pituitary surgery can be performed safely and effectively in a large non-university hospital, improving visual and/or hormonal disturbances as well as providing long-term tumour control. Patients with larger adenomas are at an increased risk to develop postoperative hypopituitarism.
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Affiliation(s)
- Charlotte Nys
- Department of Development and Regeneration, Laboratory of Tissue Plasticity in Health and Disease, Cluster of Stem Cell and Developmental Biology, KU Leuven (University of Leuven), Leuven, Belgium
| | - Georges Versyck
- Department of Neurosurgery, Ziekenhuis Oost-Limburg (ZOL), Genk, Belgium
- Department of Neurosurgery, University Hospitals Leuven, Leuven, Belgium
| | - Eveleen Buelens
- Department of Neurosurgery, Ziekenhuis Oost-Limburg (ZOL), Genk, Belgium
| | - Koen Engelborghs
- Department of Neurosurgery, Ziekenhuis Oost-Limburg (ZOL), Genk, Belgium
| | - Erwin Cornips
- Department of Neurosurgery, Ziekenhuis Oost-Limburg (ZOL), Genk, Belgium
| | | | - Hugo Vankelecom
- Department of Development and Regeneration, Laboratory of Tissue Plasticity in Health and Disease, Cluster of Stem Cell and Developmental Biology, KU Leuven (University of Leuven), Leuven, Belgium
| | - Frank Weyns
- Department of Neurosurgery, Ziekenhuis Oost-Limburg (ZOL), Genk, Belgium
| | - Diederik Peuskens
- Department of Neurosurgery, Ziekenhuis Oost-Limburg (ZOL), Genk, Belgium
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22
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Peltz-Sinvani N, Percik R, Uri I, Kfir SK, Tirosh A, Tirosh A. Low risk for all-cause mortality among patients with lung neuroendocrine tumors co-diagnosed with pituitary adenomas. Endocrine 2021; 73:745-751. [PMID: 33982234 DOI: 10.1007/s12020-021-02740-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/24/2020] [Accepted: 04/21/2021] [Indexed: 10/21/2022]
Abstract
PURPOSE Lung neoplasms often co-occur with pituitary adenoma (PA). However, whether co-diagnosis of lung neuroendocrine tumors (LNETs) and PA constitute a unique entity and the impact of such co-diagnosis on patients' outcome is yet to be defined. The study objective was to compare patients' clinical characteristics with LNET to patients co-diagnosed with PA. METHODS A Retrospective, case-control study based on the Surveillance, Epidemiology, and End Results (SEER) registry database between 2000 and 2016. A total of 2947 patients with LNET, including 2913 with LNET alone ("Sporadic") and 34 patients with both LNET and PA ("LNET-PA"). RESULTS PA preceded LNET diagnosis in 85.3% of patients and had higher rates among LNET patients (34/2947) than with any cancer (p < 0.00001) and compared to patients with non-small cell lung cancer (NSCLC) (15/2378, p = 0.047). LNET-PA patients were younger at diagnosis compared with NSCLC patients and PA (p = 0.04). Among patients <60 years with LNET, co-diagnosis with PA was associated with lower all-cause mortality (ACM) risk (Log-rank test, p = 0.03). Adjusted ACM risk of patients with LNET-PA was lower than sporadic LNET (hazard ratio 0.553, 95% confidence interval 0.309-0.99, p = 0.046), especially among Caucasians, and lower overall-mortality risk in patients <60 years with borderline statistical significance (p = 0.071). CONCLUSIONS Patients with both LNET and PA constitute a distinct morbidity and mortality profile than sporadic LNET, possibly suggesting an undefined MEN syndrome. Additional studies to further investigate patients' natural course and genetic profile with these neoplasms are needed.
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Affiliation(s)
- Naama Peltz-Sinvani
- Division of Endocrinology, Diabetes and Metabolism, The Chaim Sheba Medical Center, Tel-HaShomer, Ramat-Gan, Israel
- Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel
| | - Ruth Percik
- Division of Endocrinology, Diabetes and Metabolism, The Chaim Sheba Medical Center, Tel-HaShomer, Ramat-Gan, Israel
- Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel
| | - Inbal Uri
- Division of Endocrinology, Diabetes and Metabolism, The Chaim Sheba Medical Center, Tel-HaShomer, Ramat-Gan, Israel
- Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel
| | - Sapir Kon Kfir
- Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel
- Department of Internal Medicine D, The Chaim Sheba Medical Center, Tel-HaShomer, Ramat-Gan, Israel
| | - Amir Tirosh
- Division of Endocrinology, Diabetes and Metabolism, The Chaim Sheba Medical Center, Tel-HaShomer, Ramat-Gan, Israel
- Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel
| | - Amit Tirosh
- Division of Endocrinology, Diabetes and Metabolism, The Chaim Sheba Medical Center, Tel-HaShomer, Ramat-Gan, Israel.
- Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel.
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Lines KE, Gluck AK, Thongjuea S, Bountra C, Thakker RV, Gorvin CM. The bromodomain inhibitor JQ1+ reduces calcium-sensing receptor activity in pituitary cell lines. J Mol Endocrinol 2021; 67:83-94. [PMID: 34223822 PMCID: PMC8345903 DOI: 10.1530/jme-21-0030] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/30/2021] [Accepted: 07/05/2021] [Indexed: 12/05/2022]
Abstract
Corticotrophinomas represent 10% of all surgically removed pituitary adenomas, however, current treatment options are often not effective, and there is a need for improved pharmacological treatments. Recently, JQ1+, a bromodomain inhibitor that promotes gene transcription by binding acetylated histone residues and recruiting transcriptional machinery, has been shown to reduce proliferation in a murine corticotroph cell line, AtT20. RNA-Seq analysis of AtT20 cells following treatment with JQ1+ identified the calcium-sensing receptor (CaSR) gene as significantly downregulated, which was subsequently confirmed using real-time PCR and Western blot analysis. CaSR is a G protein-coupled receptor that plays a central role in calcium homeostasis but can elicit non-calcitropic effects in multiple tissues, including the anterior pituitary where it helps regulate hormone secretion. However, in AtT20 cells, CaSR activates a tumour-specific cAMP pathway that promotes ACTH and PTHrP hypersecretion. We hypothesised that the Casr promoter may harbour binding sites for BET proteins, and using chromatin immunoprecipitation (ChIP)-sequencing demonstrated that the BET protein Brd3 binds to the promoter of the Casr gene. Assessment of CaSR signalling showed that JQ1+ significantly reduced Ca2+e-mediated increases in intracellular calcium (Ca2+i) mobilisation and cAMP signalling. However, the CaSR-negative allosteric modulator, NPS-2143, was unable to reduce AtT20 cell proliferation, indicating that reducing CaSR expression rather than activity is likely required to reduce pituitary cell proliferation. Thus, these studies demonstrate that reducing CaSR expression may be a viable option in the treatment of pituitary tumours. Moreover, current strategies to reduce CaSR activity, rather than protein expression for cancer treatments, may be ineffective.
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Affiliation(s)
- Kate E Lines
- Academic Endocrine Unit, Oxford Centre for Diabetes, Endocrinology and Metabolism, Radcliffe Department of Medicine, University of Oxford, Oxford,UK
- Correspondence should be addressed to K E Lines or C M Gorvin: or
| | - Anna K Gluck
- Academic Endocrine Unit, Oxford Centre for Diabetes, Endocrinology and Metabolism, Radcliffe Department of Medicine, University of Oxford, Oxford,UK
| | - Supat Thongjuea
- Centre for Computational Biology, MRC Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, University of Oxford, Oxford, UK
| | - Chas Bountra
- Centre for Medicines Discovery, Nuffield Department of Medicine, University of Oxford, Oxford, UK
| | - Rajesh V Thakker
- Academic Endocrine Unit, Oxford Centre for Diabetes, Endocrinology and Metabolism, Radcliffe Department of Medicine, University of Oxford, Oxford,UK
| | - Caroline M Gorvin
- Academic Endocrine Unit, Oxford Centre for Diabetes, Endocrinology and Metabolism, Radcliffe Department of Medicine, University of Oxford, Oxford,UK
- Institute of Metabolism and Systems Research and Centre for Endocrinology, Diabetes and Metabolism, University of Birmingham, Birmingham, UK
- Centre of Membrane Proteins and Receptors (COMPARE), University of Birmingham, Birmingham, UK
- Correspondence should be addressed to K E Lines or C M Gorvin: or
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Park YW, Eom J, Kim S, Kim H, Ahn SS, Ku CR, Kim EH, Lee EJ, Kim SH, Lee SK. Radiomics With Ensemble Machine Learning Predicts Dopamine Agonist Response in Patients With Prolactinoma. J Clin Endocrinol Metab 2021; 106:e3069-e3077. [PMID: 33713414 DOI: 10.1210/clinem/dgab159] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/22/2020] [Indexed: 11/19/2022]
Abstract
CONTEXT Early identification of the response of prolactinoma patients to dopamine agonists (DA) is crucial in treatment planning. OBJECTIVE To develop a radiomics model using an ensemble machine learning classifier with conventional magnetic resonance images (MRIs) to predict the DA response in prolactinoma patients. DESIGN Retrospective study. SETTING Severance Hospital, Seoul, Korea. PATIENTS A total of 177 prolactinoma patients who underwent baseline MRI (109 DA responders and 68 DA nonresponders) were allocated to the training (n = 141) and test (n = 36) sets. Radiomic features (n = 107) were extracted from coronal T2-weighed MRIs. After feature selection, single models (random forest, light gradient boosting machine, extra-trees, quadratic discrimination analysis, and linear discrimination analysis) with oversampling methods were trained to predict the DA response. A soft voting ensemble classifier was used to achieve the final performance. The performance of the classifier was validated in the test set. RESULTS The ensemble classifier showed an area under the curve (AUC) of 0.81 [95% confidence interval (CI), 0.74-0.87] in the training set. In the test set, the ensemble classifier showed an AUC, accuracy, sensitivity, and specificity of 0.81 (95% CI, 0.67-0.96), 77.8%, 78.6%, and 77.3%, respectively. The ensemble classifier achieved the highest performance among all the individual models in the test set. CONCLUSIONS Radiomic features may be useful biomarkers to predict the DA response in prolactinoma patients.
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Affiliation(s)
- Yae Won Park
- Department of Radiology and Research Institute of Radiological Science and Center for Clinical Imaging Data Science, Yonsei University College of Medicine, Seoul, Korea
- Pituitary Tumor Center, Severance Hospital, Seoul, Korea
| | - Jihwan Eom
- Department of Computer Science, Yonsei University, Seoul, Korea
| | - Sooyon Kim
- Department of Statistics and Data Science, Yonsei University, Seoul, Korea
| | - Hwiyoung Kim
- Department of Radiology and Research Institute of Radiological Science and Center for Clinical Imaging Data Science, Yonsei University College of Medicine, Seoul, Korea
| | - Sung Soo Ahn
- Department of Radiology and Research Institute of Radiological Science and Center for Clinical Imaging Data Science, Yonsei University College of Medicine, Seoul, Korea
- Pituitary Tumor Center, Severance Hospital, Seoul, Korea
| | - Cheol Ryong Ku
- Pituitary Tumor Center, Severance Hospital, Seoul, Korea
- Department of Endocrinology, Yonsei University College of Medicine, Seoul, Korea
| | - Eui Hyun Kim
- Pituitary Tumor Center, Severance Hospital, Seoul, Korea
- Department of Endocrinology, Yonsei University College of Medicine, Seoul, Korea
| | - Eun Jig Lee
- Pituitary Tumor Center, Severance Hospital, Seoul, Korea
- Department of Neurosurgery, Yonsei University College of Medicine, Seoul, Korea
| | - Sun Ho Kim
- Department of Neurosurgery, Ewha Womans University College of Medicine, Seoul, Korea
| | - Seung-Koo Lee
- Department of Radiology and Research Institute of Radiological Science and Center for Clinical Imaging Data Science, Yonsei University College of Medicine, Seoul, Korea
- Pituitary Tumor Center, Severance Hospital, Seoul, Korea
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Di Somma C, Scarano E, de Alteriis G, Barrea L, Riccio E, Arianna R, Savastano S, Colao A. Is there any gender difference in epidemiology, clinical presentation and co-morbidities of non-functioning pituitary adenomas? A prospective survey of a National Referral Center and review of the literature. J Endocrinol Invest 2021; 44:957-968. [PMID: 32894472 DOI: 10.1007/s40618-020-01379-2] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/23/2020] [Accepted: 07/30/2020] [Indexed: 12/19/2022]
Abstract
PURPOSE Gender differences in patients diagnosed with non-functioning Pituitary Adenomas (NFPA) in a National Referral Center for Pituitary Tumors at the Federico II University of Naples, Italy. METHODS Patients newly diagnosed with non-functioning sellar masses found on pituitary Magnetic Resonance Imaging from January 1st 2016 to December 31th 2018 underwent anthropometric measurements, basal evaluation of pituitary function, and metabolic assessment. Fatty live index (FLI) and visceral adiposity index (VAI) were calculated. RESULTS Seventy-three patients (35 males, 51.1 ± 17.0 years; 38 females, 41.8 ± 18.1 years) presented with NFPA. Lesions > 1 cm (85.7% vs. 47.3%; χ2 = 10.26, p = 0.001) and hypopituitarism (77.1% vs. 7.9%; χ2 = 33.29, p = 0.001) were more frequent in males than females. The highest sizes of pituitary adenomas were significantly associated with male gender (OR = 1.05, p = 0.049; R2 = 0.060; IC 1.00-1.10). Headache (62.8% vs. 31.6%; χ2 = 5.96, p = 0.015) and visual field deficits (57.1% vs. 26.3%; χ2 = 5.93, p = 0.015) were significantly more frequent in males than in females. There was no sex difference in obesity prevalence, but the metabolic syndrome was more common among males than females (60.6% vs. 26.3%; χ2 = 7.14, p = 0.001). FLI was also higher in males (69.6 ± 27.3 vs. 49.2 ± 31.3; p < 0.001), while there were no differences in VAI. CONCLUSIONS Apart from the possible delay in the diagnosis induced by the gender differences in symptom presentation, the higher prevalence of macroadenomas amongst NFPA in males compared with females let to hypothesize a key role of the sex hormone profile as predictive factors of their biological behavior and metabolic profile. Further studies are, however, mandatory to better support the influence of gender differences on onset, progression, and metabolic consequences of NFPA.
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Affiliation(s)
- C Di Somma
- Dipartimento di Medicina Clinica e Chirurgia, Unit of Endocrinology, Federico II University Medical School of Naples, Via Sergio Pansini 5, 80131, Naples, Italy.
| | - E Scarano
- Dipartimento di Medicina Clinica e Chirurgia, Unit of Endocrinology, Federico II University Medical School of Naples, Via Sergio Pansini 5, 80131, Naples, Italy
| | - G de Alteriis
- Dipartimento di Medicina Clinica e Chirurgia, Unit of Endocrinology, Federico II University Medical School of Naples, Via Sergio Pansini 5, 80131, Naples, Italy
| | - L Barrea
- Dipartimento di Medicina Clinica e Chirurgia, Unit of Endocrinology, Federico II University Medical School of Naples, Via Sergio Pansini 5, 80131, Naples, Italy
- Department of Clinical Medicine and Surgery, Endocrinology Unit, Centro Italiano per la cura e il Benessere del paziente con obesità (C.I.B.O), University Medical School of Naples, Via Sergio Pansini 5, 80131, Naples, Italy
| | - E Riccio
- Dipartimento di Medicina Clinica e Chirurgia, Unit of Endocrinology, Federico II University Medical School of Naples, Via Sergio Pansini 5, 80131, Naples, Italy
| | - R Arianna
- Dipartimento di Medicina Clinica e Chirurgia, Unit of Endocrinology, Federico II University Medical School of Naples, Via Sergio Pansini 5, 80131, Naples, Italy
| | - S Savastano
- Dipartimento di Medicina Clinica e Chirurgia, Unit of Endocrinology, Federico II University Medical School of Naples, Via Sergio Pansini 5, 80131, Naples, Italy
- Department of Clinical Medicine and Surgery, Endocrinology Unit, Centro Italiano per la cura e il Benessere del paziente con obesità (C.I.B.O), University Medical School of Naples, Via Sergio Pansini 5, 80131, Naples, Italy
| | - A Colao
- Dipartimento di Medicina Clinica e Chirurgia, Unit of Endocrinology, Federico II University Medical School of Naples, Via Sergio Pansini 5, 80131, Naples, Italy
- Department of Clinical Medicine and Surgery, Endocrinology Unit, Centro Italiano per la cura e il Benessere del paziente con obesità (C.I.B.O), University Medical School of Naples, Via Sergio Pansini 5, 80131, Naples, Italy
- Cattedra Unesco "Educazione alla salute e allo sviluppo sostenibile", University Federico II, Naples, Italy
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Large Scale Molecular Studies of Pituitary Neuroendocrine Tumors: Novel Markers, Mechanisms and Translational Perspectives. Cancers (Basel) 2021; 13:cancers13061395. [PMID: 33808624 PMCID: PMC8003417 DOI: 10.3390/cancers13061395] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2021] [Revised: 02/28/2021] [Accepted: 03/16/2021] [Indexed: 02/07/2023] Open
Abstract
Simple Summary Pituitary neuroendocrine tumors are non-cancerous tumors of the pituitary gland, that may overproduce hormones leading to serious health conditions or due to tumor size cause chronic headache, vertigo or visual impairment. In recent years pituitary neuroendocrine tumors are studied with the latest molecular biology methods that simultaneously investigate a large number of factors to understand the mechanisms of how these tumors develop and how they could be diagnosed or treated. In this review article, we have studied literature reports, compiled information and described molecular factors that could affect the development and clinical characteristics of pituitary neuroendocrine tumors, discovered factors that overlap between several studies using large scale molecular analysis and interpreted the potential involvement of these factors in pituitary tumor development. Overall, this study provides a valuable resource for understanding the biology of pituitary neuroendocrine tumors. Abstract Pituitary neuroendocrine tumors (PitNETs) are non-metastatic neoplasms of the pituitary, which overproduce hormones leading to systemic disorders, or tumor mass effects causing headaches, vertigo or visual impairment. Recently, PitNETs have been investigated in large scale (exome and genome) molecular analyses (transcriptome microarrays and sequencing), to uncover novel markers. We performed a literature analysis on these studies to summarize the research data and extrapolate overlapping gene candidates, biomarkers, and molecular mechanisms. We observed a tendency in samples with driver mutations (GNAS, USP8) to have a smaller overall mutational rate, suggesting driver-promoted tumorigenesis, potentially changing transcriptome profiles in tumors. However, direct links from drivers to signaling pathways altered in PitNETs (Notch, Wnt, TGF-β, and cell cycle regulators) require further investigation. Modern technologies have also identified circulating nucleic acids, and pinpointed these as novel PitNET markers, i.e., miR-143-3p, miR-16-5p, miR-145-5p, and let-7g-5p, therefore these molecules must be investigated in the future translational studies. Overall, large-scale molecular studies have provided key insight into the molecular mechanisms behind PitNET pathogenesis, highlighting previously reported molecular markers, bringing new candidates into the research field, and reapplying traditional perspectives to newly discovered molecular mechanisms.
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Brandi ML, Agarwal SK, Perrier ND, Lines KE, Valk GD, Thakker RV. Multiple Endocrine Neoplasia Type 1: Latest Insights. Endocr Rev 2021; 42:133-170. [PMID: 33249439 PMCID: PMC7958143 DOI: 10.1210/endrev/bnaa031] [Citation(s) in RCA: 119] [Impact Index Per Article: 29.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/14/2020] [Indexed: 02/06/2023]
Abstract
Multiple endocrine neoplasia type 1 (MEN1), a rare tumor syndrome that is inherited in an autosomal dominant pattern, is continuing to raise great interest for endocrinology, gastroenterology, surgery, radiology, genetics, and molecular biology specialists. There have been 2 major clinical practice guidance papers published in the past 2 decades, with the most recent published 8 years ago. Since then, several new insights on the basic biology and clinical features of MEN1 have appeared in the literature, and those data are discussed in this review. The genetic and molecular interactions of the MEN1-encoded protein menin with transcription factors and chromatin-modifying proteins in cell signaling pathways mediated by transforming growth factor β/bone morphogenetic protein, a few nuclear receptors, Wnt/β-catenin, and Hedgehog, and preclinical studies in mouse models have facilitated the understanding of the pathogenesis of MEN1-associated tumors and potential pharmacological interventions. The advancements in genetic diagnosis have offered a chance to recognize MEN1-related conditions in germline MEN1 mutation-negative patients. There is rapidly accumulating knowledge about clinical presentation in children, adolescents, and pregnancy that is translatable into the management of these very fragile patients. The discoveries about the genetic and molecular signatures of sporadic neuroendocrine tumors support the development of clinical trials with novel targeted therapies, along with advancements in diagnostic tools and surgical approaches. Finally, quality of life studies in patients affected by MEN1 and related conditions represent an effort necessary to develop a pharmacoeconomic interpretation of the problem. Because advances are being made both broadly and in focused areas, this timely review presents and discusses those studies collectively.
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Affiliation(s)
| | | | - Nancy D Perrier
- The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | | | - Gerlof D Valk
- University Medical Center Utrecht, CX Utrecht, the Netherlands
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Saeger W, Koch A. Clinical Implications of the New WHO Classification 2017 for Pituitary Tumors. Exp Clin Endocrinol Diabetes 2021; 129:146-156. [PMID: 33690870 DOI: 10.1055/a-1310-7900] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/17/2023]
Abstract
According to the WHO classification 2017 of Pituitary Tumors adenomas are classified not only by structure and immunostaining for pituitary hormones but also by expression of the pituitary transcription factors Pit-1, T-pit and SF-1. By these factors, three cell lineages can be identified: Pit-1 for the GH-, Prolactin- and TSH-cell lineage, T-pit for the ACTH-cell lineage, and SF-1 for the gonadotrophic cell lineage. By this principle, all GH and/or Prolactin producing and all TSH producing adenomas must be positive for Pit-1, all corticotrophic adenomas for T-pit, and all gonadotrophic for SF-1. In adenomas without expression of pituitary hormones immunostainings for the transcription factors have to be examined. If these are also negative the criteria for an endocrine inactive null cell adenoma are fulfilled. If one transcription factor is positive the corresponding cell lineage indicates a potential hormonal activity of the adenoma. So Pit-1 expressing hormone-negative adenomas can account for acromegaly, hyperprolactinemia, or TSH hyperfunction. T-pit positive hormone negative adenomas can induce Cushing's disease, and SF-1 positive hormone negative tumors indicate gonadotrophic adenomas. Instead of the deleted atypical adenoma of the WHO classification of 2004 now (WHO classification 2017) criteria exist for the identification of aggressive adenomas with a conceivably worse prognosis. Some adenoma subtypes are described as aggressive "per se" without necessity of increased morphological signs of proliferation. All other adenoma subtypes must also be designated as aggressive if they show signs of increased proliferation (mitoses, Ki-67 index>3-5%, clinically rapid tumor growth) and invasion. By these criteria about one third of pituitary adenoma belong to the group of aggressive adenomas with potentially worse prognosis. The very rare pituitary carcinoma (0.1 % of pituitary tumors) is defined only by metastases. Many of them develop after several recurrences of Prolactin or ACTH secreting adenomas. The correlation of clinical findings and histological classification of pituitary adenomas is very important since every discrepancy has to be discussed between clinicians and pathologists. Based on data of the German Registry of Pituitary Tumors a table for examinations of correlations is shown in this review.
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Affiliation(s)
- Wolfgang Saeger
- Institute of Pathology and Neuropathology of the University of Hamburg, UKE, Hamburg, Germany
| | - Arend Koch
- Institute of Neuropathology, Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany
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Lu J, Cai L, Wu Z, Lin W, Xu J, Zhu Z, Wang C, Li Q, Su Z. Surgery and Medical Treatment in Microprolactinoma: A Systematic Review and Meta-Analysis. Int J Endocrinol 2021; 2021:9930059. [PMID: 34504526 PMCID: PMC8423556 DOI: 10.1155/2021/9930059] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/15/2021] [Accepted: 08/19/2021] [Indexed: 12/27/2022] Open
Abstract
OBJECTIVE Dopamine agonists (DAs) are recommended as the first-line treatment for prolactinomas; however, tumour recurrence after drug withdrawal remains a clinical problem. Recent studies have reported high remission rates via surgery in microprolactinomas. The aim of this systematic review and meta-analysis was to compare the clinical result of DA treatment with surgery as initial therapy in patients with treatment-naive microprolactinoma. METHODS A comprehensive literature search for studies and reports regarding microprolactinoma patients treated with DAs and/or surgery published between January 1970 and November 2020 was conducted using four electronic databases (PubMed, Embase, Google Scholar, and the Cochrane Library). Clinical treatment outcome was evaluated by the biochemical remission of serum prolactin level to normal after treatment. The I 2 statistic was used to quantify heterogeneity. Pooled data were analysed according to a random effect model. RESULTS Eighteen studies with 661 patients were included for analysis. The DA treatment group achieved a higher remission rate at ≥12 months follow-up (96% vs. 86%; P=0.019). Surgery showed a higher remission rate than the DA treatment group after the treatment withdrawal (78% vs. 44%; P=0.003). Patients with preoperative prolactin level of ≤200 ng/mL had a higher remission rate than patients with preoperative prolactin level of >200 ng/mL (92% vs. 40%; P=0.029). CONCLUSION Surgery showed a high remission rate in treatment-naive microprolactinoma patients after treatment withdrawal and may be an alternative first-line treatment strategy in addition to DAs, particularly in patients with a preoperative prolactin level of ≤200 ng/mL.
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Affiliation(s)
- Jianglong Lu
- Department of Neurosurgery, First Affiliated Hospital of Wenzhou Medical University, Wenzhou 325000, China
| | - Lin Cai
- Department of Neurosurgery, First Affiliated Hospital of Wenzhou Medical University, Wenzhou 325000, China
| | - Zerui Wu
- Department of Neurosurgery, First Affiliated Hospital of Wenzhou Medical University, Wenzhou 325000, China
| | - Weiwei Lin
- Department of Neurosurgery, First Affiliated Hospital of Wenzhou Medical University, Wenzhou 325000, China
| | - Jiadong Xu
- Department of Neurosurgery, First Affiliated Hospital of Wenzhou Medical University, Wenzhou 325000, China
| | - Zhangzhang Zhu
- Department of Neurosurgery, First Affiliated Hospital of Wenzhou Medical University, Wenzhou 325000, China
| | - Chengde Wang
- Department of Neurosurgery, First Affiliated Hospital of Wenzhou Medical University, Wenzhou 325000, China
| | - Qun Li
- Department of Neurosurgery, First Affiliated Hospital of Wenzhou Medical University, Wenzhou 325000, China
| | - Zhipeng Su
- Department of Neurosurgery, First Affiliated Hospital of Wenzhou Medical University, Wenzhou 325000, China
- Department of Neurosurgery, Wencheng Country People's Hospital, Wenzhou 325000, China
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Majd N, Waguespack SG, Janku F, Fu S, Penas-Prado M, Xu M, Alshawa A, Kamiya-Matsuoka C, Raza SM, McCutcheon IE, Naing A. Efficacy of pembrolizumab in patients with pituitary carcinoma: report of four cases from a phase II study. J Immunother Cancer 2020; 8:jitc-2020-001532. [PMID: 33427689 PMCID: PMC7757504 DOI: 10.1136/jitc-2020-001532] [Citation(s) in RCA: 31] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 11/15/2020] [Indexed: 12/17/2022] Open
Abstract
Pituitary carcinoma is an aggressive tumor characterized by metastatic spread beyond the sellar region. Symptoms can be debilitating due to hormonal excess and survival is poor. Pituitary carcinomas recur despite conventional multimodality treatments. Given the recent advances in the use of immune checkpoint inhibitors (CPIs) to treat various solid cancers, there has been interest in exploring the role of immunotherapy for treating aggressive, refractory pituitary tumors. We treated 4 patients with pituitary carcinoma with pembrolizumab as part of a phase II clinical trial. Two patients (patients 1 and 2) with functioning corticotroph pituitary carcinomas (refractory to surgery, radiotherapy and chemotherapy) had partial radiographic (60% and 32% per Immune-Related Response Evaluation Criteria In Solid Tumors, respectively) and hormonal responses. Patient 1’s response continues 42 months after initiation of pembrolizumab and his tumor tissue obtained after treatment with temozolomide demonstrated a hypermutator phenotype with MSH2 and MSH6 gene mutations. Patient 2’s tumor after exposure to temozolomide was not sampled, but prior somatic mutational testing was negative. One patient with a non-functioning corticotroph tumor (patient 3) had a best response of stable disease for 4 months. One patient with a prolactin-secreting carcinoma (patient 4) had progressive disease. The latter 2 patients’ tumors did not demonstrate a hypermutator phenotype after treatment with temozolomide. Programmed death-ligand 1 staining was negative in all tumors. We report 2 cases of corticotroph pituitary carcinoma responsive to pembrolizumab after prior exposure to alkylating agents. The role of CPIs in treating patients with pituitary carcinoma, the relationship between tumor subtype and response to immunotherapy and mechanisms of hypermutation in this orphan disease require further study. Trial registration number: NCT02721732.
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Affiliation(s)
- Nazanin Majd
- Department of Neuro-Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
| | - Steven G Waguespack
- Department of Endocrine Neoplasia and Hormonal Disorders, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
| | - Filip Janku
- Department of Investigational Cancer Therapeutics, University of Texas at MD Anderson Cancer Center, Houston, Texas, USA
| | - Siqing Fu
- Department of Investigational Cancer Therapeutics, University of Texas at MD Anderson Cancer Center, Houston, Texas, USA
| | - Marta Penas-Prado
- Department of Neuro-Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
| | - Mingxuan Xu
- Department of Investigational Cancer Therapeutics, University of Texas at MD Anderson Cancer Center, Houston, Texas, USA
| | - Anas Alshawa
- Department of Investigational Cancer Therapeutics, University of Texas at MD Anderson Cancer Center, Houston, Texas, USA
| | - Carlos Kamiya-Matsuoka
- Department of Neuro-Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
| | - Shaan M Raza
- Department of Neurosurgery, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
| | - Ian E McCutcheon
- Department of Neurosurgery, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
| | - Aung Naing
- Department of Investigational Cancer Therapeutics, University of Texas at MD Anderson Cancer Center, Houston, Texas, USA
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Frara S, Rodriguez-Carnero G, Formenti AM, Martinez-Olmos MA, Giustina A, Casanueva FF. Pituitary Tumors Centers of Excellence. Endocrinol Metab Clin North Am 2020; 49:553-564. [PMID: 32741488 DOI: 10.1016/j.ecl.2020.05.010] [Citation(s) in RCA: 46] [Impact Index Per Article: 9.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
Pituitary tumors are common and require complex and sophisticated procedures for both diagnosis and therapy. To maintain the highest standards of quality, it is proposed to manage patients in pituitary tumors centers of excellence (PTCOEs) with patient-centric organizations, with expert clinical endocrinologists and neurosurgeons forming the core. That core needs to be supported by experts from different disciplines such as neuroradiology, neuropathology, radiation oncology, neuro-ophthalmology, otorhinolaryngology, and trained nursing. To provide high-level medical care to patients with pituitary tumors, PTCOEs further pituitary science through research publication, presentation of results at meetings, and performing clinical trials.
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Affiliation(s)
- Stefano Frara
- Institute of Endocrinology, Università Vita-Salute San Raffaele, Via Olgettina Milano, 58, Milano, Milan 20132, Italy
| | - Gemma Rodriguez-Carnero
- Division of Endocrinology, Complejo Hospitalario Universitario de Santiago (USC/SERGAS), Instituto de Investigacion Sanitaria de Santiago (IDIS), Rúa da Choupana, S/N, Santiago de Compostela, A Coruña 15706, Spain
| | - Ana M Formenti
- Institute of Endocrinology, Università Vita-Salute San Raffaele, Via Olgettina Milano, 58, Milano, Milan 20132, Italy
| | - Miguel A Martinez-Olmos
- Division of Endocrinology, Complejo Hospitalario Universitario de Santiago (USC/SERGAS), Instituto de Investigacion Sanitaria de Santiago (IDIS), Rúa da Choupana, S/N, Santiago de Compostela, A Coruña 15706, Spain; CIBER Fisiopatología de la Obesidad y la Nutrición (CIBERobn), Instituto de Salud Carlos III, Madrid, Spain
| | - Andrea Giustina
- Institute of Endocrinology, Università Vita-Salute San Raffaele, Via Olgettina Milano, 58, Milano, Milan 20132, Italy
| | - Felipe F Casanueva
- Division of Endocrinology, Complejo Hospitalario Universitario de Santiago (USC/SERGAS), Instituto de Investigacion Sanitaria de Santiago (IDIS), Rúa da Choupana, S/N, Santiago de Compostela, A Coruña 15706, Spain; CIBER Fisiopatología de la Obesidad y la Nutrición (CIBERobn), Instituto de Salud Carlos III, Madrid, Spain.
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de Souza MR, Fagundes CF, Rabelo NN, Teixeira MJ, Figueiredo EG. Association between intracranial aneurysm and meningiomas: An integrative survival Analysis with identification of prognostic factors. Clin Neurol Neurosurg 2020; 198:106128. [PMID: 32810762 DOI: 10.1016/j.clineuro.2020.106128] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2020] [Revised: 07/06/2020] [Accepted: 07/30/2020] [Indexed: 12/13/2022]
Abstract
OBJECTIVE To analyze prognostic factors in clinical association between intracranial aneurysm (IA) and meningioma. Prognostic factors on overall survival (OS) were evaluated. METHODS We selected articles, published from January 1944 to December 2018 on the Medical databases (Web of Sciences, Medline and EMBASE) and included case series and reports. Clinical information was obtained and variables associated with the primary outcome of 27-mo survival were identified through Cox regression models. RESULTS The study evaluated 77 patients. Female represented 76.6 % (n = 59), a ratio of 3.27 female: 1 male. The age range was 7-84 years old, with an average of 54.74 (SD: 14.30). Age and sex were not significant statistically different between the two groups for overall survival (OS) (log-rank P = 0.806), (log-rank P = 0.983) respectively. 77.9 % (n = 60) were ipsilateral, the same side was 4 times more common in univariate analysis (P = 0.052; 95 % CI, 0.924-17.319). Most aneurysms were detected in the internal carotid artery, 29.87 %. In Clinical data, 62.33 % (n = 48) had exclusive tumor symptoms, while 25.97 % (n = 20) presented exclusively subarachnoid hemorrhage (SAH). In multivariate analysis, although there is an independent protective factor for those who did not have SAH (HR; 0.099; CI; 0.010-0.986; P = 0.049) and the treatment is an independent predictor for OS (HR, 42.096; CI, 4.270-415.056; P = 0.01). CONCLUSION This is the first study to approach this association. This is not just an occasional finding, but it seems to have a shared pathophysiology. Unruptured aneurysms and treatment modality were protective independent factors for OS. Prospective studies are warranted to provide definitive answers.
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Affiliation(s)
- Matheus Rodrigues de Souza
- Mato Grosso State University, Mato Grosso, Tancredo Neves Avenue, 1095, Cáceres, State of Mato Grosso, 78200-000, Brazil
| | - Caroline Ferreira Fagundes
- Mato Grosso State University, Mato Grosso, Tancredo Neves Avenue, 1095, Cáceres, State of Mato Grosso, 78200-000, Brazil
| | - Nicollas Nunes Rabelo
- Department of Neurosurgery, Santa Casa Hospital, Saudade Avenue, 456, Ribeirão Preto, State of São Paulo, 14085-000, Brazil
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Vasilev V, Daly AF, Zacharieva S, Beckers A. Clinical and Molecular Update on Genetic Causes of Pituitary Adenomas. Horm Metab Res 2020; 52:553-561. [PMID: 32299111 DOI: 10.1055/a-1143-5930] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Pituitary adenomas are benign tumors with variable functional characteristics that can have a significant impact on patients. The majority arise sporadically, but an inherited genetic susceptibility is increasingly being recognized. Recent advances in genetics have widened the scope of our understanding of pituitary tumorigenesis. The clinical and genetic characteristics of pituitary adenomas that develop in the setting of germline-mosaic and somatic GNAS mutations (McCune-Albright syndrome and sporadic acromegaly), germline MEN1 mutations (multiple endocrine neoplasia type 1), and germline PRKAR1A mutations (Carney complex) have been well described. Non-syndromic familial cases of isolated pituitary tumors can occur as familial isolated pituitary adenomas (FIPA); mutations/deletions of the AIP gene have been found in a minority of these. Genetic alterations in GPR101 have been identified recently as causing X-linked acro-gigantism (X-LAG) leading to very early-onset pediatric gigantism. Associations of pituitary adenomas with other tumors have been described in syndromes like multiple endocrine neoplasia type 4, pheochromocytoma-paraganglioma with pituitary adenoma association (3PAs) syndrome and some of their genetic causes have been elucidated. The genetic etiologies of a significant proportions of sporadic corticotropinomas have recently been identified with the discovery of USP8 and USP48 mutations. The elucidation of genetic and molecular pathophysiology in pituitary adenomas is a key factor for better patient management and effective follow-up.
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Affiliation(s)
- Vladimir Vasilev
- Department of Endocrinology, CHU de Liège, Liège Université, Liège, Belgium
- Department of Endocrinology, Medical University, Sofia, Bulgaria
| | - Adrian F Daly
- Department of Endocrinology, CHU de Liège, Liège Université, Liège, Belgium
| | | | - Albert Beckers
- Department of Endocrinology, CHU de Liège, Liège Université, Liège, Belgium
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AlMalki MH, Ahmad MM, Brema I, AlDahmani KM, Pervez N, Al-Dandan S, AlObaid A, Beshyah SA. Contemporary Management of Clinically Non-functioning Pituitary Adenomas: A Clinical Review. CLINICAL MEDICINE INSIGHTS-ENDOCRINOLOGY AND DIABETES 2020; 13:1179551420932921. [PMID: 32636692 PMCID: PMC7318824 DOI: 10.1177/1179551420932921] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/14/2020] [Accepted: 05/18/2020] [Indexed: 12/25/2022]
Abstract
Non-functioning pituitary adenomas (NFPAs) are benign pituitary tumours that constitute about one-third of all pituitary adenomas. They typically present with symptoms of mass effects resulting in hypopituitarism, visual symptoms, or headache. Most NFPAs are macroadenomas (>1 cm in diameter) at diagnosis that can occasionally grow quite large and invade the cavernous sinus causing acute nerve compression and some patients may develop acute haemorrhage due to pituitary apoplexy. The progression from benign to malignant pituitary tumours is not fully understood; however, genetic and epigenetic abnormalities may be involved. Non-functioning pituitary carcinoma is extremely rare accounting for only 0.1% to 0.5 % of all pituitary tumours and presents with cerebrospinal, meningeal, or distant metastasis along with the absence of features of hormonal hypersecretion. Pituitary surgery through trans-sphenoidal approach has been the treatment of choice for symptomatic NFPAs; however, total resection of large macroadenomas is not always possible. Recurrence of tumours is frequent and occurs in 51.5% during 10 years of follow-up and negatively affects the overall prognosis. Adjuvant radiotherapy can decrease and prevent tumour growth but at the cost of significant side effects. The presence of somatostatin receptor types 2 and 3 (SSTR3 and SSTR2) and D2-specific dopaminergic receptors (D2R) within NFPAs has opened a new perspective of medical treatment for such tumours. The effect of dopamine agonist from pooled results on patients with NFPAs has emerged as a very promising treatment modality as it has resulted in reduction of tumour size in 30% of patients and stabilization of the disease in about 58%. Despite the lack of long-term studies on the mortality, the available limited evidence indicates that patients with NFPA have higher standardized mortality ratios (SMR) than the general population, with women particularly having higher SMR than men. Older age at diagnosis and higher doses of glucocorticoid replacement therapy are the only known predictors for increased mortality.
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Affiliation(s)
- Mussa H AlMalki
- Obesity, Endocrine and Metabolism Centre, King Fahad Medical City, Riyadh, Saudi Arabia.,Faculty of Medicine, King Saud Bin Abdulaziz University of Health Sciences, Riyadh, Saudi Arabia
| | - Maswood M Ahmad
- Obesity, Endocrine and Metabolism Centre, King Fahad Medical City, Riyadh, Saudi Arabia
| | - Imad Brema
- Obesity, Endocrine and Metabolism Centre, King Fahad Medical City, Riyadh, Saudi Arabia
| | - Khaled M AlDahmani
- Department of Endocrinology, Tawam Hospital in Affiliation with Johns Hopkins Medicine, Al Ain, United Arab Emirates.,College of Medicine and Health Sciences (CMHS), UAE University, Al Ain, United Arab Emirates
| | - Nadeem Pervez
- Department of Radiation Oncology, Tawam Hospital in affiliation with Johns Hopkins Medicine, Al Ain, United Arab Emirates
| | - Sadeq Al-Dandan
- Department of Histopathology, Maternity and Children Hospital, Al-Hasa, Saudi Arabia
| | - Abdullah AlObaid
- Department of Neurosurgery, National Neuroscience Institute, King Fahad Medical City, Riyadh, Saudi Arabia
| | - Salem A Beshyah
- Department of Medicine, Dubai Medical College, Dubai, United Arab Emirates.,Department of Endocrinology, Mediclinic Airport, Abu Dhabi, United Arab Emirates
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KARTAL BAYKAN E, KARAÜZÜM YALÇIN N, AYDIN Ü. Prolaktinoma Tanılı Hastalarda Prediyabet Sıklığı. DICLE MEDICAL JOURNAL 2020. [DOI: 10.5798/dicletip.755773] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/14/2022] Open
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Chen J, Schmidt RE, Dahiya S. Pituitary Adenoma in Pediatric and Adolescent Populations. J Neuropathol Exp Neurol 2020; 78:626-632. [PMID: 31115468 PMCID: PMC6581558 DOI: 10.1093/jnen/nlz040] [Citation(s) in RCA: 21] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022] Open
Abstract
Pituitary adenomas are rare in children and adolescents and although mostly benign, they can sometimes be challenging to manage due to their locally invasive nature. In this study, we examined the clinicopathologic features of 42 pituitary adenomas in patients ≤21 years of age. The youngest patient was 8 years old (median age: 18 years), and the female-to-male ratio was 1.8:1. Five patients had recurrence after resection. There was no obvious difference between the recurrent rates in the typical (11.7%) and atypical adenomas (12.5%) based on the 2004 WHO classification. However, the recurrence rate was much higher in adenomas with an elevated proliferation index of ≥3% (20.8%) or with evidence of local invasion (18.2%). Adenomas with combination of an elevated proliferation index of ≥3% and imaging evidence of local invasion had the highest recurrence rate of 25%. In summary, pituitary adenomas are more frequent in adolescents as compared with children and are more common in girls. An elevated proliferation index of ≥3% and evidence of local invasion on imaging seem to correlate with a high probability of recurrence. Furthermore, we observe rarity of α-thalassemia/mental retardation syndrome X-linked (ATRX) protein loss (surrogate to ATRX mutation) in these tumors without any connotation on prognosis.
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Affiliation(s)
- Jie Chen
- Division of Neuropathology, Department of Pathology and Immunology, Washington University School of Medicine, St Louis, MO 63110
| | - Robert E Schmidt
- Division of Neuropathology, Department of Pathology and Immunology, Washington University School of Medicine, St Louis, MO 63110
| | - Sonika Dahiya
- Division of Neuropathology, Department of Pathology and Immunology, Washington University School of Medicine, St Louis, MO 63110
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Araujo-Castro M, Berrocal VR, Pascual-Corrales E. Pituitary tumors: epidemiology and clinical presentation spectrum. Hormones (Athens) 2020; 19:145-155. [PMID: 31933100 DOI: 10.1007/s42000-019-00168-8] [Citation(s) in RCA: 35] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/16/2019] [Accepted: 12/16/2019] [Indexed: 02/07/2023]
Abstract
Pituitary tumors (PTs) are a heterogeneous group of lesions of the central nervous system that are usually benign. Most of them occur sporadically, but 5% can do so within family syndromes, usually at a young age. There are differences by sex, age, race, and genetic factors in the prevalence of different tumor cell types and clinical presentation. Functioning-PTs (FPTs) are usually diagnosed earlier than non-functioning PTs (NFPTs). However, this depends on the PT type. Headaches and visual disturbances are the most frequent mass-effect symptoms, but seizures or hydrocephalus may also occur. Pituitary apoplexy is another possible mode of presentation, and it requires special attention because of its potential severity. PTs in pregnancy, childhood, and old age present a series of clinical peculiarities that must be taken into account when evaluating these patients. Ectopic PTs (EPTs) are uncommon and share the same clinical-epidemiological data as eutopic PTs, but, depending on their location, other types of clinical manifestations may appear. Silent PTs are often detected as an incidentaloma or due to neurologic symptoms related to mass-effect. Aggressive PTs and pituitary carcinomas (PCs), which are very rare, are characterized by multiple local recurrences and metastases, respectively. This review addresses the epidemiology and clinical presentation of PTs, from the classical hormonal and mass-effect symptoms to the different rare presentations, such as pituitary apoplexy, hydrocephalus, or diabetes insipidus. Moreover, special situations of the presentation of PTs are discussed, namely, PTs in pregnancy, childhood, and the elderly, EPTs, silent and aggressive PTs, and PCs.
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Affiliation(s)
- Marta Araujo-Castro
- Neuroendocrinology Unit, Endocrinology Department, Ramón y Cajal University Hospital, Madrid, Spain.
| | | | - Eider Pascual-Corrales
- Neuroendocrinology Unit, Endocrinology Department, Ramón y Cajal University Hospital, Madrid, Spain
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Wang X, Guo RZ, Ma L, Ding QY, Meng JH, Chen YG, Wu JH. Antiprolactinoma Effect of Hordenine by Inhibiting MAPK Signaling Pathway Activation in Rats. EVIDENCE-BASED COMPLEMENTARY AND ALTERNATIVE MEDICINE : ECAM 2020; 2020:3107290. [PMID: 32382283 PMCID: PMC7195642 DOI: 10.1155/2020/3107290] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/24/2019] [Revised: 02/20/2020] [Accepted: 03/09/2020] [Indexed: 11/17/2022]
Abstract
Prolactinomas are harmful to human health, and the clinical first-line treatment drug is bromocriptine. However, 20% prolactinomas patients did not respond to bromocriptine. Hordenine is an alkaloid separated from Fructus Hordei Germinatus, which showed significant antihyperprolactinemia activity in rats. The aim of this study was to explore the effect and mechanism of hordenine on prolactinomas in rats. The study used estradiol to induce prolactinomas, which caused the activation of the pituitary mitogen-activated protein kinase (MAPK) pathway in rats significantly. The treatment of hordenine restored estradiol, induced the overgrowth of pituitary gland, and reduced the prolactin (PRL) accumulation in the serum and pituitary gland of rats by blocking the MAPK (p38, ERK1/2, and JNK) activation and production of inflammatory cytokines, tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), and interleukin-6 (IL-6). The antiprolactinoma effect of hordenine was mediated by inhibiting the MAPK signaling pathway activation in rats.
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Affiliation(s)
- Xiong Wang
- Department of Pharmacy, Tongren Hospital Affiliated to Wuhan University (The Third Hospital of Wuhan), Wuhan, Hubei, China
| | - Run-zhu Guo
- Department of Pharmacy, Wuhan Asia Heart Hospital, Wuhan, Hubei, China
| | - Li Ma
- Department of Pharmacy, Tongren Hospital Affiliated to Wuhan University (The Third Hospital of Wuhan), Wuhan, Hubei, China
| | - Qiao-yan Ding
- College of Pharmacy, Hubei University of Chinese Medicine, Wuhan, Hubei, China
| | - Jun-hua Meng
- Department of Pharmacy, Tongren Hospital Affiliated to Wuhan University (The Third Hospital of Wuhan), Wuhan, Hubei, China
| | - Yong-gang Chen
- Department of Pharmacy, Tongren Hospital Affiliated to Wuhan University (The Third Hospital of Wuhan), Wuhan, Hubei, China
| | - Jin-hu Wu
- Department of Pharmacy, Tongren Hospital Affiliated to Wuhan University (The Third Hospital of Wuhan), Wuhan, Hubei, China
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Lines KE, Filippakopoulos P, Stevenson M, Müller S, Lockstone HE, Wright B, Knapp S, Buck D, Bountra C, Thakker RV. Effects of epigenetic pathway inhibitors on corticotroph tumour AtT20 cells. Endocr Relat Cancer 2020; 27:163-174. [PMID: 31935194 PMCID: PMC7040567 DOI: 10.1530/erc-19-0448] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/16/2019] [Accepted: 01/13/2020] [Indexed: 12/13/2022]
Abstract
Medical treatments for corticotrophinomas are limited, and we therefore investigated the effects of epigenetic modulators, a new class of anti-tumour drugs, on the murine adrenocorticotropic hormone (ACTH)-secreting corticotrophinoma cell line AtT20. We found that AtT20 cells express members of the bromo and extra-terminal (BET) protein family, which bind acetylated histones, and therefore, studied the anti-proliferative and pro-apoptotic effects of two BET inhibitors, referred to as (+)-JQ1 (JQ1) and PFI-1, using CellTiter Blue and Caspase Glo assays, respectively. JQ1 and PFI-1 significantly decreased proliferation by 95% (P < 0.0005) and 43% (P < 0.0005), respectively, but only JQ1 significantly increased apoptosis by >50-fold (P < 0.0005), when compared to untreated control cells. The anti-proliferative effects of JQ1 and PFI-1 remained for 96 h after removal of the respective compound. JQ1, but not PFI-1, affected the cell cycle, as assessed by propidium iodide staining and flow cytometry, and resulted in a higher number of AtT20 cells in the sub G1 phase. RNA-sequence analysis, which was confirmed by qRT-PCR and Western blot analyses, revealed that JQ1 treatment significantly altered expression of genes involved in apoptosis, such as NFκB, and the somatostatin receptor 2 (SSTR2) anti-proliferative signalling pathway, including SSTR2. JQ1 treatment also significantly reduced transcription and protein expression of the ACTH precursor pro-opiomelanocortin (POMC) and ACTH secretion by AtT20 cells. Thus, JQ1 treatment has anti-proliferative and pro-apoptotic effects on AtT20 cells and reduces ACTH secretion, thereby indicating that BET inhibition may provide a novel approach for treatment of corticotrophinomas.
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Affiliation(s)
- K E Lines
- OCDEM, Radcliffe Department of Medicine, University of Oxford, Churchill Hospital, Oxford, UK
| | | | - M Stevenson
- OCDEM, Radcliffe Department of Medicine, University of Oxford, Churchill Hospital, Oxford, UK
| | - S Müller
- Structural Genomics Consortium, Buchmann Institute for Life Sciences, Goethe-University Frankfurt, Frankfurt, Germany
| | - H E Lockstone
- Oxford Genomics Centre, Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK
| | - B Wright
- Oxford Genomics Centre, Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK
| | - S Knapp
- Structural Genomics Consortium, Buchmann Institute for Life Sciences, Goethe-University Frankfurt, Frankfurt, Germany
- Institute of Pharmaceutical Chemistry, Goethe-University Frankfurt, Frankfurt, Germany
| | - D Buck
- Oxford Genomics Centre, Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK
| | - C Bountra
- Structural Genomics Consortium, University of Oxford, Oxford, UK
| | - R V Thakker
- OCDEM, Radcliffe Department of Medicine, University of Oxford, Churchill Hospital, Oxford, UK
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40
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Dai C, Liang S, Sun B, Kang J. The Progress of Immunotherapy in Refractory Pituitary Adenomas and Pituitary Carcinomas. Front Endocrinol (Lausanne) 2020; 11:608422. [PMID: 33362722 PMCID: PMC7761748 DOI: 10.3389/fendo.2020.608422] [Citation(s) in RCA: 40] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/20/2020] [Accepted: 11/10/2020] [Indexed: 12/14/2022] Open
Abstract
Most pituitary adenomas (PAs) are considered benign tumors, but approximately 0.2% can present metastasis and are classified as pituitary carcinomas (PCs). Refractory PAs lie between benign adenomas and true malignant PC and are defined as aggressive-invasive PAs characterized by a high Ki-67 index, rapid growth, frequent recurrence, and resistance to conventional treatments, including temozolomide. It is notoriously difficult to manage refractory PAs and PC because of the limited therapeutic options. As a promising therapeutic approach, cancer immunotherapy has been experimentally used for the treatment of many tumors, including pituitary tumors. The purpose of this review is to report the progress of immunotherapy in pituitary tumors, including refractory PAs and PCs. The tumor immune microenvironment has been recognized as a key contributor to tumorigenesis, progression, and prognosis. One study indicated that the number of CD68+ macrophages was positively correlated with tumor size and Knosp classification grade for tumor invasiveness. The infiltration of CD4+ and CD8+ T cells was relatively scant in these adenomas, but pituitary growth hormone (GH) adenomas exhibited significantly more CD4+ and CD8+ T cells than non-GH adenomas. These results suggest an association of CD68+ macrophage infiltration with an increase in pituitary tumor size and invasiveness. Another study suggested that a lower number of CD8+ lymphocytes is associated with cavernous sinus invasion and resistance to treatment with first-generation somatostatin analogs in acromegaly patients, highlighting a potential role of the tumor immune microenvironment in determining the prognosis of somatotroph pituitary tumors. Preclinical studies have indicated that widely varying degrees of programmed death-ligand 1 (PD-L1) expression and tumor-infiltrating lymphocytes (TILs) are found among different subtypes. Functional PAs and aggressive PAs express significantly higher levels of PD-L1 and TILs than other subtypes, indicating that PD-1 blockade might be a promising alternative therapy for patients with aggressive PAs. PD-L1 transcript and protein levels were found to be significantly increased in functioning (GH and prolactin-expressing) pituitary tumors compared to nonfunctioning (null cell and silent gonadotroph) adenomas. Moreover, primary pituitary tumors harbored higher levels of PD-L1 mRNA than recurrent tumors. These findings suggest the possibility of considering checkpoint blockade immunotherapy for functioning pituitary tumors refractory to conventional management. Animal models of Cushing's disease also demonstrated PD-L1 and TIL expression in cultured tumors and murine models, as well as the effectiveness of checkpoint blockade therapy in reducing the tumor mass, decreasing hormone secretion, and increasing the survival rate. Clinical studies show that immunotherapy may be an effective treatment in patients with pituitary tumors. One corticotroph carcinoma patient showed a significant reduction in hormone levels and shrinkage of the tumor size of primary and metastatic lesions immediately after investigational treatment with ipilimumab and nivolumab. However, another patient with corticotroph adenoma progressed rapidly after four cycles of anti-PD-1 (pembrolizumab) treatment. To date, there are two registered clinical trials of immunotherapy for pituitary tumors. One of them is the phase II clinical trial of nivolumab combined with ipilimumab for patients with aggressive pituitary tumors (NCT04042753). The other one is also a phase II clinical trial of the combination of nivolumab and ipilimumab for rare tumors, including pituitary tumors (NCT02834013). Both clinical trials are in the stage of recruiting patients and have not been completed. In summary, the results from preclinical research and clinical studies indicated that immunotherapy might be a promising alternative therapy for PCs and refractory PAs resistant to conventional treatments. The combination of immunotherapy and radiotherapy or temozolomide may have synergistic effects compared to a single treatment. More preclinical and clinical studies are needed to further indicate the exact efficacy of immunotherapy in pituitary tumors.
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Affiliation(s)
- Congxin Dai
- Department of Neurosurgery, Beijing Tongren Hospital, Capital Medical University, Beijing, China
| | - Siyu Liang
- Eight-Year Program of Clinical Medicine, Peking Union Medical College Hospital (PUMCH), Chinese Academe of Medical Sciences & Peking Union Medical College (CAMS & PUMC), Beijing, China
| | - Bowen Sun
- Department of Neurosurgery, Beijing Tongren Hospital, Capital Medical University, Beijing, China
| | - Jun Kang
- Department of Neurosurgery, Beijing Tongren Hospital, Capital Medical University, Beijing, China
- *Correspondence: Jun Kang,
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Wang C, Tan C, Wen Y, Zhang D, Li G, Chang L, Su J, Wang X. FOXP1-induced lncRNA CLRN1-AS1 acts as a tumor suppressor in pituitary prolactinoma by repressing the autophagy via inactivating Wnt/β-catenin signaling pathway. Cell Death Dis 2019; 10:499. [PMID: 31235696 PMCID: PMC6591247 DOI: 10.1038/s41419-019-1694-y] [Citation(s) in RCA: 52] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2019] [Revised: 05/07/2019] [Accepted: 05/13/2019] [Indexed: 12/23/2022]
Abstract
As the commonest type of functional pituitary tumor, prolactinoma takes up around 40-60% of functional pituitary tumors. Despite dedications attributed to the treatment of prolactinoma, complete cure remains difficult. Hence, it is of significance to bring to light the underlying mechanism of prolactinoma. Long noncoding RNAs (lncRNAs) are a group of transcripts which can regulate various biological processes. In the present study, we explored an lncRNA that was differentially downregulated in prolactinoma samples. LncRNA clarin 1 antisense RNA 1 (CLRN1-AS1) was downregulated in 42 patient samples and inactivated the Wnt/β-catenin signaling pathway. Functionally, CLRN1-AS1 suppressed cell proliferation, promoted apoptosis, and inhibited autophagy. Subcellular fractionation assay revealed that CLRN1-AS1 was located in the cytoplasm of prolactinoma cells. Based on bioinformatics analysis and mechanism experiments, we determined that CLRN1-AS1 acted as a competing endogenous RNA (ceRNA) by sponging miR-217 to upregulate the dickkopf WNT signaling pathway inhibitor 1 (DKK1). Furthermore, Forkhead box P1 (FOXP1) was verified to be a transcription suppressor of CLRN1-AS1. In summary, this study revealed that FOXP1-induced CLRN1-AS1 regulated cellular functions in pituitary prolactinoma by sponging miR-217 to release the DKK1/Wnt/β-catenin signaling pathway.
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Affiliation(s)
- Chao Wang
- Department of Neurosurgery, The Affiliated Cancer Hospital of Harbin Medical University, No.150, Haping Road, Nangang, Harbin, 150001, Heilongjiang, China.
| | - Chunlei Tan
- Department of Neurosurgery, The Affiliated Cancer Hospital of Harbin Medical University, No.150, Haping Road, Nangang, Harbin, 150001, Heilongjiang, China
| | - Yuan Wen
- Department of Neurosurgery, The Affiliated Cancer Hospital of Harbin Medical University, No.150, Haping Road, Nangang, Harbin, 150001, Heilongjiang, China
| | - Dongzhi Zhang
- Department of Neurosurgery, The Affiliated Cancer Hospital of Harbin Medical University, No.150, Haping Road, Nangang, Harbin, 150001, Heilongjiang, China
| | - Guofu Li
- Department of Neurosurgery, The Affiliated Cancer Hospital of Harbin Medical University, No.150, Haping Road, Nangang, Harbin, 150001, Heilongjiang, China
| | - Liang Chang
- Department of Neurosurgery, The Affiliated Cancer Hospital of Harbin Medical University, No.150, Haping Road, Nangang, Harbin, 150001, Heilongjiang, China
| | - Jun Su
- Department of Neurosurgery, The Affiliated Cancer Hospital of Harbin Medical University, No.150, Haping Road, Nangang, Harbin, 150001, Heilongjiang, China
| | - Xin Wang
- Department of Neurosurgery, The Affiliated Cancer Hospital of Harbin Medical University, No.150, Haping Road, Nangang, Harbin, 150001, Heilongjiang, China
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Németh K, Darvasi O, Likó I, Szücs N, Czirják S, Reiniger L, Szabó B, Krokker L, Pállinger É, Igaz P, Patócs A, Butz H. Comprehensive analysis of circulating microRNAs in plasma of patients with pituitary adenomas. J Clin Endocrinol Metab 2019; 104:4151-4168. [PMID: 31112271 DOI: 10.1210/jc.2018-02479] [Citation(s) in RCA: 32] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/16/2018] [Accepted: 05/15/2019] [Indexed: 12/14/2022]
Abstract
BACKGROUND Circulating miRNAs in pituitary adenoma would help patient care especially in non-functioning adenoma cases as minimally invasive biomarkers of tumor recurrence and progression. AIM Our aim was to investigate plasma miRNA profile in patients with pituitary adenoma. MATERIALS AND METHODS 149 plasma and extracellular vesicle (preoperative, early- and late postoperative) samples were collected from 45 pituitary adenoma patients. Adenomas were characterized based on anterior pituitary hormones and transcription factors by immunostaining. MiRNA next generation sequencing was performed on 36 samples (discovery set). Individual TaqMan assay was used for validation on extended sample set. PA tissue miRNAs were evaluated by TaqMan array and literature data. RESULTS Global downregulation of miRNA expression was observed in plasma samples of pituitary adenoma patients compared to normal samples. Expression of 29 miRNAs and isomiR variants were able to distinguish preoperative plasma samples and normal controls. MiRNAs with altered expression in both plasma and different adenoma tissues were identified. 3, 7 and 66 miRNAs expressed differentially between preoperative and postoperative plasma samples in growth hormone secreting, FSH/LH+ and hormone-immunonegative groups, respectively. MiR-143-3p was downregulated in late- but not in early postoperative plasma samples compared to preoperative ones exclusively in FSH/LH+ adenomas. Plasma level of miR-143-3p discriminated these samples with 81.8% sensitivity and 72.3% specificity (AUC=0.79; p=0.02). CONCLUSIONS Differentially expressed miRNAs in pituitary adenoma tissues have low abundance in plasma minimizing their role as biomarkers. Plasma miR-143-3p decreases in patients with FSH/LH+ adenoma indicated successful surgery, but its application for evaluating tumor recurrence needs further investigation.
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Affiliation(s)
- Kinga Németh
- "Momentum" Hereditary Endocrine Tumours Research Group Semmelweis University, Budapest, Hungary
| | - Ottó Darvasi
- "Momentum" Hereditary Endocrine Tumours Research Group Semmelweis University, Budapest, Hungary
| | - István Likó
- "Momentum" Hereditary Endocrine Tumours Research Group Semmelweis University, Budapest, Hungary
| | - Nikolette Szücs
- 2nd Department of Internal Medicine, Semmelweis University, Budapest, Hungary
| | - Sándor Czirják
- National Institute of Clinical Neurosciences, Budapest, Hungary
| | - Lilla Reiniger
- 1st Department of Pathology and Experimental Cancer Research, Semmelweis University, Budapest, Hungary
| | - Borbála Szabó
- "Momentum" Hereditary Endocrine Tumours Research Group Semmelweis University, Budapest, Hungary
- 2nd Department of Internal Medicine, Semmelweis University, Budapest, Hungary
| | - Lilla Krokker
- "Momentum" Hereditary Endocrine Tumours Research Group Semmelweis University, Budapest, Hungary
- 2nd Department of Internal Medicine, Semmelweis University, Budapest, Hungary
| | - Éva Pállinger
- Department of Genetics, Cell- and Immunobiology, Semmelweis University, Budapest, Hungary
| | - Péter Igaz
- 2nd Department of Internal Medicine, Semmelweis University, Budapest, Hungary
- MTA-SE Molecular Medicine Research Group, Hungarian Academy of Sciences and Semmelweis University, Budapest, Hungary
| | - Attila Patócs
- "Momentum" Hereditary Endocrine Tumours Research Group Semmelweis University, Budapest, Hungary
- Department of Laboratory Medicine, Semmelweis University, Budapest, Hungary
| | - Henriett Butz
- "Momentum" Hereditary Endocrine Tumours Research Group Semmelweis University, Budapest, Hungary
- Department of Laboratory Medicine, Semmelweis University, Budapest, Hungary
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Chanson P, Maiter D. The epidemiology, diagnosis and treatment of Prolactinomas: The old and the new. Best Pract Res Clin Endocrinol Metab 2019; 33:101290. [PMID: 31326373 DOI: 10.1016/j.beem.2019.101290] [Citation(s) in RCA: 121] [Impact Index Per Article: 20.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Prevalence and incidence of prolactinomas are approximately 50 per 100,000 and 3-5 new cases/100,000/year. The pathophysiological mechanism of hyperprolactinemia-induced gonadotropic failure involves kisspeptin neurons. Prolactinomas in males are larger, more invasive and less sensitive to dopamine agonists (DAs). Macroprolactin, responsible for pseudohyperprolactinemia is a frequent pitfall of prolactin assay. DAs still represent the primary therapy for most prolactinomas, but neurosurgery has regained interest, due to progress in surgical techniques and a high success rate in microprolactinoma, as well as to some underestimated side effects of long-term DA treatment, such as impulse control disorders or impaired quality of life. Recent data show that the suspected effects of DAs on cardiac valves in patients with prolactinomas are reassuring. Finally, temozolomide has emerged as a valuable treatment for rare cases of aggressive and malignant prolactinomas that do not respond to all other conventional treatments.
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Affiliation(s)
- Philippe Chanson
- Assistance Publique-Hôpitaux de Paris (AP-HP), Service d'Endocrinologie et des Maladies de la Reproduction, Centre de Référence des Maladies Rares de l'Hypophyse, Hôpital de Bicêtre, F-94275, Le Kremlin-Bicêtre, France; UMR-S1185 Université Paris-Sud, Univ Paris-Saclay, F-94276, Le Kremlin-Bicêtre, France; Institut National de la Santé et de la Recherche Médicale (Inserm) U1185, F-94276, Le Kremlin Bicêtre, France.
| | - Dominique Maiter
- Service d'Endocrinologie et Nutrition, Cliniques Universitaires Saint-Luc, Université Catholique de Louvain, Brussels, Belgium
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Carey RM, Kuan EC, Workman AD, Patel NN, Kohanski MA, Tong CCL, Chen J, Palmer JN, Adappa ND, Brant JA. A Population-Level Analysis of Pituitary Carcinoma from the National Cancer Database. J Neurol Surg B Skull Base 2019; 81:180-186. [PMID: 32206537 DOI: 10.1055/s-0039-1683435] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2018] [Accepted: 02/04/2019] [Indexed: 10/27/2022] Open
Abstract
Objectives Pituitary carcinoma is a rare entity with fewer than 200 total cases reported in the English literature. Analysis of the population-level data from the National Cancer Database (NCDB) affords the opportunity to study this poorly understood tumor type. Methods The NCDB was queried for site, histology, and metastasis codes corresponding to pituitary carcinoma. Statistical analyses were performed to determine factors associated with overall survival (OS). Results A total of 92 patients with pituitary carcinoma met inclusion criteria. The 1 and 5 years of OS for all patients was 93.3% (95% confidence interval [CI]: 88.2-98.6%) and 80.0% (95% CI: 71.6-89.4%), respectively. Patients with invasive primary tumor behavior had 1 and 5 years of OS of 69.2% (95% CI: 48.2-99.5%) and 52.7% (95% CI: 31.2-89.2%), respectively. Multivariate analysis demonstrated that compared with benign primary behavior, invasive behavior had increased all-cause mortality (hazard ratio [HR], 1,296, 95% CI: 15.1- > 2,000). Surgery without adjuvant radiation or chemotherapy was the most common therapy (48.9%), followed by no treatment (40.2%). Compared with surgery alone, no treatment had worse OS (HR, 11.83, 95% CI: 1.41-99.56). Increasing age and female sex were both associated with increased mortality. Conclusions The most common treatment for pituitary carcinoma is surgery alone followed by no surgery. Surgery alone has significantly better OS compared with no treatment. The efficacy of radiation, chemotherapy, and neurohormonal treatments needs to be examined with prospective studies.
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Affiliation(s)
- Ryan M Carey
- Department of Otorhinolaryngology-Head and Neck Surgery, University of Pennsylvania, Perelman School of Medicine, Philadelphia, Pennsylvania, United States
| | - Edward C Kuan
- Department of Otorhinolaryngology-Head and Neck Surgery, University of Pennsylvania, Perelman School of Medicine, Philadelphia, Pennsylvania, United States
| | - Alan D Workman
- Department of Otorhinolaryngology-Head and Neck Surgery, University of Pennsylvania, Perelman School of Medicine, Philadelphia, Pennsylvania, United States
| | - Neil N Patel
- Department of Otorhinolaryngology-Head and Neck Surgery, University of Pennsylvania, Perelman School of Medicine, Philadelphia, Pennsylvania, United States
| | - Michael A Kohanski
- Department of Otorhinolaryngology-Head and Neck Surgery, University of Pennsylvania, Perelman School of Medicine, Philadelphia, Pennsylvania, United States
| | - Charles C L Tong
- Department of Otorhinolaryngology-Head and Neck Surgery, University of Pennsylvania, Perelman School of Medicine, Philadelphia, Pennsylvania, United States
| | - Jinbo Chen
- Department of Biostatistics and Epidemiology, University of Pennsylvania, Perelman School of Medicine, Philadelphia, Pennsylvania, United States
| | - James N Palmer
- Department of Otorhinolaryngology-Head and Neck Surgery, University of Pennsylvania, Perelman School of Medicine, Philadelphia, Pennsylvania, United States
| | - Nithin D Adappa
- Department of Otorhinolaryngology-Head and Neck Surgery, University of Pennsylvania, Perelman School of Medicine, Philadelphia, Pennsylvania, United States
| | - Jason A Brant
- Department of Otorhinolaryngology-Head and Neck Surgery, University of Pennsylvania, Perelman School of Medicine, Philadelphia, Pennsylvania, United States
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Pepe S, Korbonits M, Iacovazzo D. Germline and mosaic mutations causing pituitary tumours: genetic and molecular aspects. J Endocrinol 2019; 240:R21-R45. [PMID: 30530903 DOI: 10.1530/joe-18-0446] [Citation(s) in RCA: 30] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/31/2018] [Accepted: 11/07/2018] [Indexed: 12/24/2022]
Abstract
While 95% of pituitary adenomas arise sporadically without a known inheritable predisposing mutation, in about 5% of the cases they can arise in a familial setting, either isolated (familial isolated pituitary adenoma or FIPA) or as part of a syndrome. FIPA is caused, in 15-30% of all kindreds, by inactivating mutations in the AIP gene, encoding a co-chaperone with a vast array of interacting partners and causing most commonly growth hormone excess. While the mechanisms linking AIP with pituitary tumorigenesis have not been fully understood, they are likely to involve several pathways, including the cAMP-dependent protein kinase A pathway via defective G inhibitory protein signalling or altered interaction with phosphodiesterases. The cAMP pathway is also affected by other conditions predisposing to pituitary tumours, including X-linked acrogigantism caused by duplications of the GPR101 gene, encoding an orphan G stimulatory protein-coupled receptor. Activating mosaic mutations in the GNAS gene, coding for the Gα stimulatory protein, cause McCune-Albright syndrome, while inactivating mutations in the regulatory type 1α subunit of protein kinase A represent the most frequent genetic cause of Carney complex, a syndromic condition with multi-organ manifestations also involving the pituitary gland. In this review, we discuss the genetic and molecular aspects of isolated and syndromic familial pituitary adenomas due to germline or mosaic mutations, including those secondary to AIP and GPR101 mutations, multiple endocrine neoplasia type 1 and 4, Carney complex, McCune-Albright syndrome, DICER1 syndrome and mutations in the SDHx genes underlying the association of familial paragangliomas and phaeochromocytomas with pituitary adenomas.
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Affiliation(s)
- Sara Pepe
- Centre for Endocrinology, William Harvey Research Institute, Barts and the London School of Medicine, Queen Mary University of London, London, UK
- Department of Medical Biotechnologies, University of Siena, Siena, Italy
| | - Márta Korbonits
- Centre for Endocrinology, William Harvey Research Institute, Barts and the London School of Medicine, Queen Mary University of London, London, UK
| | - Donato Iacovazzo
- Centre for Endocrinology, William Harvey Research Institute, Barts and the London School of Medicine, Queen Mary University of London, London, UK
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Maiter D. Management of Dopamine Agonist-Resistant Prolactinoma. Neuroendocrinology 2019; 109:42-50. [PMID: 30481756 DOI: 10.1159/000495775] [Citation(s) in RCA: 98] [Impact Index Per Article: 16.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/06/2018] [Accepted: 11/25/2018] [Indexed: 11/19/2022]
Abstract
Dopamine agonists are usually very effective in the treatment of prolactinomas. Nonetheless, a subset of individuals does not respond satisfactorily to these agents, and this resistance is characterized by failure to achieve normoprolactinemia and a 30% or more reduction in maximal tumor diameter (in the case of macroprolactinoma) under maximally tolerated doses. The overall prevalence of dopamine agonist resistance is 20-30% for bromocriptine (BRC) and around 10% for cabergoline (CAB). The 2 main predictive factors are male gender and tumor invasiveness. The management of drug-resistant prolactinomas includes several options. Any BRC-resistant patient should be switched to CAB which will normalize prolactin in 80% of patients. As long as adverse effects do not develop, dose escalation of CAB is reasonable, with the expectation that subsequent dose reduction will be possible. Echocardiographic monitoring is advised in such patients because of the potential association with cardiac valvular fibrosis. Also, maintaining maximal CAB doses at 3.5 mg/week may lead to progressive hormonal control in a significant proportion of patients. Complete resistance to CAB is infrequent. In a study of 122 patients with a macroprolactinoma, only 7 (6%) could not achieve control despite maximal CAB doses for > 12 months. A large resistant prolactinoma is also an indication for transsphenoidal neurosurgery, aiming at a debulking which may improve postoperative medical control. For patients who harbor aggressive prolactinomas, radiotherapy may be considered. However, normal prolactinemia will eventually occur in only one-third of patients after many years. Finally, temozolomide may be a therapeutic option in malignant/aggressive prolactinomas.
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Affiliation(s)
- Dominique Maiter
- Division of Endocrinology and Nutrition, Cliniques Universitaires Saint-Luc, Université Catholique de Louvain, Brussels, Belgium,
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47
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van den Broek MFM, van Nesselrooij BPM, Verrijn Stuart AA, van Leeuwaarde RS, Valk GD. Clinical Relevance of Genetic Analysis in Patients With Pituitary Adenomas: A Systematic Review. Front Endocrinol (Lausanne) 2019; 10:837. [PMID: 31920960 PMCID: PMC6914701 DOI: 10.3389/fendo.2019.00837] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/13/2019] [Accepted: 11/18/2019] [Indexed: 12/19/2022] Open
Abstract
Pituitary adenomas (PA) are amongst the most prevalent intracranial tumors, causing complications by hormonal overproduction or deficiency and tumor mass effects, with 95% of cases occurring sporadically. Associated germline mutations (AIP, MEN1, CDKN1B, PRKAR1A, SDHx) and Xq26.3 microduplications are increasingly identified, but the clinical consequences in sporadic PA remain unclear. This systematic review evaluates predictors of a genetic cause of sporadic PA and the consequences for treatment outcome. We undertook a sensitive MEDLINE/Pubmed, EMBASE, and Web of Science search with critical appraisal of identified studies. Thirty-seven studies on predictors of mutations and 10 studies on the influence on treatment outcome were included. AIP and MEN1 mutations were associated with young age of PA diagnosis. AIP mutations were also associated with gigantism and macroadenomas at time of diagnosis. Xq26.3 microduplications were associated with PA below the age of five. AIP and MEN1 mutation analysis is therefore recommended in young patients (≤30 years). AIP mutation analysis is specifically recommended for patients with PA induced gigantism and macroadenoma. Screening for Xq26.3 microduplications is advisable in children below the age of five with increased growth velocity due to PA. There is no evidence supporting mutation analysis of other genes in sporadic PA. MEN1 mutation related prolactinoma respond well to dopamine agonists while AIP mutation associated somatotroph and lactotroph adenoma are frequently resistant to medical treatment. In patients harboring an Xq26.3 microduplication treatment is challenging, although outcome is not different from other patients with PA induced gigantism. Effective use of genetic analysis may lead to early disease identification, while knowledge of the impact of germline mutations on susceptibility to various treatment modalities helps to determine therapeutic strategies, possibly lowering disease morbidity.
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Affiliation(s)
| | | | - Annemarie A. Verrijn Stuart
- Department of Paediatrics, Wilhelmina Children's Hospital, University Medical Center Utrecht, Utrecht, Netherlands
| | | | - Gerlof D. Valk
- Department of Endocrine Oncology, University Medical Center Utrecht, Utrecht, Netherlands
- *Correspondence: Gerlof D. Valk
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48
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Cai F, Hong Y, Xu J, Wu Q, Reis C, Yan W, Wang W, Zhang J. A Novel Mutation of Aryl Hydrocarbon Receptor Interacting Protein Gene Associated with Familial Isolated Pituitary Adenoma Mediates Tumor Invasion and Growth Hormone Hypersecretion. World Neurosurg 2018; 123:e45-e59. [PMID: 30447469 DOI: 10.1016/j.wneu.2018.11.021] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/23/2018] [Revised: 11/02/2018] [Accepted: 11/04/2018] [Indexed: 12/19/2022]
Abstract
BACKGROUND Germline mutations in the aryl hydrocarbon receptor-interacting protein (AIP) gene were identified in nearly 20% of families with familial isolated pituitary adenoma. Some variants of AIP have been confirmed to induce tumor cell proliferation and invasiveness; however, the mechanism is still unclear. METHODS A novel missense mutation (c.512C>T, p.T171I) was discovered in 3 patients from a Chinese family with familial isolated pituitary adenoma. In silico and multiplex ligation-dependent probe amplification analysis predicted the mutation to be pathogenic. GH3 and 293FT cell lines were used to verify the variant's effect on cell proliferation (Cell Counting Kit-8), invasiveness (Transwell) and growth hormone (GH) secretion (enzyme-linked immunosorbent assay) by transfection with different vectors: control, blank vector, wild-type AIP, p.T171I variant (experimental group), p.Q315* variant, and AIP small interfering RNA. Furthermore, Zac1, Sstr2, interleukin (IL)-6, and Stat3/phosphorylation-Stat3 expression (reverse transcription polymerase chain reaction, Western blot) in each group was also evaluated. RESULTS The experimental group, p.Q315* variant group, and AIP small interfering RNA-overexpressing group promoted cell proliferation at 24 and 48 hours, respectively (compared with the control group; P < 0.01 for both). Similarly, the cells in the experimental group manifested more invasion and GH secretion compared with the control group (P < 0.01 and P < 0.05, respectively). Furthermore, the experimental group cells expressed less Sstr2 (a prerequisite for the responsiveness to somatostatin analogues) and Zac1 (tumor suppressor gene), but more IL-6 and phosphorylated-Stat3 (GH-secretion related). CONCLUSIONS The novel AIP mutation c.512C>T (p.T171I) is a pathogenic variant that promoted cell proliferation, invasiveness, and GH secretion through regulation of Sstr2, Zac1, and IL-6/phosphorylated-Stat3 expression.
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Affiliation(s)
- Feng Cai
- Department of Neurosurgery, the Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, China
| | - Yuan Hong
- Department of Neurosurgery, the Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, China
| | - Jinghong Xu
- Department of Pathology, the Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, China
| | - Qun Wu
- Department of Neurosurgery, the Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, China
| | - Cesar Reis
- Department of Preventive Medicine, Loma Linda University School of Medicine, Loma Linda, California, USA; Department of Physiology and Pharmacology, Loma Linda University School of Medicine, Loma Linda, California, USA
| | - Wei Yan
- Department of Neurosurgery, the Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, China
| | - Wei Wang
- Department of Neurosurgery, the Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, China
| | - Jianmin Zhang
- Department of Neurosurgery, the Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, China.
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Gökosmanoğlu F. Prolaktinoma’lı Olgularımızın Klinik Değerlendirilmesi. ACTA MEDICA ALANYA 2018. [DOI: 10.30565/medalanya.420906] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/18/2022] Open
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50
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Hu B, Mao Z, Jiang X, He D, Wang Z, Wang X, Zhu Y, Wang H. Role of TGF-β1/Smad3-mediated fibrosis in drug resistance mechanism of prolactinoma. Brain Res 2018; 1698:204-212. [PMID: 30055965 DOI: 10.1016/j.brainres.2018.07.024] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2018] [Revised: 07/19/2018] [Accepted: 07/26/2018] [Indexed: 10/28/2022]
Abstract
Prolactinomas are the most common functional pituitary adenomas. While dopamine agonists are a primary method of therapeutic treatment, the rate of resistance to these drugs continues to increase each year. During previous long-term clinical investigations, we found that partial resistant prolactinomas exhibited significantly more fibrosis than did sensitive adenomas, suggesting a role of fibrosis in their drug resistance. Furthermore, resistant adenomas with extensive fibrosis mainly express type I and type III collagens. Since TGF-β1 is the key factor in the initiation and development of tissue fibrosis, including in the pituitary, in this study, we aimed to determine whether TGF-β1 mediated fibrosis in prolactinomas and whether fibrosis was related to prolactinoma drug resistance. Using immunochemistry and western blotting, we found that the TGF-β1/Smad3 signaling pathway-related proteins were elevated in resistant prolactinoma specimens with high degrees of fibrosis compared to levels in sensitive samples, suggesting that this pathway may play a role in prolactinoma fibrosis. In vitro, TGF-β1 stimulation promoted collagen expression in normal HS27 fibroblasts. Furthermore, the sensitivity of rat prolactinoma MMQ cells to bromocriptine decreased when they were co-cultured with HS27 cells treated with TGF-β1. The TGF-β1/Smad3 signaling-specific inhibitor SB431542 counteracted these effects, indicating that TGF-β1/Smad3-mediated fibrosis was involved in the drug-resistant mechanisms of prolactinomas. These results indicate that SB431542 may serve as a promising novel treatment for preventing fibrosis and further improving the drug resistance of prolactinomas.
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Affiliation(s)
- Bin Hu
- Department of Neurosurgery and Pituitary Tumor Center, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Zhigang Mao
- Department of Neurosurgery and Pituitary Tumor Center, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Xiaobing Jiang
- Department of Neurosurgery, Cancer Center, Sun Yat-sen University, Guangzhou, China
| | - Dongsheng He
- Department of Neurosurgery and Pituitary Tumor Center, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Zongming Wang
- Department of Neurosurgery and Pituitary Tumor Center, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Xin Wang
- Department of Histology and Embryology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China
| | - Yonghong Zhu
- Department of Histology and Embryology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China.
| | - Haijun Wang
- Department of Neurosurgery and Pituitary Tumor Center, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.
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