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Deng C, Yang S, Pu C, Bai X, Tian C, Feng M. Temozolomide Treatment in Refractory Pituitary Adenomas and Pituitary Carcinomas. Neuroendocrinology 2025; 115:335-350. [PMID: 39778549 PMCID: PMC11991747 DOI: 10.1159/000543427] [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: 05/26/2024] [Accepted: 01/03/2025] [Indexed: 01/11/2025]
Abstract
BACKGROUND Temozolomide (TMZ), a nonclassical alkylating agent, possesses lipophilic properties that allow it to cross the blood-brain barrier, making it active within the central nervous system. Furthermore, the adverse reactions of the TMZ are relatively mild, which is why it is currently recommended as a first-line chemotherapy drug for refractory pituitary adenomas (RPAs) and pituitary carcinomas (PCs). SUMMARY Systematic evaluations indicate a radiological response rate of 41% and a hormonal response rate of 53%, underscoring TMZ clinical efficacy, particularly when combined with radiotherapy. Functional tumors demonstrate a higher response rate compared to nonfunctional tumors. While the optimal duration of TMZ treatment remains undetermined, studies suggest that longer therapy durations may lead to better prognoses. Additionally, prior to TMZ administration, it is advisable to conduct immunohistochemical analysis of O6-methylguanine-DNA methyltransferase, MSH2, MSH6, MLH1, PMS2, and N-methylpurine DNA glycosylase to assess the potential impact of repair mechanisms such as direct repair, mismatch repair pathway, and base excision repair on TMZ treatment. The efficacy of TMZ analogs, combined TMZ therapies, and TMZ with nanomaterials following TMZ treatment failure remains uncertain. KEY MESSAGES The involvement of experienced multidisciplinary pituitary teams in all management decisions for RPAs/PCs patients is essential.
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Affiliation(s)
- Congcong Deng
- Department of Neurosurgery, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, China
| | - Shuangjian Yang
- Department of Neurosurgery, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, China
| | - Changqin Pu
- Department of Neurosurgery, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, China
| | - Xuexue Bai
- Department of Neurosurgery, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, China
| | - Chenxin Tian
- Department of Neurosurgery, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, China
| | - Ming Feng
- Department of Neurosurgery, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, China
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Xu D, Wang L, Zheng M. Advancements in Molecular Diagnosis and Pharmacotherapeutic Strategies for Invasive Pituitary Adenomas. Immun Inflamm Dis 2024; 12:e70098. [PMID: 39688352 PMCID: PMC11650491 DOI: 10.1002/iid3.70098] [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: 08/14/2024] [Revised: 11/20/2024] [Accepted: 11/26/2024] [Indexed: 12/18/2024] Open
Abstract
BACKGROUND The overwhelming majority of pituitary tumors consist of pituitary adenomas (PAs), which have recently also been termed pituitary neuroendocrine tumors (PitNETs). Clinically significant PAs occur in approximately one in every 1000 individuals, while other types of pituitary tumors, such as craniopharyngiomas and pituicytomas, are significantly less common. Although PAs are generally benign, a subset of them exhibits malignant-like biological traits. They tend to infiltrate and grow aggressively into adjacent tissues and organs, including the dura mater, cavernous sinus, and sphenoid sinus. This invasive behavior often results in the destruction of the normal anatomical architecture of the sella turcica and skull base. Clinically, such tumors are classified as invasive PAs (IPAs), emphasizing their aggressive and destructive nature. OBJECTIVE AND SIGNIFICANCE Currently, the diagnostic indicators for IPAs frequently suffer from suboptimal sensitivity and specificity. The invasiveness assessment of PAs lacks a definitive gold standard and instead serves as a predictive tool, with a greater number of indicators met suggesting a higher likelihood of invasiveness. Consequently, a comprehensive approach that integrates imaging, pathological, molecular biological, and other disciplinary metrics is crucial for accurate evaluation. Despite surgery being the primary treatment modality for IPAs, their malignant-like behavior complicates complete resection, resulting in lower resection rates and heightened postoperative recurrence, necessitating multiple surgeries. Therefore, adjunctive drug therapy is often necessary for IPA patients. Preoperative drug therapy can shrink tumor size, facilitating resection and postoperative recovery, mitigating hormone imbalances, delaying recurrence, and enhancing patients' quality of life. CONCLUSIONS This article comprehensively reviews the diagnostic criteria for assessing the invasiveness of PAs in the domains of imaging, pathology, and molecular biology, provides an overview of the current research status of drug therapy for these conditions, and deepens our insight into the biological and therapeutic aspects of the tumor microenvironment in PAs.
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Affiliation(s)
- Dingkai Xu
- Department of NeurosurgeryThe First Hospital of Lanzhou UniversityLanzhouChina
| | - Ling Wang
- Department of EndocrinologyLiangzhou HospitalWuweiGansuChina
| | - Maohua Zheng
- Department of NeurosurgeryThe First Hospital of Lanzhou UniversityLanzhouChina
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DE Alcubierre D, Carretti AL, Ducray F, Jouanneau E, Raverot G, Ilie MD. Aggressive pituitary tumors and carcinomas: medical treatment beyond temozolomide. Minerva Endocrinol (Torino) 2024; 49:321-334. [PMID: 38240681 DOI: 10.23736/s2724-6507.23.04058-7] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/13/2024]
Abstract
Aggressive pituitary tumors are a subset of pituitary neoplasms, characterized by unusually fast growth rate, invasiveness and overall resistance to optimized standard treatment. When metastases are present, the term pituitary carcinoma is employed. After failure of standard treatments, current guidelines recommend first-line temozolomide monotherapy. However, a significant number of patients do not respond to temozolomide, or experience disease progression following its discontinuation; in these latter cases, re-challenge with temozolomide is generally advised, although the reported outcomes have been less satisfactory. Although no alternative therapies have been formally recommended after temozolomide failure, growing evidence regarding potential second- or third-line therapeutic strategies has emerged. In the present work, we reviewed the available evidence published up to April 2023 involving the most relevant therapies employed so far, namely immune checkpoint inhibitors, bevacizumab, peptide radionuclide receptor therapy, tyrosine kinase inhibitors and mTOR inhibitors. For each treatment, we report efficacy and safety outcomes, along with data regarding potential predictors of response. Overall, immune checkpoint inhibitors and bevacizumab are showing the most promise as therapeutic options after temozolomide failure. The former showed better responses in pituitary carcinomas. Peptide radionuclide receptor therapy has also showed some efficacy in these tumors, while tyrosine kinase inhibitors and mTOR inhibitors have exhibited so far limited or no efficacy. Further studies, as well as an individualized, patient-tailored approach, are clearly needed. In addition, we report an unpublished case of a silent corticotroph pituitary carcinoma that progressed under dual immunotherapy, and then showed stable disease under a combination of lomustine and bevacizumab.
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Affiliation(s)
- Dario DE Alcubierre
- Department of Experimental Medicine, Sapienza University, Rome, Italy
- Inserm U1052, CNRS UMR5286, Cancer Research Center of Lyon, Claude Bernard Lyon1 University, Lyon, France
| | - Anna L Carretti
- Department of Experimental Medicine, Sapienza University, Rome, Italy
- Department of Endocrinology, Reference Center for Rare Pituitary Diseases HYPO, Groupement Hospitalier Est Hospices Civils de Lyon, Bron, France
| | - François Ducray
- Service of Neuro-Oncology, Groupement Hospitalier Est Hospices Civils de Lyon, Bron, France
| | - Emmanuel Jouanneau
- Inserm U1052, CNRS UMR5286, Cancer Research Center of Lyon, Claude Bernard Lyon1 University, Lyon, France
- Department of Pituitary and Skull Base Neurosurgical, Reference Center for Rare Pituitary Diseases HYPO, Groupement Hospitalier Est Hospices Civils de Lyon, Bron, France
| | - Gérald Raverot
- Inserm U1052, CNRS UMR5286, Cancer Research Center of Lyon, Claude Bernard Lyon1 University, Lyon, France -
- Department of Endocrinology, Reference Center for Rare Pituitary Diseases HYPO, Groupement Hospitalier Est Hospices Civils de Lyon, Bron, France
| | - Mirela D Ilie
- Inserm U1052, CNRS UMR5286, Cancer Research Center of Lyon, Claude Bernard Lyon1 University, Lyon, France
- Department of Endocrinology, C.I. Parhon National Institute of Endocrinology, Bucharest, Romania
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Ilie MD, De Alcubierre D, Carretti AL, Jouanneau E, Raverot G. Therapeutic targeting of the pituitary tumor microenvironment. Pharmacol Ther 2023; 250:108506. [PMID: 37562699 DOI: 10.1016/j.pharmthera.2023.108506] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2023] [Revised: 07/28/2023] [Accepted: 08/07/2023] [Indexed: 08/12/2023]
Abstract
The tumor microenvironment (TME), the complex environment in which tumors develop, has been increasingly targeted for cancer treatment in recent years. Aggressive pituitary tumors and pituitary carcinomas have been so far targeted with immune-checkpoint inhibitors (28 cases, including a large cohort), and anti-angiogenic drugs (34 cases), specifically bevacizumab (30 cases), sunitinib (three cases), and apatinib (one case). Here, we reviewed all these cases, reporting tumor response, potential predictors of response, as well as adverse events. Given that the histological type could potentially influence treatment response, we present the existing data separately for each type. Briefly, under ICIs, complete response was noted in one case, partial response in a third of cases, stable disease in 10% of cases, while 54% of tumors progressed. Under BVZ monotherapy, most cases (57%) showed stable disease, while 36% of tumors progressed; partial response was reported in only one case. The three cases treated with sunitinib monotherapy progressed. Regarding predictive factors of response, the tumor type (aggressive pituitary tumor versus pituitary carcinoma) appears as the strongest predictor of response to ICIs. To date, no predictor of response to anti-angiogenic drugs in the treatment of pituitary carcinomas and aggressive pituitary tumors has been identified. The interest of BZV add-on to first- or second-line chemotherapy warrants further investigation. In addition, we discuss perspectives regarding the TME-targeting in aggressive pituitary tumors and pituitary carcinomas, including perspectives on immunotherapy, anti-angiogenic drugs, as well as on other TME components, namely stromal cells, extracellular matrix, and secreted molecules.
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Affiliation(s)
- Mirela-Diana Ilie
- Inserm U1052, CNRS UMR5286, Cancer Research Center of Lyon, Lyon, France; Lyon 1 University, Villeurbanne, France; Endocrinology Department, "C.I. Parhon" National Institute of Endocrinology, Bucharest, Romania
| | - Dario De Alcubierre
- Inserm U1052, CNRS UMR5286, Cancer Research Center of Lyon, Lyon, France; Department of Experimental Medicine, Sapienza University of Rome, Rome, Italy
| | - Anna Lucia Carretti
- Department of Experimental Medicine, Sapienza University of Rome, Rome, Italy; Endocrinology Department, Reference Center for Rare Pituitary Diseases HYPO, "Groupement Hospitalier Est" Hospices Civils de Lyon, Bron, France
| | - Emmanuel Jouanneau
- Inserm U1052, CNRS UMR5286, Cancer Research Center of Lyon, Lyon, France; Lyon 1 University, Villeurbanne, France; Neurosurgery Department, Reference Center for Rare Pituitary Diseases HYPO, "Groupement Hospitalier Est" Hospices Civils de Lyon, Bron, France
| | - Gérald Raverot
- Inserm U1052, CNRS UMR5286, Cancer Research Center of Lyon, Lyon, France; Lyon 1 University, Villeurbanne, France; Endocrinology Department, Reference Center for Rare Pituitary Diseases HYPO, "Groupement Hospitalier Est" Hospices Civils de Lyon, Bron, France.
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5
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Zhou Y, Zhang A, Fang C, Yuan L, Shao A, Xu Y, Zhou D. Oxidative stress in pituitary neuroendocrine tumors: Affecting the tumor microenvironment and becoming a new target for pituitary neuroendocrine tumor therapy. CNS Neurosci Ther 2023; 29:2744-2759. [PMID: 37341156 PMCID: PMC10493678 DOI: 10.1111/cns.14315] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2023] [Revised: 05/29/2023] [Accepted: 06/07/2023] [Indexed: 06/22/2023] Open
Abstract
Pituitary adenomas (PAs), or pituitary neuroendocrine tumors (PitNETs), are commonly found in the anterior pituitary gland. Although the majority of PitNETs are benign and stable, several tumors have malignant characteristics. The tumor microenvironment (TME) plays an important role in the process of tumorigenesis and is composed of several types of cells. Various cells in the TME are significantly affected by oxidative stress. It has been reported that immunotherapeutic strategies have good effects in several cancers. However, the clinical potential of immunotherapies in PitNETs has not yet been fully discussed. Oxidative stress can regulate PitNET cells and immune cells in the TME, thus affecting the immune status of the TME of PitNETs. Therefore, modulation of oxidative stress-regulated immune cells using a combination of several agents and the immune system to suppress PitNETs is a promising therapeutic direction. In this review, we systematically analyzed the oxidative stress process within PitNET cells and various immune cells to elucidate the potential value of immunotherapy.
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Affiliation(s)
- Yuhang Zhou
- The First Clinical Medical CollegeHeilongjiang University of Chinese MedicineHarbinChina
- Health Management CenterTongde Hospital of Zhejiang ProvinceHangzhouChina
| | - Anke Zhang
- Department of Neurosurgery, The Second Affiliated Hospital, School of MedicineZhejiang UniversityHangzhouChina
| | - Chaoyou Fang
- Department of Neurosurgery, Shanghai General Hospital, School of MedicineShanghai Jiao Tong UniversityShanghaiChina
| | - Ling Yuan
- School of Public Health, School of MedicineShanghai Jiaotong UniversityShanghaiChina
| | - Anwen Shao
- Department of Neurosurgery, The Second Affiliated Hospital, School of MedicineZhejiang UniversityHangzhouChina
| | - Yuanzhi Xu
- Department of Neurosurgery, Huashan Hospital, School of MedicineFudan UniversityShanghaiChina
| | - Danyang Zhou
- Health Management CenterTongde Hospital of Zhejiang ProvinceHangzhouChina
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Burman P, Casar-Borota O, Perez-Rivas LG, Dekkers OM. Aggressive Pituitary Tumors and Pituitary Carcinomas: From Pathology to Treatment. J Clin Endocrinol Metab 2023; 108:1585-1601. [PMID: 36856733 PMCID: PMC10271233 DOI: 10.1210/clinem/dgad098] [Citation(s) in RCA: 33] [Impact Index Per Article: 16.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/21/2022] [Revised: 01/13/2023] [Accepted: 02/15/2023] [Indexed: 03/02/2023]
Abstract
Aggressive pituitary tumors (APTs) and pituitary carcinomas (PCs) are heterogeneous with regard to clinical presentation, proliferative markers, clinical course, and response to therapy. Half of them show an aggressive course only many years after the first apparently benign presentation. APTs and PCs share several properties, but a Ki67 index greater than or equal to 10% and extensive p53 expression are more prevalent in PCs. Mutations in TP53 and ATRX are the most common genetic alterations; their detection might be of value for early identification of aggressiveness. Treatment requires a multimodal approach including surgery, radiotherapy, and drugs. Temozolomide is the recommended first-line chemotherapy, with response rates of about 40%. Immune checkpoint inhibitors have emerged as second-line treatment in PCs, with currently no evidence for a superior effect of dual therapy compared to monotherapy with PD-1 blockers. Bevacizumab has resulted in partial response (PR) in few patients; tyrosine kinase inhibitors and everolimus have generally not been useful. The effect of peptide receptor radionuclide therapy is limited as well. Management of APT/PC is challenging and should be discussed within an expert team with consideration of clinical and pathological findings, age, and general condition of the patient. Considering that APT/PCs are rare, new therapies should preferably be evaluated in shared standardized protocols. Prognostic and predictive markers to guide treatment decisions are needed and are the scope of ongoing research.
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Affiliation(s)
- Pia Burman
- Department of Endocrinology, Skåne University Hospital, Lund
University, 205 02 Malmö, Sweden
| | - Olivera Casar-Borota
- Department of Immunology, Genetics, and Pathology; Uppsala
University, 751 85 Uppsala, Sweden
- Department of Clinical Pathology, Uppsala University
Hospital, 751 85 Uppsala, Sweden
| | - Luis Gustavo Perez-Rivas
- Medizinische Klinik und Poliklinik IV, Klinikum der Universität München,
Ludwig-Maximilians-Universität München, 80804
Munich, Germany
| | - Olaf M Dekkers
- Department of Internal Medicine (Section of Endocrinology & Clinical
Epidemiology), Leiden University Medical Centre, 2333 ZA
Leiden, The Netherlands
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7
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Marques P. The Effects of Peptide Receptor Radionuclide Therapy on the Neoplastic and Normal Pituitary. Cancers (Basel) 2023; 15:2710. [PMID: 37345047 PMCID: PMC10216433 DOI: 10.3390/cancers15102710] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2023] [Revised: 05/07/2023] [Accepted: 05/08/2023] [Indexed: 06/23/2023] Open
Abstract
Pituitary neuroendocrine tumours (PitNETs) are usually benign and slow-growing; however, in some cases, they may behave aggressively and become resistant to conventional treatments. Therapeutic options for aggressive or metastatic PitNETs are limited, and currently mainly consist of temozolomide, with little experience of other emerging approaches, including peptide receptor radionuclide therapy (PRRT). Somatostatin receptor expression in PitNETs explains the effectiveness of somatostatin analogues for treating PitNETs, particularly those hypersecreting pituitary hormones, such as growth hormone or adrenocorticotropic hormone. The expression of such receptors in pituitary tumour cells has provided the rationale for using PRRT to treat patients with aggressive or metastatic PitNETs. However, the PRRT efficacy in this setting remains unestablished, as knowledge on this today is based only on few case reports and small series of cases, which are reviewed here. A total of 30 PRRT-treated patients have been thus far reported: 23 aggressive PitNETs, 5 carcinomas, and 2 of malignancy status unspecified. Of the 27 published cases with information regarding the response to PRRT, 5 (18%) showed a partial response, 8 (30%) had stable disease, and 14 (52%) had progressive disease. No major adverse effects have been reported, and there is also no increased risk of clinically relevant hypopituitarism in patients with pituitary or non-pituitary neuroendocrine tumours following PRRT. PRRT may be regarded as a safe option for patients with aggressive or metastatic PitNETs if other treatment approaches are not feasible or have failed in controlling the disease progression, with tumour shrinkage occurring in up to a fifth of cases, while about a third of aggressive pituitary tumours may achieve stable disease. Here, the data on PRRT in the management of patients with aggressive pituitary tumours are reviewed, as well as the effects of PRRT on the pituitary function in other PRRT-treated cancer patients.
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Affiliation(s)
- Pedro Marques
- Pituitary Tumor Unit, Endocrinology Department, Hospital CUF Descobertas, 1998-018 Lisbon, Portugal;
- Faculdade de Medicina, Universidade Católica Portuguesa, 2635-631 Lisbon, Portugal
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Robertson IJ, Gregory TA, Waguespack SG, Penas-Prado M, Majd NK. Recent Therapeutic Advances in Pituitary Carcinoma. JOURNAL OF IMMUNOTHERAPY AND PRECISION ONCOLOGY 2023; 6:74-83. [PMID: 37214211 PMCID: PMC10195013 DOI: 10.36401/jipo-22-25] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 09/01/2022] [Revised: 10/07/2022] [Accepted: 10/18/2022] [Indexed: 05/24/2023]
Abstract
Pituitary carcinoma (PC) is a rare, aggressive malignancy that comprises 0.1-0.2% of all pituitary tumors. PC is defined anatomically as a pituitary tumor that metastasizes outside the primary intrasellar location as noncontiguous lesions in the central nervous system or as metastases to other organs. Similar to pituitary adenoma, PC originates from various cell types of the pituitary gland and can be functioning or nonfunctioning, with the former constituting the majority of the cases. Compression of intricate skull-based structures, excessive hormonal secretion, impaired pituitary function from therapy, and systemic metastases lead to debilitating symptoms and a poor survival outcome in most cases. PC frequently recurs despite multimodality treatments, including surgical resection, radiotherapy, and biochemical and cytotoxic treatments. There is an unmet need to better understand the pathogenesis and molecular characterization of PC to improve therapeutic strategies. As our understanding of the role of signaling pathways in the tumorigenesis of and malignant transformation of PC evolves, efforts have focused on targeted therapy. In addition, recent advances in the use of immune checkpoint inhibitors to treat various solid cancers have led to an interest in exploring the role of immunotherapy for the treatment of aggressive refractory pituitary tumors. Here, we review our current understanding of the pathogenesis, molecular characterization, and treatment of PC. Particular attention is given to emerging treatment options, including targeted therapy, immunotherapy, and peptide receptor radionuclide therapy.
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Affiliation(s)
- Ian J. Robertson
- Department of Internal Medicine, Walter Reed National Military Medical Center, Bethesda, MD, USA
| | - Timothy A. Gregory
- Department of Neuro-Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Steven G. Waguespack
- Department of Endocrine Neoplasia and Hormonal Disorders, Division of Internal Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Marta Penas-Prado
- Neuro-Oncology Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA
| | - Nazanin K. Majd
- Department of Neuro-Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
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Aydin B, Beklen H, Arga KY, Bayrakli F, Turanli B. Epigenomic and transcriptomic landscaping unraveled candidate repositioned therapeutics for non-functioning pituitary neuroendocrine tumors. J Endocrinol Invest 2023; 46:727-747. [PMID: 36306107 DOI: 10.1007/s40618-022-01923-2] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/02/2022] [Accepted: 09/12/2022] [Indexed: 10/31/2022]
Abstract
PURPOSE Non-functioning pituitary neuroendocrine tumors are challengingly diagnosed tumors in the clinic. Transsphenoidal surgery remains the first-line treatment. Despite the development of state-of-the-art techniques, no drug therapy is currently approved for the treatment. There are also no randomized controlled trials comparing therapeutic strategies or drug therapy for the management after surgery. Therefore, novel therapeutic interventions for the therapeutically challenging NF-PitNETs are urgently needed. METHODS We integrated epigenome and transcriptome data (both coding and non-coding) that elucidate disease-specific signatures, in addition to biological and pharmacological data, to utilize rational pathway and drug prioritization in NF-PitNETs. We constructed an epigenome- and transcriptome-based PPI network and proposed hub genes. The signature-based drug repositioning based on the integration of multi-omics data was performed. RESULTS The construction of a disease-specific network based on three different biological levels revealed DCC, DLG5, ETS2, FOXO1, HBP1, HMGA2, PCGF3, PSME4, RBPMS, RREB1, SMAD1, SOCS1, SOX2, YAP1, ZFHX3 as hub proteins. Signature-based drug repositioning using hub proteins yielded repositioned drug candidates that were confirmed in silico via molecular docking. As a result of molecular docking simulations, palbociclib, linifanib, trametinib, eplerenone, niguldipine, and zuclopenthixol showed higher binding affinities with hub genes compared to their inhibitors and were proposed as potential repositioned therapeutics for the management of NF-PitNETs. CONCLUSION The proposed systems' biomedicine-oriented multi-omics data integration for drug repurposing to provide promising results for the construction of effective clinical therapeutics. To the best of our knowledge, this is the first study reporting epigenome- and transcriptome-based drug repositioning for NF-PitNETs using in silico confirmations.
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Affiliation(s)
- B Aydin
- Department of Bioengineering, Faculty of Engineering and Architecture, Konya Food and Agriculture University, Konya, Turkey
| | - H Beklen
- Department of Bioengineering, Faculty of Engineering, Marmara University, RTE Basibuyuk Campus, 34720, Istanbul, Turkey
| | - K Y Arga
- Department of Bioengineering, Faculty of Engineering, Marmara University, RTE Basibuyuk Campus, 34720, Istanbul, Turkey
- Genetic and Metabolic Diseases Research and Investigation Center (GEMHAM), Marmara University, Istanbul, Turkey
| | - F Bayrakli
- Department of Neurosurgery, Faculty of Medicine, Marmara University, Istanbul, Turkey
- Institute of Neurological Sciences, Marmara University, Istanbul, Turkey
| | - B Turanli
- Department of Bioengineering, Faculty of Engineering, Marmara University, RTE Basibuyuk Campus, 34720, Istanbul, Turkey.
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Abstract
The majority of anterior pituitary tumors behave benignly, that is, they grow slowly and do not metastasize, and were therefore called adenomas. However, they would frequently invade adjacent structures, leading to recurrence. One of the misleading assumptions in their previous classification was the simplistic distinction made between adenoma and carcinoma. In the upcoming WHO 2022 classification, a new terminology will be introduced: pituitary neuroendocrine tumor (PitNET) which is consistent with that used for other neuroendocrine neoplasms. In general, aggressive PitNETs are invasive and proliferative tumors with frequent recurrences, resistant to conventional treatments, and yet virtually without metastases. At present, no single morphological or histological marker has been shown as yet to reliably predict their aggressive behavior. In terms of treatment, temozolomide (TMZ) had been considered promising and the sole therapeutic option for aggressive and malignant PitNETs following failure of standard therapies. However, recent reports have disclosed that TMZ does not provide long-term control of many aggressive PitNETs. A further multidisciplinary approach is necessary for both reliable prediction and successful management of aggressive PitNETs.
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Affiliation(s)
- Hiroshi Nishioka
- Department of Hypothalamic and Pituitary Surgery, Toranomon Hospital, Tokyo 105-8470, Japan
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11
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Burman P, Trouillas J, Losa M, McCormack A, Petersenn S, Popovic V, Theodoropoulou M, Raverot G, Dekkers OM, the ESE survey collaborators. Aggressive pituitary tumours and carcinomas, characteristics and management of 171 patients. Eur J Endocrinol 2022; 187:593-605. [PMID: 36018781 PMCID: PMC9513638 DOI: 10.1530/eje-22-0440] [Citation(s) in RCA: 55] [Impact Index Per Article: 18.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/15/2022] [Accepted: 08/26/2022] [Indexed: 11/08/2022]
Abstract
OBJECTIVE To describe clinical and pathological characteristics and treatment outcomes in a large cohort of aggressive pituitary tumours (APT)/pituitary carcinomas (PC). DESIGN Electronic survey August 2020-May 2021. RESULTS 96% of 171 (121 APT, 50 PC), initially presented as macro/giant tumours, 6 were microadenomas (5 corticotroph). Ninety-seven tumours, initially considered clinically benign, demonstrated aggressive behaviour after 5.5 years (IQR: 2.8-12). Of the patients, 63% were men. Adrenocorticotrophic hormone (ACTH)-secreting tumours constituted 30% of the APT/PC, and the gonadotroph subtypes were under-represented. Five out of 13 silent corticotroph tumours and 2/6 silent somatotroph tumours became secreting. Metastases were observed after median 6.3 years (IQR 3.7-12.1) from diagnosis. At the first surgery, the Ki67 index was ≥3% in 74/93 (80%) and ≥10% in 38/93 (41%) tumours. An absolute increase of Ki67 ≥ 10% after median of 6 years from the first surgery occurred in 18/49 examined tumours. Tumours with an aggressive course from outset had higher Ki67, mitotic counts, and p53. Temozolomide treatment in 156/171 patients resulted in complete response in 9.6%, partial response in 30.1%, stable disease in 28.1%, and progressive disease in 32.2% of the patients. Treatment with bevacizumab, immune checkpoint inhibitors, and peptide receptor radionuclide therapy resulted in partial regression in 1/10, 1/6, and 3/11, respectively. Median survival in APT and PC was 17.2 and 11.3 years, respectively. Tumours with Ki67 ≥ 10% and ACTH-secretion were associated with worse prognosis. CONCLUSION APT/PCs exhibit a wide and challenging spectrum of behaviour. Temozolomide is the first-line chemotherapy, and other oncological therapies are emerging. Treatment response continues to be difficult to predict with currently studied biomarkers.
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Affiliation(s)
- Pia Burman
- Department of Endocrinology, Skåne University Hospital Malmö, University of Lund, Lund, Sweden
- Correspondence should be addressed to P Burman;
| | | | - Marco Losa
- Marco Losa Department of Neurosurgery, IRCCS San Raffaele Scientific Institute, Vita-Salute San Raffaele University, Milan, Italy
| | - Ann McCormack
- St Vincent’s Hospital and Garvan Institute of Medical Research, Sydney, Australia
| | | | | | - Marily Theodoropoulou
- Medizinische Klinik und Poliklinik IV, LMU Klinikum, Ludwig-Maximilians-Universität München, Germany
| | - Gerald Raverot
- Fédération d’Endocrinologie, Groupement Hospitalier Est, Hospices Civils de Lyon, University of Lyon-Est de Lyon, Bron, France
| | - Olaf M Dekkers
- Department of Internal Medicine (Section Endocrinology) & Clinical Epidemiology, Leiden University Medical Centre, Leiden, The Netherlands
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12
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Raghu ALB, Everson MC, Helal A, Kiyofuji S, Clarke MJ, Link MJ. Delayed Craniospinal Metastasis of Aggressive Nonfunctioning Pituitary Adenomas as Pituitary Carcinomas. Skull Base Surg 2022; 83:e253-e259. [DOI: 10.1055/s-0041-1725024] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2020] [Accepted: 01/13/2021] [Indexed: 10/22/2022]
Abstract
Abstract
Background Clinical behavior of pituitary neoplasms is peculiar and notoriously difficult to predict. While aggressive tumors are common, metastasis is very rare, can be highly delayed, and there are no histological or clinical features to meaningfully predict this happening. Endocrinologically silent tumors are particularly difficult, as there is less opportunity to detect early metastasis. Together, this amounts to a situation of uncertainty over the appropriate management of such tumors before and after metastasis.
Case Description The authors report two cases of nonfunctioning aggressive pituitary adenoma (APA) each requiring two transsphenoidal surgeries, a transcranial resection and radiotherapy. Both these tumors subsequently metastasized caudally along the neuraxis, years later, as a null cell carcinoma associated with a germline CHEK2 mutation and a silent Crooke's cell carcinoma. The former represents a novel oncogenetic association.
Conclusion Delayed drop dural metastasis of pituitary carcinoma is becoming increasingly recognized. Surgical resection of the distant disease to confirm the diagnosis and relieve the mass effect, followed by temozolomide chemotherapy, is the current treatment of choice. The need for both long-term follow-up in patients with APA, and a high degree of suspicion toward dural-based radiographic findings is emphasized.
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Affiliation(s)
- Ashley L. B. Raghu
- Nuffield Department of Surgical Sciences, University of Oxford, Oxford, United Kingdom
| | - Megan C. Everson
- Department of Neurologic Surgery, Mayo Clinic, Rochester, Minnesota, United States
| | - Ahmed Helal
- Department of Neurologic Surgery, Mayo Clinic, Rochester, Minnesota, United States
| | - Satoshi Kiyofuji
- Department of Neurologic Surgery, Mayo Clinic, Rochester, Minnesota, United States
| | - Michelle J. Clarke
- Department of Neurologic Surgery, Mayo Clinic, Rochester, Minnesota, United States
| | - Michael J. Link
- Department of Neurologic Surgery, Mayo Clinic, Rochester, Minnesota, United States
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13
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Kontogeorgos G, Thodou E, Osamura RY, Lloyd RV. High-risk pituitary adenomas and strategies for predicting response to treatment. Hormones (Athens) 2022; 21:1-14. [PMID: 35061210 DOI: 10.1007/s42000-021-00333-y] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/17/2021] [Accepted: 10/18/2021] [Indexed: 12/30/2022]
Abstract
High-risk pituitary adenomas are aggressive. They show clinical and imaging features similar to those of carcinomas, including infiltration of the surrounding brain structures, but lack cerebrospinal or systemic metastases. In addition, they display distinct behavior, including tendency for fast growth and frequent recurrences, which are difficult to control. The term "high-risk" adenoma was first introduced in the 4th edition of the World Health Organization Classification of Endocrine Tumors in 2017. Five defined adenoma types belong to this category, including sparsely granulated somatotroph, lactotroph in men, Crooke cell, silent corticotroph, and plurihormonal PIT-1 positive adenomas. The morphological and immunohistochemical characteristics of high-risk adenomas are herein described in detail. In addition, the clinical features and the treatment options are presented. This review focuses on predictive markers assessed by immunohistochemistry, which help clinicians to design the appropriate treatment strategies for high-risk adenomas. Somatostatin receptor status predicts effectiveness of postsurgical treatment with somatostatin analogs, and MGMT expression predicts response to treatment with temozolomide. This comprehensive review presents the clinical and pathological features of high-risk pituitary adenomas, underlines the contribution of immunohistochemistry, and emphasizes the leading role of pathology in the design of optimal clinical management.
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Affiliation(s)
- George Kontogeorgos
- Division of Endocrinology, First Propaedeutic Department of Internal Medicine, Laikon Hospital, National and Kapodistrian University of Athens, Athens, Greece.
- Department of Pathology and Pituitary Tumor Reference Center, G. Gennimatas General Hospital of Athens, Athens, Greece.
| | - Eleni Thodou
- Department of Pathology, University of Thessaly, Larissa, Greece
| | - Robert Y Osamura
- Department of Pathology, Nippon Koukan Hospital, Kawasaki, Kanagawa, Japan
| | - Ricardo V Lloyd
- Department of Pathology and Laboratory Medicine, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA
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14
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Voellger B, Zhang Z, Benzel J, Wang J, Lei T, Nimsky C, Bartsch JW. Targeting Aggressive Pituitary Adenomas at the Molecular Level-A Review. J Clin Med 2021; 11:jcm11010124. [PMID: 35011868 PMCID: PMC8745122 DOI: 10.3390/jcm11010124] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2021] [Revised: 12/11/2021] [Accepted: 12/21/2021] [Indexed: 12/14/2022] Open
Abstract
Pituitary adenomas (PAs) are mostly benign endocrine tumors that can be treated by resection or medication. However, up to 10% of PAs show an aggressive behavior with invasion of adjacent tissue, rapid proliferation, or recurrence. Here, we provide an overview of target structures in aggressive PAs and summarize current clinical trials including, but not limited to, PAs. Mainly, drug targets in PAs are based on general features of tumor cells such as immune checkpoints, so that programmed cell death 1 (ligand 1) (PD-1/PD-L1) targeting may bear potential to cure aggressive PAs. In addition, epidermal growth factor receptor (EGFR), mammalian target of rapamycin (mTOR), vascular endothelial growth factor (VEGF), fibroblast growth factor (FGF) and their downstream pathways are triggered in PAs, thereby modulating tumor cell proliferation, migration and/or tumor angiogenesis. Temozolomide (TMZ) can be an effective treatment of aggressive PAs. Combination of TMZ with 5-Fluorouracil (5-FU) or with radiotherapy could strengthen the therapeutic effects as compared to TMZ alone. Dopamine agonists (DAs) are the first line treatment for prolactinomas. Dopamine receptors are also expressed in other subtypes of PAs which renders DAs potentially suitable to treat other subtypes of PAs. Furthermore, targeting the invasive behavior of PAs could improve therapy. In this regard, human matrix metalloproteinase (MMP) family members and estrogens receptors (ERs) are highly expressed in aggressive PAs, and numerous studies demonstrated the role of these proteins to modulate invasiveness of PAs. This leaves a number of treatment options for aggressive PAs as reviewed here.
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Affiliation(s)
- Benjamin Voellger
- Department of Neurosurgery, University Hospital Marburg, Baldingerstr., 35033 Marburg, Germany; (Z.Z.); (J.B.); (J.W.); (C.N.); (J.-W.B.)
- Correspondence: ; Tel.: +49-6421-58-66447
| | - Zhuo Zhang
- Department of Neurosurgery, University Hospital Marburg, Baldingerstr., 35033 Marburg, Germany; (Z.Z.); (J.B.); (J.W.); (C.N.); (J.-W.B.)
- Department of Neurosurgery, Tongji Hospital, Tongji Medical College of Huazhong University of Science and Technology, Wuhan 430030, China;
| | - Julia Benzel
- Department of Neurosurgery, University Hospital Marburg, Baldingerstr., 35033 Marburg, Germany; (Z.Z.); (J.B.); (J.W.); (C.N.); (J.-W.B.)
- Deutsches Krebsforschungszentrum (DKFZ) Heidelberg, Im Neuenheimer Feld 280, 69120 Heidelberg, Germany
| | - Junwen Wang
- Department of Neurosurgery, University Hospital Marburg, Baldingerstr., 35033 Marburg, Germany; (Z.Z.); (J.B.); (J.W.); (C.N.); (J.-W.B.)
- Department of Neurosurgery, Tongji Hospital, Tongji Medical College of Huazhong University of Science and Technology, Wuhan 430030, China;
| | - Ting Lei
- Department of Neurosurgery, Tongji Hospital, Tongji Medical College of Huazhong University of Science and Technology, Wuhan 430030, China;
| | - Christopher Nimsky
- Department of Neurosurgery, University Hospital Marburg, Baldingerstr., 35033 Marburg, Germany; (Z.Z.); (J.B.); (J.W.); (C.N.); (J.-W.B.)
| | - Jörg-Walter Bartsch
- Department of Neurosurgery, University Hospital Marburg, Baldingerstr., 35033 Marburg, Germany; (Z.Z.); (J.B.); (J.W.); (C.N.); (J.-W.B.)
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15
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Das L, Rai A, Salunke P, Ahuja CK, Sood A, Radotra BD, Sood R, Korbonits M, Dutta P. Temozolomide Nonresponsiveness in Aggressive Prolactinomas and Carcinomas: Management and Outcomes. J Endocr Soc 2021; 6:bvab190. [PMID: 35059545 PMCID: PMC8763612 DOI: 10.1210/jendso/bvab190] [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: 10/06/2021] [Indexed: 11/19/2022] Open
Abstract
Context Temozolomide (TMZ) is endorsed as the treatment of choice in aggressive or malignant pituitary adenomas. Objective Herein we describe a case of an aggressive prolactinoma that was resistant to TMZ. We performed a literature review of similar nonresponsive, aggressive prolactinomas. Methods A 40-year-old woman presented with a giant prolactinoma that required cabergoline, transsphenoidal surgery, and radiotherapy to achieve near-normal prolactin and apparently no residual tumor. A year later, she presented with multiple cranial nerve involvement due to a recurrent tumor extending to the infratemporal fossa. She underwent transfrontal surgery, second radiotherapy, and was started on TMZ. Despite 8 cycles of temozolomide (200 mg/m2, 5/28-day cycle), she had progressive disease and ultimately succumbed to the disease. PubMed/MEDLINE, Google Scholar, and prior review articles were searched for manuscripts about patients with aggressive prolactinomas who had been treated with TMZ. Data on demography, duration of therapy, and management outcomes were analyzed in those with progressive disease. Results We identified 94 cases of patients with aggressive/malignant prolactinomas in the literature who had received TMZ. Progressive disease despite TMZ was present in 36 cases (38%). There was a male preponderance (65%) among these and 40% had aggressive prolactinomas, whereas the rest had carcinomas. Patients received a median of 8 cycles (interquartile range, 3.5-11.5) of TMZ. O6‐methylguanine‐DNA‐methyltransferase (MGMT) immunostaining was negative in 35%. Overall mortality at the time of publication was 40%, at a duration varying from 2 to 20 years from diagnosis. Conclusion TMZ resistance in aggressive/malignant prolactinomas is challenging. Progressive disease on optimal TMZ treatment entails the use of newer agents.
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Affiliation(s)
- Liza Das
- Department of Endocrinology, Postgraduate institute of Medical Education and Research, (PGIMER), Chandigarh 160012, India
| | - Ashutosh Rai
- Department of Endocrinology, PGIMER, Chandigarh, India
- Newton fellow Barts and the London school of Medicine
| | - Pravin Salunke
- Department of Neurosurgery, PGIMER, Chandigarh 160012, India
| | | | - Ashwani Sood
- Department of Nuclear Medicine, PGIMER, Chandigarh 160012, India
| | | | - Ridhi Sood
- Department of Histopathology, PGIMER, Chandigarh 160012, India
| | - Márta Korbonits
- Centre for Endocrinology, William Harvey Research Institute, Barts and The London School of Medicine, Queen Mary University of London, London E1 4NS, UK
| | - Pinaki Dutta
- Department of Endocrinology, Postgraduate institute of Medical Education and Research, (PGIMER), Chandigarh 160012, India
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16
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Dai C, Liang S, Sun B, Li Y, Kang J. Anti-VEGF Therapy in Refractory Pituitary Adenomas and Pituitary Carcinomas: A Review. Front Oncol 2021; 11:773905. [PMID: 34869016 PMCID: PMC8635636 DOI: 10.3389/fonc.2021.773905] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2021] [Accepted: 10/27/2021] [Indexed: 12/24/2022] Open
Abstract
Most pituitary tumors are considered benign adenomas, and only 0.1%–0.2% of them present metastasis and are defined as pituitary carcinomas (PCs). Refractory pituitary adenomas (PAs) lie between benign adenomas and true malignant PCs and are defined as aggressive-invasive PAs, characterized by a high Ki-67 index, rapid growth, frequent recurrence, and resistance to conventional treatments. Refractory PAs and PCs are notoriously difficult to manage because of limited therapeutic options. Vascular endothelial growth factor (VEGF) plays a crucial role in angiogenesis not only during development but also during pathological processes in pituitary tumors. Recently, increasing numbers of preclinical studies and clinical research have demonstrated that anti-VEGF therapy plays an important role in pituitary tumors. The purpose of this review is to report the role of VEGF in the development and pathology of pituitary tumors and the progress of anti-VEGF therapy in pituitary tumors, including refractory PAs and PCs. Previous preclinical studies indicated that cyclin-dependent kinase 5 (CDK5)-mediated VEGF expression might play a crucial role in the development of PAs. Vascular endothelial growth inhibitors have been reported as independent predictors of invasion in human PAs and have been indicated as markers for poor outcome. Furthermore, several studies have reported that angiogenesis decreases tumor sizes in experimental animal models of pituitary tumors. The expression of VEGF is relatively high in PAs; therefore, anti-VEGF therapy has been used in some refractory PAs and PCs. To date, anti-VEGF has been reported as monotherapy, in combination with temozolomide (TMZ), TMZ and radiotherapy, and with pasireotide, which might be a promising alternative therapy for refractory PAs and PCs resistant to conventional treatments. However, the role of anti-VEGF therapy in pituitary tumors is still controversial due to a lack of large-scale clinical trials. In summary, the results from preclinical studies and clinical trials indicated that anti-VEGF therapy monotherapy or in combination with other treatments may be a promising alternative therapy for refractory PAs and PCs resistant to conventional treatments. More preclinical studies and clinical trials are needed to further evaluate the exact efficacy of anti-VEGF in refractory PAs and PCs.
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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
| | - Yong Li
- Department of Neurosurgery, Beijing Tongren Hospital, Capital Medical University, Beijing, China
| | - Jun Kang
- Department of Neurosurgery, Beijing Tongren Hospital, Capital Medical University, Beijing, China
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17
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Dai C, Sun B, Guan S, Wang W, Liu H, Li Y, Zhang J, Kang J. Evolution of a refractory prolactin-secreting pituitary adenoma into a pituitary carcinoma: report of a challenging case and literature review. BMC Endocr Disord 2021; 21:217. [PMID: 34715828 PMCID: PMC8555299 DOI: 10.1186/s12902-021-00874-8] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/05/2020] [Accepted: 10/15/2021] [Indexed: 12/29/2022] Open
Abstract
BACKGROUND Pituitary carcinomas (PCs), defined as distant metastases of pituitary neoplasms, are very rare malignancies. Because the clinical presentation of PCs is variable, early diagnosis and management remain challenging. PCs are always refractory to comprehensive treatments, and patients with PCs have extremely poor prognoses. CASE PRESENTATION We describe one case of a prolactin-secreting pituitary adenoma (PA) refractory to conventional therapy that evolved into a PC with intraspinal metastasis. A 34-year-old female was diagnosed with an invasive prolactin-secreting PA in 2009 and was unresponsive to medical treatment with bromocriptine. The tumor was gross totally removed via transsphenoidal surgery (TSS). However, the patient experienced multiple tumor recurrences or regrowth despite comprehensive treatments, including medical therapy, two gamma knife radiosurgeries (GKSs), and four frontal craniotomies. In 2016, she was found to have an intradural extramedullary mass at the level of the fourth lumbar vertebra. The intraspinal lesion was completely resected and was confirmed as a metastatic PC based on histomorphology and immunohistochemical staining. The literature on the diagnosis, molecular pathogenesis, treatment, and prognosis of patients with prolactin-secreting PCs was reviewed. CONCLUSION PCs are very rare neoplasms with variable clinical features and poor prognosis. Most PCs usually arise from aggressive PAs refractory to conventional therapy. There is no reliable marker to identify aggressive PAs with a risk for progression to PCs; thus, it is difficult to diagnose these PCs early until the presence of metastatic lesions. It is still very challenging to manage patients with PCs due to a lack of standardized protocols for diagnosis and treatment. Establishing molecular biomarkers and the pathobiology of PCs could help in the early identification of aggressive PAs most likely to evolve into PCs.
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Affiliation(s)
- Congxin Dai
- Department of Neurosurgery, Beijing Tongren Hospital, Capital Medical University, Beijing, 100730, China
| | - Bowen Sun
- Department of Neurosurgery, Beijing Tongren Hospital, Capital Medical University, Beijing, 100730, China
| | - Shusen Guan
- Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University, Beijing, 100730, China
| | - Wei Wang
- Department of Neurosurgery, Beijing Tongren Hospital, Capital Medical University, Beijing, 100730, China
| | - Honggang Liu
- Department of Pathology, Beijing Tongren Hospital, Capital Medical University, Beijing, 100730, China
| | - Yong Li
- Department of Neurosurgery, Beijing Tongren Hospital, Capital Medical University, Beijing, 100730, China
| | - Jialiang Zhang
- Department of Neurosurgery, Beijing Tongren Hospital, Capital Medical University, Beijing, 100730, China
| | - Jun Kang
- Department of Neurosurgery, Beijing Tongren Hospital, Capital Medical University, Beijing, 100730, China.
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18
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Shen AJJ, King J, Colman PG, Yates CJ. Diagnosis and Management of Adrenocorticotropic Hormone-Secreting Pituitary Carcinoma: A Case Report and Review of the Literature. FUTURE RARE DISEASES 2021; 1. [DOI: 10.2217/frd-2021-0007] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/30/2021] [Accepted: 07/14/2021] [Indexed: 01/05/2025]
Affiliation(s)
- Angeline JJ Shen
- Department of Medicine, The University of Melbourne, Grattan Street, Parkville, Victoria, 3050, Australia
- Department of Diabetes & Endocrinology, The Royal Melbourne Hospital, Grattan Street, Parkville, Victoria, 3050, Australia
| | - James King
- Department of Neurosurgery, The Royal Melbourne Hospital, Grattan Street, Parkville, Victoria, 3050, Australia
| | - Peter G Colman
- Department of Medicine, The University of Melbourne, Grattan Street, Parkville, Victoria, 3050, Australia
- Department of Diabetes & Endocrinology, The Royal Melbourne Hospital, Grattan Street, Parkville, Victoria, 3050, Australia
| | - Christopher J Yates
- Department of Medicine, The University of Melbourne, Grattan Street, Parkville, Victoria, 3050, Australia
- Department of Diabetes & Endocrinology, The Royal Melbourne Hospital, Grattan Street, Parkville, Victoria, 3050, Australia
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19
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Kumar N, Rai A, Dutta P, Gupta P, Singh P, Mukherjee KK, Dhandapani S. Noncontiguous Radiation-Induced Brain Necrosis (RIBN) in a Patient with Aggressive Pituitary Adenoma and the Utility of Bevacizumab. Neurol India 2021; 69:1055-1057. [PMID: 34507446 DOI: 10.4103/0028-3886.325385] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/04/2022]
Affiliation(s)
- Narendra Kumar
- Department of Radiotherapy, Graduate Institute of Medical Education and Research, Chandigarh, India
| | - Ashutosh Rai
- Department of Endocrinology, Graduate Institute of Medical Education and Research, Chandigarh, India
| | - Pinaki Dutta
- Department of Endocrinology, Graduate Institute of Medical Education and Research, Chandigarh, India
| | - Prakamya Gupta
- Department of Indian Council of Medical Research, Graduate Institute of Medical Education and Research, Chandigarh, India
| | - Paramjeet Singh
- Department of Radiology, Graduate Institute of Medical Education and Research, Chandigarh, India
| | - Kanchan K Mukherjee
- Department of Neurosurgery, Graduate Institute of Medical Education and Research, Chandigarh, India
| | - Sivashanmugam Dhandapani
- Department of Neurosurgery, Graduate Institute of Medical Education and Research, Chandigarh, India
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20
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MicroRNAs as Potential Biomarkers in Pituitary Adenomas. Noncoding RNA 2021; 7:ncrna7030055. [PMID: 34564317 PMCID: PMC8482103 DOI: 10.3390/ncrna7030055] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2021] [Revised: 08/27/2021] [Accepted: 08/30/2021] [Indexed: 12/16/2022] Open
Abstract
Pituitary adenomas (PAs) are one of the most common lesions of intracranial neoplasms, occurring in approximately 15% of the general population. They are typically benign, although some adenomas show aggressive behavior, exhibiting rapid growth, drug resistance, and invasion of surrounding tissues. Despite ongoing improvements in diagnostic and therapeutic strategies, late first diagnosis is common, and patients with PAs are prone to relapse. Therefore, earlier diagnosis and prevention of recurrence are of importance to improve patient care. MicroRNAs (miRNAs) are short non-coding single stranded RNAs that regulate gene expression at the post-transcriptional level. An increasing number of studies indicate that a deregulation of their expression patterns is related with pituitary tumorigenesis, suggesting that these small molecules could play a critical role in contributing to tumorigenesis and the onset of these tumors by acting either as oncosuppressors or as oncogenes, depending on the biological context. This paper provides an overview of miRNAs involved in PA tumorigenesis, which might serve as novel potential diagnostic and prognostic non-invasive biomarkers, and for the future development of miRNA-based therapeutic strategies for PAs.
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21
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Kontogeorgos G. Update on pituitary adenomas in the 2017 World Health Organization classification: innovations and perspectives. Hormones (Athens) 2021; 20:287-291. [PMID: 33453046 DOI: 10.1007/s42000-020-00269-9] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/15/2020] [Accepted: 12/22/2020] [Indexed: 02/07/2023]
Abstract
The World Health Organization (WHO) classifications of tumors offer invaluable support in the diagnosis of tumors, with every new edition including novel information and diagnostic updates. The new 2017 WHO Classification of Tumors of Endocrine Organs, 4th edition, includes innovations in both terminology and diagnostic guidelines for pituitary adenomas, along with new entities, molecular information, and novel treatment modalities. The recommended reporting system of pituitary adenomas is based on morphology and assessment of the hormonal content by immunohistochemistry. Electron microscopy and immunohistochemistry for Ki-67 and p53 and transcription factors, while presenting additional information, are not recommended for routine diagnosis. Other markers may also yield information of prognostic and predictive significance. In sum, the 2017 WHO classification provides pathologists and clinicians with new and comprehensive information of great use for the diagnosis and treatment of pituitary tumors.
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Affiliation(s)
- George Kontogeorgos
- Endocrine Unit, First Propaedeutic Department of Internal Medicine, Laikon Hospital, National and Kapodistrian University of Athens, Athens, Greece.
- Department of Pathology, G. Gennimatas, Athens General Hospital, 154 Messogion Ave., BLDG#1, 115 27, Athens, Greece.
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22
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Liu X, Dai C, Feng M, Li M, Chen G, Wang R. Diagnosis and treatment of refractory pituitary adenomas: a narrative review. Gland Surg 2021; 10:1499-1507. [PMID: 33968701 DOI: 10.21037/gs-20-873] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Although aggressive pituitary adenomas (PAs) have been proposed and widely discussed for more than a decade, there is no general agreement regarding their definition, diagnosis or management. As one of the largest pituitary centers in China, we have diagnosed and treated more than fifty cases of aggressive PA and 3 pituitary carcinomas in the past 5 years and proposed a new term, i.e., refractory PAs, to define these adenomas. The definitions of aggressive and refractory PAs overlap with each other, though there are some differences between them. We interpret the definition for refractory PA in this review, emphasizing that more attention and early identification of these adenomas are needed. Although temozolomide (TMZ) has been used to treat pituitary carcinomas and refractory PA since 2006, which has significantly improved the prognosis of these patients, treatment of refractory PA is a tremendous challenge for endocrinologists and neurosurgeons. Overall, refractory PA is defined as PA with a Ki-67 labeling index ≥3%, a faster growth rate than that of normal PA, infiltration of surrounding tissues, recurrence or regrowth in the early postoperative period, and continued growth and/or secretion of excessive hormones despite attempts to control it. These criteria for refractory PA are stricter than for aggressive PA. The diagnosis and treatment of refractory PA requires the collaboration of a multidisciplinary team to achieve the best results.
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Affiliation(s)
- Xiaohai Liu
- Department of Neurosurgery, Xuanwu Hospital Capital Medical University, Beijing, China.,Chinese Pituitary Specialists Congress, Beijing, China
| | - Congxin Dai
- Chinese Pituitary Specialists Congress, Beijing, China.,Department of Neurosurgery, Tongren Hospital Capital Medical University, Beijing, China
| | - Ming Feng
- Chinese Pituitary Specialists Congress, Beijing, China.,Department of Neurosurgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Mingchu Li
- Department of Neurosurgery, Xuanwu Hospital Capital Medical University, Beijing, China.,Chinese Pituitary Specialists Congress, Beijing, China
| | - Ge Chen
- Department of Neurosurgery, Xuanwu Hospital Capital Medical University, Beijing, China.,Chinese Pituitary Specialists Congress, Beijing, China
| | - Renzhi Wang
- Chinese Pituitary Specialists Congress, Beijing, China.,Department of Neurosurgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
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23
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Petersenn S. Medical Therapy of Aggressive Pituitary Tumors. Exp Clin Endocrinol Diabetes 2021; 129:186-193. [PMID: 33690871 DOI: 10.1055/a-1331-6939] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 10/22/2022]
Abstract
The rare aggressive pituitary adenoma presents a special challenge, due to the heterogenous presentation of the disease. The prognosis of aggressive pituitary adenomas has been improved due to recent studies demonstrating clinically-relevant efficacy of temozolomide, which is now considered first-line chemotherapy. However, there is limited data on second-line therapies in patients with treatment failure. This review presents a summary on the potential of medical therapies in aggressive pituitary tumors.
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24
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Yamamoto M, Nakao T, Ogawa W, Fukuoka H. Aggressive Cushing's Disease: Molecular Pathology and Its Therapeutic Approach. Front Endocrinol (Lausanne) 2021; 12:650791. [PMID: 34220707 PMCID: PMC8242934 DOI: 10.3389/fendo.2021.650791] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/08/2021] [Accepted: 05/26/2021] [Indexed: 12/13/2022] Open
Abstract
Cushing's disease is a syndromic pathological condition caused by adrenocorticotropic hormone (ACTH)-secreting pituitary adenomas (ACTHomas) mediated by hypercortisolemia. It may have a severe clinical course, including infection, psychiatric disorders, hypercoagulability, and metabolic abnormalities, despite the generally small, nonaggressive nature of the tumors. Up to 20% of ACTHomas show aggressive behavior, which is related to poor surgical outcomes, postsurgical recurrence, serious clinical course, and high mortality. Although several gene variants have been identified in both germline and somatic changes in Cushing's disease, the pathophysiology of aggressive ACTHomas is poorly understood. In this review, we focused on the aggressiveness of ACTHomas, its pathology, the current status of medical therapy, and future prospects. Crooke's cell adenoma (CCA), Nelson syndrome, and corticotroph pituitary carcinoma are representative refractory pituitary tumors that secrete superphysiological ACTH. Although clinically asymptomatic, silent corticotroph adenoma is an aggressive ACTH-producing pituitary adenoma. In this review, we summarize the current understanding of the pathophysiology of aggressive ACTHomas, including these tumors, from a molecular point of view based on genetic, pathological, and experimental evidence. The treatment of aggressive ACTHomas is clinically challenging and usually resistant to standard treatment, including surgery, radiotherapy, and established medical therapy (e.g., pasireotide and cabergoline). Temozolomide is the most prescribed pharmaceutical treatment for these tumors. Reports have shown that several treatments for patients with refractory ACTHomas include chemotherapy, such as cyclohexyl-chloroethyl-nitrosourea combined with 5-fluorouracil, or targeted therapies against several molecules including vascular endothelial growth factor receptor, cytotoxic T lymphocyte antigen 4, programmed cell death protein 1 (PD-1), and ligand for PD-1. Genetic and experimental evidence indicates that some possible therapeutic candidates are expected, such as epidermal growth factor receptor tyrosine kinase inhibitor, cyclin-dependent kinase inhibitor, and BRAF inhibitor. The development of novel treatment options for aggressive ACTHomas is an emerging task.
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Affiliation(s)
- Masaaki Yamamoto
- Division of Diabetes and Endocrinology, Kobe University Hospital, Kobe, Japan
| | | | - Wataru Ogawa
- Division of Diabetes and Endocrinology, Kobe University Graduate School of Medicine, Kobe, Japan
| | - Hidenori Fukuoka
- Division of Diabetes and Endocrinology, Kobe University Hospital, Kobe, Japan
- *Correspondence: Hidenori Fukuoka,
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Cooper O, Bonert V, Liu NA, Mamelak AN. Treatment of Aggressive Pituitary Adenomas: A Case-Based Narrative Review. Front Endocrinol (Lausanne) 2021; 12:725014. [PMID: 34867776 PMCID: PMC8634600 DOI: 10.3389/fendo.2021.725014] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/14/2021] [Accepted: 10/28/2021] [Indexed: 12/29/2022] Open
Abstract
Management of aggressive pituitary adenomas is challenging due to a paucity of rigorous evidence supporting available treatment approaches. Recent guidelines emphasize the need to maximize standard therapies as well as the use of temozolomide and radiation therapy to treat disease recurrence. However, often these adenomas continue to progress over time, necessitating the use of additional targeted therapies which also impact quality of life and long-term outcomes. In this review, we present 9 cases of aggressive pituitary adenomas to illustrate the importance of a multidisciplinary, individualized approach. The timing and rationale for surgery, radiation therapy, temozolomide, somatostatin receptor ligands, and EGFR, VEGF, and mTOR inhibitors in each case are discussed within the context of evidence-based guidelines and clarify strategies for implementing an individualized approach in the management of these difficult-to-treat-adenomas.
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Affiliation(s)
- Odelia Cooper
- Pituitary Center, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, CA, United States
- *Correspondence: Odelia Cooper,
| | - Vivien Bonert
- Pituitary Center, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, CA, United States
| | - Ning-Ai Liu
- Pituitary Center, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, CA, United States
| | - Adam N. Mamelak
- Pituitary Center, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, CA, United States
- Department of Neurosurgery, Cedars-Sinai Medical Center, Los Angeles, CA, United States
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Osterhage K, Rotermund R, Droste M, Dierlamm J, Saeger W, Petersenn S, Aberle J, Flitsch J. Bevacizumab in Aggressive Pituitary Adenomas - Experience with 3 Patients. Exp Clin Endocrinol Diabetes 2020; 129:178-185. [PMID: 33285600 DOI: 10.1055/a-1260-3975] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 10/22/2022]
Abstract
OBJECTIVE To investigate bevacizumab as alternative treatment of aggressive pituitary adenomas after exhaustion of standard therapies. DESIGN AND METHODS Retrospectively, 3 patients undergoing microscopic transsphenoidal surgery of aggressive pituitary adenomas from 2008 till 2018 that were treated with bevacizumab were identified. Development of disease and treatment were evaluated. RESULTS Two patients suffered from ACTH-secreting adenomas, one from a non-functioning adenoma. All patients underwent multiple surgical, chemo- and radiotherapeutical approaches including temozolomide, showing favorable results in one patient. Deterioration of clinical condition in all patients led to an individual, palliative attempt of bevacizumab. Patients 1 and 2 showed a decrease of ACTH after first administrations, but therapy had to be ended shortly after due to a further deterioration of their condition. Patient 3 showed a stabilization of the disease for 18 months. Patients died 8, 15 and 7 years after initial diagnosis, respectively, and 2, 4, and 24 months after initiation of bevacizumab therapy, respectively. CONCLUSION The demonstrated results suggest a considerable effect of bevacizumab in aggressive pituitary adenomas. The advanced stage of disease in all three patients, the overall short period of administration and just one patient showing a clinical benefit do not allow a general statement on the effectiveness. At the current stage of clinical experience, an approach with bevacizumab can be considered as an individual palliative attempt of treatment, when standard treatments are exhausted. Our results underline the need for further studies to evaluate this drug as potential player in therapy resistant aggressive pituitary tumors.
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Affiliation(s)
- Katharina Osterhage
- Department of Neurosurgery, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Roman Rotermund
- Department of Neurosurgery, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | | | - Judith Dierlamm
- Department of Oncology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Wolfgang Saeger
- Institute of Neuropathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | | | - Jens Aberle
- Department of Endocrinology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Jörg Flitsch
- Department of Neurosurgery, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
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Lin AL, Donoghue MTA, Wardlaw SL, Yang TJ, Bodei L, Tabar V, Geer EB. Approach to the Treatment of a Patient with an Aggressive Pituitary Tumor. J Clin Endocrinol Metab 2020; 105:5905925. [PMID: 32930787 PMCID: PMC7566322 DOI: 10.1210/clinem/dgaa649] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/22/2020] [Accepted: 09/11/2020] [Indexed: 12/21/2022]
Abstract
A small subset of pituitary adenomas grows despite maximal treatment with standard therapies; namely, surgery and radiotherapy. These aggressive tumors demonstrate 2 patterns of growth: they may be locally aggressive or metastasize distantly, either hematogenously or through the spinal fluid. Further surgery and radiotherapy may be helpful for palliation of symptoms, but they are rarely definitive in the management of these malignant tumors. The only chemotherapy with established activity in the treatment of pituitary tumors is the alkylating agent temozolomide. At most, 50% of patients exhibit an objective response to temozolomide and the median time to progression is short; thus, there remains a significant unmet need for effective treatments within this patient population. Several targeted agents have reported activity in this tumor type-including small molecule inhibitors, checkpoint inhibitors, and other biologics-but remain investigational at this time.
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Affiliation(s)
- Andrew L Lin
- Department of Neurology, Memorial Sloan Kettering Cancer Center, New York, New York
- Department of Neurosurgery, Memorial Sloan Kettering Cancer Center, New York, New York
- Multidisciplinary Pituitary and Skull Base Center, Memorial Sloan Kettering Cancer Center, New York, New York
- Correspondence and Reprint Requests: Andrew Lin, Memorial Sloan Kettering Cancer Center, 1275 York Ave, New York, NY 10065, USA. E-mail:
| | - Mark T A Donoghue
- Center for Molecular Oncology, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Sharon L Wardlaw
- Department of Medicine, Columbia University Medical Center, New York, New York
| | - T Jonathan Yang
- Department of Radiation Oncology, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Lisa Bodei
- Department of Radiology, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Viviane Tabar
- Department of Neurosurgery, Memorial Sloan Kettering Cancer Center, New York, New York
- Multidisciplinary Pituitary and Skull Base Center, Memorial Sloan Kettering Cancer Center, New York, New York
- Program in Cell Biology and Genetics, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Eliza B Geer
- Department of Neurosurgery, Memorial Sloan Kettering Cancer Center, New York, New York
- Multidisciplinary Pituitary and Skull Base Center, Memorial Sloan Kettering Cancer Center, New York, New York
- Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York
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Abstract
A subset of pituitary tumors present an aggressive behavior that remains difficult to predict, and in rare cases they metastasize. The current European Society for Endocrinology (ESE) guidelines for the management of aggressive pituitary tumors and carcinomas provide valuable guidance, but several issues remain unaddressed because of the scarcity of data in the literature. This article presents key clinical aspects regarding aggressive pituitary tumors and carcinomas, and also discusses some of the unanswered questions of the ESE guidelines, focusing on both diagnosis and treatment.
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Affiliation(s)
- Mirela Diana Ilie
- Endocrinology Department VI, "C.I.Parhon" National Institute of Endocrinology, 34-36 Aviatorilor Boulevard, Bucharest 011863, Romania. https://twitter.com/the_hormone_doc
| | - Emmanuel Jouanneau
- Neurosurgery Department, Reference Center for Rare Pituitary Diseases HYPO, "Groupement Hospitalier Est" Hospices Civils de Lyon, "Claude Bernard" Lyon 1 University, Hôpital Pierre Wertheimer, 59 Pinel Boulevard, Lyon, Bron 69677, France
| | - Gérald Raverot
- Endocrinology Department, Reference Center for Rare Pituitary Diseases HYPO, "Groupement Hospitalier Est" Hospices Civils de Lyon, "Claude Bernard" Lyon 1 University, Hôpital Louis Pradel, 59 Pinel Boulevard, Lyon, Bron 69677, France.
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Marques P, Grossman AB, Korbonits M. The tumour microenvironment of pituitary neuroendocrine tumours. Front Neuroendocrinol 2020; 58:100852. [PMID: 32553750 DOI: 10.1016/j.yfrne.2020.100852] [Citation(s) in RCA: 25] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/07/2020] [Revised: 05/26/2020] [Accepted: 06/02/2020] [Indexed: 02/06/2023]
Abstract
The tumour microenvironment (TME) includes a variety of non-neoplastic cells and non-cellular elements such as cytokines, growth factors and enzymes surrounding tumour cells. The TME emerged as a key modulator of tumour initiation, progression and invasion, with extensive data available in many cancers, but little is known in pituitary tumours. However, the understanding of the TME of pituitary tumours has advanced thanks to active research in this field over the last decade. Different immune and stromal cell subpopulations, and several cytokines, growth factors and matrix remodelling enzymes, have been characterised in pituitary tumours. Studying the TME in pituitary tumours may lead to a better understanding of tumourigenic mechanisms, identification of biomarkers useful to predict aggressive disease, and development of novel therapies. This review summarises the current knowledge on the different TME cellular/non-cellular elements in pituitary tumours and provides an overview of their role in tumourigenesis, biological behaviour and clinical outcomes.
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Affiliation(s)
- Pedro Marques
- Centre for Endocrinology, William Harvey Research Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, UK.
| | - Ashley B Grossman
- Centre for Endocrinology, William Harvey Research Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, UK.
| | - Márta Korbonits
- Centre for Endocrinology, William Harvey Research Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, UK.
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Petersenn S, Heaney AP. Targeted systemic and peptide radio-ligand therapy for aggressive pituitary tumors and carcinomas. Rev Endocr Metab Disord 2020; 21:277-286. [PMID: 32415583 DOI: 10.1007/s11154-020-09554-9] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Aggressive pituitary tumors comprise a rare but challenging subset of pituitary tumors. A major issue currently is the absence of a holistic definition that reliably identifies these tumors in a prospective manner. Although comprehensive evaluation of patient gender, age, local invasiveness, treatment responses, radiological and histopathological features may be informative to assess the potential for aggressiveness, a definitive diagnosis of this entity cannot be confidently made until disease progression is actually observed despite standard medical and surgical therapy. Failure to diagnose these aggressive pituitary tumors early may impede initiation of suitable intensive stepwise multimodal treatments, and lessen their ultimate therapeutic success. Even though current therapeutic options for aggressive pituitary tumors are suboptimal in many cases, large-scale randomized prospective clinic trials are impractical and will likely never be conducted due to the rarity of this disease entity. Therefore, the majority of novel therapies in this subset of tumors derive from case reports or small case series, which greatly reduces their validity to make strong recommendations. This chapter, as part of this series on aggressive pituitary tumors, focuses on the role of systemic targeted medical and peptide radio-receptor therapy in treatment of aggressive pituitary tumors and carcinomas, and discusses future directions in these fields.
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Affiliation(s)
- Stephan Petersenn
- Departments of Medicine, ENDOC Center for Endocrine Tumors, Hamburg, Germany
| | - Anthony P Heaney
- Departments of Medicine & Neurosurgery (1&2), University of California, Los Angeles, USA.
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Xu L, Khaddour K, Chen J, Rich KM, Perrin RJ, Campian JL. Pituitary carcinoma: Two case reports and review of literature. World J Clin Oncol 2020; 11:91-102. [PMID: 32133278 PMCID: PMC7046923 DOI: 10.5306/wjco.v11.i2.91] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/23/2019] [Revised: 12/11/2019] [Accepted: 12/15/2019] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Pituitary carcinoma is a rare type of malignancy that can be very difficult to diagnose and treat. Many cases were diagnosed at autopsy. Delays in diagnosis often adversely impact patients' outcomes. Even with prompt diagnosis, treatment decisions remain challenging in the absence of randomized controlled trials.
CASE SUMMARY We report two cases of pituitary carcinoma in men with a history of pituitary adenoma. In the first case, a 55-year-old man was initially diagnosed with pituitary macroadenoma. He underwent subtotal debulking of the tumor followed by adjuvant radiotherapy. Subsequently, he developed relapsed disease and multifocal intracranial metastases and a diagnosis of pituitary carcinoma was rendered. He passed away despite several lines of systemic therapies including temozolomide, lomustine and bevacizumab. Another 52-year-old man was diagnosed with atypical pituitary adenoma with presentation of sudden onset of vision loss in the right eye. He had recurrent pituitary carcinoma with spinal metastases, treated with surgery, radiation and temozolomide.
CONCLUSION Pituitary carcinoma is a rare neoplasm with poor prognosis that is difficult to diagnose and treat. The small number of cases restricts our ability to design randomized clinical trials. Management is largely driven by retrospective studies and case series. Establishing molecular biomarkers and comprehensive genomic profiling could help in decisions about diagnosis and management of pituitary carcinoma.
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Affiliation(s)
- Lai Xu
- Divisions of Hematology and Oncology, Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110, United States
| | - Karam Khaddour
- Divisions of Hematology and Oncology, Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110, United States
| | - Jie Chen
- Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110, United States
| | - Keith M Rich
- Department of Neurological Surgery, Washington University School of Medicine, St. Louis, MO 63110, United States
| | - Richard J Perrin
- Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110, United States
| | - Jian Li Campian
- Divisions of Hematology and Oncology, Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110, United States
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Abstract
PURPOSE Aggressive prolactinomas are defined as radiologically invasive tumors which cannot be cured by surgery, and that have an unusually rapid rate of tumor growth despite dopamine agonist treatment and surgery. In some cases, metastasis occurs, defining prolactin carcinoma which is the second most frequent pituitary carcinoma. METHODS A literature search was performed to review the available data on the treatment of aggressive pituitary prolactinomas or carcinomas. RESULTS When optimal standard therapies (high dose cabergoline, surgery and radiotherapy) failed, temozolomide, an alkylating drug, is currently the best option, allowing to control tumor growth in about 50% of treated prolactinomas and improving overall survival of these patients. However, long-term complete response occurs in a limited subgroup of tumors. Alternative drugs could be discussed in a subset of aggressive prolactinomas either before temozolomide (pasireotide, peptide receptor radionuclide therapy…) or after temozolomide failure. CONCLUSION Despite the significant improvement obtained with the use of temozolomide, a need for alternative drugs persists since a majority of these tumors are resistant or will recur during the follow-up. Patients suffering from such a rare condition should have access to clinical trials available for other types of rare cancers, such as tyrosine kinase inhibitors or immunotherapy.
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Affiliation(s)
- Hélène Lasolle
- INSERM U1052, CNRS UMR5286, Cancer Research Center of Lyon, 69008, Lyon, Auvergne-Rhône-Alpes, France
- Lyon 1 University, 69100, Villeurbanne, Auvergne-Rhône-Alpes, France
- Endocrinology Department, Reference Center for Rare Pituitary Diseases HYPO, "Groupement Hospitalier Est" Hospices Civils de Lyon, Auvergne-Rhône-Alpes, 69677, Bron, France
| | - Mirela Diana Ilie
- Endocrinology Department, "C.I.Parhon" National Institute of Endocrinology, 011863, Bucharest, Bucharest-Ilfov, Romania
| | - Gérald Raverot
- INSERM U1052, CNRS UMR5286, Cancer Research Center of Lyon, 69008, Lyon, Auvergne-Rhône-Alpes, France.
- Lyon 1 University, 69100, Villeurbanne, Auvergne-Rhône-Alpes, France.
- Endocrinology Department, Reference Center for Rare Pituitary Diseases HYPO, "Groupement Hospitalier Est" Hospices Civils de Lyon, Auvergne-Rhône-Alpes, 69677, Bron, France.
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Abstract
Consensus guidelines recommend dopamine agonists (DAs) as the mainstay treatment for prolactinomas. In most patients, DAs achieve tumor shrinkage and normoprolactinemia at well tolerated doses. However, primary or, less often, secondary resistance to DAs may be also encountered representing challenging clinical scenarios. This is particularly true for aggressive prolactinomas in which surgery and radiotherapy may not achieve tumor control. In these cases, alternative medical treatments have been considered but data on their efficacy should be interpreted within the constraints of publication bias and of lack of relevant clinical trials. The limited reports on somatostatin analogues have shown conflicting results, but cases with optimal outcomes have been documented. Data on estrogen modulators and metformin are scarce and their usefulness remains to be evaluated. In many aggressive lactotroph tumors, temozolomide has demonstrated optimal outcomes, whereas for other cytotoxic agents, tyrosine kinase inhibitors and for inhibitors of mammalian target of rapamycin (mTOR), higher quality evidence is needed. Finally, promising preliminary results from in vitro and animal reports need to be further assessed and, if appropriate, translated in human studies.
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Affiliation(s)
- P Souteiro
- Department of Endocrinology, Diabetes and Metabolism, Centro Hospitalar Universitário de São João, Porto, Portugal
- Faculty of Medicine of University of Porto, Porto, Portugal
- Instituto de Investigação e Inovação em Saúde, University of Porto, Porto, Portugal
- Institute of Metabolism and Systems Research (IMSR), College of Medical and Dental Sciences, University of Birmingham, IBR Tower, Level 2, Birmingham, B15 2TT, UK
- Centre for Endocrinology, Diabetes and Metabolism, Birmingham Health Partners, Birmingham, UK
- Department of Endocrinology, Queen Elizabeth Hospital, University Hospitals Birmingham NHS Foundation Trust, Birmingham, UK
| | - N Karavitaki
- Institute of Metabolism and Systems Research (IMSR), College of Medical and Dental Sciences, University of Birmingham, IBR Tower, Level 2, Birmingham, B15 2TT, UK.
- Centre for Endocrinology, Diabetes and Metabolism, Birmingham Health Partners, Birmingham, UK.
- Department of Endocrinology, Queen Elizabeth Hospital, University Hospitals Birmingham NHS Foundation Trust, Birmingham, UK.
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Lamb LS, Sim HW, McCormack AI. Exploring the Role of Novel Medical Therapies for Aggressive Pituitary Tumors: A Review of the Literature-"Are We There Yet?". Cancers (Basel) 2020; 12:cancers12020308. [PMID: 32012988 PMCID: PMC7072681 DOI: 10.3390/cancers12020308] [Citation(s) in RCA: 27] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2020] [Accepted: 01/22/2020] [Indexed: 12/14/2022] Open
Abstract
Aggressive pituitary tumors account for up to 10% of pituitary tumors and are characterized by resistance to medical treatment and multiple recurrences despite standard therapies, including surgery, radiotherapy, and chemotherapy. They are associated with increased morbidity and mortality, particularly pituitary carcinomas, which have mortality rates of up to 66% at 1 year after diagnosis. Novel targeted therapies under investigation include mammalian target of rapamycin (mTOR), tyrosine kinase, and vascular endothelial growth factor (VEGF) inhibitors. More recently, immune checkpoint inhibitors have been proposed as a potential treatment option for pituitary tumors. An increased understanding of the molecular pathogenesis of aggressive pituitary tumors is required to identify potential biomarkers and therapeutic targets. This review discusses novel approaches to the management of aggressive pituitary tumors and the role of molecular profiling.
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Affiliation(s)
- Lydia S. Lamb
- Department of Endocrinology, St Vincent’s Hospital, Sydney, NSW 2010, Australia;
- Garvan Institute of Medical Research, Sydney, NSW 2010, Australia;
| | - Hao-Wen Sim
- Garvan Institute of Medical Research, Sydney, NSW 2010, Australia;
- St Vincent’s Clinical School, University of New South Wales, Sydney, NSW 2010, Australia
- Kinghorn Cancer Centre, Sydney, NSW 2010, Australia
| | - Ann I. McCormack
- Department of Endocrinology, St Vincent’s Hospital, Sydney, NSW 2010, Australia;
- Garvan Institute of Medical Research, Sydney, NSW 2010, Australia;
- St Vincent’s Clinical School, University of New South Wales, Sydney, NSW 2010, Australia
- Correspondence: ; Tel.: +61-2-9295-8489
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Wang X, Fang Y, Zhou Y, Guo X, Xu K, Li C, Zhang J, Hong Y. SDF-1α/MicroRNA-134 Axis Regulates Nonfunctioning Pituitary Neuroendocrine Tumor Growth via Targeting VEGFA. Front Endocrinol (Lausanne) 2020; 11:566761. [PMID: 33362712 PMCID: PMC7756115 DOI: 10.3389/fendo.2020.566761] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/28/2020] [Accepted: 11/09/2020] [Indexed: 12/28/2022] Open
Abstract
BACKGROUND Nonfunctioning pituitary neuroendocrine tumor (NF-PitNET) is difficult to resect. Except for surgery, there is no effective treatment for NF-PitNET. MicroRNA-134 (miR-134) has been reported to inhibit proliferation and invasion ability of tumor cells. Herein, the mechanism underlying the effect of miR-134 on alleviating NF-PitNET tumor cells growth is explored. METHODS Mouse pituitary αT3-1 cells were transfected with miR-134 mimics and inhibitor, followed by treatment with stromal cell-derived factor-1α (SDF-1α) in vitro. MiR-134 expression level: we used quantitative real-time PCR (qRT-PCR) to detect the expression of miR-134. Cell behavior level: cell viability and invasion ability were assessed using a cell counting kit-8 (CCK8) assay and Transwell invasion assay respectively. Cytomolecular level: tumor cell proliferation was evaluated by Ki-67 staining; propidium iodide (PI) staining analyzed the effect of miR-134 on cell cycle arrest; western blot analysis and immunofluorescence staining evaluated tumor migration and invasive ability. Additionally, we collected 27 NF-PitNET tumor specimens and related clinical data. The specimens were subjected to qRT-PCR to obtain the relative miR-134 expression level of each specimen; linear regression analysis was used to analyze the miR-134 expression level in tumor specimens and the age of the NF-PitNET population, gender, tumor invasion, prognosis, and other indicators. RESULTS In vitro experiment, miR-134 was observed to significantly inhibit αT3-1 cells proliferation characterized by inhibited cell viability and expressions of vascular endothelial growth factor A (VEGFA) and cell cycle transition from G1 to S phase (P < 0.01). VEGFA was verified as a target of miR-134. Additionally, miR-134-induced inhibition of αT3-1 cell proliferation and invasion was attenuated by SDF-1α and VEGFA overexpression (P < 0.01). In primary NF-PitNET tumor analysis, miR-134 expression level was negatively correlated with tumor invasion (P = 0.003). CONCLUSION The regulation of the SDF-1α/miR-134/VEGFA axis represents a novel mechanism in the pathogenesis of NF-PitNETs and may serve as a potential therapeutic target for the treatment of NF-PitNETs.
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Affiliation(s)
- Xiaoyu Wang
- Department of Neurosurgery, The Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China
| | - Yuanjian Fang
- Department of Neurosurgery, The Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China
| | - Yunxiang Zhou
- Department of Surgical Oncology, The Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China
| | - Xiaoming Guo
- Department of Neurosurgery, The Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China
| | - Ke Xu
- Department of Neurosurgery, The Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China
| | - Chenguang Li
- Department of Neurosurgery, The Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China
| | - Jianmin Zhang
- Department of Neurosurgery, The Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China
- Brain Research Institute, Zhejiang University, Hangzhou, Zhejiang, China
- Collaborative Innovation Center for Brain Science, Zhejiang University, Hangzhou, Zhejiang, China
- *Correspondence: Jianmin Zhang, ; Yuan Hong,
| | - Yuan Hong
- Department of Neurosurgery, The Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China
- *Correspondence: Jianmin Zhang, ; Yuan Hong,
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Lamb LS, Sim HW, McCormack AI. Case Report: A Case of Pituitary Carcinoma Treated With Sequential Dual Immunotherapy and Vascular Endothelial Growth Factor Inhibition Therapy. Front Endocrinol (Lausanne) 2020; 11:576027. [PMID: 33312158 PMCID: PMC7708326 DOI: 10.3389/fendo.2020.576027] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/25/2020] [Accepted: 10/19/2020] [Indexed: 12/18/2022] Open
Abstract
Aggressive pituitary tumors (APTs) are associated with significant morbidity and mortality, and effective treatment options are limited. Immune checkpoint inhibitors (ICIs) have revolutionized clinical cancer care; however, there is little experience with these agents in the management of APTs. Vascular endothelial growth factor (VEGF) targeted therapy has reported success in a small number of APT case reports. Here we describe a case of pituitary carcinoma responding to ICI therapy and subsequently VEGF inhibition. We discuss the possible mechanisms and experience with ICI therapy and VEGF inhibitors in the management of APTs, biomarkers that may predict response, and the potential role of combination therapies including ICIs and temozolomide.
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Affiliation(s)
- Lydia S. Lamb
- Garvan Institute of Medical Research, Sydney, NSW, Australia
- St Vincent’s Clinical School, University of New South Wales, Sydney, NSW, Australia
| | - Hao-Wen Sim
- St Vincent’s Clinical School, University of New South Wales, Sydney, NSW, Australia
- The Kinghorn Cancer Centre, Sydney, NSW, Australia
| | - Ann I. McCormack
- Garvan Institute of Medical Research, Sydney, NSW, Australia
- St Vincent’s Clinical School, University of New South Wales, Sydney, NSW, Australia
- Department of Endocrinology, St Vincent’s Hospital, Sydney, NSW, Australia
- *Correspondence: Ann I. McCormack,
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Serioli S, Doglietto F, Fiorindi A, Biroli A, Mattavelli D, Buffoli B, Ferrari M, Cornali C, Rodella L, Maroldi R, Gasparotti R, Nicolai P, Fontanella MM, Poliani PL. Pituitary Adenomas and Invasiveness from Anatomo-Surgical, Radiological, and Histological Perspectives: A Systematic Literature Review. Cancers (Basel) 2019; 11:E1936. [PMID: 31817110 PMCID: PMC6966643 DOI: 10.3390/cancers11121936] [Citation(s) in RCA: 43] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2019] [Revised: 11/27/2019] [Accepted: 11/28/2019] [Indexed: 12/20/2022] Open
Abstract
Invasiveness in pituitary adenomas has been defined and investigated from multiple perspectives, with varying results when its predictive value is considered. A systematic literature review, following PRISMA guidelines, was performed, searching PubMed and Scopus databases with terms that included molecular markers, histological, radiological, anatomical and surgical data on invasiveness of pituitary adenomas. The results showed that differing views are still present for anatomical aspects of the sellar region that are relevant to the concept of invasiveness; radiological and histological diagnoses are still limited, but might improve in the future, especially if they are related to surgical findings, which have become more accurate thanks to the introduction of the endoscope. The aim is to achieve a correct distinction between truly invasive pituitary adenomas from those that, in contrast, present with extension in the parasellar area through natural pathways. At present, diagnosis of invasiveness should be based on a comprehensive analysis of radiological, intra-operative and histological findings.
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Affiliation(s)
- Simona Serioli
- Neurosurgery, Department of Surgical Specialties, Radiological Sciences and Public Health, University of Brescia, 25123 Brescia, Italy; (S.S.); (A.F.); (A.B.); (C.C.); (M.M.F.)
| | - Francesco Doglietto
- Neurosurgery, Department of Surgical Specialties, Radiological Sciences and Public Health, University of Brescia, 25123 Brescia, Italy; (S.S.); (A.F.); (A.B.); (C.C.); (M.M.F.)
- Neurosurgery, Spedali Civili Hospital, 25123 Brescia, Italy
| | - Alessandro Fiorindi
- Neurosurgery, Department of Surgical Specialties, Radiological Sciences and Public Health, University of Brescia, 25123 Brescia, Italy; (S.S.); (A.F.); (A.B.); (C.C.); (M.M.F.)
| | - Antonio Biroli
- Neurosurgery, Department of Surgical Specialties, Radiological Sciences and Public Health, University of Brescia, 25123 Brescia, Italy; (S.S.); (A.F.); (A.B.); (C.C.); (M.M.F.)
| | - Davide Mattavelli
- Otorhinolaryngology–Head and Neck Surgery, Department of Surgical Specialties, Radiological Sciences and Public Health, University of Brescia, 25123 Brescia, Italy; (D.M.); (M.F.); (P.N.)
| | - Barbara Buffoli
- Section of Anatomy and Physiopathology, Department of Clinical and Experimental Sciences, University of Brescia, 25123 Brescia, Italy; (B.B.); (L.R.)
| | - Marco Ferrari
- Otorhinolaryngology–Head and Neck Surgery, Department of Surgical Specialties, Radiological Sciences and Public Health, University of Brescia, 25123 Brescia, Italy; (D.M.); (M.F.); (P.N.)
| | - Claudio Cornali
- Neurosurgery, Department of Surgical Specialties, Radiological Sciences and Public Health, University of Brescia, 25123 Brescia, Italy; (S.S.); (A.F.); (A.B.); (C.C.); (M.M.F.)
- Neurosurgery, Spedali Civili Hospital, 25123 Brescia, Italy
| | - Luigi Rodella
- Section of Anatomy and Physiopathology, Department of Clinical and Experimental Sciences, University of Brescia, 25123 Brescia, Italy; (B.B.); (L.R.)
| | - Roberto Maroldi
- Radiology, Department of Surgical Specialties, Radiological Sciences and Public Health, University of Brescia, 25123 Brescia, Italy;
| | - Roberto Gasparotti
- Neuroradiology, Department of Surgical Specialties, Radiological Sciences and Public Health, University of Brescia, 25123 Brescia, Italy;
| | - Piero Nicolai
- Otorhinolaryngology–Head and Neck Surgery, Department of Surgical Specialties, Radiological Sciences and Public Health, University of Brescia, 25123 Brescia, Italy; (D.M.); (M.F.); (P.N.)
| | - Marco Maria Fontanella
- Neurosurgery, Department of Surgical Specialties, Radiological Sciences and Public Health, University of Brescia, 25123 Brescia, Italy; (S.S.); (A.F.); (A.B.); (C.C.); (M.M.F.)
- Neurosurgery, Spedali Civili Hospital, 25123 Brescia, Italy
| | - Pietro Luigi Poliani
- Section of Pathology, Department of Molecular and Translational Medicine, University of Brescia, 25123 Brescia, Italy
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Kontogeorgos G, Thodou E. Is MGMT the best marker to predict response of temozolomide in aggressive pituitary tumors? Alternative markers and prospective treatment modalities. Hormones (Athens) 2019; 18:333-337. [PMID: 31721137 DOI: 10.1007/s42000-019-00145-1] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/03/2019] [Accepted: 10/15/2019] [Indexed: 01/02/2023]
Affiliation(s)
- George Kontogeorgos
- First Propaedeutic Department of Internal Medicine, Laikon Hospital, National and Kapodistrian University of Athens, 75 Mikras Asias Str., Athens, 11527, Attica, Greece.
- Department of Pathology, "G. Gennimatas" Athens General Hospital, Athens, Greece.
| | - Eleni Thodou
- Department of Pathology, University of Thessaly, School of Medicine, Larissa, Greece
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Iglesias P, Magallón R, Mitjavila M, Rodríguez Berrocal V, Pian H, Díez JJ. Multimodal therapy in aggressive pituitary tumors. ACTA ACUST UNITED AC 2019; 67:469-485. [PMID: 31740190 DOI: 10.1016/j.endinu.2019.08.004] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/19/2019] [Revised: 07/19/2019] [Accepted: 08/01/2019] [Indexed: 01/09/2023]
Abstract
The concept of aggressive pituitary tumor (APT) has been precisely defined in recent years. These tumors are characterized by morphological (radiological or histopathological) data of invasion, proliferative activity superior to that of typical adenomas and a clinical behavior characterized by resistance to standard therapies and frequent recurrences. The absence of cerebrospinal or distant metastases differentiates them from the pituitary carcinoma. APTs account for about 10% of all pituitary neoplasm. Proper diagnostic implies participation not only of radiological and hormonal investigation but also a thorough pathological assessment including proliferation markers and immunohistochemistry for hormones and transcription factors. Surgical resection, aiming gross total resection or tumor debulking, is the mainstay initial therapy in most patients. Most patients with APTs need more than one surgical intervention, pituitary radiation, sometimes on more than one occasion, and multiple sequential or combined medical treatments, to finally be doomed to unusual treatments, such as alkylating agents (temozolomide alone or in combination), molecular targeted therapies, or peptide receptor radionuclide therapy. Multimodal therapy, implemented by experts, preferably in specialized centers with high volume caseload, is the only way to improve the prognosis of patients with these uncommon tumors. The research needs in this area are multiple and include a greater knowledge of the molecular biology of these tumors, establishment of protocols for monitoring and sequencing of treatments, development of multicenter studies and international registries.
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Affiliation(s)
- Pedro Iglesias
- Department of Endocrinology, Hospital Universitario Puerta de Hierro-Majadahonda, Madrid, Spain.
| | - Rosa Magallón
- Department of Radiation Oncology, Hospital Universitario Puerta de Hierro-Majadahonda, Madrid, Spain
| | - Mercedes Mitjavila
- Department of Nuclear Medicine, Hospital Universitario Puerta de Hierro-Majadahonda, Madrid, Spain
| | | | - Héctor Pian
- Department of Pathology, Hospital Universitario, Ramón y Cajal, Madrid, Spain
| | - Juan J Díez
- Department of Endocrinology, Hospital Universitario Puerta de Hierro-Majadahonda, Madrid, Spain
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Ilie MD, Vasiljevic A, Raverot G, Bertolino P. The Microenvironment of Pituitary Tumors-Biological and Therapeutic Implications. Cancers (Basel) 2019; 11:cancers11101605. [PMID: 31640258 PMCID: PMC6826349 DOI: 10.3390/cancers11101605] [Citation(s) in RCA: 43] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2019] [Revised: 10/16/2019] [Accepted: 10/17/2019] [Indexed: 02/07/2023] Open
Abstract
The tumor microenvironment (TME) includes resident and infiltrative non-tumor cells, as well as blood and lymph vessels, extracellular matrix molecules, and numerous soluble factors, such as cytokines and chemokines. While the TME is now considered to be a prognostic tool and a therapeutic target for many cancers, little is known about its composition in pituitary tumors. This review summarizes our current knowledge of the TME within pituitary tumors and the strong interest in TME as a therapeutic target. While we cover the importance of angiogenesis and immune infiltrating cells, we also address the role of the elusive folliculostellate cells, the emerging literature on pituitary tumor-associated fibroblasts, and the contribution of extracellular matrix components in these tumors. The cases of human pituitary tumors treated with TME-targeting therapies are reviewed and emerging concepts of vascular normalization and combined therapies are presented. Together, this snapshot overview of the current literature pinpoints not only the underestimated role of TME components in pituitary tumor biology, but also the major promise it may offer for both prognosis and targeted therapeutics.
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Affiliation(s)
- Mirela Diana Ilie
- Cancer Research Centre of Lyon (CRCL), INSERM U1052, CNRS UMR5286, Claude Bernard University, 69008 Lyon, France, (M.D.I.).
- "Claude Bernard" Lyon 1 University, University of Lyon, 69100 Villeurbanne, France.
- Endocrinology Department, "C.I.Parhon" National Institute of Endocrinology, 011863 Bucharest, Romania.
| | - Alexandre Vasiljevic
- Cancer Research Centre of Lyon (CRCL), INSERM U1052, CNRS UMR5286, Claude Bernard University, 69008 Lyon, France, (M.D.I.).
- "Claude Bernard" Lyon 1 University, University of Lyon, 69100 Villeurbanne, France.
- Pathology Department, "Groupement Hospitalier Est" Hospices Civils de Lyon, 69677 Bron, France.
| | - Gérald Raverot
- Cancer Research Centre of Lyon (CRCL), INSERM U1052, CNRS UMR5286, Claude Bernard University, 69008 Lyon, France, (M.D.I.).
- "Claude Bernard" Lyon 1 University, University of Lyon, 69100 Villeurbanne, France.
- Endocrinology Department, "Groupement Hospitalier Est" Hospices Civils de Lyon, 69677 Bron, France.
| | - Philippe Bertolino
- Cancer Research Centre of Lyon (CRCL), INSERM U1052, CNRS UMR5286, Claude Bernard University, 69008 Lyon, France, (M.D.I.).
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Wang Z, Gao L, Guo X, Feng C, Deng K, Lian W, Xing B. Identification of microRNAs associated with the aggressiveness of prolactin pituitary tumors using bioinformatic analysis. Oncol Rep 2019; 42:533-548. [PMID: 31173251 PMCID: PMC6609352 DOI: 10.3892/or.2019.7173] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2019] [Accepted: 05/23/2019] [Indexed: 12/14/2022] Open
Abstract
Aggressive prolactin pituitary tumors, which exhibit aggressive behaviors and resistance to conventional treatments, are a huge challenge for neurosurgeons. Many studies have investigated the roles of microRNAs (miRNAs) in pituitary tumorigenesis, invasion and metastasis, but few have explored aggressiveness‑associated miRNAs in aggressive pituitary tumors. Differentially expressed miRNAs (DEMs) between aggressive and nonaggressive prolactin pituitary tumors were screened using the GSE46294 miRNA expression profile downloaded from the GEO database. The potential target genes of the top three most highly upregulated and downregulated DEMs were predicted by miRTarBase, and potential functional annotation and pathway enrichment analysis were performed using the DAVID database. Protein‑protein interaction (PPI) and miRNA‑hub gene interaction networks were constructed by Cytoscape software. A total of 43 DEMs were identified, including 19 upregulated and 24 downregulated miRNAs, between aggressive and nonaggressive prolactin pituitary tumors. One hundred and seventy and 680 target genes were predicted for the top three most highly upregulated and downregulated miRNAs, respectively, and these genes were involved in functional enrichment pathways, such as regulation of transcription from RNA polymerase II promoter, DNA‑templated transcription, Wnt signaling pathway, protein binding, and transcription factor activity (sequence‑specific DNA binding). In the PPI network, the top 10 genes with the highest degree of connectivity of the upregulated and downregulated DEMs were selected as hub genes. By constructing an miRNA‑hub gene network, it was found that most hub genes were potentially modulated by hsa‑miR‑489 and hsa‑miR‑520b. Targeting hsa‑miR‑489 and hsa‑miR‑520b may provide new clues for the diagnosis and treatment of aggressive prolactin pituitary tumors.
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Affiliation(s)
- Zihao Wang
- Department of Neurosurgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Dongcheng, Beijing 100730, P.R. China
- China Pituitary Disease Registry Center, Chinese Pituitary Adenoma Cooperative Group, Dongcheng, Beijing 100730, P.R. China
| | - Lu Gao
- Department of Neurosurgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Dongcheng, Beijing 100730, P.R. China
- China Pituitary Disease Registry Center, Chinese Pituitary Adenoma Cooperative Group, Dongcheng, Beijing 100730, P.R. China
| | - Xiaopeng Guo
- Department of Neurosurgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Dongcheng, Beijing 100730, P.R. China
- China Pituitary Disease Registry Center, Chinese Pituitary Adenoma Cooperative Group, Dongcheng, Beijing 100730, P.R. China
| | - Chenzhe Feng
- Department of Neurosurgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Dongcheng, Beijing 100730, P.R. China
- China Pituitary Disease Registry Center, Chinese Pituitary Adenoma Cooperative Group, Dongcheng, Beijing 100730, P.R. China
| | - Kan Deng
- Department of Neurosurgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Dongcheng, Beijing 100730, P.R. China
- China Pituitary Disease Registry Center, Chinese Pituitary Adenoma Cooperative Group, Dongcheng, Beijing 100730, P.R. China
| | - Wei Lian
- Department of Neurosurgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Dongcheng, Beijing 100730, P.R. China
- China Pituitary Disease Registry Center, Chinese Pituitary Adenoma Cooperative Group, Dongcheng, Beijing 100730, P.R. China
| | - Bing Xing
- Department of Neurosurgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Dongcheng, Beijing 100730, P.R. China
- China Pituitary Disease Registry Center, Chinese Pituitary Adenoma Cooperative Group, Dongcheng, Beijing 100730, P.R. China
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Dutta P, Reddy KS, Rai A, Madugundu AK, Solanki HS, Bhansali A, Radotra BD, Kumar N, Collier D, Iacovazzo D, Gupta P, Raja R, Gowda H, Pandey A, Devgun JS, Korbonits M. Surgery, Octreotide, Temozolomide, Bevacizumab, Radiotherapy, and Pegvisomant Treatment of an AIP Mutation‒Positive Child. J Clin Endocrinol Metab 2019; 104:3539-3544. [PMID: 31125088 PMCID: PMC6619489 DOI: 10.1210/jc.2019-00432] [Citation(s) in RCA: 34] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/22/2019] [Accepted: 05/20/2019] [Indexed: 12/21/2022]
Abstract
CONTEXT Inactivating germline mutations in the aryl hydrocarbon receptor interacting protein (AIP) gene are linked to pituitary adenoma predisposition. Here, we present the youngest known patient with AIP-related pituitary adenoma. CASE DESCRIPTION The patient presented at the age of 4 years with pituitary apoplexy and left ptosis with severe visual loss following a 1-year history of abdominal pain, headaches, and rapid growth. His IGF-1 level was 5× the upper limit of normal, and his random GH level was 1200 ng/mL. MRI showed a 43 × 24 × 35‒mm adenoma with suprasellar extension invading the left cavernous sinus (Knosp grade 4). After transsphenoidal surgery, histology showed a grade 2A sparsely granulated somatotropinoma with negative O6-methylguanine-DNA methyltransferase and positive vascular endothelial growth factor staining. Genetic testing identified a heterozygous germline nonsense AIP mutation (p.Arg81Ter). Exome sequencing of the tumor revealed that it had lost the entire maternal chromosome-11, rendering it hemizygous for chromosome-11 and therefore lacking functional copies of AIP in the tumor. He was started on octreotide, but because the tumor rapidly regrew and IGF-1 levels were unchanged, temozolomide was initiated, and intensity-modulated radiotherapy was administered 5 months after surgery. Two months later, bevacizumab was added, resulting in excellent tumor response. Although these treatments stabilized tumor growth over 4 years, IGF-1 was normalized only after pegvisomant treatment, although access to this medication was intermittent. At 3.5 years of follow-up, gamma knife treatment was administered, and pegvisomant dose increase was indicated. CONCLUSION Multimodal treatment with surgery, long-acting octreotide, radiotherapy, temozolomide, bevacizumab, and pegvisomant can control genetically driven, aggressive, childhood-onset somatotropinomas.
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Affiliation(s)
- Pinaki Dutta
- Department of Endocrinology, Postgraduate Institution of Medical Education and Research, Chandigarh, India
| | - Kavita S Reddy
- Institute of Bioinformatics, International Tech Park, Bangalore, Karnataka, India
| | - Ashutosh Rai
- Department of Translational and Regenerative Medicine, Postgraduate Institution of Medical Education and Research, Chandigarh, India
| | - Anil K Madugundu
- Institute of Genetic Medicine, Division of Proteomics, Mayo Clinic, Rochester, Minnesota
- Manipal Academy of Higher Education, Manipal, Karnataka, India
- Center for Individualized Medicine and Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota
| | - Hitendra S Solanki
- Department of Translational and Regenerative Medicine, Postgraduate Institution of Medical Education and Research, Chandigarh, India
- School of Biotechnology, KIIT University, Bhubaneswar, India
| | - Anil Bhansali
- Department of Endocrinology, Postgraduate Institution of Medical Education and Research, Chandigarh, India
| | - Bishan D Radotra
- Department of Histopathology, Postgraduate Institution of Medical Education and Research, Chandigarh, India
| | - Narendra Kumar
- Department of Radiotherapy, Postgraduate Institution of Medical Education and Research, Chandigarh, India
| | - David Collier
- Centre for Endocrinology, William Harvey Research Institute, Barts and The London School of Medicine, Queen Mary University of London, London, United Kingdom
| | - Donato Iacovazzo
- Centre for Endocrinology, William Harvey Research Institute, Barts and The London School of Medicine, Queen Mary University of London, London, United Kingdom
| | | | - Remya Raja
- Department of Translational and Regenerative Medicine, Postgraduate Institution of Medical Education and Research, Chandigarh, India
| | - Harsha Gowda
- Department of Translational and Regenerative Medicine, Postgraduate Institution of Medical Education and Research, Chandigarh, India
| | - Akhilesh Pandey
- Institute of Genetic Medicine, Division of Proteomics, Mayo Clinic, Rochester, Minnesota
- Center for Individualized Medicine and Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota
| | - Jagtar Singh Devgun
- Department of Pathology, Maharishi Markandeshwar Institute of Medical Science and Research, Ambala, Haryana, India
| | - Márta Korbonits
- Centre for Endocrinology, William Harvey Research Institute, Barts and The London School of Medicine, Queen Mary University of London, London, United Kingdom
- Correspondence and Reprint Requests: Márta Korbonits, MD, PhD Centre for of Endocrinology, William Harvey Research Institute, Barts and The London School of Medicine, Queen Mary University of London, Charterhouse Square, London EC1M 6BQ, United Kingdom. E-mail:
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Ilie MD, Lasolle H, Raverot G. Emerging and Novel Treatments for Pituitary Tumors. J Clin Med 2019; 8:jcm8081107. [PMID: 31349718 PMCID: PMC6723109 DOI: 10.3390/jcm8081107] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2019] [Revised: 07/21/2019] [Accepted: 07/23/2019] [Indexed: 02/06/2023] Open
Abstract
A subset of pituitary neuroendocrine tumors (PitNETs) have an aggressive behavior, showing resistance to treatment and/or multiple recurrences in spite of the optimal use of standard therapies (surgery, conventional medical treatments, and radiotherapy). To date, for aggressive PitNETs, temozolomide (TMZ) has been the most used therapeutic option, and has resulted in an improvement in the five-year survival rate in responders. However, given the fact that roughly only one third of patients showed a partial or complete radiological response on the first course of TMZ, and even fewer patients responded to a second course of TMZ, other treatment options are urgently needed. Emerging therapies consist predominantly of peptide receptor radionuclide therapy (20 cases), vascular endothelial growth factor receptor-targeted therapy (12 cases), tyrosine kinase inhibitors (10 cases), mammalian target of rapamycin (mTOR) inhibitors (six cases), and more recently, immune checkpoint inhibitors (one case). Here, we present the available clinical cases published in the literature for each of these treatments. The therapies that currently show the most promise (based on the achievement of partial radiological response in a certain number of cases) are immune checkpoint inhibitors, peptide receptor radionuclide therapy, and vascular endothelial growth factor receptor-targeted therapy. In the future, further improvement of these therapies and the development of other novel therapies, their use in personalized medicine, and a better understanding of combination therapies, will hopefully result in better outcomes for patients bearing aggressive PitNETs.
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Affiliation(s)
- Mirela Diana Ilie
- INSERM U1052, CNRS UMR5286, Cancer Research Center of Lyon, 28 Laennec Street, 69008 Lyon, France
- "Claude Bernard" Lyon 1 University, University of Lyon, 43 "11 Novembre 1918" Boulevard, 69100 Villeurbanne, France
- Endocrinology Department, "C.I.Parhon" National Institute of Endocrinology, 34-36 Aviatorilor Boulevard, 011863 Bucharest, Romania
| | - Hélène Lasolle
- INSERM U1052, CNRS UMR5286, Cancer Research Center of Lyon, 28 Laennec Street, 69008 Lyon, France
- "Claude Bernard" Lyon 1 University, University of Lyon, 43 "11 Novembre 1918" Boulevard, 69100 Villeurbanne, France
- "Groupement Hospitalier Est" Hospices Civils de Lyon, Endocrinology Department, Reference Center for Rare Pituitary Diseases HYPO, 59 Pinel Boulevard, 69677 Bron, France
| | - Gérald Raverot
- INSERM U1052, CNRS UMR5286, Cancer Research Center of Lyon, 28 Laennec Street, 69008 Lyon, France.
- "Claude Bernard" Lyon 1 University, University of Lyon, 43 "11 Novembre 1918" Boulevard, 69100 Villeurbanne, France.
- "Groupement Hospitalier Est" Hospices Civils de Lyon, Endocrinology Department, Reference Center for Rare Pituitary Diseases HYPO, 59 Pinel Boulevard, 69677 Bron, France.
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Rotman LE, Vaughan TB, Hackney JR, Riley KO. Long-Term Survival After Transformation of an Adrenocorticotropic Hormone–Secreting Pituitary Macroadenoma to a Silent Corticotroph Pituitary Carcinoma. World Neurosurg 2019; 122:417-423. [PMID: 30447452 DOI: 10.1016/j.wneu.2018.11.011] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2018] [Revised: 10/31/2018] [Accepted: 11/02/2018] [Indexed: 10/27/2022]
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Wang Y, He Q, Meng X, Zhou S, Zhu Y, Xu J, Tao R. Apatinib (YN968D1) and temozolomide in recurrent invasive pituitary adenoma: case report and literature review. World Neurosurg 2019; 124:319-322. [PMID: 30639490 DOI: 10.1016/j.wneu.2018.12.174] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2018] [Revised: 12/19/2018] [Accepted: 12/20/2018] [Indexed: 11/27/2022]
Abstract
BACKGROUND Invasive pituitary adenomas often recurred after postoperative radiotherapy and are difficult to treat. Temozolomide (TMZ) is an alkylating cytostaticum and has been reported to reduce pituitary tumor size and hormone hypersecretion, However, this is far from enough. Pituitary adenomas have relatively high expression of vascular endothelial growth factor. Therefore, antiangiogenic agent has been used in a small number of aggressive or malignant pituitary tumors after recurrence. Apatinib (YN968D1) is a small-molecule antiangiogenic agent that selectively inhibits VEGFR-2 and also mildly inhibits c-Kit and c-Src tyrosine kinases, abundant in invasive pituitary adenomas. CASE PRESENTATION present a 41-year-old female with a growth hormone (GH)-secreting invasive pituitary adenoma causing menstrual disorder and headache symptoms. Over three years, she underwent four surgeries and a stereotactic radiosurgery, but the results were poor. Two months after the fourth operation, she started treatment with temozolomide (200mg/m2, d1-5, 28d, orally) and apatinib (0.425g, daily, orally). Her GH level dropped to normal with a >90% decrease in tumor size, after 1-year treatment. There was no evidence of recurrence by imaging or by serum GH levels over 31.5 months of follow-up. CONCLUSION we successfully treated this patient with recurrent invasive pituitary adenoma with temozolomide and apatinib for 31.5 months without recurrence. Angiogenesis is an active process in the cases of invasive pituitary adenomas that cannot be controlled by conventional therapy.
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Affiliation(s)
- Yong Wang
- Department of Neurosurgery, Shandong Cancer Hospital affiliated to Shandong University, Shandong Academy of Medical Sciences, No.440. Jiyan Road, Jinan, 250117, China.
| | - Qiaowei He
- Department of Neurosurgery, Qingdao University affiliated Yantai Yuhuangding Hospital, No.20 Road yuhuangding. Yantai, 264000, China.
| | - Xiangji Meng
- Department of Neurosurgery, Shandong Cancer Hospital affiliated to Shandong University, Shandong Academy of Medical Sciences, No.440. Jiyan Road, Jinan, 250117, China.
| | - Shizhen Zhou
- Department of Neurosurgery, Shandong Cancer Hospital affiliated to Shandong University, Shandong Academy of Medical Sciences, No.440. Jiyan Road, Jinan, 250117, China.
| | - Yufang Zhu
- Department of Neurosurgery, Shandong Cancer Hospital affiliated to Shandong University, Shandong Academy of Medical Sciences, No.440. Jiyan Road, Jinan, 250117, China.
| | - Jun Xu
- Department of Neurosurgery, Shandong Cancer Hospital affiliated to Shandong University, Shandong Academy of Medical Sciences, No.440. Jiyan Road, Jinan, 250117, China.
| | - Rongjie Tao
- Department of Neurosurgery, Shandong Cancer Hospital affiliated to Shandong University, Shandong Academy of Medical Sciences, No.440. Jiyan Road, Jinan, 250117, China.
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Zubeldía-Brenner L, De Winne C, Perrone S, Rodríguez-Seguí SA, Willems C, Ornstein AM, Lacau-Mengido I, Vankelecom H, Cristina C, Becu-Villalobos D. Inhibition of Notch signaling attenuates pituitary adenoma growth in Nude mice. Endocr Relat Cancer 2019; 26:13-29. [PMID: 30121620 DOI: 10.1530/erc-18-0337] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/24/2018] [Accepted: 08/08/2018] [Indexed: 12/16/2022]
Abstract
Preclinical and clinical studies support that Notch signaling may play an important oncogenic role in cancer, but there is scarce information for pituitary tumors. We therefore undertook a functional study to evaluate Notch participation in pituitary adenoma growth. Tumors generated in Nude mice by subcutaneous GH3 somatolactotrope cell injection were treated in vivo with DAPT, a γ-secretase inhibitor, thus inactivating Notch signaling. This treatment led to pituitary tumor reduction, lower prolactin and GH tumor content and a decrease in angiogenesis. Furthermore, in silico transcriptomic and epigenomic analyses uncovered several tumor suppressor genes related to Notch signaling in pituitary tissue, namely Btg2, Nr4a1, Men1, Zfp36 and Cnot1. Gene evaluation suggested that Btg2, Nr4a1 and Cnot1 may be possible players in GH3 xenograft growth. Btg2 mRNA expression was lower in GH3 tumors compared to the parental line, and DAPT increased its expression levels in the tumor in parallel with the inhibition of its volume. Cnot1 mRNA levels were also increased in the pituitary xenografts by DAPT treatment. And the Nr4a1 gene was lower in tumors compared to the parental line, though not modified by DAPT. Finally, because DAPT in vivo may also be acting on tumor microenvironment, we determined the direct effect of DAPT on GH3 cells in vitro. We found that DAPT decreases the proliferative, secretory and migration potential of GH3 cells. These results position selective interruption of Notch signaling as a potential therapeutic tool in adjuvant treatments for aggressive or resistant pituitary tumors.
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Affiliation(s)
| | - Catalina De Winne
- Instituto de Biología y Medicina Experimental, IBYME-CONICET, Buenos Aires, Argentina
| | - Sofía Perrone
- Centro de Investigaciones y Transferencia del Noroeste de la Provincia de Buenos Aires, CITNOBA (UNNOBA-CONICET), Universidad Nacional del Noroeste de la Provincia de Buenos Aires, Buenos Aires, Argentina
| | - Santiago A Rodríguez-Seguí
- Departamento de Fisiología y Biología Molecular y Celular, Universidad de Buenos Aires, Facultad de Ciencias Exactas y Naturales, Buenos Aires, Argentina
- CONICET-Universidad de Buenos Aires, Instituto de Fisiología, Biología Molecular y Neurociencias (IFIBYNE), Buenos Aires, Argentina
| | - Christophe Willems
- Department of Development and Regeneration, Cluster Stem Cell and Developmental Biology, Unit of Stem Cell Research, KU Leuven (University of Leuven), Leuven, Belgium
| | - Ana María Ornstein
- Instituto de Biología y Medicina Experimental, IBYME-CONICET, Buenos Aires, Argentina
| | - Isabel Lacau-Mengido
- Instituto de Biología y Medicina Experimental, IBYME-CONICET, Buenos Aires, Argentina
| | - Hugo Vankelecom
- Department of Development and Regeneration, Cluster Stem Cell and Developmental Biology, Unit of Stem Cell Research, KU Leuven (University of Leuven), Leuven, Belgium
| | - Carolina Cristina
- Centro de Investigaciones y Transferencia del Noroeste de la Provincia de Buenos Aires, CITNOBA (UNNOBA-CONICET), Universidad Nacional del Noroeste de la Provincia de Buenos Aires, Buenos Aires, Argentina
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47
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Dai C, Liu X, Ma W, Wang R. The Treatment of Refractory Pituitary Adenomas. Front Endocrinol (Lausanne) 2019; 10:334. [PMID: 31191457 PMCID: PMC6548863 DOI: 10.3389/fendo.2019.00334] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/27/2018] [Accepted: 05/09/2019] [Indexed: 12/22/2022] Open
Abstract
Refractory pituitary adenomas (PAs) are defined as aggressive-invasive PAs characterized by a high Ki-67 index, rapid growth, frequent recurrence, and resistance to conventional treatments. It is notoriously difficult to manage refractory PAs because the efficacy of current therapeutic options is limited. The purpose of this review is to address currently employed and promising therapeutic strategies for the treatment of refractory PAs. Except for prolactinomas, neurosurgery is the first-line option, but most refractory PAs often recur or re-grow after initial surgery and require further treatments. Medical therapy, radiotherapy and re-operation are explored when surgery has failed to completely resect tumors; however, refractory PAs are usually resistant to these treatments. As a salvage treatment, temozolomide (TMZ) has shown promising results and is currently used for all types of refractory PAs. However, not all refractory PAs are responsive to TMZ treatment, and some of these PAs are resistant to TMZ. Although targeted therapies such as vascular endothelial growth factor, epidermal growth factor and mTOR inhibitors have also been used to treat refractory PAs, the effectiveness of these targeted therapies is still not known due to a lack of data from randomized prospective trials. As a novel therapeutic method, cancer immunotherapy is a promising strategy for the treatment of refractory PAs, but further preclinical research and clinical trials are needed to assess the efficacy of this new approach. In summary, early identification and a multidisciplinary approach are required to treat refractory PAs.
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Trouillas J, Delgrange E, Wierinckx A, Vasiljevic A, Jouanneau E, Burman P, Raverot G. Clinical, Pathological, and Molecular Factors of Aggressiveness in Lactotroph Tumours. Neuroendocrinology 2019; 109:70-76. [PMID: 30943495 DOI: 10.1159/000499382] [Citation(s) in RCA: 47] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/29/2019] [Accepted: 03/05/2019] [Indexed: 11/19/2022]
Abstract
The behaviour of lactotroph tumours varies between benign tumours, those cured by treatment, and that of aggressive tumours, and carcinomas with metastasis. Identification of clinical, pathological and molecular factors is essential for the early identification of patients that may have such aggressive tumours. Plasma prolactin levels and tumour size and invasion, per se, are not prognostic factors. However, tumours appearing at a young age (<20 years), especially in boys, and the presence of genetic predisposition have a poorer prognosis. In addition, lactotroph tumours in men differ from those in women, being larger, more often invasive, and resistant to dopamine agonists. They are also more often high-grade with a high risk of recurrence and malignancy. The expression of estrogen receptor α is lower than in women and is closely correlated to aggressiveness. Proliferation markers (Ki-67 expression: ≥3%, mitotic count n > 2) are correlated to invasion and proliferation, but, taken alone, their prognostic value is debatable. Based on a 5-tiered clinicopathological classification, and taking into account invasion and proliferation, a grade 2b (aggressive) lactotroph tumour has a 20× risk of progression compared to a grade 1a (benign) tumour. Moreover, lactotroph tumours are the second-most frequent aggressive and malignant tumour. Other factors, such as the expression of growth factors (vascular endothelial growth factor [VEGF] and epidermal growth factor [EGF]), the genes regulating invasion, differentiation and proliferation, adhesion molecules (E-cadherin), matrix metalloproteinase 9, and chromosome abnormalities (chromosomes 11, 19, and 1), have also been correlated with aggressiveness. Currently, clinical signs, a prognostic classification, and molecular and genetic markers may all help the clinician in the early identification of aggressive lactotroph tumours and enable stratification of their management.
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Affiliation(s)
- Jacqueline Trouillas
- Université de Lyon 1, Université de Lyon, Lyon, France,
- Faculté de Médecine Lyon-Est, Lyon, France,
| | - Etienne Delgrange
- Service d'Endocrinologie, CHU UCL Namur, Université catholique de Louvain, Mont-sur-Meuse, Belgium
| | - Anne Wierinckx
- Université de Lyon 1, Université de Lyon, Lyon, France
- Centre de Recherche en Cancérologie de Lyon (CRCL), INSERM U1052, CNRS UMR5286, Université de Lyon, Lyon, France
- ProfileXpert, SFR-Est, CNRS UMR-S3453, INSERM US7, Lyon, France
| | - Alexandre Vasiljevic
- Université de Lyon 1, Université de Lyon, Lyon, France
- Faculté de Médecine Lyon-Est, Lyon, France
- Centre de Recherche en Cancérologie de Lyon (CRCL), INSERM U1052, CNRS UMR5286, Université de Lyon, Lyon, France
- Centre de Pathologie et de Neuropathologie Est, Groupement Hospitalier Est, Hospices Civils de Lyon, Bron, France
| | - Emmanuel Jouanneau
- Université de Lyon 1, Université de Lyon, Lyon, France
- Centre de Recherche en Cancérologie de Lyon (CRCL), INSERM U1052, CNRS UMR5286, Université de Lyon, Lyon, France
- Service de Neurochirurgie Groupement Hospitalier Est, Hospices Civils de Lyon, Bron, France
| | - Pia Burman
- Department of Endocrinology, Skåne University Hospital, Malmö, University of Lund, Lund, Sweden
| | - Gerald Raverot
- Université de Lyon 1, Université de Lyon, Lyon, France
- Faculté de Médecine Lyon-Est, Lyon, France
- Centre de Recherche en Cancérologie de Lyon (CRCL), INSERM U1052, CNRS UMR5286, Université de Lyon, Lyon, France
- Départment d'Endocrinologie, Centre de Référence pour les Maladies Hypophysaires Rares (HYPO), Groupement Hospitalier EST, Hospices Civils de Lyon, Bron, France
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49
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Abstract
Pituitary adenomas are unique in multiple ways. They are rarely malignant in terms of metastases; yet, they may be aggressive. Their cancerous potential is defined in a classic oncological way by the ability to metastasise, and therefore, it has been crucial to differentiate this process from aggressive behaviour, characterised as a particularly invasive and/or recurrent behaviour and resistance to common modalities of therapy. Recently, however, important changes have been introduced to the diagnosis and management of aggressive and malignant pituitary tumours including the 4th edition of the World Health Organization (WHO) classification for endocrine tumours (2017) as well as ESE Clinical Guidelines (2018), although an attempt to establish predictive and/or prognostic markers of clinical aggressiveness remains difficult. In this review, we focus on a group of pituitary tumours causing significant problems in clinical practice and requiring multidisciplinary input. We summarise updates in definitions of tumour invasiveness, aggressiveness and malignant transformation, as well as histological classification, and emphasise the new considerations regarding aggressive and malignant potential and its relationship to therapeutic strategies.
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Affiliation(s)
- Dorota Dworakowska
- Department of Hypertension and Diabetes, Medical University of Gdańsk, Gdańsk, Poland
- Guys Richard Dimbleby Department of Cancer Research, Kings College London, London, UK
- Endocard LTD, London, UK
| | - Ashley B Grossman
- Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Oxford, UK
- Centre for Endocrinology, William Harvey Institute, Barts and the London School of Medicine, London, UK
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50
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Syro LV, Rotondo F, Ortiz LD, Kovacs K. 65 YEARS OF THE DOUBLE HELIX: Treatment of pituitary tumors with temozolomide: an update. Endocr Relat Cancer 2018. [PMID: 29535142 DOI: 10.1530/erc-18-0015] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
Temozolomide is an alkylating chemotherapeutic agent used in malignant neuroendocrine neoplasia, melanoma, brain metastases and an essential component of adjuvant therapy in the treatment of glioblastoma multiforme and anaplastic astrocytoma. Since 2006, it has been used for the treatment of pituitary carcinomas and aggressive pituitary adenomas. Here, we discuss the current indications and results of temozolomide therapy in pituitary tumors, as well as frequently asked questions regarding temozolomide treatment, duration of therapy, dosage, tumor recurrence and resistance.
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Affiliation(s)
- Luis V Syro
- Department of NeurosurgeryHospital Pablo Tobon Uribe and Clinica Medellin, Medellin, Colombia
| | - Fabio Rotondo
- Division of PathologyDepartment of Laboratory Medicine, St. Michael's Hospital, University of Toronto, Toronto, Ontario, Canada
| | - Leon D Ortiz
- Division of Neuro-OncologyInstituto de Cancerologia, Clinica Las Americas. Medellin, Colombia
| | - Kalman Kovacs
- Division of PathologyDepartment of Laboratory Medicine, St. Michael's Hospital, University of Toronto, Toronto, Ontario, Canada
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