☆ 4.7 Review

Therapeutic targeting of the pituitary tumor microenvironment

PHARMACOLOGY & THERAPEUTICS (2023)

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Article Endocrinology & Metabolism

The hallmarks of cancer horizontal ellipsis in pituitary tumors?

Daniel Marrero-Rodriguez et al.

Summary: This review evaluates the biological processes underlying malignant transformation and their relevance to the development of pituitary adenomas. It addresses various processes such as genome instability, epigenetic reprogramming, angiogenesis, proliferative signals, immune evasion, and inflammation in relation to pituitary tumors. Additionally, it discusses the existence of oncogene-induced senescence in these tumors. Understanding these processes can provide insights into the resistance of pituitary tumors to malignant transformation and contribute to the development of novel anticancer treatments.

REVIEWS IN ENDOCRINE & METABOLIC DISORDERS (2023)

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Review Endocrinology & Metabolism

Biological and Therapeutic Implications of the Tumor Microenvironment in Pituitary Adenomas

Mirela-Diana Ilie et al.

Summary: This article provides an overview of the implications and therapeutic applications of the tumor microenvironment in pituitary adenomas (PAs). The different components and functions of the tumor microenvironment have complex roles in the biology of PAs. Current treatments targeting the tumor microenvironment, such as immune-checkpoint inhibitors and bevacizumab, have shown some degree of efficacy.

ENDOCRINE REVIEWS (2023)

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Article Endocrinology & Metabolism

The microenvironment of pituitary adenomas: biological, clinical and therapeutical implications

Pedro Marques et al.

Summary: The microenvironment of pituitary adenomas (PAs), consisting of non-tumoral cells and signaling molecules, plays a crucial role in tumor initiation, progression, and invasion. Recent studies have characterized immune and stromal cell populations, as well as various cytokines, chemokines, and growth factors in PAs. Key genes and immune-related molecules and pathways have also been investigated, with immune checkpoint regulators showing promise as targets for immunotherapy. Understanding the microenvironment of PAs provides insights into the complex biology of PAs and has implications for diagnosis, clinical management, and treatment of aggressive and refractory PAs.

PITUITARY (2022)

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Article Medicine, Research & Experimental

Angpt2/Tie2 autostimulatory loop controls tumorigenesis

Ninelia Minaskan Karabid et al.

Summary: Invasive nonfunctioning pituitary neuroendocrine tumors (PitNETs) are difficult to remove and current therapies often fail. This study investigated the ANGPT2/TIE2 axis in NF-PitNETs and found that PitNET cells express functional TIE2 receptors and secrete bioactive ANGPT2, which promotes tumor cell growth. Inhibition of this signaling pathway showed promise in inhibiting PitNET growth in various models. Therefore, the ANGPT2/TIE2 axis could be a potential therapeutic target for NF-PitNETs.

EMBO MOLECULAR MEDICINE (2022)

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Review Biotechnology & Applied Microbiology

Emerging therapeutic opportunities for integrin inhibitors

R. J. Slack et al.

Summary: Integrins play crucial roles in cell adhesion and signaling, making them potential therapeutic targets. This review discusses the challenges and development of integrin inhibitors, particularly those targeting integrins with an alpha v-subunit. Opportunities exist for learning from previous trials and exploring new modalities in integrin drug design.

NATURE REVIEWS DRUG DISCOVERY (2022)

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Article Clinical Neurology

Complete Response of a Patient With a Mismatch Repair Deficient Aggressive Pituitary Adenoma to Immune Checkpoint Inhibitor Therapy: A Case Report

Sanjit Shah et al.

Summary: This is a case report highlighting the utility of immunotherapy in treating aggressive pituitary adenomas (APAs). The patient experienced complete resolution of recurrent APA and improved survival compared to the expected life expectancy. APAs are tumors with frequent recurrence and short median expected length of survival.

NEUROSURGERY (2022)

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Review Cell Biology

Targeting Integrins for Cancer Therapy-Disappointments and Opportunities

Cecilia Bergonzini et al.

Summary: Integrins play a crucial role in mediating adhesive interactions between cells and their environment, and their dysregulation is closely associated with cancer progression. Despite promising preclinical results, targeting integrin adhesion complexes in clinical trials for cancer therapy has not met expectations so far, possibly due to variable integrin expression, redundancy in integrin function, distinct roles at different disease stages, and sequestering by tumor-derived extracellular vesicles. However, improving therapeutic delivery at the tumor site through integrin binding ligands is emerging as a successful approach in enhancing the efficacy and safety of conventional therapeutics.

FRONTIERS IN CELL AND DEVELOPMENTAL BIOLOGY (2022)

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Review Biochemistry & Molecular Biology

The VEGF/VEGFR Axis Revisited: Implications for Cancer Therapy

Peace Mabeta et al.

Summary: The VEGF/VEGFR axis plays a crucial role in angiogenesis and tumor vascularization. Current therapies targeting VEGF and its receptors have shown limited effectiveness and undesirable off-target effects. Recent studies have identified VEGF splice variants that modulate angiogenesis, and their expression is regulated by cues within the tumor microenvironment. These variants challenge the established norm of VEGF signaling and their aberrant expression has been observed in several cancers, highlighting the need for further research on their role in cancer and their impact on antiangiogenic therapies.

INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES (2022)

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Review Oncology

Immunotherapy in aggressive pituitary tumors and carcinomas: a systematic review

Mirela Diana Ilie et al.

Summary: ICIs therapy shows promise in treating pituitary carcinomas and aggressive pituitary tumors, with significant efficacy observed in corticotroph and lactotroph tumors. A high tumor mutational burden is considered the most promising predictive marker.

ENDOCRINE-RELATED CANCER (2022)

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Article Endocrinology & Metabolism

Immunotherapy in pituitary carcinomas and aggressive pituitary tumors

Gerald Raverot et al.

Summary: There is currently no evidence-based treatment for aggressive pituitary tumors and pituitary carcinomas after temozolomide failure, and the survival rate for these patients is very low. Immune-checkpoint inhibitors have shown some potential, but further research is needed to determine their efficacy and predictive factors.

BEST PRACTICE & RESEARCH CLINICAL ENDOCRINOLOGY & METABOLISM (2022)

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Article Endocrinology & Metabolism

Real-life efficacy and predictors of response to immunotherapy in pituitary tumors: a cohort study

Mirela Diana Ilie et al.

Summary: This study evaluated the real-life efficacy of immune-checkpoint inhibitors (ICIs) in treating pituitary carcinomas (PCs) and aggressive pituitary tumors (APTs). The efficacy of ICIs was found to be lower than previously reported, and predictive factors of response were lacking.

EUROPEAN JOURNAL OF ENDOCRINOLOGY (2022)

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Article Endocrinology & Metabolism

Aggressive pituitary tumours and carcinomas, characteristics and management of 171 patients

Pia Burman et al.

Summary: This study describes the characteristics and treatment outcomes of aggressive pituitary tumors (APT) and pituitary carcinomas (PC). Temozolomide is the first-line chemotherapy, but other therapies are also emerging. Predicting treatment response remains challenging with current biomarkers.

EUROPEAN JOURNAL OF ENDOCRINOLOGY (2022)

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Review Oncology

Immunotherapy for Aggressive and Metastatic Pituitary Neuroendocrine Tumors (PitNETs): State-of-the Art

Tiziana Feola et al.

Summary: This study reviewed the effects of ICIs on aggressive/metastatic PitNETs and found that about half of TMZ-resistant PitNETs showed significant benefits from ICIs, with high PDL1 expression associated with remarkable responses but potentially not essential.

CANCERS (2022)

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Article Endocrinology & Metabolism

Immune checkpoint inhibitor therapy for ACTH-secreting pituitary carcinoma: a new emerging treatment?

Bastiaan Sol et al.

Summary: This case report suggests that combination therapy with ipilimumab and nivolumab ICI may achieve disease stabilization in patients with ACTH-secreting pituitary carcinoma refractory to TMZ. It provides support for the potential role of ICI in the treatment of pituitary carcinoma.

EUROPEAN JOURNAL OF ENDOCRINOLOGY (2021)

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Article Endocrinology & Metabolism

Bevacizumab in Aggressive Pituitary Adenomas - Experience with 3 Patients

Katharina Osterhage et al.

Summary: Bevacizumab shows some effect in treating aggressive pituitary adenomas, but the small sample size, short treatment duration, and only one patient showing clinical benefit do not allow for a general statement on its effectiveness. Further studies are needed to evaluate its potential in therapy resistant aggressive pituitary tumors.

EXPERIMENTAL AND CLINICAL ENDOCRINOLOGY & DIABETES (2021)

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Article Endocrinology & Metabolism

Immune profiling of pituitary tumors reveals variations in immune infiltration and checkpoint molecule expression

Yu Mei et al.

Summary: Pituitary tumors exhibit varying levels of immune cell infiltration and expression of immune checkpoint regulators depending on functional status and presence of tumor initiating cells. Primary tumors show higher expression of PD-L1 and LAG3, while VISTA expression is reduced. Functional tumors may have a particularly immunosuppressive microenvironment, warranting further studies on immune checkpoint blockade, potentially requiring combination therapy.

PITUITARY (2021)

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Article Endocrinology & Metabolism

PD-L1 Is Preferentially Expressed in PIT-1 Positive Pituitary Neuroendocrine Tumours

John Turchini et al.

Summary: The study found that PD-L1 expression is common in somatotrophs, lactotrophs, and PIT-1 positive plurihormonal PitNETs, but rare in transcription factor negative, hormone negative PitNETs, gonadotrophs, and corticotrophs. If immunotherapy is to be explored as a therapeutic option for PitNETs, it may be most beneficial in the PD-L1 high subgroup.

ENDOCRINE PATHOLOGY (2021)

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Article Multidisciplinary Sciences

Baseline microvessel density predicts response to neoadjuvant bevacizumab treatment of locally advanced breast cancer

Kristi Kruger et al.

Summary: High baseline microvessel density (MVD) significantly predicted response to bevacizumab treatment, while high proliferative microvessel density (pMVD), glomeruloid microvascular proliferation (GMP), and the angiogenesis signature score did not predict pathologic complete response (pCR) but were associated with aggressive tumor features.

SCIENTIFIC REPORTS (2021)

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Therapeutic Targeting of the Tumor Microenvironment

Leire Bejarano et al.

Summary: This review provides a comprehensive analysis of the current therapies targeting the TME, combining a discussion of the underlying basic biology with clinical evaluation of different therapeutic approaches, and highlighting the challenges and future perspectives.

CANCER DISCOVERY (2021)

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Review Endocrinology & Metabolism

Aggressive pituitary tumours and pituitary carcinomas

Gerald Raverot et al.

Summary: Anterior pituitary tumors are usually benign but can exhibit aggressive behavior, potentially developing into pituitary carcinomas. Current treatment approaches primarily involve surgery or radiotherapy, with standard medical treatments often ineffective and the need for personalized use of emerging therapies for better outcomes.

NATURE REVIEWS ENDOCRINOLOGY (2021)

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Article Endocrinology & Metabolism

Synergism of Checkpoint Inhibitors and Peptide Receptor Radionuclide Therapy in the Treatment of Pituitary Carcinoma

Andrew L. Lin et al.

Summary: Checkpoint inhibitors and Lu-177-DOTATATE may be effective treatments for aggressive pituitary tumors, especially in patients who have progressed on temozolomide. Combination therapy with checkpoint inhibitors and radiation therapy may lead to a synergistic abscopal response, which could be beneficial for certain patients with aggressive pituitary tumors.

JOURNAL OF THE ENDOCRINE SOCIETY (2021)

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Article Endocrinology & Metabolism

Synergism of Checkpoint Inhibitors and Peptide Receptor Radionuclide Therapy in the Treatment of Pituitary Carcinoma

Andrew L. Lin et al.

Summary: This case report demonstrates the potential of immunotherapy in treating aggressive pituitary tumors, with a patient showing sustained response to ipilimumab and nivolumab. Combining immunotherapy with other treatments such as surgery, external beam radiation, and Lu-177-DOTATATE may provide effective management for patients with these challenging tumors.

JOURNAL OF THE ENDOCRINE SOCIETY (2021)

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Article Medicine, Research & Experimental

Lactate-induced M2 polarization of tumor-associated macrophages promotes the invasion of pituitary adenoma by secreting CCL17

Anke Zhang et al.

Summary: The study found a positive association between lactate and PA invasion. Invasive PAs were found to have high infiltration of M2-like TAMs. Lactate secreted by PA cells promoted M2 polarization via mTORC2 and ERK signaling pathways, while activated TAMs secreted CCL17 to promote PA invasion through the CCL17/CCR4/mTORC1 axis. High CCL17 expression was associated with larger tumor size, greater invasion, and higher susceptibility to postoperative recurrence in human PAs.

THERANOSTICS (2021)

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Article Oncology

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

Mario Caccese et al.

ANTI-CANCER DRUGS (2020)

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Targeting PD-L1 Initiates Effective Antitumor Immunity in a Murine Model of Cushing Disease

Hanna R. Kemeny et al.

CLINICAL CANCER RESEARCH (2020)

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In silico analysis of the immunological landscape of pituitary adenomas

Jacky T. Yeung et al.

JOURNAL OF NEURO-ONCOLOGY (2020)

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The adverse events associated with combination immunotherapy in cancers: Challenges and chances

Minglei Zhuo et al.

ASIA-PACIFIC JOURNAL OF CLINICAL ONCOLOGY (2020)

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Pedro Marques et al.

FRONTIERS IN NEUROENDOCRINOLOGY (2020)

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Immune Landscape of Pituitary Tumors Reveals Association Between Macrophages and Gonadotroph Tumor Invasion

Moitza Principe et al.

JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM (2020)

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Treatment Options for Gonadotroph Tumors: Current State and Perspectives

Mirela Diana Ilie et al.

JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM (2020)

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The Immune Profile of Pituitary Adenomas and a Novel Immune Classification for Predicting Immunotherapy Responsiveness

Zihao Wang et al.

JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM (2020)

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Immunotherapy in Corticotroph and Lactotroph Aggressive Tumors and Carcinomas: Two Case Reports and a Review of the Literature

Camille Duhamel et al.

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Mirela Diana Ilie et al.

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A decade of immune-checkpoint inhibitors in cancer therapy

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Case Report: A Case of Pituitary Carcinoma Treated With Sequential Dual Immunotherapy and Vascular Endothelial Growth Factor Inhibition Therapy

Lydia S. Lamb et al.

FRONTIERS IN ENDOCRINOLOGY (2020)

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Efficacy of pembrolizumab in patients with pituitary carcinoma: report of four cases from a phase II study

Nazanin Majd et al.

JOURNAL FOR IMMUNOTHERAPY OF CANCER (2020)

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Lai Xu et al.

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An Institutional Experience of Tumor Progression to Pituitary Carcinoma in a 15-Year Cohort of 1055 Consecutive Pituitary Neuroendocrine Tumors

Omalkhaire M. Alshaikh et al.

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French Endocrine Society Guidance on endocrine side effects of immunotherapy

F. Castinetti et al.

ENDOCRINE-RELATED CANCER (2019)

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VEGF, VEGF165b and EG-VEGF expression is specifically related with hormone profile in pituitary adenomas

Ana Silvia Corlan et al.

EUROPEAN JOURNAL OF HISTOCHEMISTRY (2019)

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Tumor microenvironment defines the invasive phenotype of AIP-mutation-positive pituitary tumors

Sayka Barry et al.

ONCOGENE (2019)

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Stratifying nonfunctional pituitary adenomas into two groups distinguished by macrophage subtypes

Garima Yagnik et al.

Oncotarget (2019)

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Article Clinical Neurology

Long-Term Survival After Transformation of an Adrenocorticotropic Hormone-Secreting Pituitary Macroadenoma to a Silent Corticotroph Pituitary Carcinoma

Lauren E. Rotman et al.

WORLD NEUROSURGERY (2019)

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Osama E. Rahma et al.

CLINICAL CANCER RESEARCH (2019)

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Surgery, Octreotide, Temozolomide, Bevacizumab, Radiotherapy, and Pegvisomant Treatment of an AIP Mutation-Positive Child

Pinaki Dutta et al.

JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM (2019)

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Analysis of Tumor Angiogenesis and Immune Microenvironment in Non-Functional Pituitary Endocrine Tumors

Mizuto Sato et al.

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Breelyn A. Wilky

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Pedro Marques et al.

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Pedro Marques et al.

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Article Endocrinology & Metabolism

European Society of Endocrinology Clinical Practice Guidelines for the management of aggressive pituitary tumours and carcinomas

Gerald Raverot et al.

EUROPEAN JOURNAL OF ENDOCRINOLOGY (2018)

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Article Endocrinology & Metabolism

Treatment of aggressive pituitary tumours and carcinomas: results of a European Society of Endocrinology (ESE) survey 2016

Ann McCormack et al.

EUROPEAN JOURNAL OF ENDOCRINOLOGY (2018)

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The expression profile of PD-L1 and CD8(+) lymphocyte in pituitary adenomas indicating for immunotherapy

Peng-fei Wang et al.

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Qing Yao et al.

TRENDS IN PHARMACOLOGICAL SCIENCES (2018)

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Marked Response of a Hypermutated ACTH-Secreting Pituitary Carcinoma to Ipilimumab and Nivolumab

Andrew L. Lin et al.

JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM (2018)

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Norbert Chauvet et al.

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Successful treatment of pituitary carcinoma with concurrent radiation, temozolomide, and bevacizumab after resection

Waseem Touma et al.

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Claire Viallard et al.

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Rakesh R. Ramjiawan et al.

ANGIOGENESIS (2017)

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Increased expression of programmed death ligand 1 (PD-L1) in human pituitary tumors

Yu Mei et al.

ONCOTARGET (2016)

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Immune Cell Infiltrates in Pituitary Adenomas: More Macrophages in Larger Adenomas and More T Cells in Growth Hormone Adenomas

Jian-Qiang Lu et al.

ENDOCRINE PATHOLOGY (2015)

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Maria Kurowska et al.

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CDK5 and Its Activator P35 in Normal Pituitary and in Pituitary Adenomas: Relationship to VEGF Expression

Weiyan Xie et al.

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Liufu Deng et al.

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Angiogenesis in Pituitary Adenomas: Human Studies and New Mutant Mouse Models

Carolina Cristina et al.

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Diether Lambrechts et al.

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L. Claesson-Welsh et al.

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Enhanced nestin expression and small blood vessels in human pituitary adenomas

Maria Ines Perez-Millan et al.

PITUITARY (2013)

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Article Endocrinology & Metabolism

Over-expression of vascular endothelial growth factor in pituitary adenomas is associated with extrasellar growth and recurrence

Ruth Sanchez-Ortiga et al.

PITUITARY (2013)

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Article Oncology

Predictive Value of Intratumoral Microvascular Density in Patients with Advanced Non-small Cell Lung Cancer Receiving Chemotherapy Plus Bevacizumab

Yuan-Yuan Zhao et al.

JOURNAL OF THORACIC ONCOLOGY (2012)

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Article Endocrinology & Metabolism

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Leon D. Ortiz et al.

PITUITARY (2012)

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Douglas Hanahan et al.

CELL (2011)

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Interleukin-8 production from human somatotroph adenoma cells is stimulated by interleukin-1β and inhibited by growth hormone releasing hormone and somatostatin

Signe Diness Vindelov et al.

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PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA (2011)

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Hiroya Hashizume et al.

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Article Endocrinology & Metabolism

Tumor Infiltrating Lymphocytes But Not Serum Pituitary Antibodies Are Associated with Poor Clinical Outcome after Surgery in Patients with Pituitary Adenoma

Isabella Lupi et al.

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Endoglin and CD-34 immunoreactivity in the assessment of microvessel density in normal pituitary and adenoma subtypes

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Pasireotide, a multiple somatostatin receptor subtypes ligand, reduces cell viability in non-functioning pituitary adenomas by inhibiting vascular endothelial growth factor secretion

Maria Chiara Zatelli et al.

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