scholarly journals MON-287 Expression of Programmed Death-Ligand 1 (PD-L1) in Human Pituitary Neuroendocrine Tumor

2020 ◽  
Vol 4 (Supplement_1) ◽  
Author(s):  
Valentine Suteau ◽  
Alexandre Collin ◽  
Philippe Menei ◽  
Patrice Rodien ◽  
Marie-Christine Rousselet ◽  
...  
Keyword(s):  
Pituitary Tumors ◽  
Human Pituitary ◽  
Ki 67 ◽  
Programmed Death Ligand 1 ◽  
Standard Management ◽  
Programmed Death ◽  
In Vitro Diagnostic ◽  
Proliferative Markers ◽  
Grade 3

Abstract Introduction Some Pituitary NeuroEndocrine Tumors (PitNET) present an aggressive evolution and are resistant to standard management. Immunotherapy have shown durable efficacy in a variety of malignancies. The aim of this study was to explore the programmed death-ligand 1 (PD-L1) expression in varied subtypes of pituitary adenomas with assessment of their clinical behavior at diagnosis and follow-up. Methods We conducted a retrospective monocentric study, including all patients operated a PitNET between 2012 and 2018. PDL-1 immunostaining were performed using an European Conformity-In-Vitro-Diagnostic labeled anti-PDL1 antibody (Clone 22C3). PD-L1 immunostaining was evaluated as the percentage of tumor cell showing positive membrane staining, into four grades: grade 0 = <1%, grade 1 = 1 to 5%, grade 2 = 6 to 49% and grade 3 = ≥ 50%. PD-L1 expression was compared with tumor features (secretion, proliferation, invasion) and outcome. Results The study included one hundred and thirty-nine PitNET, including 84 (60%) nonfunctioning adenomas. Twenty-five PitNET were PD-L1 positive (18%), including 3 grade 3, 8 grade 2 and 14 grade 1. PD-L1 expression was not different between functioning and non-functioning adenomas (p=0.26). Among sixteen tumors with proliferative markers (Ki-67 ≥ 3% and p53 positive), only one was PD-L1 positive. Conclusion In our series, pituitary tumors rarely exhibit PD-L1 expression and this immune marker did not seem to be associated with any biological characteristic or behavior of the pituitary tumors. Thus, PD-L1 staining is necessary before considering PD-L1 blockage in PitNET, in case of therapeutic impasse.

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

Oncotarget ◽  
2016 ◽  
Vol 7 (47) ◽  
pp. 76565-76576 ◽  
Author(s):  
Yu Mei ◽  
Wenya Linda Bi ◽  
Noah F. Greenwald ◽  
Ziming Du ◽  
Nathalie Y. R. Agar ◽  
...  
Keyword(s):  
Pituitary Tumors ◽  
Human Pituitary ◽  
Programmed Death Ligand 1 ◽  
Programmed Death

Expression of programmed death-ligand 1 (PD-L1) in human pituitary neuroendocrine tumor

2020 ◽  
Vol 69 (10) ◽  
pp. 2053-2061 ◽  
Author(s):  
Valentine Suteau ◽  
Alexandre Collin ◽  
Philippe Menei ◽  
Patrice Rodien ◽  
Marie-Christine Rousselet ◽  
...  
Keyword(s):  
Neuroendocrine Tumor ◽  
Human Pituitary ◽  
Programmed Death Ligand 1 ◽  
Programmed Death

scholarly journals Long-Term Outcomes and Retreatment Among Patients With Previously Treated, Programmed Death-Ligand 1‒Positive, Advanced Non‒Small-Cell Lung Cancer in the KEYNOTE-010 Study

2020 ◽  
Vol 38 (14) ◽  
pp. 1580-1590 ◽  
Author(s):  
Roy S. Herbst ◽  
Edward B. Garon ◽  
Dong-Wan Kim ◽  
Byoung Chul Cho ◽  
Jose L. Perez-Gracia ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Adverse Events ◽  
Small Cell ◽  
Small Cell Lung ◽  
Long Term Outcomes ◽  
Programmed Death Ligand 1 ◽  
Programmed Death ◽  
Previously Treated ◽  
Grade 3

PURPOSE In the KEYNOTE-010 study, pembrolizumab improved overall survival (OS) versus docetaxel in previously treated, programmed death-ligand 1 (PD-L1)‒expressing advanced non‒small-cell lung cancer (NSCLC) in patients with a tumor proportion score (TPS) ≥ 50% and ≥ 1%. We report KEYNOTE-010 long-term outcomes, including after 35 cycles/2 years or second-course pembrolizumab. METHODS Of 1,033 patients randomly assigned (intention to treat), 690 received up to 35 cycles/2 years of pembrolizumab 2 mg/kg (n = 344) or 10 mg/kg (n = 346) every 3 weeks, and 343 received docetaxel 75 mg/m2 every 3 weeks. Eligible patients with disease progression after 35 cycles/2 years of pembrolizumab could receive second-course treatment (up to 17 cycles). Pembrolizumab doses were pooled because no between-dose difference was observed at primary analysis. RESULTS Pembrolizumab continued to improve OS over docetaxel in the PD-L1 TPS ≥ 50% and ≥ 1% groups (hazard ratio [HR], 0.53; 95% CI, 0.42 to 0.66; P < .00001; and HR, 0.69; 95% CI, 0.60 to 0.80; P < .00001, respectively) after a 42.6-month (range, 35.2-53.2 months) median follow-up. Estimated 36-month OS rates were 34.5% versus 12.7% and 22.9% versus 11.0%, respectively. Grade 3-5 treatment-related adverse events occurred in 16% versus 37% of patients, respectively. Seventy-nine of 690 patients completed 35 cycles/2 years of pembrolizumab; 12-month OS and progression-free survival rates after completing treatment were 98.7% (95% CI, 91.1% to 99.8%) and 72.5% (95% CI, 59.9% to 81.8%), respectively. Seventy-five patients (95%) had objective response (RECIST v1.1, blinded independent central review) and 48 (64%) had ongoing response. Grade 3-5 treatment-related adverse events occurred in 17.7% of patients. Fourteen patients received second-course pembrolizumab: 5 completed 17 cycles, 6 (43%) had partial response, and 5 (36%) had stable disease. CONCLUSION Pembrolizumab provided long-term OS benefit over docetaxel, with manageable safety, durable responses among patients receiving 2 years of treatment, and disease control with second-course treatment, further supporting pembrolizumab for previously treated, PD-L1‒expressing advanced NSCLC.

Hypoxia-inducible factor 1α in regulation of programmed death: Ligand 1 in glioma under hypoxia microenvironment.

2017 ◽  
Vol 35 (7_suppl) ◽  
pp. 103-103
Author(s):  
Man Hu ◽  
Song Xue ◽  
Jinming Yu ◽  
Bingjie Fan ◽  
Ji Ma ◽  
...  
Keyword(s):  
Mrna Expression ◽  
Survival Time ◽  
Immune Escape ◽  
Hypoxia Inducible Factor ◽  
High Grade ◽  
Programmed Death Ligand 1 ◽  
Hypoxia Inducible Factor 1Α ◽  
Programmed Death ◽  
High Grade Gliomas

103 Background: Glioma is a highly lethal tumor that is known for its immune inhibitory capabilities. Despite great progress in treatment modalities, the median survival time of high-grade gliomas patients is only about 11.1 months. Gliomas are aberrantly expressed programmed death–ligand 1 (PD-L1) which results in tumor-induced immune suppression. Hypoxia is well known to induce aggressiveness, promotes tumor progression and resistance to chemotherapy and radiotherapy. Recently, studies have indicated that hypoxia play a prominent role in tumor immune escape. The aim of the study was to explore the relationship between PD-L1 and hypoxia inducible factor 1α (HIF-1α) and the role in the progression of gliomas. Methods: We adopted immunohistochemistry methods to detect expressions of PD-L1 and HIF-1α in 64 surgical specimens (23 cases for low-grade and 41 cases for high-grade gliomas, respectively). Immunoreactivity was analyzed in association with patients’ clinical characteristics or survival time. Expression of the PD-L1 and HIF-1α was analyzed in three GBM cell lines, U343, U373, and U251, under in vitro hypoxia (12, 24 or 72 h at 0.1% O2). Reverse transcriptase-polymerase chain reaction (RT-PCR) was carried out to detect the mRNA expression of PD-L1 and HIF-1α. Results: PD-L1 and HIF-1α protein expression was detected in 81.25% and 84.73% of glioma specimens, respectively. The expression of PD-L1 protein is positively correlated with HIF-1α (r = 0.52; p= 0.013). Kaplan–Meier analysis revealed a significant effect of PD-L1 grade on cumulative overall survival. Patients with negative PD-L1 expression survive longer than those with positive expression ( p= 0.007). PD-L1 and HIF-1α mRNA was most consistently upregulated in relation to duration of in-vitro hypoxia (72h, p= 0.007). There was a significant and positive relationship between the PD-L1 and HIF-1α mRNA expression (r = 0.45; p= 0.01). Conclusions: The present study showed a role for hypoxia/HIF-1α in driving immune escape and provided a potential novel cancer immunotherapy targeting hypoxia to block PD-L1 expression, which may boost the immune system in cancer patients.

scholarly journals A diagnostic marker set for invasion, proliferation, and aggressiveness of prolactin pituitary tumors

2007 ◽  
Vol 14 (3) ◽  
pp. 887-900 ◽  
Author(s):  
Anne Wierinckx ◽  
Carole Auger ◽  
Pauline Devauchelle ◽  
Arlette Reynaud ◽  
Pascale Chevallier ◽  
...  
Keyword(s):  
Polysialic Acid ◽  
Pituitary Tumors ◽  
Case Control ◽  
Control Analysis ◽  
Human Pituitary ◽  
Ki 67 ◽  
Non Invasive ◽  
Gene Profiles ◽  
Case Control Analysis ◽  
Rat Tumors

Although most pituitary tumors are benign, some are invasive or aggressive. In the absence of specific markers of malignancy, only tumors with metastases are considered malignant. To identify markers of invasion and aggressiveness, we focused on prolactin (PRL) tumors in the human and rat. Using radiology and histological methods, we classified 25 human PRL tumors into three groups (non-invasive, invasive, and aggressive–invasive) and compared them with a model of transplantable rat PRL tumors with benign and malignant lineages. Combining histological(mitoses and labeling for Ki-67, P53, pituitary transforming tumor gene (PTTG), and polysialic acid neural cell adhesion molecule) and transcriptomic (microarrays and q-RTPCR) methods with clinical data (post-surgical outcome with case–control statistical analysis), we found nine genes implicated in invasion (ADAMTS6, CRMP1, and DCAMKL3) proliferation (PTTG, ASK, CCNB1, AURKB, and CENPE), or pituitary differentiation (PITX1) showing differential expression in the three groups of tumors (P = 0.015 to 0.0001). A case–control analysis, comparing patients in remission (9 controls) and patients with persistent or recurrent tumors (14 cases) revealed that eight out of the nine genes were differentially up- or downregulated (P = 0.05 to 0.002), with only PTTG showing no correlation with clinical course (P = 0.258). These combined histological and transcriptomic analyses improve the pathological diagnosis of PRL tumors, indicating a reliable procedure for predicting tumor aggressiveness and recurrence potential. The similar gene profiles found between non-invasive human and benign rat tumors, as well as between aggressive–invasive human and malignant rat tumors provide new insights into malignancy in human pituitary tumors.

scholarly journals Two Distinctive POMC Promoters Modify Gene Expression in Cushing’s Disease

2021 ◽  
Author(s):  
Takako Araki ◽  
Yukiko Tone ◽  
Masaaki Yamamoto ◽  
Hiraku Kameda ◽  
Anat Ben-Shlomo ◽  
...  
Keyword(s):  
Cushing’S Disease ◽  
Methylation Status ◽  
Regulatory Region ◽  
Pituitary Tumors ◽  
Cushing's Disease ◽  
Human Pituitary ◽  
Ectopic Acth ◽  
Pomc Gene ◽  
Acth Secreting

Abstract Context Mechanisms underlying pituitary corticotroph adenoma ACTH production are poorly understood, yet circulating ACTH levels closely correlate with adenoma phenotype and clinical outcomes. Objective We characterized the 5’ ends of proopiomelanocortin (POMC) gene transcripts, which encode the precursor polypeptide for ACTH, in order to investigate additional regulatory mechanisms of POMC gene transcription and ACTH production. Methods We examined 11 normal human pituitary tissues, 32 ACTH-secreting tumors, as well as 6 silent pituitary corticotroph adenomas (SCA) that immunostain for but do not secrete ACTH. Results We identified a novel regulatory region located near the intron2/exon3 junction in the human POMC gene, which functions as a second promoter and an enhancer. In vitro experiments demonstrated that CREB binds the second promoter and regulates its transcriptional activity. The second promoter is highly methylated in SCA, partially demethylated in normal pituitary tissue, and highly demethylated in pituitary and ectopic ACTH-secreting tumors. In contrast, the first promoter is demethylated in all POMC-expressing cells and is highly demethylated only in pituitary ACTH-secreting tumors harboring the USP8 mutation. Demethylation patterns of the second promoter correlate with clinical phenotypes of Cushing’s disease. Conclusion We identified a second POMC promoter regulated by methylation status in ACTH-secreting pituitary tumors. Our findings open new avenues for elucidating subcellular regulation of the hypothalamic-pituitary-adrenal axis and suggest the second POMC promoter may be a target for therapeutic intervention to suppress excess ACTH production.

Elevated Expression of Programmed Death Ligand1 in Human Pituitary Tumors

2016 ◽  
Vol 77 (S 01) ◽  
Author(s):  
Yu Mei ◽  
Wenya Bi ◽  
Ziming Du ◽  
Nathalie Agar ◽  
Gavin Dunn ◽  
...  
Keyword(s):  
Pituitary Tumors ◽  
Human Pituitary ◽  
Programmed Death ◽  
Elevated Expression

scholarly journals How to Classify Pituitary Neuroendocrine Tumors (PitNET)s in 2020

Cancers ◽  
2020 ◽  
Vol 12 (2) ◽  
pp. 514 ◽  
Author(s):  
Jacqueline Trouillas ◽  
Marie-Lise Jaffrain-Rea ◽  
Alexandre Vasiljevic ◽  
Gérald Raverot ◽  
Federico Roncaroli ◽  
...  
Keyword(s):  
Neuroendocrine Tumors ◽  
Early Recognition ◽  
Pituitary Tumors ◽  
Operative Management ◽  
Prognostic Impact ◽  
Null Cell ◽  
Ki 67 ◽  
Standardized Report ◽  
Proliferative Markers ◽  
Morphologic Type

Adenohypophyseal tumors, which were recently renamed pituitary neuroendocrine tumors (PitNET), are mostly benign, but may present various behaviors: invasive, “aggressive” and malignant with metastases. They are classified into seven morphofunctional types and three lineages: lactotroph, somatotroph and thyrotroph (PIT1 lineage), corticotroph (TPIT lineage) or gonadotroph (SF1 lineage), null cell or immunonegative tumor and plurihormonal tumors. The WHO 2017 classification suggested that subtypes, such as male lactotroph, silent corticotroph and Crooke cell, sparsely granulated somatotroph, and silent plurihormonal PIT1 positive tumors, should be considered as “high risk” tumors. However, the prognostic impact of these subtypes and of each morphologic type remains controversial. In contrast, the French five-tiered classification, taking into account the invasion, the immuno-histochemical (IHC) type, and the proliferative markers (Ki-67 index, mitotic count, p53 positivity), has a prognostic value validated by statistical analysis in 4 independent cohorts. A standardized report for the diagnosis of pituitary tumors, integrating all these parameters, has been proposed by the European Pituitary Pathology Group (EPPG). In 2020, the pituitary pathologist must be considered as a member of the multidisciplinary pituitary team. The pathological diagnosis may help the clinician to adapt the post-operative management, including appropriate follow-up and early recognition and treatment of potentially aggressive forms.

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