Context:
Although pituitary tumors are common, pituitary carcinoma is very rare and is only diagnosed when pituitary tumor noncontiguous with the sellar region is demonstrated. Diagnosis is ...difficult, resulting in delays that may adversely effect outcome that is traditionally poor. Barriers to earlier diagnosis and management strategies for pituitary carcinoma are discussed.
Evidence Acquisition:
PubMed was employed to identify relevant studies, a review of the literature was conducted, and data were summarized and integrated from the author's perspective.
Evidence Synthesis:
The available data highlight the difficulties in diagnosis and management and practical challenges in conducting clinical trials in this rare condition. They suggest that earlier diagnosis with aggressive multimodal therapy may be advantageous in some cases.
Conclusions:
Although pituitary carcinoma remains difficult to diagnose and treat, recent developments have led to improved outcomes in selected cases. With broader use of molecular markers, efforts to modify current histopathological criteria for pituitary carcinoma diagnosis may now be possible. This would assist earlier diagnosis and, in combination with targeted therapies, potentially improve long-term survival.
Abstract
Context
Cushing disease (CD) is a life-threatening disorder. Therapeutic goals include symptom relief, biochemical control, and tumor growth inhibition. Current medical therapies for CD by ...and large exert no action on tumor growth.
Objective
To identify drugs that inhibit corticotroph tumor adrenocorticotropic hormone (ACTH) secretion and growth.
Design
High throughput screen employing a novel “gain of signal” ACTH AlphaLISA assay.
Setting
Academic medical center.
Patients
Corticotroph tumor tissues from patients with CD.
Interventions
None.
Main outcome measures
Potent inhibitors of corticotroph tumor ACTH secretion and growth.
Results
From a kinase inhibitor library, we identified the dual PI3K/HDAC inhibitor CUDC-907 as a potent inhibitor of murine and human corticotroph tumor ACTH secretion (median effective concentration 1-5 nM), and cell proliferation (median inhibitory concentration 5 nM). In an in vivo murine corticotroph tumor xenograft model, orally administered CUDC-907 (300 mg/kg) reduced corticotroph tumor volume (TV cm3, control 0.17 ± 0.05 vs CUDC-907 0.07 ± 0.02, P < .05) by 65% and suppressed plasma ACTH (ACTH pg/mL control 206 ± 27 vs CUDC-907 47 ± 7, P < .05) and corticosterone (corticosterone ng/mL control 180 ± 87 vs CUDC-907 27 ± 5, P < .05) levels by 77% and 85% respectively compared with controls. We also demonstrated that CUDC-907 acts through HDAC1/2 inhibition at the proopiomelanocortin transcriptional level combined with its PI3K-mediated inhibition of corticotroph cell viability to reduce ACTH secretion.
Conclusions
Given its potent efficacy in in vitro and in vivo models of CD, combined with proven safety and tolerance in clinical trials, we propose CUDC-907 may be a promising therapy for CD.
Somatostatin receptor (SSTR) PET has demonstrated a significant improvement over conventional imaging (CI) in patients with neuroendocrine tumors (NETs). SSTR PET should replace 111In-pentetreotide ...scintigraphy (OctreoScan; Mallinckrodt) in all indications in which the latter is currently being used. These appropriate use criteria (AUC) are intended to aid referring medical practitioners in the appropriate use of SSTR PET for imaging of patients with NETs. The indications were evaluated in well-differentiated NETs. Of the 12 clinical scenarios evaluated, 9 were graded as appropriate: initial staging after the histologic diagnosis of NET, evaluation of an unknown primary, evaluation of a mass suggestive of NET not amenable to endoscopic or percutaneous biopsy, staging of NET before planned surgery, monitoring of NET seen predominantly on SSTR PET, evaluation of patients with biochemical evidence and symptoms of a NET, evaluation of patients with biochemical evidence of a NET without evidence on CI or a prior histologic diagnosis, restaging at time of clinical or laboratory progression without progression on CI, and new indeterminate lesion on CI with unclear progression. Representatives from the Society of Nuclear Medicine and Molecular Imaging (SNMMI), the American College of Radiology (ACR), the American Society of Clinical Oncology (ASCO), the North American Neuroendocrine Tumor Society (NANETS), the European Association of Nuclear Medicine (EANM), the Endocrine Society, the Society of Surgical Oncology, the National Comprehensive Cancer Network (NCCN), the American College of Physicians (ACP), the American Gastroenterological Association (AGA), and the World Conference on Interventional Oncology (WCIO) assembled under the auspices of an autonomous workgroup to develop the following AUC.
Context:
Glucocorticoids are powerful steroid hormones that regulate development, metabolism, and immune response. However, glucocorticoid unresponsiveness or resistance is observed in the treatment ...of inflammatory, autoimmune, and lymphoproliferative diseases and significantly limits their efficacy.
Objective:
In Cushing's disease, although some glucocorticoid-mediated suppression of pituitary-derived ACTH is seen, corticotroph tumors exhibit relative resistance to glucocorticoid action. We previously demonstrated that testicular orphan receptor 4 (TR4) binds to the pro-opiomelanocortin (POMC) promoter to induce corticotroph tumor POMC expression and ACTH secretion, and we hypothesized that TR4 may interact with glucocorticoid signaling to modulate POMC expression and action.
Results:
Here we demonstrate that TR4 abrogates glucocorticoid receptor (GR)- or dexamethasone-mediated POMC and activator protein-1 transrepression in both murine and human pituitary corticotroph tumor cells. Co-immunoprecipitation studies indicate that TR4 and GR interact directly with each other, resulting in TR4-mediated disruption of GR binding to the POMC promoter.
Conclusion:
These results demonstrate that TR4 binds GR to play an important role in glucocorticoid-directed corticotroph tumor POMC regulation in addition to modulating glucocorticoid actions on other GR targets. Characterization of this pathway may offer important insights into glucocorticoid resistance and may identify a novel approach for the treatment of Cushing's disease and the glucocorticoid-resistant states.
We demonstrate a direct physical interaction between TR4 and GR to disrupt GR binding the promoter of POMC, underlying the derangement of the negative feedback observed in human corticotroph tumors.
Abstract
Context
Aggressive prolactin (PRL)-secreting pituitary adenomas that are resistant to conventional therapy with dopamine agonists, surgery, and radiation pose a therapeutic challenge. The ...mammalian target of rapamycin (mTOR) inhibitor everolimus is approved to treat neuroendocrine tumors (NETs), and cotreatment with the somatostatin receptor ligand octreotide improved median progression-free survival in patients with metastatic pancreatic NETs.
Patient, Intervention, and Results
We describe off-label everolimus treatment of a prolactinoma (PRLoma) refractory to cabergoline, repeat surgical resection, and radiation therapy. Addition of everolimus to cabergoline led to decreased PRL levels and tumor regression after 5 months. Tumor size remained stable for 12 months, and although PRL levels rose, they remained below pretreatment levels. Immunohistochemical (IHC) evaluation of expression of key mTOR pathway drivers of cell proliferation revealed elevated phosphorylated (p-)AKT, p-4EBP1, and p-S6 in the index patient’s tumor. IHC analysis of seven additional PRLomas demonstrated increased expression of nuclear p-AKT, cytoplasmic p-S6, and globally increased p-4EBP1 in the PRLomas compared with 11 autopsy-derived normal pituitary tissues. In in vitro studies in murine mammosomatotroph tumor GH3 cells, we observed that both the dopamine agonist cabergoline and the mTOR inhibitor everolimus inhibited GH3 cell proliferation and PRL secretion as single agents, and the synergistic effect was noted with combination treatment only on inhibition of PRL secretion but not proliferation.
Conclusions
In summary, our findings demonstrate that the mTOR pathway is activated in PRLomas and that everolimus exhibits antiproliferative actions in vitro. We suggest that everolimus may be a novel therapeutic option for some aggressive PRL-secreting tumors unresponsive to conventional treatments.
Our findings suggest that everolimus may be a novel therapeutic option for selected patients with aggressive PRL-secreting tumors unresponsive to conventional treatments.
Objectives
Neurocytomas (NCs) are rare intracranial tumors that can often be surgically resected. However, disease course is unpredictable in many patients and medical therapies are lacking. We have ...used whole exome sequencing to explore the molecular etiology for neurocytoma and assist in target identification to develop novel therapeutic interventions.
Methods
We used whole exome sequencing (WES) to compare the molecular landscape of 21 primary & recurrent NCs to five normal cerebellar control samples. WES data was analyzed using the Qiagen Clinical Insight program, variants of interest (VOI) were interrogated using ConSurf, ScoreCons, & Ingenuity Pathway Analysis Software to predict their potential functional effects, and Copy number variations (CNVs) in the genes of interest were analyzed by Genewiz (Azenta Life Sciences).
Results
Of 40 VOI involving thirty-six genes, 7 were pathogenic, 17 likely-pathogenic, and 16 of uncertain-significance. Of seven pathogenic NC associated variants,
Glucosylceramidase beta 1
GBA1
c.703T > C (p.S235P) was mutated in 5/21 (24%),
Coagulation factor VIII
F8
c.3637dupA (p.I1213fs*28) in 4/21 (19%),
Phenylalanine hydroxylase
PAH
c.975C > A (p.Y325*) in 3/21 (14%), and
Fanconi anemia complementation group C
FANCC
c.1162G > T (p.G388*),
Chromodomain helicase DNA binding protein 7
CHD7
c.2839C > T (p.R947*),
Myosin VIIA
MYO7A
c.940G > T (p.E314*) and
Dynein axonemal heavy chain 11
DNAH11
c.3544C > T (p.R1182*) in 2/21 (9.5%) NCs respectively. CNVs were noted in 85% of these latter 7 genes. Interestingly, a
Carboxy-terminal domain RNA polymerase II polypeptide A small phosphatase 2
CTDSP2
c.472G > A (p.E158K) of uncertain significance was also found in > 70% of NC cases.
Interpretation
The variants of interest we identified in the NCs regulate a variety of neurological processes including cilia motility, cell metabolism, immune responses, and DNA damage repair and provide novel insights into the molecular pathogenesis of these extremely rare tumors.
Full text
Available for:
EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
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.
Full text
Available for:
EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OBVAL, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Adipose tissue is an important metabolic organ that is crucial for whole-body insulin sensitivity and energy homeostasis. Highly refined fructose intake increases visceral adiposity although the ...mechanism(s) remain unclear. Differentiation of preadipocytes to mature adipocytes is a highly regulated process that is associated with characteristic sequential changes in adipocyte gene expression. We demonstrate that fructose treatment of murine 3T3-L1 cells incubated in standard differentiation medium increases adipogenesis and adipocyte-related gene expression. We further show that the key fructose transporter, GluT5, is expressed in early-stage adipocyte differentiation but is not expressed in mature adipocytes. GluT5 overexpression or knockdown increased and decreased adipocyte differentiation, respectively, and treatment of 3T3-L1 cells with a specific GluT5 inhibitor decreased adipocyte differentiation. Epidymal white adipose tissue was reduced in GluT5−/− mice compared with wild-type mice, and mouse embryonic fibroblasts derived from GluT5−/− mice exhibited impaired adipocyte differentiation. Taken together, these results demonstrate that fructose and GluT5 play an important role in regulating adipose differentiation.
Objective Provide insights into the defective POMC processing and invasive behavior in silent pituitary corticotroph tumors. Design and methods Single-cell RNAseq was used to compare the cellular ...makeup and transcriptome of silent and active corticotroph tumors. Results A series of transcripts related to hormone processing peptidases and genes involved in the structural organization of secretory vesicles were reduced in silent compared to active corticotroph tumors. Most relevant to their invasive behavior, silent corticotroph tumors exhibited several features of epithelial-to-mesenchymal transition, with increased expression of mesenchymal genes along with the loss of transcripts that regulate hormonal biogenesis and secretion. Silent corticotroph tumor vascular smooth muscle cell and pericyte stromal cell populations also exhibited plasticity in their mesenchymal features. Conclusions Our findings provide novel insights into the mechanisms of impaired POMC processing and invasion in silent corticotroph tumors and suggest that a common transcriptional reprogramming mechanism simultaneously impairs POMC processing and activates tumor invasion.
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