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International Journal of Molecular... Nov 2023Pituitary neuroendocrine tumors (PitNETs) are divided into multiple histological subtypes, which determine their clinical and biological variable behavior. Despite their...
Pituitary neuroendocrine tumors (PitNETs) are divided into multiple histological subtypes, which determine their clinical and biological variable behavior. Despite their benign evolution, in some cases, prolactin (PRL) and growth hormone (GH)-secreting PitNETs may have aggressive behavior. In this study, we investigated the potential predictive role of ER∝, alongside the clinicopathological classification of PitNETs (tumor diameter, tumor type, and tumor grade). A retrospective study was conducted with 32 consecutive cases of PRL- and mixed GH- and PRL-secreting PitNETs (5 patients with prolactinomas and 27 with acromegaly, among them, 7 patients with GH- and PRL- co-secretion) who underwent transsphenoidal intervention. Tumor specimens were histologically and immunohistochemical examined: anterior pituitary hormones, ki-67 labeling index, CAM 5.2, and ER∝; ER∝ expression was correlated with basal PRL levels at diagnosis (rho = 0.60, < 0.01) and postoperative PRL levels (rho = 0.58, < 0.001). In our study, the ER∝ intensity score was lower in female patients. Postoperative maximal tumor diameter correlated with Knosp grade ( = 0.02); CAM 5.2 pattern (densely/sparsely granulated/mixed densely and sparsely granulated) was correlated with postoperative PRL level ( = 0.002), and with ki-67 ( < 0.001). The IGF1 level at diagnosis was correlated with the postoperative GH nadir value in the oral glucose tolerance test (OGTT) (rho = 0.52, < 0.05). Also, basal PRL level at diagnosis was correlated with postoperative tumor diameter ( = 0.63, < 0.001). At univariate logistic regression, GH nadir in OGTT test at diagnostic, IGF1, gender, and invasion were independent predictors of remission for mixed GH- and PRL-secreting Pit-NETs; ER∝ can be used as a prognostic marker and loss of ER∝ expression should be considered a sign of lower differentiation and a likely indicator of poor prognosis. A sex-related difference can be considered in the evolution and prognosis of these tumors, but further studies are needed to confirm this hypothesis.
Topics: Humans; Female; Adenoma; Retrospective Studies; Ki-67 Antigen; Pituitary Neoplasms; Prolactinoma; Prolactin; Neuroendocrine Tumors
PubMed: 38003353
DOI: 10.3390/ijms242216162 -
Frontiers in Endocrinology 2023The invasive behavior of nonfunctioning pituitary neuroendocrine tumors (NF-PitNEts) affects complete resection and indicates a poor prognosis. Cancer immunotherapy has...
INTRODUCTION
The invasive behavior of nonfunctioning pituitary neuroendocrine tumors (NF-PitNEts) affects complete resection and indicates a poor prognosis. Cancer immunotherapy has been experimentally used for the treatment of many tumors, including pituitary tumors. The current study aimed to screen the key immune-related genes in NF-PitNEts with invasion.
METHODS
We used two cohorts to explore novel biomarkers in NF-PitNEts. The immune infiltration-associated differentially expressed genes (DEGs) were obtained based on high/low immune scores, which were calculated through the ESTIMATE algorithm. The abundance of immune cells was predicted using the ImmuCellAI database. WGCNA was used to construct a coexpression network of immune cell-related genes. Random forest analysis was used to select the candidate genes associated with invasion. The expression of key genes was verified in external validation set using quantitative real-time polymerase chain reaction (qRT‒PCR).
RESULTS
The immune and invasion related DEGs was obtained based on the first dataset of NF-PitNEts (n=112). The immune cell-associated modules in NF-PitNEts were calculate by WGCNA. Random forest analysis was performed on 81 common genes intersected by immune-related genes, invasion-related genes, and module genes. Then, 20 of these genes with the highest RF score were selected to construct the invasion and immune-associated classification model. We found that this model had high prediction accuracy for tumor invasion, which had the largest area under the receiver operating characteristic curve (AUC) value in the training dataset from the first dataset (n=78), the self-test dataset from the first dataset (n=34), and the independent test dataset (n=73) (AUC=0.732/0.653/0.619). Functional enrichment analysis revealed that 8 out of the 20 genes were enriched in multiple signaling pathways. Subsequently, the 8-gene (BMP6, CIB2, FABP5, HOMER2, MAML3, NIN, PRKG2 and SIDT2) classification model was constructed and showed good efficiency in the first dataset (AUC=0.671). In addition, the expression levels of these 8 genes were verified by qRT‒PCR.
CONCLUSION
We identified eight key genes associated with invasion and immunity in NF-PitNEts that may play a fundamental role in invasive progression and may provide novel potential immunotherapy targets for NF-PitNEts.
Topics: Humans; Pituitary Neoplasms; Neuroendocrine Tumors; Pituitary Diseases; Neoplastic Processes; Biomarkers; Tumor Microenvironment; Fatty Acid-Binding Proteins; Nucleotide Transport Proteins
PubMed: 37522128
DOI: 10.3389/fendo.2023.1131693 -
Best Practice & Research. Clinical... Dec 2023Growth hormone (GH) deficiency (GHD) is one of the most prevalent deficiencies in patients with hypopituitarism and several cohort studies have demonstrated an increased... (Meta-Analysis)
Meta-Analysis Review
Growth hormone (GH) deficiency (GHD) is one of the most prevalent deficiencies in patients with hypopituitarism and several cohort studies have demonstrated an increased mortality risk in hypopituitary patients with a presumed GHD. The cause of the excess mortality is most likely multifactorial, including the etiology of the hypopituitarism, non-physiological replacement therapies (mostly glucocorticoid), tumor treatment and its side effects as well as untreated GHD. Several years later, other cohort studies that investigated life expectancy in patients with hypopituitarism on GH replacement therapy (GHRT) that showed a normalized mortality. By comparison of the distribution of characteristics of interest between cohorts, we discuss the existing literature to answer the following question: does growth hormone replacement really improve mortality rates in adult patients with hypopituitarism and GHD? We also conducted a meta-analysis of these studies. Since the literature suffers from selection and time bias (improvement of tumor management and other pituitary hormone replacement therapies), there is no high-quality evidence that replacement therapy for GHD really improves mortality. However, the available data does suggest that GHRT plays a significant part in the normalization of the mortality in patients with hypopituitarism.
Topics: Adult; Humans; Hypopituitarism; Dwarfism, Pituitary; Human Growth Hormone; Growth Hormone; Pituitary Neoplasms; Hormone Replacement Therapy
PubMed: 37914564
DOI: 10.1016/j.beem.2023.101835 -
PloS One 2023General anesthesia can disturb the hormone levels in surgical patients. Hormone deficiency is one of the major symptoms of craniopharyngioma (CP) in pediatric patients.... (Randomized Controlled Trial)
Randomized Controlled Trial
OBJECTIVE
General anesthesia can disturb the hormone levels in surgical patients. Hormone deficiency is one of the major symptoms of craniopharyngioma (CP) in pediatric patients. The aim of this prospective randomized controlled clinical study is to evaluate whether propofol and sevoflurane influence the perioperative hormone levels in these patients and to determine which anesthesia technique causes less impact on hormone levels.
MATERIALS
Sixty-four ASA I and II pediatric patients with CP undergoing elective neurosurgery were randomly divided into the sevoflurane group (S group, n = 32) and the propofol group (P group, n = 32). Anesthesia was maintained with sevoflurane and propofol until the end of the operation. Demographic information, operation information and hemodynamic variables were recorded. The levels of hormones were evaluated preoperatively as the baseline (T0), 1h after the beginning of the operation (T1), immediately at the end of the operation (T2) and 72 h postoperatively (T3).
RESULTS
There were no significant differences in the two groups in terms of patients' demographics and intraoperative information, such as operation duration, blood loss and transfusion volumes, and fluid infusion volume (P>0.05). In both groups, compared to those at T0, the levels of TSH, FT3, TT3 and ACTH at T1, T2 and T3 were significantly lower. The levels of FSH, PRL and GH at T3 were also significantly lower (P<0.05). The FT3 and TT3 levels of both groups at T2 and T3 were significantly lower than those at T1, but the ACTH level was significantly increased (P<0.05). Compared to the levels at T2, the TSH, FT3, FT4 and ACTH levels of the two groups at T3 were significantly reduced (P<0.05). The baseline hormone levels of both groups were similar (P>0.05). At T1, the FT3, TT3, FT4, TT4 and ACTH levels in the P group were significantly lower than those in the S group (P<0.05). At T2, the TT3 and ACTH levels of the P group were significantly lower than those of the S group (P<0.05) At T3, the TT4 level in the P group was significantly lower than that of the S group (P<0.05).
CONCLUSION
Propofol and sevoflurane could reduce the levels of hormones intraoperatively and postoperatively in pediatric patients with craniopharyngioma. However, propofol reduced hormone levels more intensively, mainly intraoperatively. Postoperatively, propofol and sevoflurane had similar inhibition effects on the shift in hormone levels. Therefore, in pediatric patients with craniopharyngioma undergoing neurosurgery, sevoflurane might be the preferred anesthetic because it causes less interruption of hormone levels. However, because of their similar postoperative effects, which long-term effects of sevoflurane or propofol could produce optimal clinical situations? Thus more extensive clinical studies are needed.
TRIAL REGISTRATION
Clinical trial registration. This trail was registered at Chinese Clinical Trial Registry (http://www.chictr.org.cn, Jun Xiong) on 28/12/2021, registration number was ChiCTR2100054885.
Topics: Humans; Child; Propofol; Sevoflurane; Craniopharyngioma; Anesthesia, General; Pituitary Neoplasms; Adrenocorticotropic Hormone; Thyrotropin; Methyl Ethers; Anesthetics, Inhalation
PubMed: 37506116
DOI: 10.1371/journal.pone.0288863 -
Frontiers in Endocrinology 2023Aggressive prolactinomas (APRLs) pose a significant clinical challenge due to their high rate of regrowth and potentially life-threatening complications. In this study,... (Review)
Review
INTRODUCTION
Aggressive prolactinomas (APRLs) pose a significant clinical challenge due to their high rate of regrowth and potentially life-threatening complications. In this study, we present a case of a patient with an APRL who had a trial of multiple therapeutic modalities with the aim to provide a review of molecular abnormalities and management of APRLs by corroborating our experience with previous literature.
METHODS
A total of 268 articles were reviewed and 46 were included. Case reports and series, and studies that investigated the molecular and/or genetic analysis of APRLs were included. Special care was taken to include studies describing prolactinomas that would fall under the APRL subtype according to the European Society of Endocrinology guidelines; however, the author did not label the tumor as "aggressive" or "atypical". Addiontionally, we present a case report of a 56-year-old man presented with an invasive APRL that was resistant to multiple treatment modalities.
RESULTS
Literature review revealed multiple molecular abnormalities of APRLs including mutations in and/or deregulation of ADAMTS6, MMP-9, PITX1, VEGF, POU6F2, CDKN2A, and Rb genes. Mismatch repair genes, downregulation of microRNAs, and hypermethylation of specific genes including RASSF1A, p27, and MGMT were found to be directly associated with the aggressiveness of prolactinomas. APRL receptor analysis showed that low levels of estrogen receptor (ER) and an increase in somatostatin receptors (SSTR5) and epidermal growth factor receptors (EGFR) were associated with increased invasiveness and higher proliferation activity. Our patient had positive immunohistochemistry staining for PD-L1, MSH2, and MSH6, while microarray analysis revealed mutations in the CDKN2A and POU6F2 genes. Despite undergoing two surgical resections, radiotherapy, and taking dopamine agonists, the tumor continued to progress. The patient was administered pazopanib, which resulted in a positive response and the patient remained progression-free for six months. However, subsequent observations revealed tumor progression. The patient was started on PD-L1 inhibitor pembrolizumab, yet the tumor continued to progress.
CONCLUSION
APRLs are complex tumors that require a multidisciplinary management approach. Knowledge of the molecular underpinnings of these tumors is critical for understanding their pathogenesis and identifying potential targets for precision medical therapy.
Topics: Male; Humans; Middle Aged; Prolactinoma; Pituitary Neoplasms; Indazoles; POU Domain Factors
PubMed: 37529607
DOI: 10.3389/fendo.2023.1195792 -
Japanese Journal of Radiology Aug 2023Many types of tumors can develop in the pituitary gland. In the recently revised 5th editions of the World Health Organization (WHO) classifications (2021 WHO... (Review)
Review
Many types of tumors can develop in the pituitary gland. In the recently revised 5th editions of the World Health Organization (WHO) classifications (2021 WHO Classification of Central Nervous System Tumors and the 2022 WHO Classification of Endocrine and Neuroendocrine Tumors), various changes have been made to the tumors other than pituitary neuroendocrine tumor (PitNET)/pituitary adenoma, as well as PitNET. Adamantinomatous craniopharyngioma and papillary craniopharyngioma are now considered separate tumors in the 5th edition of the WHO classification. Tumors positive for thyroid transcription factor 1, a marker of posterior pituitary cells, are now grouped together in the pituicyte tumor family in the 5th edition of the WHO classification of Endocrine and Neuroendocrine Tumors. Poorly differentiated chordoma is newly listed in the 5th edition of the WHO Classification of Endocrine and Neuroendocrine Tumors. In this paper, we present the latest WHO classification of pituitary tumors (adamantinomatous craniopharyngioma, papillary craniopharyngioma, pituitary blastoma, pituicyte tumor family, tumors of pituitary origin other than those of the pituicyte tumor family, germinoma, meningioma, chordoma, metastatic tumors, lymphoma, and pituitary incidentaloma), review diseases requiring differentiation from tumors (pituitary abscess, hypophysitis, pituitary hyperplasia, Rathke's cleft cyst, arachnoid cyst, and aneurysm), and discuss diagnoses based on imaging findings.
Topics: Humans; Pituitary Neoplasms; Craniopharyngioma; Chordoma; Pituitary Gland; Pituitary Diseases; Adenoma; Neuroendocrine Tumors; Meningeal Neoplasms; World Health Organization
PubMed: 36913010
DOI: 10.1007/s11604-023-01407-0 -
Frontiers in Endocrinology 2023We previously described that a short version of the acute octreotide test (sAOT) can predict the response to first-generation somatostatin receptor ligands (SRLs) in...
INTRODUCTION
We previously described that a short version of the acute octreotide test (sAOT) can predict the response to first-generation somatostatin receptor ligands (SRLs) in patients with acromegaly. We have prospectively reassessed the sAOT in patients from the ACROFAST study using current ultra-sensitive GH assays. We also studied the correlation of sAOT with tumor expression of E-cadherin and somatostatin receptor 2 (SSTR2) .
METHODS
A total of 47 patients treated with SRLs for 6 months were evaluated with the sAOT at diagnosis and correlated with SRLs' response. Those patients whose IGF1 decreased to <3SDS from normal value were considered and those whose IGF1 was ≥3SDS, were considered . The 2 hours GH value (GH) after s.c. administration of 100 mcg of octreotide was used to define predictive cutoffs. E-cadherin and SSTR2 immunostaining in somatotropinoma tissue were investigated in 24/47 and 18/47 patients, respectively.
RESULTS
In all, 30 patients were responders and 17 were non-responders. GH was 0.68 (0.25-1.98) ng/mL in responders vs 2.35 (1.59-9.37) ng/mL in non-responders (p<0.001). GH = 1.4ng/mL showed the highest ability to identify responders (accuracy of 81%, sensitivity of 73.3%, and specificity of 94.1%). GH = 4.3ng/mL was the best cutoff for non-response prediction (accuracy of 74%, sensitivity of 35.3%, and specificity of 96.7%). Patients with E-cadherin-positive tumors showed a lower GH than those with E-cadherin-negative tumors [0.9 (0.3-2.1) vs 3.3 (1.5-12.1) ng/mL; p<0.01], and patients with positive E-cadherin presented a higher score of SSTR2 (7.5 ± 4.2 vs 3.3 ± 2.1; p=0.01).
CONCLUSION
The sAOT is a good predictor tool for assessing response to SRLs and correlates with tumor E-cadherin and SSTR2 expression. Thus, it can be useful in clinical practice for therapeutic decision-making in patients with acromegaly.
Topics: Humans; Octreotide; Acromegaly; Somatostatin; Treatment Outcome; Pituitary Neoplasms; Adenoma; Cadherins
PubMed: 38027102
DOI: 10.3389/fendo.2023.1269787 -
Endocrine Jan 2024Assessment of pituitary adenoma (PA) volume and extent of resection (EOR) through manual segmentation is time-consuming and likely suffers from poor interrater...
PURPOSE
Assessment of pituitary adenoma (PA) volume and extent of resection (EOR) through manual segmentation is time-consuming and likely suffers from poor interrater agreement, especially postoperatively. Automated tumor segmentation and volumetry by use of deep learning techniques may provide more objective and quick volumetry.
METHODS
We developed an automated volumetry pipeline for pituitary adenoma. Preoperative and three-month postoperative T1-weighted, contrast-enhanced magnetic resonance imaging (MRI) with manual segmentations were used for model training. After adequate preprocessing, an ensemble of convolutional neural networks (CNNs) was trained and validated for preoperative and postoperative automated segmentation of tumor tissue. Generalization was evaluated on a separate holdout set.
RESULTS
In total, 193 image sets were used for training and 20 were held out for validation. At validation using the holdout set, our models (preoperative / postoperative) demonstrated a median Dice score of 0.71 (0.27) / 0 (0), a mean Jaccard score of 0.53 ± 0.21/0.030 ± 0.085 and a mean 95 percentile Hausdorff distance of 3.89 ± 1.96./12.199 ± 6.684. Pearson's correlation coefficient for volume correlation was 0.85 / 0.22 and -0.14 for extent of resection. Gross total resection was detected with a sensitivity of 66.67% and specificity of 36.36%.
CONCLUSIONS
Our volumetry pipeline demonstrated its ability to accurately segment pituitary adenomas. This is highly valuable for lesion detection and evaluation of progression of pituitary incidentalomas. Postoperatively, however, objective and precise detection of residual tumor remains less successful. Larger datasets, more diverse data, and more elaborate modeling could potentially improve performance.
Topics: Humans; Pituitary Neoplasms; Magnetic Resonance Imaging; Adenoma; Neoplasm, Residual; Image Processing, Computer-Assisted
PubMed: 37749388
DOI: 10.1007/s12020-023-03529-x -
Cancer Imaging : the Official... Sep 2023Fluorine-Fluoro-deoxy-glucose (F-FDG) positron emission tomography (PET) is widely used for diagnosing various malignant tumors and evaluating metabolic activities....
BACKGROUND
Fluorine-Fluoro-deoxy-glucose (F-FDG) positron emission tomography (PET) is widely used for diagnosing various malignant tumors and evaluating metabolic activities. Although the usefulness of F-FDG PET has been reported in several endocrine diseases, studies on pituitary disease are extremely limited. To evaluate whether dexamethasone (DEX) suppression can improve F-FDG PET for the localization of adrenocorticotropic hormone-secreting adenomas in the pituitary gland in Cushing's disease (CD).
METHODS
We included 22 patients with CD who underwent PET imaging before and after DEX administration. We compared the success rates of PET before and after DEX suppression, magnetic resonance imaging (MRI), and bilateral inferior petrosal sinus sampling (BIPSS). We determined the final locations of adenomas based on intraoperative multiple-staged resection and tumor tissue identification using frozen sections. Standardized uptake value (SUV) were analyzed to confirm the change of intensity of adenomas on PET.
RESULTS
Twenty-two patients were included (age at diagnosis: 37 [13-56] years), and most were women (90.91%). Pituitary adenomas compared to normal pituitaries showed increased maximum SUV after DEX suppression but without statistical significance (1.13 versus. 1.21, z=-0.765, P = 0.444). After DEX suppression, the mean and maximum SUV of adenomas showed a positive correlation with nadir cortisol levels in high-dose DEX suppression test (Rho = 0.554, P = 0.007 and Rho = 0.503, P = 0.017, respectively). In reference sites, mean SUV of cerebellum was significantly decreased (7.65 vs. 6.40, P = 0.006), but those of the thalamus and gray matter was increased after DEX suppression (thalamus, 8.70 vs. 11.20, P = 0.010; gray matter, 6.25 vs. 7.95, P = 0.010).
CONCLUSION
DEX suppression did not improve F-FDG PET/CT localization in patients with CD.
Topics: Humans; Female; Adolescent; Young Adult; Adult; Middle Aged; Male; Pituitary Neoplasms; Adrenocorticotropic Hormone; Fluorodeoxyglucose F18; Positron Emission Tomography Computed Tomography; Positron-Emission Tomography; Dexamethasone
PubMed: 37700359
DOI: 10.1186/s40644-023-00600-8 -
Acta Neurochirurgica Oct 2023Sustained cure of acromegaly can only be achieved by surgery. Most growth hormone (GH) secreting pituitary adenomas are macroadenomas (≥ 10 mm) at diagnosis, with...
PURPOSE
Sustained cure of acromegaly can only be achieved by surgery. Most growth hormone (GH) secreting pituitary adenomas are macroadenomas (≥ 10 mm) at diagnosis, with reported surgical cure rates of approximately 50%. Long-term data on disease control rates after surgery are limited. Our aim was to estimate short- and long-term rates of biochemical control after pituitary surgery in acromegaly and identify predictive factors.
METHODS
Patients operated for GH-secreting pituitary adenomas between 2005-2020 were included from the local pituitary registry (n = 178). Disease activity and treatment data were recorded at one-year (short-term) and five-year (long-term) postoperative follow-up. Biochemical control was defined as insulin-like growth factor 1 (IGF-1) ≤ 1.2 × upper limit of normal value. Multivariate regression models were used to identify factors potentially predicting biochemical control.
RESULTS
A total of 178 patients with acromegaly (median age at diagnosis 49 (IQR: 38-59) years, 46% women) were operated for a pituitary adenoma. Biochemical control was achieved by surgery in 53% at short-term and 41% at long-term follow-up, without additional treatment for acromegaly. Biochemical control rates by surgery were of same magnitude in paired samples (45% vs. 41%, p = 0.213) for short- and long-term follow-up, respectively. At short-term, 62% of patients with microadenomas and 51% with macroadenomas, achieved biochemical control. At long-term, the biochemical control rate was 58% for microadenomas and 37% for macroadenomas (p = 0.058). With adjunctive treatment, 82% achieved biochemical control at long-term. Baseline IGF-1 levels significantly predicted biochemical control by surgery at short-term (OR: 0.98 (95% CI: 0.96-0.99), p = 0.011), but not at long-term (OR: 0.76 (95% CI: 0.57-1.00), p = 0.053).
CONCLUSION
In unselected patients with acromegaly, the long-term biochemical control rate remains modest. Our findings indicate a need to identify patients at an earlier stage and improve therapeutic methods and surgical outcomes.
Topics: Humans; Female; Adult; Middle Aged; Male; Acromegaly; Insulin-Like Growth Factor I; Pituitary Gland; Growth Hormone-Secreting Pituitary Adenoma; Pituitary Neoplasms; Adenoma; Treatment Outcome; Retrospective Studies; Human Growth Hormone
PubMed: 37665404
DOI: 10.1007/s00701-023-05772-7