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Genome Medicine Apr 2024Pituitary neuroendocrine tumors (PitNETs) are common gland neoplasms demonstrating distinctive transcription factors. Although the role of immune cells in PitNETs has...
Single-cell transcriptomics reveal distinct immune-infiltrating phenotypes and macrophage-tumor interaction axes among different lineages of pituitary neuroendocrine tumors.
BACKGROUND
Pituitary neuroendocrine tumors (PitNETs) are common gland neoplasms demonstrating distinctive transcription factors. Although the role of immune cells in PitNETs has been widely recognized, the precise immunological environment and its control over tumor cells are poorly understood.
METHODS
The heterogeneity, spatial distribution, and clinical significance of macrophages in PitNETs were analyzed using single-cell RNA sequencing (scRNA-seq), bulk RNA-seq, spatial transcriptomics, immunohistochemistry, and multiplexed quantitative immunofluorescence (QIF). Cell viability, cell apoptosis assays, and in vivo subcutaneous xenograft experiments have confirmed that INHBA-ACVR1B influences the process of tumor cell apoptosis.
RESULTS
The present study evaluated scRNA-seq data from 23 PitNET samples categorized into 3 primary lineages. The objective was to explore the diversity of tumors and the composition of immune cells across these lineages. Analyzed data from scRNA-seq and 365 bulk RNA sequencing samples conducted in-house revealed the presence of three unique subtypes of tumor immune microenvironment (TIME) in PitNETs. These subtypes were characterized by varying levels of immune infiltration, ranging from low to intermediate to high. In addition, the NR5A1 lineage is primarily associated with the subtype characterized by limited infiltration of immune cells. Tumor-associated macrophages (TAMs) expressing CX3CR1, C1Q, and GPNMB showed enhanced contact with tumor cells expressing NR5A1 + , TBX19, and POU1F1, respectively. This emphasizes the distinct interaction axes between TAMs and tumor cells based on their lineage. Moreover, the connection between CX3CR1 macrophages and tumor cells via INHBA-ACVR1B regulates tumor cell apoptosis.
CONCLUSIONS
In summary, the different subtypes of TIME and the interaction between TAM and tumor cells offer valuable insights into the control of TIME that affects the development of PitNET. These findings can be utilized as prospective targets for therapeutic interventions.
Topics: Humans; Neuroendocrine Tumors; Pituitary Neoplasms; Single-Cell Analysis; Tumor Microenvironment; Transcriptome; Animals; Mice; Macrophages; Tumor-Associated Macrophages; Gene Expression Regulation, Neoplastic; Gene Expression Profiling; Phenotype; Apoptosis; Cell Lineage
PubMed: 38658971
DOI: 10.1186/s13073-024-01325-4 -
BMC Cancer Apr 2024Emerging evidence suggests that the gut microbiota is associated with various intracranial neoplastic diseases. It has been observed that alterations in the gut...
BACKGROUND
Emerging evidence suggests that the gut microbiota is associated with various intracranial neoplastic diseases. It has been observed that alterations in the gut microbiota are present in gliomas, meningiomas, and pituitary neuroendocrine tumors (Pit-NETs). However, the correlation between gut microbiota and craniopharyngioma (CP), a rare embryonic malformation tumor in the sellar region, has not been previously mentioned. Consequently, this study aimed to investigate the gut microbiota composition and metabolic patterns in CP patients, with the goal of identifying potential therapeutic approaches.
METHODS
We enrolled 15 medication-free and non-operated patients with CP and 15 healthy controls (HCs), conducting sequential metagenomic and metabolomic analyses on fecal samples to investigate changes in the gut microbiota of CP patients.
RESULTS
The composition of gut microbiota in patients with CP compared to HCs show significant discrepancies at both the genus and species levels. The CP group exhibits greater species diversity. And the metabolic patterns between the two groups vary markedly.
CONCLUSIONS
The gut microbiota composition and metabolic patterns in patients with CP differ significantly from the healthy population, presenting potential new therapeutic opportunities.
Topics: Humans; Craniopharyngioma; Gastrointestinal Microbiome; Male; Female; Adult; Pituitary Neoplasms; Feces; Middle Aged; Case-Control Studies; Young Adult; Adolescent; Metabolomics; Metagenomics; Metabolome
PubMed: 38658858
DOI: 10.1186/s12885-024-12283-w -
Pituitary Jun 2024Prolactinomas are common tumours that significantly reduce quality-of-life (QOL) due to sellar mass effect, secondary hypogonadism, and the peripheral effects of...
BACKGROUND
Prolactinomas are common tumours that significantly reduce quality-of-life (QOL) due to sellar mass effect, secondary hypogonadism, and the peripheral effects of prolactin. Understanding the factors that influence QOL would provide insights into therapeutic targets to optimise patient outcomes and improve wellbeing in prolactinoma.
METHODS
A systematic review was performed in accordance with the PRISMA statement. Studies that reported patient QoL using validated metrics were included. Bias and methodological rigour were assessed using the MINORS criteria.
RESULTS
A total of 18 studies were identified studies were available for review, comprising 877 patients. Most were small cross-sectional studies at high risk of bias. Prolactinoma exhibit worse QOL than healthy controls, particularly mental and psychosocial wellbeing. QOL is also worse than patients with non-functional adenomas, but better than those with Cushing's disease and acromegaly. QOL correlates with prolactin levels, and approaches population baseline with prolonged biochemical control. Dopamine agonists and surgery both improve overall QOL, however improvements are more rapid with surgery.
CONCLUSION
Poor quality of life in prolactinoma is multifactorial, related to biochemical control, side effects of therapy, and sellar mass effect. Targeting persistent symptoms, reducing healthcare costs, and reducing side-effects of therapy are avenues to improving QOL in patients with prolactinoma.
Topics: Prolactinoma; Humans; Quality of Life; Pituitary Neoplasms; Dopamine Agonists
PubMed: 38656635
DOI: 10.1007/s11102-024-01392-1 -
Neurosurgical Review Apr 2024To analyse the imaging findings of papillary glioneuronal tumors (PGNTs), in order to improve the accuracy of preoperative diagnosis of this tumor. The clinical and...
To analyse the imaging findings of papillary glioneuronal tumors (PGNTs), in order to improve the accuracy of preoperative diagnosis of this tumor. The clinical and imaging manifestations of 36 cases of PGNT confirmed by pathology were analyzed retrospectively. A total of 17 males and 19 females, averaging 22.47 (± 11.23) years. Initial symptoms included epilepsy in ten, headache in seven, and others in 19 cases. 97.2% (35/36) of the lesions were located in the supratentorial area, and 80.5% (29/36) in the intraventricular or deep white matter adjacent to the lateral ventricles. Twenty-four of the lesions (66.7%) were mixed cystic and solid, four (11.1%) were cystic with mural nodules, four (11.1%) were cystic, and four (11.1%) were solid. Four cases of PGNT of cystic imaging showed a "T2-FLAIR mismatch" sign. 69.4% (25/36) had septations. Nine lesions (25%) were accompanied by edema, and 9 (25%) of the mixed cystic and solid lesions were accompanied by hemorrhage. Among the 18 patients who underwent computed tomography (CT) or susceptibility-weighted imaging (SWI), nine had lesions with calcification. PGNTs mostly manifest as cystic mass with mural nodules or mixed cystic and solid mass in the white matter around the supratentorial ventricle, and the cystic part of the lesion is mostly accompanied by septations. Pure cystic lesions may exhibit the sign of "T2-FLAIR mismatch". PGNT is rarely accompanied by edema but sometimes by calcification and hemorrhage. Patients often present with seizures, headaches, and mass effect symptoms.
Topics: Humans; Male; Female; Adult; Adolescent; Young Adult; Child; Magnetic Resonance Imaging; Retrospective Studies; Brain Neoplasms; Tomography, X-Ray Computed; Middle Aged; Ganglioglioma; Child, Preschool
PubMed: 38649515
DOI: 10.1007/s10143-024-02393-1 -
Frontiers in Endocrinology 2024Prolactinomas (PRLs) are prevalent pituitary adenomas associated with metabolic changes and increased cardiovascular morbidity. This study examined clinical, endocrine,...
Metabolic and inflammatory parameters in relation to baseline characterization and treatment outcome in patients with prolactinoma: insights from a retrospective cohort study at a single tertiary center.
BACKGROUND
Prolactinomas (PRLs) are prevalent pituitary adenomas associated with metabolic changes and increased cardiovascular morbidity. This study examined clinical, endocrine, metabolic, and inflammatory profiles in PRL patients, aiming to identify potential prognostic markers.
METHODS
The study comprised data from 59 PRL patients gathered in a registry at the University Hospital of Zurich. Diagnostic criteria included MRI findings and elevated serum prolactin levels. We assessed baseline and follow-up clinical demographics, metabolic markers, serum inflammation-based scores, and endocrine parameters. Treatment outcomes were evaluated based on prolactin normalization, tumor shrinkage, and cabergoline dosage.
RESULTS
The PRL cohort exhibited a higher prevalence of overweight/obesity, prediabetes/diabetes mellitus, and dyslipidemia compared to the general population. Significant correlations were found between PRL characteristics and BMI, HbA1c, and fT4 levels. Follow-up data indicated decreases in tumor size, tumor volume, prolactin levels, and LDL-cholesterol, alongside increases in fT4 and sex hormones levels. No significant associations were observed between baseline parameters and tumor shrinkage at follow-up. A positive association was noted between PRL size/volume and the time to achieve prolactin normalization, and a negative association with baseline fT4 levels.
CONCLUSION
This study underscores the metabolic significance of PRL, with notable correlations between PRL parameters and metabolic indices. However, inflammatory markers were not significantly correlated with patient stratification or outcome prediction. These findings highlight the necessity for standardized follow-up protocols and further research into the metabolic pathogenesis in PRL patients.
Topics: Humans; Prolactinoma; Female; Male; Adult; Retrospective Studies; Middle Aged; Pituitary Neoplasms; Treatment Outcome; Inflammation; Tertiary Care Centers; Cabergoline; Prolactin; Prognosis; Follow-Up Studies; Cohort Studies; Young Adult
PubMed: 38645431
DOI: 10.3389/fendo.2024.1363939 -
Chinese Clinical Oncology Apr 2024The role of adjuvant radiotherapy (RT) after gross total resection (GTR) of the World Health Organization (WHO) grade II ependymoma is controversial. Therefore, we aimed... (Meta-Analysis)
Meta-Analysis
BACKGROUND
The role of adjuvant radiotherapy (RT) after gross total resection (GTR) of the World Health Organization (WHO) grade II ependymoma is controversial. Therefore, we aimed to compare the outcomes of adjuvant RT against observation after GTR of WHO grade II ependymoma. We also compared the outcomes of adjuvant RT against observation after subtotal resection (STR) of WHO grade II ependymoma and performed further subgroup analysis by age and tumor location.
METHODS
PubMed and Embase were systematically reviewed for studies published up till 25 November 2022. Studies that reported individual-participant data on patients who underwent surgery followed by adjuvant RT/observation for WHO grade II ependymoma were included. The exposure was whether adjuvant RT was administered, and the outcomes were recurrence and overall survival (OS). Subgroup analyses were performed by the extent of resection (GTR or STR), tumor location (supratentorial or infratentorial), and age at the first surgery (<18 or ≥18 years old).
RESULTS
Of the 4,647 studies screened, three studies reporting a total of 37 patients were included in the analysis. Of these 37 patients, 67.6% (25 patients) underwent GTR, and 51.4% (19 patients) underwent adjuvant RT. Adjuvant RT after GTR was not significantly associated with both recurrence (odds ratio =5.50; 95% confidence interval: 0.64-60.80; P=0.12) and OS (P=0.16). Adjuvant RT was also not significantly associated with both recurrence and OS when the cohort was analyzed as a whole and on subgroup analysis by age and tumor location. However, adjuvant RT was associated with significantly longer OS after STR (P=0.03) with the median OS being 6.33 years, as compared to 0.40 years for patients who underwent STR followed by observation.
CONCLUSIONS
Based on our meta-analysis of 37 patients, administration of adjuvant RT after GTR was not significantly associated with improvement in OS or recurrence in patients with WHO grade II ependymoma. However, due to the small number of patients included in the analysis, further prospective controlled studies are warranted.
Topics: Humans; Ependymoma; Radiotherapy, Adjuvant; Female; Male; Neoplasm Grading; World Health Organization
PubMed: 38644544
DOI: 10.21037/cco-23-136 -
Acta Neuropathologica Communications Apr 2024We aimed to identify the druggable cell-intrinsic vulnerabilities and target-based drug therapies for PitNETs using the high-throughput drug screening (HTS) and genomic...
We aimed to identify the druggable cell-intrinsic vulnerabilities and target-based drug therapies for PitNETs using the high-throughput drug screening (HTS) and genomic sequencing methods. We examined 9 patient-derived PitNET primary cells in HTS. Based on the screening results, the potential target genes were analyzed with genomic sequencing from a total of 180 PitNETs. We identified and verified one of the most potentially effective drugs, which targeted the Histone deacetylases (HDACs) both in in vitro and in vivo PitNET models. Further RNA sequencing revealed underlying molecular mechanisms following treatment with the representative HDACs inhibitor, Panobinostat. The HTS generated a total of 20,736 single-agent dose responses which were enriched among multiple inhibitors for various oncogenic targets, including HDACs, PI3K, mTOR, and proteasome. Among these drugs, HDAC inhibitors (HDACIs) were, on average, the most potent drug class. Further studies using in vitro, in vivo, and isolated PitNET primary cell models validated HDACIs, especially Panobinostat, as a promising therapeutic agent. Transcriptional surveys revealed substantial alterations to the Nrf2 signaling following Panobinostat treatment. Moreover, Nrf2 is highly expressed in PitNETs. The combination of Panobinostat and Nrf2 inhibitor ML385 had a synergistic effect on PitNET suppression. The current study revealed a class of effective anti-PitNET drugs, HDACIs, based on the HTS and genomic sequencing. One of the representative compounds, Panobinostat, may be a potential drug for PitNET treatment via Nrf2-mediated redox modulation. Combination of Panobinostat and ML385 further enhance the effectiveness for PitNET treatment.
Topics: Humans; Panobinostat; NF-E2-Related Factor 2; Neuroendocrine Tumors; Histone Deacetylase Inhibitors; Signal Transduction; Pituitary Neoplasms
PubMed: 38637883
DOI: 10.1186/s40478-024-01775-2 -
Frontiers in Endocrinology 2024Double pituitary adenomas (DPA) are a rare clinical condition, and our knowledge of them is limited. Missing the second lesion leading to incomplete biochemical...
OBJECTIVE
Double pituitary adenomas (DPA) are a rare clinical condition, and our knowledge of them is limited. Missing the second lesion leading to incomplete biochemical remission after surgery is an important challenge in DPA management. This study aims to analyze independent prognostic factors in DPA patients and summarize clinical experiences to prevent surgical failure.
METHODS
Two cases of DPA patients with Cushing's disease diagnosed and surgically treated at Peking Union Medical College Hospital are reported. A literature review was performed on the online database Pubmed, and 57 DPA patients from 22 retrieved articles were included. Demographic characteristics, endocrine manifestations, diagnostic methods, tumor size, and immunohistochemical features of 59 patients were analyzed. Binary logistic regression models were used to identify independent prognostic factors affecting postoperative biochemical remission.
RESULTS
Among 59 DPA patients, the mean ± SD age was 43.64 ± 14.42 years, with 61.02% being female (n = 36). The most common endocrine manifestations were Cushing's syndrome (23/59, 38.98%) and acromegaly (20/59, 33.90%). The most prevalent immunohistochemical types were ACTH-immunopositive (31/118, 26.27%) and GH-immunopositive (31/118, 26.27%) tumors. Microadenomas (<1cm) were the most frequent in terms of tumor size (62/92, 67.39%). The detection rate for double lesions on 3.0T MRI was 50.00% (14/28), which significantly higher than 1.5T MRI (P = 0.034). Univariate analysis revealed that female, Cushing's syndrome and only single lesion detected by surgical exploration were associated with significantly worse prognosis (P<0.05). Multivariate analysis identified double lesion detected by surgical exploration (OR = 0.08, P = 0.003) and contiguous type tumor (OR = 0.06, P = 0.017) as independent protective factors for DPA patients.
CONCLUSIONS
The double lesion detected by surgical exploration is independently associated with a better prognosis for DPA patients. Comprehensive intraoperative exploration are crucial measures to avoid missing causative lesions.
Topics: Adult; Female; Humans; Male; Middle Aged; Acromegaly; Adenoma; Cushing Syndrome; Pituitary ACTH Hypersecretion; Pituitary Neoplasms
PubMed: 38628582
DOI: 10.3389/fendo.2024.1373869 -
BMC Endocrine Disorders Apr 2024Headache is a common occurrence after endoscopic endonasal surgery (EES) for pituitary adenomas and significantly impacts the quality of life of patients. This study...
BACKGROUND
Headache is a common occurrence after endoscopic endonasal surgery (EES) for pituitary adenomas and significantly impacts the quality of life of patients. This study aims to investigate the effectiveness of nasal irrigation in relieving postoperative headache after EES.
METHODS
A retrospective analysis was conducted on a cohort of 101 patients (Cohort I) who underwent EES for pituitary adenomas to explore the risk factors associated with postoperative headache. Another cohort of 72 patients (Cohort II) who received adjuvant nasal irrigation following surgery was enrolled for further analysis. The Headache Impact Test (HIT-6) was used to score the severity of headache, and patients with a HIT score > 55 were classified as having headache.
RESULTS
In Cohort I, 21.78% of patients experienced headache one month after EES, which decreased to 5.94% at the three-month follow-up. Multivariate analysis revealed that postoperative nasal sinusitis (OR = 3.88, 95%CI 1.16-13.03, p = 0.028) and Hardy's grade C-D (OR = 10.53, 95%CI 1.02-109.19, p = 0.049) independently predicted the presence of postoperative headache at one month. At the three-month follow-up, patients with sinusitis had higher HIT-6 scores compared to those without sinusitis (44.43 ± 9.78 vs. 39.72 ± 5.25, p = 0.017). In Cohort II, the incidence of sinusitis at three months was significantly lower than that in Cohort I (p = 0.028). Importantly, both the incidence of headache and HIT-6 scores in Cohort II were significantly lower than those in Cohort I at the one- and three-month follow-ups.
CONCLUSIONS
Postoperative sinusitis is an independent risk factor for the development of headache following EES for pituitary adenomas. Prophylactic nasal irrigation helps relieve postoperative headache, possibly by preventing the occurrence of sinusitis.
Topics: Humans; Pituitary Neoplasms; Retrospective Studies; Quality of Life; Treatment Outcome; Endoscopy; Headache; Sinusitis; Nasal Lavage
PubMed: 38622616
DOI: 10.1186/s12902-024-01573-w -
International Journal of Molecular... Apr 2024Clinically non-functioning pituitary adenomas (CNFPAs) are the second most frequent sellar tumor among studies on community-dwelling adults. They are characterized by...
Clinically non-functioning pituitary adenomas (CNFPAs) are the second most frequent sellar tumor among studies on community-dwelling adults. They are characterized by the absence of hormonal hypersecretion syndrome, and patients present with compressive symptoms, such as a headache and visual field defects. Immunohistochemically, most CNFPAs are of gonadotrope differentiation, with only a few of them being truly null cell adenomas. Although these tumors express receptors for one or more hypothalamic releasing hormones, to what extent this has an impact on the biological and clinical behavior of these neoplasms remains to be defined. In this research, we evaluated the basal and hypothalamic secretagogue-stimulated intracellular calcium mobilization in 13 CNFPAs, trying to correlate this response to the phenotypic features of the patients. Our results indicate that the recurrence of a CNFPA correlates positively with cellular responsiveness, as measured by spontaneous intracellular calcium activity and the ability to respond to multiple hypothalamic secretagogues. We conclude that this finding may be a useful tool for predicting the clinicopathologic behavior of CNFPAs, by testing the variation of cellular responsiveness to hypothalamic secretagogues.
Topics: Adult; Humans; Pituitary Neoplasms; Calcium; Calcium Signaling; Neoplasm Recurrence, Local; Secretagogues; Calcium, Dietary; Neoplasms, Second Primary
PubMed: 38612778
DOI: 10.3390/ijms25073968