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Journal of Endocrinological... Jun 2024At present, various treatment strategies are available for pituitary adenomas, including medications, surgery and radiation. The guidelines indicate that pharmacological...
PURPOSE
At present, various treatment strategies are available for pituitary adenomas, including medications, surgery and radiation. The guidelines indicate that pharmacological treatments, such as bromocriptine (BRC) and cabergoline (CAB), are important treatments for prolactinomas, but drug resistance is an urgent problem that needs to be addressed. Therefore, exploring the mechanism of drug resistance in prolactinomas is beneficial for clinical treatment.
METHODS
In our research, BRC-induced drug-resistant cells were established. Previous RNA sequencing data and an online database were used for preliminary screening of resistance-related genes. Cell survival was determined by Cell Counting Kit-8 (CCK-8) assay, colony formation assays and flow cytometry. Quantitative real-time polymerase chain reaction (qRT‒PCR), western blotting, immunohistochemistry, immunofluorescence and Co-immunoprecipitation (Co-IP) were used to assess the molecular changes and regulation. The therapeutic efficacy of BRC and FGFR4 inhibitor fisogatinib (FISO) combination was evaluated in drug-resistant cells and xenograft tumors in nude mice.
RESULTS
Consistent with the preliminary results of RNA sequencing and database screening, fibroblast growth factor 19 (FGF19) expression was elevated in drug-resistant cells and tumor samples. With FGF19 silencing, drug-resistant cells exhibited increased sensitivity to BRC and decreased intracellular phosphorylated fibroblast growth factor receptor 4 (FGFR4) levels. After confirming that FGF19 binds to FGFR4 in prolactinoma cells, we found that FGF19/FGFR4 regulated prolactin (PRL) synthesis through the ERK1/2 and JNK signaling pathways. Regarding the effect of targeting FGF19/FGFR4 on BRC efficacy, FISO and BRC synergistically inhibited the growth of tumor cells, promoted apoptosis and reduced PRL levels.
CONCLUSION
Overall, our study revealed FGF19/FGFR4 as a new mechanism involved in the drug resistance of prolactinomas, and combination therapy targeting the pathway could be helpful for the treatment of BRC-induced drug-resistant prolactinomas.
PubMed: 38926262
DOI: 10.1007/s40618-024-02408-0 -
Journal of Gastroenterology and... Jun 2024There are no previous studies in which computer-aided diagnosis (CAD) diagnosed colorectal cancer (CRC) subtypes correctly. In this study, we developed an original CAD...
BACKGROUND AND AIM
There are no previous studies in which computer-aided diagnosis (CAD) diagnosed colorectal cancer (CRC) subtypes correctly. In this study, we developed an original CAD for the diagnosis of CRC subtypes.
METHODS
Pretraining for the CAD based on ResNet was performed using ImageNet and five open histopathological pretraining image datasets (HiPreD) containing 3 million images. In addition, sparse attention was introduced to improve the CAD compared to other attention networks. One thousand and seventy-two histopathological images from 29 early CRC cases at Kyoto Prefectural University of Medicine from 2019 to 2022 were collected (857 images for training and validation, 215 images for test). All images were annotated by a qualified histopathologist for segmentation of normal mucosa, adenoma, pure well-differentiated adenocarcinoma (PWDA), and moderately/poorly differentiated adenocarcinoma (MPDA). Diagnostic ability including dice sufficient coefficient (DSC) and diagnostic accuracy were evaluated.
RESULTS
Our original CAD, named Colon-seg, with the pretraining of both HiPreD and ImageNET showed a better DSC (88.4%) compared to CAD without both pretraining (76.8%). Regarding the attentional mechanism, Colon-seg with sparse attention showed a better DSC (88.4%) compared to other attentional mechanisms (dual: 79.7%, ECA: 80.7%, shuffle: 84.7%, SK: 86.9%). In addition, the DSC of Colon-seg (88.4%) was better than other types of CADs (TransUNet: 84.7%, MultiResUnet: 86.1%, Unet++: 86.7%). The diagnostic accuracy of Colon-seg for each histopathological type was 94.3% for adenoma, 91.8% for PWDA, and 92.8% for MPDA.
CONCLUSION
A deep learning-based CAD for CRC subtype differentiation was developed with pretraining and fine-tuning of abundant histopathological images.
PubMed: 38923607
DOI: 10.1111/jgh.16661 -
Diagnostic Cytopathology Jun 2024Mammary analogue secretory carcinoma (MASC) is a rare salivary gland tumor which shares its histologic, immunohistochemical, and genetic features with the secretory...
Mammary analogue secretory carcinoma (MASC) is a rare salivary gland tumor which shares its histologic, immunohistochemical, and genetic features with the secretory carcinoma (SC) of breast. In this case report, we describe a case of MASC in a young adolescent male with swelling in the right angle of mandible which is a relatively rare site to present along with its correlation of cytological, histological, and immunohistochemical features. A 16-year-old male came with the complaint of swelling in the right angle of mandible since 2 years. Contrast-enhanced computed tomography (CECT) neck revealed differential diagnosis of nerve sheath tumor, pleomorphic adenoma, and adenoid cystic neoplasm was kept, and subsequently fine-needle aspiration cytology (FNAC) was done. FNAC was done in which differential diagnosis of myoepithelial neoplasm, acinic cell carcinoma, and SC was given. Surgical excision was done followed by histopathological examination. Immunohistochemistry panel was also applied, and final diagnosis of SC was rendered. SC has distinct cytological, histological, and immunohistochemical features which should be recognized by the pathologists for the appropriate management of the patient.
PubMed: 38923370
DOI: 10.1002/dc.25377 -
Histopathology Jun 2024Sclerosing lesions of the breast encompass a spectrum of benign and malignant entities and often pose a diagnostic challenge. Awareness of key morphologic features and... (Review)
Review
Sclerosing lesions of the breast encompass a spectrum of benign and malignant entities and often pose a diagnostic challenge. Awareness of key morphologic features and pitfalls in the assessment of morphology and immunophenotype is essential to avoid over- or underdiagnosis and ensure optimal clinical management. This review summarizes nonneoplastic sclerosing lesions such as radial scar/complex sclerosing lesion, sclerosing adenosis, sclerosing intraductal papilloma, sclerosing variants of ductal adenoma and nipple adenoma, and fibroadenoma with extensive sclerosis, including their clinical presentation, characteristic morphology, differential diagnostic considerations, appropriate immunohistochemical work-up, when needed, and the clinical significance. In addition, atypical or neoplastic entities (such as atypical ductal hyperplasia, ductal carcinoma in situ, low-grade adenosquamous carcinoma, and fibromatosis-like metaplastic carcinoma) that can involve these sclerosing lesions are also briefly discussed.
PubMed: 38923027
DOI: 10.1111/his.15252 -
Virchows Archiv : An International... Jun 2024Mixed adenoma-neuroendocrine tumor (MANET) comprises adenoma and well-differentiated neuroendocrine tumor (NET) components. Given the limited information on this due to...
Mixed adenoma-neuroendocrine tumor (MANET) comprises adenoma and well-differentiated neuroendocrine tumor (NET) components. Given the limited information on this due to its rarity, we aimed to clarify the clinicopathologic features and optimal management of gastric MANETs in a case series and literature review. Nine patients with gastric MANETs, including eight male and one female patient (mean age, 72 years), were identified from the institutional pathology archive. Endoscopically, the tumors appeared as flat elevated lesions with sizes ranging from 0.8 to 4.4 cm. One patient had familial adenomatous polyposis, and no patient had autoimmune gastritis. All MANETs developed in the gastric body mucosa exhibiting chronic metaplastic atrophic gastritis. The glandular components were intestinal-type low-grade adenoma, and focal high-grade dysplasia was also recognized in three cases. The NET component was in middle/deep lamina propria in six cases and confined to deep lamina propria in the remaining three cases. Minimal cytologic atypia was found in the NET component, with no recognizable mitosis and a Ki-67 labeling index of < 2%. The NET component mostly showed diffuse positivity for serotonin and CDX2, suggesting that it consists of enterochromaffin cells. Diffuse p53 immunostaining was observed only in the high-grade adenomatous component of one case. No recurrence was observed during the follow-up period of 2-94 months. Correct distinction between the NET and poorly differentiated carcinoma components is crucial to prevent overtreatment of gastric MANETs. Considering its indolent nature, endoscopic resection is the primary recommendation for gastric MANETs as well as for pure adenomas.
PubMed: 38922356
DOI: 10.1007/s00428-024-03851-3 -
ELife Jun 2024mutation is a driver mutation in the serrated pathway to colorectal cancers. BRAF drives tumorigenesis through constitutive downstream extracellular signal-regulated...
mutation is a driver mutation in the serrated pathway to colorectal cancers. BRAF drives tumorigenesis through constitutive downstream extracellular signal-regulated kinase (ERK) activation, but high-intensity ERK activation can also trigger tumor suppression. Whether and how oncogenic ERK signaling can be intrinsically adjusted to a 'just-right' level optimal for tumorigenesis remains undetermined. In this study, we found that FAK (Focal adhesion kinase) expression was reduced in -mutant adenomas/polyps in mice and patients. In ; mice, deletion maximized BRAF's oncogenic activity and increased cecal tumor incidence to 100%. Mechanistically, our results showed that Fak loss, without jeopardizing BRAF-induced ERK pathway transcriptional output, reduced EGFR (epidermal growth factor receptor)-dependent ERK phosphorylation. Reduction in ERK phosphorylation increased the level of Lgr4, promoting intestinal stemness and cecal tumor formation. Our findings show that a 'just-right' ERK signaling optimal for -induced cecal tumor formation can be achieved via Fak loss-mediated downregulation of ERK phosphorylation.
Topics: Animals; Proto-Oncogene Proteins B-raf; Phosphorylation; Mice; Humans; Cecal Neoplasms; Focal Adhesion Kinase 1; Extracellular Signal-Regulated MAP Kinases; MAP Kinase Signaling System; ErbB Receptors; Carcinogenesis; Receptors, G-Protein-Coupled; Male
PubMed: 38921956
DOI: 10.7554/eLife.94605 -
Cells Jun 2024Pleural mesothelioma (PM) is a highly aggressive tumor that is caused by asbestos exposure and lacks effective therapeutic regimens. Current procedures for PM diagnosis...
Pleural mesothelioma (PM) is a highly aggressive tumor that is caused by asbestos exposure and lacks effective therapeutic regimens. Current procedures for PM diagnosis are invasive and can take a long time to reach a definitive result. Small extracellular vesicles (sEVs) have been identified as important communicators between tumor cells and their microenvironment via their cargo including circular RNAs (circRNAs). CircRNAs are thermodynamically stable, highly conserved, and have been found to be dysregulated in cancer. This study aimed to identify potential biomarkers for PM diagnosis by investigating the expression of specific circRNA gene pattern (hsa_circ_0007386) in cells and sEVs using digital polymerase chain reaction (dPCR). For this reason, 5 PM, 14 non-PM, and one normal mesothelial cell line were cultured. The sEV was isolated from the cells using the gold standard ultracentrifuge method. The RNA was extracted from both cells and sEVs, cDNA was synthesized, and dPCR was run. Results showed that hsa_circ_0007386 was significantly overexpressed in PM cell lines and sEVs compared to non-PM and normal mesothelial cell lines ( < 0.0001). The upregulation of hsa_circ_0007386 in PM highlights its potential as a diagnostic biomarker. This study underscores the importance and potential of circRNAs and sEVs as cancer diagnostic tools.
Topics: Humans; RNA, Circular; Extracellular Vesicles; Biomarkers, Tumor; Mesothelioma; Cell Line, Tumor; Pleural Neoplasms; Gene Expression Regulation, Neoplastic; Mesothelioma, Malignant
PubMed: 38920665
DOI: 10.3390/cells13121037 -
JCEM Case Reports Jun 2024Chiari 1 malformation (CM1) is a rare finding that has been described with growth hormone (GH)-secreting pituitary adenomas and with an endothelial PAS domain protein 1...
Chiari 1 malformation (CM1) is a rare finding that has been described with growth hormone (GH)-secreting pituitary adenomas and with an endothelial PAS domain protein 1 gain-of-function mutation syndrome. We describe the first reported case of a patient diagnosed with CM1 and nonfunctioning pituitary and adrenal incidentalomas. Our case describes a 45-year-old female who was found to have cerebellar tonsillar ectopia consistent with CM1, a pituitary tumor, and bilateral adrenal incidentalomas. She was diagnosed after presenting with 2 weeks of upper extremity weakness and paresthesia. A comprehensive endocrine workup including insulin like growth factor (IGF-1) was normal. She underwent posterior fossa decompression without complication. Pituitary adenectomy was not pursued as there was no evidence of compression of the chiasm or the surrounding structures. In previous case reports it has been proposed that GH-secreting adenomas contribute to CM1 by causing hypertrophy of soft tissue structures in the skull base, overcrowding the posterior fossa. Given that our patient had normal IGF-1 levels, there could be a different underlying mechanism that contributed to the concomitant occurrence of CM1 with the pituitary and adrenal tumors.
PubMed: 38919912
DOI: 10.1210/jcemcr/luae113 -
Frontiers in Endocrinology 2024Acromegaly is a rare endocrine disorder caused by hypersecretion of growth hormone (GH) from a pituitary adenoma. Elevated GH levels stimulate excess production of...
UNLABELLED
Acromegaly is a rare endocrine disorder caused by hypersecretion of growth hormone (GH) from a pituitary adenoma. Elevated GH levels stimulate excess production of insulin-like growth factor 1 (IGF-1) which leads to the insidious onset of clinical manifestations. The most common primary central nervous system (CNS) tumors, meningiomas originate from the arachnoid layer of the meninges and are typically benign and slow-growing. Meningiomas are over twice as common in women as in men, with age-adjusted incidence (per 100,000 individuals) of 10.66 and 4.75, respectively. Several reports describe co-occurrence of meningiomas and acromegaly. We aimed to determine whether patients with acromegaly are at elevated risk for meningioma. Investigation of the literature showed that co-occurrence of a pituitary adenoma and a meningioma is a rare phenomenon, and the majority of cases involve GH-secreting adenomas. To the best of our knowledge, a systematic review examining the association between meningiomas and elevated GH levels (due to GH-secreting adenomas in acromegaly or exposure to exogenous GH) has never been conducted. The nature of the observed coexistence between acromegaly and meningioma -whether it reflects causation or mere co-association -is unclear, as is the pathophysiologic etiology.
SYSTEMATIC REVIEW REGISTRATION
https://www.crd.york.ac.uk/prospero/, identifier CRD42022376998.
Topics: Humans; Meningioma; Acromegaly; Meningeal Neoplasms; Human Growth Hormone; Risk Factors; Adenoma
PubMed: 38919490
DOI: 10.3389/fendo.2024.1407615 -
Clinical Ophthalmology (Auckland, N.Z.) 2024To investigate the long-term visual outcome and their determinants after an operation in Thai pituitary adenoma (PA).
PURPOSE
To investigate the long-term visual outcome and their determinants after an operation in Thai pituitary adenoma (PA).
PATIENTS AND METHODS
A retrospective cohort study was conducted on PA patients who underwent surgery at Rajavithi Hospital. Baseline characteristics and visual parameters, including visual acuity (VA) and visual field (VF), were analyzed in relation to the visual prognosis outcome. The outcome was defined as VA improvement at 1-year postoperatively. Visual parameters were measured at each follow-up visit and compared. Factors for improved visual prognosis were evaluated using logistic regression analysis.
RESULTS
A total cohort of 87 patients (64.37% female), 62.07% showed improvement in visual outcome. Most improvement occurred immediately after surgery, evident at the 1-month visit. The mean follow-up time was 47.45 months (±28.49 SD), mean difference in VA improvement at 1-year was -0.56 logMAR (95% CI -0.73, -0.47). In multivariable logistic regression model, prolonged onset duration was associated with a reduced odds of improved visual outcome, with an odds ratio (OR) of 0.946 (95% CI 0.899-0.996, p = 0.034). Baseline characteristics, tumor volume, Hardy and Knops classification, and surgical approaches were not identified as significant predictors.
CONCLUSION
Both TSS and transcranial approaches are effective for pituitary adenoma. A prompt operation is recommended for patients with prolonged onset duration, with thorough discussion on poor postoperative visual outcomes.
PubMed: 38919405
DOI: 10.2147/OPTH.S463303