Endocrine-related cancer最新文献

Experimental models for pheochromocytoma and paraganglioma are needed for basic pathobiology research and for preclinical testing of drugs to improve treatment of patients with these tumors, especially patients with metastatic disease. The paucity of models reflects the rarity of the tumors, their slow growth, and their genetic complexity. While there are no human cell line or xenograft models that faithfully recapitulate the genotype or phenotype of these tumors, the past decade has shown progress in development and utilization of animal models, including a mouse and a rat model for SDH-deficient pheochromocytoma associated with germline Sdhb mutations. There are also innovative approaches to preclinical testing of potential treatments in primary cultures of human tumors. Challenges with these primary cultures include how to account for heterogeneous cell populations that will vary depending on the initial tumor dissociation and how to distinguish drug effects on neoplastic vs normal cells. The feasible duration for maintaining cultures must also be balanced against time required to reliably assess drug efficacy. Considerations potentially important for all in vitro studies include species differences, phenotype drift, changes that occur in the transition from tissue to cell culture, and the O2 concentration in which cultures are maintained.

Immunotherapy has shown promising efficacy for breast cancer (BC) patients. Yet the predictive biomarkers for immunotherapy response remain lacking. Based on two GEO datasets, 53 differentially expressed genes associated with durvalumab treatment response were identified. Using least absolute shrinkage and selection operator (LASSO) and univariate Cox regression, four genes (COL12A1, TNN, SCUBE2, and FDCSP) revealed prognostic value in the TCGA BC cohort. COL12A1 outperformed the others, without overlap in its survival curve. Survival analysis by Kaplan-Meier plotter demonstrated that COL12A1 was negatively associated with BC patients' prognosis. A COL12A1-based nomogram was further developed to predict the overall survival in BC patients. The calibration plot revealed an optimal agreement between nomogram prediction and actual observation. Moreover, COL12A1 expression was significantly up-regulated in BC tissues and COL12A1 knockdown impaired the proliferation of MDA-MB-231 and BT549 cells. Gene Ontology, Kyoto Encyclopedia of Genes and Genomes, and Gene Set Enrichment analysis pathway indicated that the function of COL12A1 was related to immunity-related pathways. Immunological analyses illustrated that COL12A1 was correlated with M2 macrophage infiltration and M2 macrophage markers (transforming growth factor beta 1 (TGFB1), interleukin-10, colony stimulating factor 1 receptor (CSF1R) and CD163) in BC. Immunohistochemistry staining further revealed a highly positive relationship of COL12A1 with TGF-β1. The co-incubated models of BC cells and M2 macrophges showed COL12A1 knockdown suppressed M2 macrophage infiltration. Additionally, silencing COL12A1 suppressed TGF-B1 protein expression, and treating with TGFB1 could reverse the inhibitory effects on M2 macrophage infiltration by COL12A1 knockdown. Using immunotherapy datasets, we also found elevated expression of COL12A1 predicted poor response to anti-PD-1/PD-L1 therapy. These results reinforce the current understanding of COL12A1's roles in tumorigenesis and immunotherapy response in BC.

Purpose: The purpose of this work was toinvestigate the clinicopathological characteristics at the initial diagnosis of the pituitary tumor and at pituitary carcinoma (PC) diagnosis, alongside with the management and outcomes of PCs, and identify potential prognostic factors and therapeutic strategies associated with the clinical outcome.

Methods: PubMed was searched in May 2021 for articles in English and French reporting PCs, the diagnosis of which was made on the presence of metastases. The cases without histological proof and with either another cancer present or an atypical history for a pituitary tumor were excluded.

Results: One hundred and eighty-one articles reporting 207 cases were included, which included 38% corticotroph and 29% lactotroph carcinomas. An initial Ki67 index ≥10% was associated with shorter survival after the initial diagnosis (P = 0.01). Cases with early metastases were associated with both higher initial Ki67 index (P = 0.01) and shorter survival after PC diagnosis (P = 0.001). Interestingly, cases with short survival after PC diagnosis were associated with shorter time between the initial diagnosis and PC diagnosis (P = 0.0006) and had both higher initial Ki67 index (P = 0.003) and higher Ki67 index of the metastasis (P = 0.03). In addition, cases with long survival after PC diagnosis had received more frequently both systemic treatment after PC diagnosis (P = 0.0005) and local treatment for metastases (P < 0.0001).

Conclusions: An initial Ki67 index ≥10% is associated with worse outcome and appears as a promising early marker of future metastasis. Its presence should lead to an intensified surveillance and to a more timely management. Clinicians should not hesitate to use local treatment, independent of whether systemic treatment is used.

Interest in investigating the role of the growth hormone (GH)/insulin-like growth factor 1 (IGF-1) axis in the initiation and progression of experimentally induced carcinomas has arisen due to several observations in the human population. First, subjects with Laron syndrome who lack GH signaling have significantly lower rates of cancer than people who have normal GH signaling. Second, epidemiologic studies have found strong associations between elevated circulating IGF-1 and the incidence of several common cancers. Third, women who bear children early in life have a dramatically reduced risk of developing breast cancer, which may be due to differences in hormone levels including GH. These observations have motivated multiple studies that have experimentally altered activity of the GH/IGF-1 axis in the context of experimental carcinoma models in mice and rats. Most of these studies have utilized carcinoma models for four organ systems that are also frequent sites of carcinomas in humans: the mammary gland, prostate gland, liver, and colon. This review focuses on these studies and describes some of the most common genetic models used to alter the activity of the GH/IGF-1 axis in experimentally induced carcinomas. A recurring theme that emerges from these studies is that manipulations that reduce the activity of GH or mediators of GH action also inhibit carcinogenesis in multiple model systems.

Insulinomas are rare functional pancreatic neuroendocrine tumors. While most insulinomas are indolent and cured after surgery, 10-15% of cases show aggressive or malignant tumor behavior and metastasize locally or to distant organs. Patients with metastatic insulinoma survive significantly shorter. Recognizing aggressive insulinomas can help to predict prognosis, guide therapy and determine follow-up intensity after surgery. This review offers a summary of the literature on the significant clinical, pathological, genetic and epigenetic differences between indolent and aggressive insulinomas. Aggressive insulinomas are characterized by rapid onset of symptoms, larger size, expression of ARX and alpha-1-antitrypsin and decreased or absent immunohistochemical expression of insulin, PDX1 and GLP-1R. Moreover, aggressive insulinomas often harbor ATRX or DAXX mutations, the alternative lengthening of telomeres phenotype and chromosomal instability. Tumor grade and MEN1 and YY1 mutations are less useful for predicting behavior. Aggressive insulinomas have similarities to normal alpha-cells and non-functional pancreatic neuroendocrine tumors, while indolent insulinomas remain closely related to normal beta-cells. In conclusion, indolent and aggressive insulinoma are different entities, and distinguishing these will have future clinical value in determining prognosis and treatment.

Parathyroid carcinoma is one of the least common endocrine malignancies and accounts for approximately 1% of all patients with primary hyperparathyroidism. A systematic review of peer-reviewed literature published between January 2000 and March 2022 via Medline, Embase, Cochrane Central Register of Controlled Trials, EudraCT, ClinicalTrials.gov, CINAHL and SCOPUS was conducted. Manuscripts were eligible if they included data on adult non-pregnant populations with parathyroid carcinoma. No restrictions regarding interventions, comparators or duration of follow-up were imposed. Single case reports, reviews or meta-analyses were excluded. Outcomes of interest were molecular pathogenesis, clinical presentation, differential diagnosis, treatment, follow-up and overall survival. Study quality was evaluated using the Newcastle-Ottawa Scale for observational studies. This review included 75 studies from 17 countries, reporting on more than 3000 patients with parathyroid carcinoma. CDC73 mutation has been recognised as playing a pivotal role in molecular pathogenesis. Parathyroid carcinoma typically presents with markedly increased calcium and parathyroid hormone levels. The most frequently described symptoms were bone and muscle pain or weakness. En bloc resection remains the gold standard for the surgical approach. The 5-year overall survival ranged from 60 to 93%, with resistant hypercalcaemia a significant cause of mortality. Emerging evidence indicating that targeted therapy, based on molecular biomarkers, presents a novel treatment option. The rarity of PC and need for personalised treatment warrant multidisciplinary management in a 'centre of excellence' with a track record in PC management.

Treatment for advanced adrenocortical carcinoma (ACC) consists of mitotane alone or combined with etoposide, doxorubicin, and cisplatin (EDP). Although both therapies are widely used, markers of response are still lacking. Since inflammation-based scores have been proposed as prognostic factors in ACC, we aimed to investigate their role in predicting the response to first-line chemotherapy. We performed a retrospective analysis of patients with advanced ACC treated with mitotane monotherapy or EDP ± mitotane. Clinical parameters (tumour stage at diagnosis, resection status, Ki67, time from diagnosis to treatment start, performance status, plasma mitotane levels, time in mitotane target ≥ 80%, clinically overt cortisol hypersecretion), and pretreatment inflammation-based scores (neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), monocyte-to-lymphocyte ratio, derived neutrophil-to-lymphocyte ratio) were investigated. The primary endpoints were overall survival (OS) and time-to-progression (TTP) from treatment initiation, the secondary endpoint was the best objective response to treatment. We included 90 patients (59% = women, median age = 51 years) treated with mitotane monotherapy (n = 40) or EDP ± mitotane (n = 50). In the mitotane monotherapy cohort, NLR ≥ 5 and PLR ≥ 190 predicted shorter OS (hazard ratio (HR): 145.83, 95% CI: 1.87-11,323.83; HR: 165.50, 95% CI: 1.76-15,538.04, respectively), remaining significant at multivariable analysis including clinical variables. NLR was also associated with shorter TTP (HR: 2.58, 95% CI: 1.28-5.20), but only at univariable analysis. Patients with NLR ≥ 5 showed a worse treatment response than those with NLR < 5 (P = 0.040). In the EDP ± mitotane cohort, NLR ≥ 5 predicted shorter OS (HR: 2.52, 95% CI: 1.30-4.88) and TTP (HR: 1.95, 95% CI: 1.04-3.66) at univariable analysis. In conclusion, inflammation-based scores, calculated from routinely measured parameters, may help predict response to chemotherapy in advanced ACC.

The association between growth hormone (GH) and carcinogenesis has long been postulated. The rationale for this association is that several components of the GH axis play an important role in the regulation of cell proliferation, differentiation, apoptosis, and angiogenesis and have been tested as targets for cancer therapy. Epidemiological and clinical studies have examined the association between height, growth patterns, and insulin-like growth factor 1 (IGF1) levels with the most common types of malignancies, while genome-wide association studies have revealed several height-associated genes linked to cancer and/or metastasis-driving pathways. In this context, a permissive role of the GH-IGF signaling system in the link between height and cancer risk has also been investigated. In animal and human models, genetic defects associated with GH deficiency or resistance are associated with protection from tumor development, while the risk of malignancies in acromegaly or in patients exposed to recombinant GH therapy has long been a matter of concern and scrutiny. In this review, we present a narrative and historical review covering the potential relations among height, growth patterns, GH axis, and cancer.

Insulin resistance (IR) is a well-established risk factor for breast cancer (BC) development in African American (AA) postmenopausal women. While obesity and IR are more prevalent in AA than in white women, they are under-represented in genome-wide studies for systemic regulation of IR. By examining 780 genome-wide IR single-nucleotide polymorphisms (SNPs) available in our data, we tested 4689 AA women in a Random Survival Forest framework. With 37 BC-associated lifestyle factors, we conducted a gene-environment interaction analysis to estimate risk prediction for BC with the most influential genetic and behavioral factors and evaluated their combined and joint effects on BC risk. By accounting for variations of individual SNPs in BC in the prediction model, we detected four fasting glucose-associated SNPs in PCSK1, SPC25, ADCY5, and MTNR1B and three lifestyle factors (smoking, oral contraceptive use, and age at menopause) as the most predictive markers for BC risk. Our joint analysis of risk genotypes and lifestyle with smoking revealed a synergistic effect on the increased risk of BC, particularly estrogen/progesterone positive (ER/PR+) BC, in a gene-lifestyle dose-dependent manner. The joint effect of smoking was more substantial in women with prolonged exposure to cigarette smoking and female hormones. The top genome-wide association-SNPs associated with metabolic biomarkers in combination with lifestyles synergistically increase the predictability of invasive ER/PR+ BC risk among AA women. Our findings highlight generically targeted preventive interventions for women who carry particular risk genotypes and lifestyles.

Paragangliomas (PGL) of the adrenal (also known as pheochromocytomas) or extra-adrenal neural crest-derived cells are highly heritable tumors, usually driven by single pathogenic variants that occur mutually exclusively in genes involved in multiple cellular processes, including the response to hypoxia, MAPK/ERK signaling, and WNT signaling. The discovery of driver mutations has led to active clinical surveillance with outcome implications in familial PGL. The spectrum of mutations continues to grow and reveal unique mechanisms of tumorigenesis that inform tumor biology and provide the rationale for targeted therapy. Here we review recent progress in the genetics and molecular pathogenesis of PGLs and discuss new prospects for advancing research with new disease models and ongoing clinical trials presented at the recent International Symposium of Pheochromocytomas and Paragangliomas (ISP2022) held in October 2022 in Prague.