Endocrine-related cancer最新文献

The intracellular molecular networks are highly complex and plastic. Yet, they obey the network principles discovered by systems biology. Precise mathematical models of some networks enable one to predict how molecular properties determine the function and malfunction of the network. However, the complexity is even greater than this: due to selection in evolutionary biology, the molecular networks are not only causal to cell function, but also caused by the requirement that the cell's functions be optimal. We discuss how the combination of complexity, plasticity, and this circular causality makes the networks similar to trained artificial neural networks. Causation by purpose might thereby dominate over causation by mechanism. Comparison of challenges that may cause or cure disease with actual challenges in evolutionary, developmental, or cell biology, and assessment of the learned responses thereto, might add another interesting layer of systems biology.

With increased use of somatostatin analogue (SSA) PET/CT, the prevalence of incidentaloma - at present approximately 4.5% - is anticipated to rise. As malignancy has been reported in 13% of all cases, these incidentaloma are clinically relevant. However, because of publication bias, prevalence is probably underestimated and the malignancy rate overestimated. Therefore, we assessed the prevalence, cause, malignancy rate, and tracer uptake intensity on 68Ga-DOTANOC PET. All 68Ga-DOTANOC PET/CT protocols in adults, performed between 2017 and 2024 at Antwerp University Hospital, were retrospectively screened for incidentaloma. Patient records were examined to determine the cause of non-physiological increased tracer uptake. A total of 1,951 68Ga-DOTANOC PET/CTs were performed in 1,102 subjects. A total of 145 incidentaloma (13.2%) were described in 136 subjects (mean age 64 ± 13 years; F/M 82/54), most commonly in the thyroid (n = 43), brain (n = 31), prostate (n = 23), and breast (n = 11). The cause of pathological tracer uptake was evaluated by additional imaging in 55% of incidentaloma, whereby benign thyroid nodules, meningioma, benign prostatic hyperplasia, and breast fibroma and carcinoma were the most common findings, respectively. The malignancy rate was low (6%), comprising two breast cancers, one prostate cancer, one renal cell carcinoma, and one lung cancer. This is the largest single-centre study describing the prevalence and cause of 68Ga-DOTANOC incidentaloma to date. While the prevalence is significantly higher (13.2%) than described in previous studies (4.5%), the malignancy rate was significantly lower (6 versus 13%), as was expected due to publication bias, and no thyroid cancer was diagnosed.

Locoregional therapies are a standard treatment for neuroendocrine tumors (NET) with predominant liver metastases. The efficacy of transarterial chemoembolization (TACE) using streptozotocin (STZ) has been poorly compared to transarterial embolization (TAE). Predictive biomarkers of TACE efficacy have never been explored. We studied all patients with pancreatic (panNET) or small intestine (siNET) NET and liver metastases treated between 2006 and 2022 using a standardized protocol of TACE-STZ (1,500 mg/m2) or TAE. The primary endpoint was the RECIST 1.1-defined objective response rate (ORR). The variables associated with ORR were explored using a propensity score to account for confounding factors. Secondary endpoints included the impact of tumor expression of O6-methylguanine-methyltransferase (MGMT), alkylpurine-DNA-N-glycosylase (APNG), and carbonic anhydrase IX (CAIX), and progression-free survival (PFS). Among 116 patients, 58 received TACE (15 siNET and 43 panNET) and 58 received TAE (42 siNET and 16 panNET). TACE was associated with a higher ORR than TAE (43 vs 22%, P = 0.045), which remained statistically significant on propensity-adjusted multivariable analysis (OR 2.71, 95% CI: (1.08-7.17), P = 0.038). TACE provided longer PFS than TAE in panNET patients (12.9 vs 6.4 months, P = 0.026), but not in siNET patients (16.1 vs 15.1 months, P = 0.47). Low APNG expression was predictive of higher ORR with TACE (70 vs 16%, P < 0.001), while the expression of MGMT and CAIX had no impact. TACE-STZ provided a higher ORR than TAE, although it yielded longer PFS only in patients with panNET. Low tumor expression of APNG might help select the best candidates for TACE-STZ, although this result was only exploratory.

Epitransciptomic marks, such as N6-methyladenosine (m6A) within RNA transcripts, have been implicated in multiple pro-tumorigenic activities. These modifications are controlled by writers, readers, and erasers, including the METTL3 m6A-methyltransferase. Recently, changes in expression or activity of epitranscriptomic enzymes have been shown to modulate metabolic pathways in multiple tumor types, including within endocrine-sensitive and -resistant estrogen receptor-positive (ERα+) breast cancer (ER+ BC) cells. Yet, a broad analysis of metabolic alterations, specifically with respect to METTL3 inhibition, has not been explored in these BC subtypes. Herein, we investigated the magnitude of pharmacological targeting of METTL3 (STM2457) on overall cellular metabolism in endocrine-sensitive (MCF-7 and ZR-75-1) and -resistant (LCC9 and ZR-75-1-4-OHT) ER+ BC cells. We found that STM2457 selectively decreased glycolytic activity in resistant cells and led to altered hexokinase 2 expression in LCC9 cells. STM2457 suppressed mitochondrial activity, while isotope tracing found diminished tricarboxylic acid (TCA) glucose oxidation in MCF-7 and LCC9 cell lines. This was accompanied by increased glutamine uptake and glutaminolysis, which was more pronounced in the endocrine-resistant LCC9 cells. We also observed differential expression of glutaminase 1 (GLS1) splice variants in the MCF-7 cells and an increase in the ASCT2 glutamine transporter. To determine combinatorial targeting potential, we co-treated cells with STM2457 and CB-839, which is a GLS1 inhibitor. CB-839 increased the potency of STM2457 only in the LCC9 and ZR-75-1-4-OHT endocrine-resistant cells. Our collective findings suggest that METTL3 inhibition leads to selective glycolytic and oxidative metabolic changes between these endocrine-sensitive and -resistant BC cells, which can be exploited for combinatorial therapy.

Current guidelines recommend total thyroidectomy for all T3b differentiated thyroid carcinoma (DTC) with gross strap muscle invasion, yet evidence supporting this universal approach remains limited and conflicting. We analyzed 6,920 T3b DTC patients from the SEER database (2004-2022) who underwent lobectomy (n = 282) or total thyroidectomy (n = 6,638). Overall survival (OS) served as the primary outcome. Random survival forest (RSF) with SHapley Additive exPlanations (SHAP) analysis identified interactions between surgical approach and clinical variables. Cox regression with restricted cubic splines examined age-dependent surgical effects on OS. Neither RSF nor Cox regression (HR 0.96, 95% CI: 0.68-1.37, P = 0.84) showed a significant OS difference between surgical approaches. SHAP interaction analysis revealed significant age-dependent heterogeneity. Restricted cubic splines identified age 45 as the threshold where the surgical benefit converged. In patients <45 years, total thyroidectomy demonstrated significantly superior survival outcomes compared with lobectomy (adjusted HR 3.26, 95% CI: 1.30-8.22, P = 0.012; 10-year survival 95.5 vs 98.4%). Conversely, no difference existed in patients ≥45 years (HR 0.85, 95% CI: 0.58-1.24, P = 0.40). The multiplicative interaction was 0.26 (95% CI: 0.10-0.70, P = 0.008), confirming a negative age-surgery interaction. Although this study demonstrates that surgical approach shows no significant survival difference in T3b DTC, the negative interaction effect between surgical approach and age indicates that the benefit of total thyroidectomy progressively diminishes with advancing age, providing a survival advantage only in patients younger than 45 years. These findings challenge universal total thyroidectomy recommendations and support age-stratified surgical decision-making for T3b DTC.

Abstract: Metastatic pheochromocytoma and paraganglioma (MPP) currently lack definitive curative therapies. The treatment of MPP presents a formidable challenge. Anlotinib hydrochloride, characterized as a multi-targeted tyrosine kinase receptor inhibitor, has demonstrated potential in this domain. This study, a phase 2 trial (NCT04860700), aimed to evaluate the efficacy and safety profiles of anlotinib hydrochloride in patients suffering from MPP. The primary objective was to determine the disease control rate (DCR) and objective response rate (ORR) as determined by the RECIST 1.1 criteria. Secondary objectives were to evaluate the biochemical response, progression-free survival (PFS), and safety. Twenty-nine patients with MPP were enrolled. We found that 24.1% (7/29) of patients discontinued the treatment after 1-2 cycles because of a significant increase in hormone levels or adverse events. Among 22 patients who could be evaluated by the RECIST 1.1 criteria, the overall DCR was 95.5% (21/22), and the ORR was 31.8% (7/22). The PFS was calculated to be 22.6 ± 3.2 months. There is no significant difference in ORR or PFS between patients with and without germline mutations. The most common adverse events included arterial hypertension (24/29, 82.8%), subclinical primary hypothyroidism (11/29, 37.9%), hyperlipidemia (10/29, 34.5%), rash (8/29, 27.6%), and fatigue (8/29, 27.6%). We conclude that among the evaluable patients, anlotinib showed promising efficacy with high DCR. Close monitoring remains essential because of treatment-related adverse events.

Abstract: The purpose of the study was to analyze the differences in the rate of intraoperative and postsurgical complications in patients with pheochromocytoma and sympathetic paraganglioma (PPGL) based on the use or non-use of preoperative beta-blockade. We performed a retrospective multicenter study of patients who underwent PPGL resection in 23 tertiary hospitals. Patients were classified in two groups according to presurgical treatment with beta-blockade or not. A total of 390 surgical resections of PPGLs were included: 226 in the group of beta-blockade and 164 in the group of no blockade. Beta-blockade was more frequently used in patients with higher fasting plasma glucose and plasma metanephrine levels, and treated with higher doses of phenoxybenzamine and doxazosin. The proportion of patients with proper presurgical blood pressure control was higher in patients pretreated with beta-blockade than non-pretreated (70.7 vs 59.1%, P = 0.027). However, the first group had a higher rate of intraoperative arrhythmia (9.3 vs 3.7%, P = 0.031). Nevertheless, when we adjusted for the daily doses of alpha-blockade, the differences disappeared (adjusted odds ratio (OR) 2.55 (0.83-7.89)). In multivariate analysis, the only variables independently associated with intraoperative arrhythmias were the use of phenoxybenzamine vs doxazosin (OR 8.18 (2.28-29.33)) and a lower preoperative heart rate (OR 0.95 (0.90-0.99)). As a conclusion, presurgical beta-blockade was more commonly used in patients with more active tumors. The higher rate of intraoperative arrhythmia in patients pretreated with beta-blockers seems to be related to the more frequent use of phenoxybenzamine in this group and not directly with the use of beta-blocker.

Significance statement: No previous studies have evaluated the impact of presurgical treatment with beta-blockers on patients with pheochromocytomas and sympathetic paragangliomas (PPGLs) receiving alpha-blockade on surgical outcomes, including intraoperative and postsurgical complications. Considering this context, we analyzed the differences in the rate of intraoperative and postsurgical complications in patients with PPGL based on the use or non-use of preoperative beta-blockade. We found that presurgical beta-blockade was more commonly used in patients with more clinically active tumors. The higher rate of intraoperative arrhythmia in patients pretreated with beta-blockers seems to be related to the more frequent use of phenoxybenzamine in this group and not directly with the use of beta-blocker.

We reviewed the clinical characteristics of male patients with MEN2B associated medullary thyroid cancer (MTC) with prostate lesions and analyzed available imaging and pathology data.Patients were enrolled on a National Cancer Institute (NCI) natural history protocol (NCT01660984) and a University of Texas (UT) MD Anderson Cancer Center study (DR09-0507).Thirty-six male patients (median age of MEN2B diagnosis 12.0 years, range 1.3-25.6) with the RET p.Met918Thr germline mutation were identified.Pelvic imaging was available for 28/36 (78%) patients. Prostate lesions and/or calcifications were noted in eight patients (28.6%). Lesions were identified at a median age of 20.5 years (range 13-30.5 years). Biopsies in three patients with prostate neoplasms were histologically indistinguishable from primary MTC. Two of these patients did not have other sites of distant disease at the time of prostate biopsy. Prostate lesions in males with MEN2B and MTC are more frequent than previously described. Lesions were identified in patients as young as 14 years and often contained calcifications. The prostate is a more common site of disease in patients with MEN2B than previously appreciated and may represent a distant site of metastatic MTC metastasis or a second primary calcitonin-secreting neuroendocrine tumor. Imaging of the prostate should be considered in post-pubertal MEN2B males, especially in case of unexplained increase in calcitonin or onset of urinary tract symptoms.

Radiotherapy is a mainstay treatment for localized prostate cancer (PCa). Yet, radiation resistance remains a major clinical obstacle. Here, radiation induced a BMP/CD105-dependent metabolic shift in the tumor microenvironment that facilitates PCa cell survival. Using prostate tumor models and fibroblast cultures, we show that radiation enhances epithelial BMP ligand production, which promotes fibroblastic CD105 signaling. Metabolomic analysis upon radiation revealed that fibroblastic CD105 signaling elevated key enzymes involved in mitochondrial biogenesis (PGC1α) and ketogenesis (HMGCS2). The increased production of β-hydroxybutyrate in the tumor microenvironment sustained PCa cell energy metabolism and enhanced DNA repair upon radiation stress. Blocking BMP signaling through carotuximab (ENV105), a CD105-targeting antibody, disrupted epithelial-fibroblast crosstalk, resulting in decreased β-hydroxybutyrate within the tumor microenvironment. This attenuation of fibroblast-mediated metabolic support increased DNA damage and apoptosis, sensitizing PCa cells to radiation. In subcutaneous mouse models, grafting PCa cells with CD105-KO or HMGCS2-KO fibroblasts yielded smaller tumors following radiation compared with wild-type fibroblast controls. Across subcutaneous and orthotopic models, combined treatment with carotuximab and irradiation reproducibly achieved superior tumor volume reduction relative to single-agent therapy. This study identified the BMP/CD105 axis as a key pathway in radiation resistance, highlighting the potential of targeting fibroblastic CD105 with carotuximab to enhance radiation sensitivity.