Journal of Clinical Endocrinology & Metabolism最新文献

Context: The association between colorectal cancer (CRC) and new-onset diabetes mellitus remains unclear.

Objective: To examine the association between CRC and the risk of subsequent diabetes mellitus and to further investigate the impact of chemotherapy on diabetes mellitus risk in CRC.

Methods: In this nationwide cohort study using the Taiwan Cancer Registry database (2007-2018) linked with health databases, 86 268 patients with CRC and an equal propensity score-matched cohort from the general population were enrolled. Among them, 37 277 CRC patients from the Taiwan Cancer Registry (2007-2016) were analyzed for diabetes mellitus risk associated with chemotherapy. Chemotherapy exposure within 3 years of diagnosis was categorized as no chemotherapy, < 90 days, 90 to 180 days, and > 180 days. Differences in diabetes mellitus risk were assessed across these categories.

Results: Each group involved 86 268 participants after propensity score matching. The patients with CRC had a 14% higher risk of developing diabetes mellitus than the matched general population (hazard ratio [HR]: 1.14; 95% CI, 1.09-1.20). The highest risk was observed within the first year after diagnosis, followed by a sustained elevated risk. Long-term chemotherapy (> 180 days within 3 years) was associated with a 60% to 70% increased risk of subsequent diabetes mellitus (HR: 1.64; 95% CI, 1.07-2.49).

Conclusion: Patients with CRC are associated with an elevated risk of diabetes mellitus, and long-term chemotherapy, particularly involving capecitabine, increases diabetes mellitus risk. Thus, monitoring blood glucose levels is crucial for patients with CRC, especially during extended chemotherapy.

Context: Precision medicine for pituitary neuroendocrine tumors (PitNETs) is limited by the lack of reliable research models.

Objective: To generate patient-derived organoids (PDOs), which could serve as a platform for personalized drug screening for PitNET patients.

Design: From July 2019 to May 2022, a total of 32 human PitNET specimens were collected for the establishment of organoids with an optimized culture protocol.

Setting: This study was conducted at Sun Yat-Sen University Cancer Center.

Patients: PitNET patients who were pathologically confirmed were enrolled in this study.

Interventions: Histological staining and whole-exome sequencing were utilized to confirm the pathologic and genomic features of PDOs. A drug response assay on PDOs was also performed.

Main outcome measures: PDOs retained key genetic and morphological features of their parental tumors.

Results: PDOs were successfully established from various types of PitNET samples with an overall success rate of 87.5%. Clinical nonfunctioning PitNETs-derived organoids (22/23, 95.7%) showed a higher likelihood of successful generation compared to those from functioning PitNETs (6/9, 66.7%). Preservation of cellular structure, subtype-specific neuroendocrine profiles, mutational features, and tumor microenvironment heterogeneity from parental tumors was observed. A distinctive response profile in drug tests was observed among the organoids from patients with different subtypes of PitNETs. With the validation of key characteristics from parental tumors in histological, genomic, and microenvironment heterogeneity consistency assays, we demonstrated the predictive value of the PDOs in testing individual drugs.

Conclusion: The established PDOs, retaining typical features of parental tumors, indicate a translational significance in innovating personalized treatment for refractory PitNETs.

Context: Whether continuation of dipeptidyl peptidase-4 inhibitors (DPP-4is) or switching to oral semaglutide is more beneficial for β-cell function is unclear.

Objective: To assess the efficacy of switching from DPP-4is to oral semaglutide for β-cell function compared with DPP-4i continuation.

Methods: Post hoc analysis of SWITCH-SEMA 2, a multicenter prospective randomized controlled trial on the switch to oral semaglutide vs DPP-4i continuation without dose adjustment for 24 weeks in subjects with type 2 diabetes treated with DPP-4is, was conducted. Changes in markers for glucose metabolism, including homeostatic model assessment (HOMA2) scores and disposition index (DI), were compared between the groups.

Results: A total of 146 subjects (semaglutide group, 69; DPP-4i group, 77) were analyzed. In the semaglutide group, glycemic control, liver enzyme deviations, and lipid profiles improved after 24 weeks. Regarding indices for β-cell function, changes in HOMA2-β as well as DI, reflecting the ability of β-cells to compensate for insulin resistance, were significantly higher in the semaglutide group compared with the DPP-4i group (mean change, +10.4 vs +0.6 in HOMA2-β [P = .001] and +0.09 vs 0.0 in DI [P < .001]). Improvement in DI in the semaglutide group was correlated significantly to changes in body mass index (BMI), HbA1c, and fatty liver index reflecting liver steatosis. Multiple linear regression analysis revealed that dose of semaglutide (≥ 7 mg/day), reduction in fatty liver index, and metformin nonuse were independently associated with improvement of DI.

Conclusion: Switching to oral semaglutide ameliorated β-cell function compared with DPP-4is, presumably via tissue-to-tissue crosstalk between liver and β-cells.

Context: Treatment of primary hyperparathyroidism (PHPT) and secondary hyperparathyroidism due to idiopathic hypercalciuria (SHPT-IH) is markedly different. Robust diagnostic tools to differentiate between both entities are however lacking.

Objective: Evaluate the thiazide challenge test (TCT) in clinical practice, its aid in clinical decision making, and evaluate the accuracy (sensitivity, specificity) and potentially useful parameters of the TCT.

Methods: Monocentric observational retrospective cohort study from January 2017 to November 2023 in an outpatient Endocrinology department, Ghent University Hospital (Belgium). Twenty-five adult patients with hypercalciuria, elevated parathyroid hormone (PTH), and high-normal or elevated serum calcium underwent a TCT. Outcome measures were serum, urinary biochemical parameters before and after testing, clinical and imaging outcomes, treatment, and follow-up.

Results: Patients with a TCT-based working diagnosis of PHPT show greater increases in albumin-adjusted calcium and total serum calcium concentration than patients with SHPT-IH (+0.11 ± 0.10 vs +0.0071 ± 0.10 mmol/L; P = .025 and +0.14 ± 0.12 vs +0.012 ± 0.15 mmol/L; P = .024, respectively). The TCT-based working diagnosis of PHPT has a sensitivity of 81.8%, a specificity of 77.8%, and a likelihood ratio of 3.68 of estimating a correct final diagnosis. Urinary calcium excretion, PTH, calcium-phosphorous ratio, PTH inhibition rate, and the parathyroid function index do not differ significantly in patients with PHPT compared with those with SHPT-IH.

Conclusion: The TCT aids in discriminating patients with PHPT from those with SHPT-IH based on a rise in serum calcium. Other parameters are not different between both groups. Larger prospective trials are necessary to further define the diagnostic potential of the TCT, its most appropriate biochemical outcome variables, and decision cut-offs.

Context: Hyponatremia is associated with increased risk of osteoporosis and fractures. The impact of hyponatremia on noninvasive indices of bone quality, however, is unknown.

Objective: To evaluate whether trabecular bone microarchitecture, assessed noninvasively by trabecular bone score (TBS), is altered in patients with hyponatremia.

Methods: We conducted a cross-sectional analysis of the population-based 2005-2008 cycles of the National Health and Nutrition Examination Survey, in which TBS measurement was performed. The main outcome measures were TBS values and bone mineral density (BMD) T-scores at the lumbar spine, total hip and femoral neck.

Results: A total of 4204 subjects aged 50 years or older were included (4041 normonatremic, 163 hyponatremic-90.8% with mild hyponatremia). Univariate analyses did not show any difference in TBS between patients with and without hyponatremia (1.308 ± 0.145 vs 1.311 ± 0.141, P = .806). Hyponatremic subjects had lower BMD T-score at total hip (-0.70 ± 1.46 vs -0.13 ± 1.32, P < .001) and femoral neck (-1.11 ± 1.26 vs -0.72 ± 1.14, P = .004), while no difference was observed at lumbar spine (-0.27 ± 1.63 vs -0.31 ± 1.51, P = .772). After adjustment for relevant confounders, hyponatremia was confirmed as an independent predictor of lower BMD T-score at the total hip (β = -0.20, 95% confidence interval [CI]: [-0.39, -0.02], P = .029), while the significance was lost at the femoral neck (P = .308). Again, no association between hyponatremia and lumbar spine BMD (P = .236) or TBS (P = .346) was observed.

Conclusion: Hyponatremia, at least in mild forms, is not associated with a degradation of trabecular microarchitecture, assessed noninvasively by TBS. An independent association between hyponatremia and loss of bone mass is confirmed, particularly at the total hip.

Background: Pheochromocytoma is associated with systemic inflammation but the underlying mechanisms are unclear. Therefore, we investigated the relationship between plasma metanephrine levels and hematological parameters-as a surrogate of inflammation-in patients with pheochromocytoma and the influence of preoperative α-blockade treatment.

Design and methods: We retrospectively studied 68 patients with pheochromocytoma who underwent adrenalectomy (median age, 53 years; 64.7% females) and 2 control groups matched for age, sex, and body mass index: 68 patients with nonfunctioning adrenocortical tumors and 53 with essential hypertension. The complete blood count and several inflammation-based scores (neutrophil-to-lymphocyte ratio [NLR], platelet-to-lymphocyte ratio [PLR], lymphocyte-to-monocyte ratio [LMR], systemic-immune-inflammation index [SII], prognostic-nutrition index) were assessed in all patients and, in a subset of pheochromocytomas, after adrenalectomy (n = 26) and before and after preoperative α-blockade treatment (n = 29).

Results: A higher inflammatory state, as indicated by both complete blood count and inflammation-based scores, was observed in patients with pheochromocytoma compared with nonfunctioning adrenocortical tumors and essential hypertension. Plasma metanephrine levels showed a positive correlation with NLR (r = 0.4631), PLR (r = 0.3174), and SII (r = 0.3709) and a negative correlation with LMR (r = 0.4368) and prognostic-nutrition index (r = 0.3741), even after adjustment for age, sex, ethnicity, body mass index, and tumor size (except for PLR). After adrenalectomy, we observed a reduction in NLR (P = .001), PLR (P = .003), and SII (P = .004) and a concomitant increase in LMR (P = .0002). Similarly, α-blockade treatment led to a reduction in NLR (P = .007) and SII (P = .03).

Conclusion: Inflammation-based scores in patients with pheochromocytoma showed pro-inflammatory changes that correlated with plasma metanephrine levels and are ameliorated by adrenalectomy and α-blockade.

Background: Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy syndrome is a rare disease caused by biallelic mutations of the AIRE gene, usually presenting with the triad hypoparathyroidism-adrenal failure-chronic mucocutaneous candidiasis (CMC) and nonendocrine manifestations. The aim of this study was to determine the molecular profile of the AIRE gene, the prevalence of rare manifestations, and to characterize immunological disturbances in a French cohort.

Patients and methods: A national, multicenter prospective observational study to collect genetic, clinical, biological, and immunological data (NCT03751683).

Results: Twenty-five patients (23 families) were enrolled. Eleven distinct AIRE variants were identified, 2 of which were not previously reported: an intronic variant, c.653-70G > A, and a c.1066del (p.Arg356GlyfsX22) variant (exon 9). The most common was the Finnish variant c.769C > T (16 alleles), followed by the variant c.967_979del13 (15 alleles), which seemed associated with a less severe phenotype. Seventeen out of 25 patients were homozygote. The median number of clinical manifestations was 7; 19/25 patients presented with the hypoparathyroidism-adrenal failure-CMC triad, 8/13 showed pulmonary involvement, 20/25 had ectodermal dystrophy, 8/25 had malabsorption, and 6/23 had asplenia. Fifteen out of 19 patients had natural killer cell lymphopenia with an increase in CD4+ and CD8+ T lymphocytes and an age-dependent alteration of B lymphocyte homeostasis compared with matched controls (P < .001), related to the severity of the disease. All tested sera (n = 18) were positive for anti-interferon-α, 15/18 for anti-IL-22 antibodies, and 13/18 for anti-IL-17F antibodies, without clear phenotypic correlation other than with CMC.

Conclusion: This first prospective cohort showed a high AIRE genotype variability, with 2 new gene variants. The prevalence of potentially life-threatening nonendocrine manifestations was higher with systematic screening. These manifestations could, along with age-dependent B-cell lymphopenia, contribute to disease severity. Systematic screening for all the manifestations of the syndrome would allow earlier diagnosis, supporting vaccination and targeted therapeutic approaches.

Background: This investigator-initiated phase II trial aimed to evaluate the efficacy of cabozantinib in combination with nivolumab and ipilimumab (CaboNivoIpi) in previously treated patients with radioactive iodine-refractory differentiated thyroid cancer.

Methods: Eligible patients with radioactive iodine-refractory differentiated thyroid cancer who progressed on 1 prior line of vascular endothelial growth factor receptor-targeted therapy received a 2-week run-in of cabozantinib monotherapy followed by CaboNivoIpi for 4 cycles (cycle length = 6 weeks), followed by cabozantinib plus nivolumab (cycle length = 4 weeks) until disease progression. The primary endpoint was objective response rate (ORR) within the first 6 months of treatment. A Simon optimal 2-stage design allowed for an interim analysis after accrual of 10 evaluable patients. At least 5 responses were needed to proceed to stage 2.

Results: Among 11 patients enrolled, the median age was 69 years. Prior vascular endothelial growth factor receptor-targeted therapies included lenvatinib, pazopanib, and sorafenib plus everolimus. Median follow-up was 7.9 months. Among 10 evaluable patients, ORR within the first 6 months of treatment was 10% (1 partial response). Median progression-free survival was 9 months (95% CI, 3.0-not reached) and median overall survival was 19.2 months (95% CI, 4.6-not reached). Grade 3/4 treatment-related adverse events (AEs) were noted in 55% (6/11) and grade 5 AEs in 18% (2/11) of patients. The most common treatment-related AE was hypertension. The study did not reach its prespecified efficacy threshold.

Conclusion: CaboNivoIpi had low ORRs and a high rate of grade ≥3 treatment-related AEs.

Clinical trial registration: NCT03914300.

Context: BRAFV600E and TERT promoter mutations in papillary thyroid carcinoma (PTC) have a synergistic effect on prognosis. This effect is believed to arise from MAPK activation triggered by BRAFV600E, leading to the upregulation of ETS transcription factors that bind to the mutant TERT promoter.

Objectives: To explore the role of ETS factors in relation to clinical features, BRAFV600E, and TERT promoter mutations in PTC.

Design: Transcriptomic data for 28 ETS factors were analyzed in the PTC cohort of The Cancer Genome Atlas (n = 399) and subsequently validated in a local cohort (n = 93). In vitro experiments were performed to investigate the regulatory role in relation to BRAFV600E and TERT expression.

Results: The Cancer Genome Atlas identified ETS1, ERG, FLI1, GABPA, EHF, ETV6, and SPDEF as differentially expressed genes between stages I + II and III + IV. In both cohorts, EHF was consistently associated with adverse clinical features, BRAFV600E and TERT promoter mutation/expression. Notably, in BRAFV600E mutated PTC, high EHF expression was associated with shorter disease-free survival. Cases harboring concurrent BRAFV600E, TERT promoter mutations, and high EHF expression exhibited the shortest disease-free survival. In cells harboring concurrent BRAFV600E and TERT promoter mutation, overexpression of EHF significantly increased TERT expression, whereas knockdown or pharmacological inhibition of BRAF significantly decreased both EHF and TERT expression. In addition, chromatin immunoprecipitation and quantitative PCR analysis suggested a potential binding of EHF in TERT promoter mutant cells but not in TERT promoter wild-type cells.

Conclusion: The ETS transcription factor EHF is associated with poor prognosis in PTC. This is potentially mediated by BRAF-induced upregulation of EHF, which in turn increases TERT expression in TERT promoter mutated cells.