Citations

PURPOSE Age ≥40 years is regarded as a high-risk feature and an indication for adjuvant chemoradiotherapy for patients with lower-grade glioma in clinical practice guidelines. It is unclear whether age remains a relevant prognostic factor for contemporary definitions of lower-grade gliomas in the molecular era. METHODS The Prospective Gliomas Research (PROGRES) database contains individual patient-level data from 11 prospective clinical trials or observational registries of histologically defined lower-grade 2-3 oligodendroglioma or astrocytoma. We determined the association of age (18-39 years v ≥40 years) with progression-free survival (PFS) stratified by isocitrate dehydrogenase 1 or 2 ( IDH1/2 ) status, using log-rank tests and Cox regression models. We validated our findings in a separate multi-institutional retrospective cohort (Retrospective Glioma Research [REGRES] database). RESULTS We identified 1,619 and 1,292 eligible patients in the PROGRES and REGRES cohorts, respectively. IDH -wildtype tumors were more common in patients 40 years and older (38% v 5%, odds ratio: 11.3 [95% CI, 6.5 to 19.7]). Age was associated with PFS in IDH -wildtype (5-year PFS for ≥40 v 18-39 years: 6% v 24%, hazard ratio [HR], 1.74 [95% CI, 1.21 to 2.50]) but not in IDH -mutant glioma (60% v 59%, HR, 0.89 [95% CI, 0.76 to 1.05], P interaction < .001). In IDH -wildtype tumors, older age predicted aggressive molecular features, including TERT promoter mutation (65% v 28%), EGFR amplification (41% v 15%), and chromosome +7/–10 alteration (57% v 25%). In a pooled analysis of four clinical trials, age was not predictive of a benefit from chemoradiotherapy versus radiotherapy alone for IDH -mutant glioma. CONCLUSION In the absence of additional clinical or molecular risk factors, age alone should not be considered an indication for administration or deferral of adjuvant treatment. Practice guidelines should be revised to reflect contemporary prognostic factors in the molecular era.

Abstract Progression from monoclonal gammopathy of undetermined significance (MGUS) to multiple myeloma (MM) is driven by coordinated metabolic reprogramming within clonal plasma cells and the bone marrow microenvironment. We applied high-resolution MALDI–FT-ICR mass spectrometry imaging (MSI) to archived FFPE bone-marrow biopsies, integrated with matched bone marrow plasma metabolomics, to map spatial and systemic metabolic alterations. Spatial clustering delineated plasma-cell–rich niches, while Hill-based diversity and β-diversity metrics quantified intra- and inter-compartment heterogeneity. MM niches exhibited elevated 3-hydroxykynurenine, rewired tryptophan–kynurenine flux, and increased nucleotide and bioactive lipid metabolism associated with proliferation. Notably, some MGUS-like samples displayed MM-like metabolic niches undetectable in bone marrow plasma alone, underscoring spatial heterogeneity. Cross-compartment integration revealed conserved metabolic signatures and systemic redistribution of key metabolites, consistent with ecological reorganization and niche divergence during progression. These findings establish spatial metabolomics of biopsies as a framework to dissect intramedullary metabolic heterogeneity and enable metabolite-based risk stratification in plasma-cell disorders.

Glioblastoma (GBM) is an aggressive brain tumor that often progresses despite resection and treatment. Timely and continuous assessment of GBM progression is critical to expedite secondary surgery or enrollment in clinical trials. However, current progression detection requires costly and specialized MRI examinations, which, in the absence of new symptoms or signs, are usually scheduled every 2–3 months. Here, we hypothesized that changes in daily activity are associated with GBM growth and disease progression. We found that wheel-running activity in GBM-bearing mice declined as tumors grew and preceded weight loss and circadian breakdown by over a week. Temozolomide treatment in the morning, but not evening, significantly reduced tumor size and restored daily locomotion in mice. In a pilot study of 6 patients with GBM wearing an actigraphy watch, wrist movement provided a feasible and continuous longitudinal indicator of daily activity with 1-minute resolution. After tumor resection and radiation, daily activity declined in 2 patients 19 and 55 days before detection of progression by MRI but did not change for the 4 patients with stable disease. These results suggest that daily activity tracking using wearable devices may serve as a real-time indicator and potential monitoring tool for GBM progression and treatment efficacy.

Abstract PURPOSE Age over 40 years is commonly regarded as a “high risk” feature and potential indication for adjuvant chemoradiotherapy for patients with lower grade glioma in most clinical practice guidelines. However, these recommendations are based on retrospective observations and their subsequent incorporation into legacy clinical trials. It is unclear whether age remains a relevant prognostic factor in the molecular era. METHODS The Prospective Gliomas Research [PROGRES] Database contains individual patient-level data from 11 prospective clinical trials or observational registries, including seven international trials from the RTOG, EORTC, or Alliance cooperative groups. We determined the association of age with progression-free survival (PFS) in low grade or anaplastic glioma, stratified by isocitrate dehydrogenase (IDH1/2) status. We validated our findings in a separate multi-institutional retrospective cohort (Retrospective Glioma Research [REGRES] Database). RESULTS We identified 1,619 and 1,271 eligible patients in the PROGRES and REGRES cohorts, respectively. IDH-wildtype tumors were more common in patients &gt;40 years (38% vs, 5%, odds ratio: 11.3 [95%CI 6.5 – 19.7]). Age was associated with PFS in IDH-wildtype (5-year PFS: 6% vs, 24%, P =.003) but not in IDH-mutant glioma (60% vs, 59%, P = 0.22, P value of interaction &lt;.001). In IDH-wildtype tumors, older age predicted aggressive molecular features, including TERT promoter mutation (65% vs, 28%), EGFR amplification (41% vs, 15%), and chromosome +7/-10 alteration (57% vs, 25%). Age was not predictive of a benefit from chemoradiotherapy versus radiotherapy alone in IDH-mutant glioma. CONCLUSION Older age is a putative surrogate for IDH-wildtype status, but was not an independent predictor of progression in IDH-mutant lower grade glioma and did not predict benefit from chemoradiotherapy. In the absence of additional clinical or molecular risk factors, age alone should not be considered an indication for administration or deferral adjuvant treatment. Practice guidelines should be revised to reflect contemporary prognostic factors in the molecular era.

High-grade gliomas, like glioblastoma multiforme (GBM), are the most common malignant brain tumors in adults and are treated with the chemotherapy drug temozolomide (TMZ). In humans, a retrospective analysis of patients’ overall survival suggests that morning dosing may confer a benefit over evening dosing. Circadian variation in O6-methylguanine-DNA methyltransferase (MGMT) gene expression and promoter methylation has been implicated in increased tumor cell sensitivity to TMZ in the morning. Although patient compliance with timed oral administration of TMZ was high in a prospective trial, it is not known whether differences in daily sleep patterns of patients impact the biological time of drug administration or overall survival. Using wrist actigraphy collected from 10 high-grade glioma patients, we quantified the moment of oral TMZ delivery in terms of wall clock time and internal biological time during the months after surgical tumor resection. We found that variation of daily rhythms within and between individuals caused dosing times to vary more in their internal biological time than wall clock time so that, for example, some doses taken by patients assigned for the evening (2000 h) were closer to the patient’s internal biological morning. We conclude that wrist actigraphy provides a reliable and non-invasive estimate of personal circadian time that could improve efficacy and precision of TMZ delivery. These findings may inform personalized circadian medicine and optimized times for TMZ delivery in the clinic.

Received June 8, 2022; accepted October 11, 2022 Background Recent advances in omics techniques have allowed detailed genetic characterization of cortisol-producing adrenal adenoma (CPA). In contrast, the pathophysiology of CPAs has not been elucidated in detail on the level of tumor metabolic alterations. Methods The current study conducted a comprehensive mass spectrometry imaging (MSI) map of CPAs in relation to clinical phenotypes and immunohistochemical profiles of steroidogenic enzymes. The study cohort comprised 46 patients with adrenal tumors including CPAs (n 35) and nonfunctional adenomas (n 11). Results Severity of cortisol hypersecretion was significantly correlated with 29 metabolites (adjusted P 0.05). Adrenal androgens derived from the classic androgen pathway were inversely correlated with both cortisol secretion (rs 0.41, adjusted P 0.035) and CYP11B1 expression (rs 0.77, adjusted P 2.00E-08). The extent of cortisol excess and tumor CYP11B1 expression further correlated with serotonin (rs 0.48 and 0.62, adjusted P 0.008 and 2.41E-05). Tumor size was found to be correlated with abundance of 13 fatty acids (adjusted P 0.05) and negatively associated with 9 polyunsaturated fatty acids including phosphatidic acid 38:8 (rs 0.56, adjusted P 0.009). Conclusions MSI reveals novel metabolic links between endocrine function and tumorigenesis, which will further support the understanding of CPA pathophysiology.

Abstract Transgender and gender diverse (TGD) individuals face significant barriers to accessing health care. Recent introductions of regulatory policies at state and federal levels raise concerns over the politicization of gender-affirming health care, the risks of further restricting access to quality care, and the potential criminalization of healthcare professionals who care for TGD patients. The Endocrine Society and the Pediatric Endocrine Society have published several news articles and comments in the last couple of years supporting safe and effective gender-affirming interventions as outlined in the 2017 Endocrine Society’s Clinical Practice Guidelines. The Endocrine Society Position Statement on Transgender Health also acknowledges the rapid expansion in understanding the biological underpinning of gender identity and the need for increased funding to help close gaps in knowledge about the optimal care of TGD individuals. This Policy Perspective affirms these principles in the context of pending and future legislation attempting to discriminate against TGD patients while also stressing the need for science and health care experts to inform health policies.

BACKGROUND. Adrenal aldosterone excess is the most common cause of secondary hypertension and is associated with increased cardiovascular morbidity. However, adverse metabolic risk in primary aldosteronism extends beyond hypertension, with increased rates of insulin resistance, type 2 diabetes, and osteoporosis, which cannot be easily explained by aldosterone excess. METHODS. We performed mass spectrometry–based analysis of a 24-hour urine steroid metabolome in 174 newly diagnosed patients with primary aldosteronism (103 unilateral adenomas, 71 bilateral adrenal hyperplasias) in comparison to 162 healthy controls, 56 patients with endocrine inactive adrenal adenoma, 104 patients with mild subclinical, and 47 with clinically overt adrenal cortisol excess. We also analyzed the expression of cortisol-producing CYP11B1 and aldosterone-producing CYP11B2 enzymes in adenoma tissue from 57 patients with aldosterone-producing adenoma, employing immunohistochemistry with digital image analysis. RESULTS. Primary aldosteronism patients had significantly increased cortisol and total glucocorticoid metabolite excretion (all P < 0.001), only exceeded by glucocorticoid output in patients with clinically overt adrenal Cushing syndrome. Several surrogate parameters of metabolic risk correlated significantly with glucocorticoid but not mineralocorticoid output. Intratumoral CYP11B1 expression was significantly associated with the corresponding in vivo glucocorticoid excretion. Unilateral adrenalectomy resolved both mineralocorticoid and glucocorticoid excess. Postoperative evidence of adrenal insufficiency was found in 13 (29%) of 45 consecutively tested patients. CONCLUSION. Our data indicate that glucocorticoid cosecretion is frequently found in primary aldosteronism and contributes to associated metabolic risk. Mineralocorticoid receptor antagonist therapy alone may not be sufficient to counteract adverse metabolic risk in medically treated patients with primary aldosteronism. FUNDING. Medical Research Council UK, Wellcome Trust, European Commission.

Background. The vibrational characteristics of any object are directly dependent on the physical properties of that object. Therefore, changing the physical properties of an object will cause the object to adopt changed natural frequencies. A fracture in a bone results in the loss of mechanical stability of the bone. This change in mechanical properties of a bone should result in a change of the resonant frequencies of that bone. A vibrational method for bone evaluation has been introduced. Method of approach. This method uses the radiation force of focused amplitude-modulated ultrasound to exert a vibrating force directly, and remotely, on a bone. The vibration frequency is varied in the range of interest to induce resonances in the bone. The resulting bone motion is recorded and the resonance frequencies are determined. Experiments are conducted on excised rat femurs and resonance frequencies of intact, fractured, and bonded (simulating healed) bones are measured. Results. The experiments demonstrate that changes in the resonance frequency are indicative of bone fracture and healing, i.e., the fractured bone exhibits a lower resonance frequency than the intact bone, and the resonance frequency of the bonded bone approaches that of the intact bone. Conclusion. It is concluded that the proposed radiation force method may be used as a remote and noninvasive tool for monitoring bone fracture and healing process, and the use of focused ultrasound enables one to selectively evaluate individual bones.