Hoong, Caroline W S

ABSTRACT Although animal studies have linked cellular senescence to the pathogenesis and complications of type 2 diabetes mellitus (T2DM), there is a paucity of corroborating data in humans. Thus, we measured a previously validated marker for senescent cell burden in humans, T‐cell expression of p16 mRNA, along with additional biomarkers, to compare the senescence phenotypes of postmenopausal control (lean, N = 37) and T2DM ( N = 27) participants. To control for effects of obesity alone, we included a third group of obese but non‐diabetic women ( N = 29) who were matched for body mass index to the T2DM participants. In addition, given the increase in fracture risk in T2DM despite preserved or even increased bone mineral density, we related these senescence biomarkers in the T2DM participants to skeletal microarchitectural parameters. Relative to the lean participants, T‐cell p16 and p21 Cip1 expression was increased in the T2DM, but not the obese, non‐diabetic participants. Expression of p16 and p21 Cip1 was positively associated with HbA1c and an index of skin advanced glycation end‐products. T2DM was also associated with an increase in a number of SASP factors. Among participants with T2DM, women in the highest tertile for T‐cell expression of p16 had significantly reduced tibial cortical area and thickness as compared to those in the lower two tertiles. Overall, our studies link cellular senescence to metabolic and skeletal alterations in T2DM and point to the need for further studies evaluating the role of cellular senescence in mediating skeletal fragility, as well as potentially other complications in T2DM.

Abstract Gallium-68-DOTA-Tyr3-Octreotate (Ga-68-DOTATATE) positron emission tomography/computed tomography (PET/CT) has recently been shown to have utility for the localization of phosphaturic mesenchymal tumors (PMT) that cause tumor-induced osteomalacia (TIO), a rare renal phosphate-wasting disorder. The aim of this study was to evaluate the accuracy of Ga-68-DOTATATE PET/CT in localizing PMTs causing TIO and to compare its performance with other functional imaging modalities. Prospective recruitment and retrospective chart review of 30 patients with suspected TIO and evaluation with Ga-68-DOTATATE PET/CT between 2017 and 2023 were conducted at a tertiary medical center. True positive (TP) lesions were defined by histological confirmation of PMT. There were 22 TP lesions identified among 18 patients, with a mean SUVmax of 16.8 (±10.9). Sensitivity, specificity, and accuracy of Ga-68-DOTATATE PET/CT were 85.7%, 77.8%, and 83.3% on patient-based analysis, and 84.6%, 56.3%, and 73.8% on lesion-based analysis. Lesions such as subacute fractures, parathyroid adenomas, thymus uptake, vertebral hemangiomas, bone enchondromas, liver hemangiomas, and avascular necrosis were some of the pitfalls in interpretation. Ga-68-DOTATATE PET/CT led to a significant impact on clinical management in 24 (80%) of patients. The presence of DOTATATE-avid fractures was significantly associated with a localizing scan on univariable (OR 15.0, 95% CI 2.80-110, p = .001) and multivariable analysis (OR 9.45, 95% CI 1.33-98.4, p = .003). Ga-68-DOTATATE PET/CT has good accuracy for the localization of TIO, with superior sensitivity compared to F-18-FDG PET/CT. This significantly impacted clinical treatment decisions. Although DOTATATE-avid fractures may be a source of false positives, they may also indicate a higher probability of a localizing study.

Abstract Context Tumor-induced osteomalacia (TIO), a paraneoplastic disorder characterized by renal phosphate wasting, is cured by surgical removal of the culprit tumor. Despite correct localization, some remain refractory to intervention, resulting in substantial long-term medical complications. Objective We aim to identify risk factors associated with a refractory outcome. Methods This is a retrospective cohort of 44 patients with TIO diagnosed from 1998 to 2023 who underwent targeted intervention following successfully localization. Cure was defined as maintenance of normophosphatemia without supplementation for ≥1 month, maintained at last follow-up. Results Twenty-nine patients achieved cure and 15 had a refractory outcome. On univariate Cox regression, the HR for predicting cure was 3.43 (95% CI 1.45-8.11, P = .005) for patients diagnosed after 2013 (compared to before), and that for a negative surgical tumor margin was 2.56 (95% CI 1.20-5.45, P = .015) compared to positive/unspecified margins. After adjustment for year of diagnosis, tumors originating from soft tissue (HR 2.72 vs bone, 95% CI 1.22-6.09, P = .015) or located outside the spine (HR 0.22 for spine vs nonspine, 95% CI 0.05-0.96, P = .043) had higher chances of cure. Size of tumor, age, gender, or baseline biochemistry including levels of fibroblast growth factor (FGF)23, phosphorus, 1,25-dihydroxyvitamin D, or alkaline phosphatase were not predictive of cure. Postprocedural FGF23 was the best biochemical marker of cure (area under curve 0.899, 95% CI 0.764-1.00, P < .001). Conclusion Tumors diagnosed within the past decade with clear resection margins had more favorable prognoses. With regards to tumoral factors, baseline biochemistry was uninformative in predicting cure, while bone and/or spine localizations were associated with a refractory outcome.

Abstract Normocalcemic hyperparathyroidism (NHPT) is variably defined, and information regarding complications and natural history are scarce. We aimed to describe the phenotype of NHPT in relation to hypercalcemic hyperparathyroidism (PHPT) and controls, to determine risk of progression, and to develop a predictive model for progression to PHPT. This is a retrospective chart review of 232 patients at a tertiary medical center, comparing 75 controls, 73 patients with NHPT, and 84 with PHPT. NHPT was intermediate in biochemical profile between controls and PHPT with respect to cCa, iPTH, intraindividual coefficient of variant of cCa, phosphorus, and 25(OH)D. NHPT patients had an increased adjusted risk of urolithiasis (OR 5.34, 95%CI, 2.41-12.71, P < .001) and fragility fractures (OR 4.53, 95%CI, 1.63-14.84, P = .006) versus controls, after adjustment for age, sex, and BMI. Fewer NHPT compared with PHPTH patients achieved cure with parathyroidectomy (P = .001). NHPT more often had nonlocalizing imaging or polyglandular disease (P = .005). Parathyroidectomy improved biochemical but not BMD parameters in NHPT. Over a median follow-up of 4.23 (IQR 1.76-5.31) years, NHPT patients managed expectantly experienced no change in iPTH, and progression to PHPT occurred in 9%. An XGBoost model combining 6 factors for progression (mean index 2 iPTH, mean index 2 cCa, 24-h urinary calcium, age, 25(OH)D, and presence of urolithiasis) had an area under the curve 1.00 (95%CI, 1.00-1.00, P < .001) for predicting combined progression. NHPT is a mild variant of PHPT at intermediate risk of urolithiasis and fragility fractures. Cure was less often achieved with parathyroidectomy, which did not improve BMD parameters. Progression was infrequent with conservative management. Because only a minority progressed to PHPT, in addition to lower surgical success rates, we suggest conservative management for the majority of NHPT unless risk factors for progression are identified.

Abstract Context Tumor-induced osteomalacia (TIO) is a rare condition with evidence mostly derived from case reports and case series. Objective We aimed to describe the clinical characteristics of a large cohort of patients diagnosed with TIO, with a focus on patients with nonlocalizing and malignant TIO. Methods This is a retrospective cohort of patients with TIO in an academic medical center, diagnosed between January 1998 and May 2023. We describe their demographics, biochemistries, tumor features, localization, treatment, and complications. Results Of 68 patients diagnosed with TIO, 49 (72%) were localizing and 5 (7.4%) were malignant. Of 50 patients who attempted localizing procedures, 29 (58%) achieved cure. Twenty (40%) had persistent disease due to the wrong tumor targeted, or refractory or recurrent tumors, despite up to 6 procedural attempts. There was no difference in demographics, phosphorus, or baseline fibroblast growth factor-23 (FGF23) levels between localizing vs nonlocalizing groups, and malignant vs nonmalignant groups. The lower extremity was the commonest site of localization (37%), with 47% in bone and 53% in soft tissue. Sixty percent of malignant cases were located in the trunk. Tumor size correlated with peak FGF23 (R = 0.566, P < .001) but was not associated with malignancy risk (P = .479). A cut-off FGF23 of >20 times upper limit of normal in the presence of normal renal function (P = .025) and recurrence after initial cure (P = .013) were factors significantly associated with malignancy. The nonlocalizing group had lower survival than the localizing group (P = .0097). Conclusion TIO is a condition with significant morbidity. Very high FGF23 levels and disease recurrence are associated with malignant disease. Reasons behind the observation of higher mortality in nonlocalizing TIO should be further explored.