PREDICT-GTN 1: Can we improve the FIGO scoring system in gestational trophoblastic neoplasia?

Gestational trophoblastic neoplasia (GTN) patients are treated according to the eight-variable International Federation of Gynaecology and Obstetrics (FIGO) scoring system, that aims to predict first-line single-agent chemotherapy resistance. FIGO is imperfect with one-third of low-risk patients developing disease resistance to first-line single-agent chemotherapy. We aimed to generate simplified models that improve upon FIGO. Logistic regression (LR) and multilayer perceptron (MLP) modelling (n = 4191) generated six models (M1-6). M1, all eight FIGO variables (scored data); M2, all eight FIGO variables (scored and raw data); M3, nonimaging variables (scored data); M4, nonimaging variables (scored and raw data); M5, imaging variables (scored data); and M6, pretreatment hCG (raw data) + imaging variables (scored data). Performance was compared to FIGO using true and false positive rates, positive and negative predictive values, diagnostic odds ratio, receiver operating characteristic (ROC) curves, Bland-Altman calibration plots, decision curve analysis and contingency tables. M1-6 were calibrated and outperformed FIGO on true positive rate and positive predictive value. Using LR and MLP, M1, M2 and M4 generated small improvements to the ROC curve and decision curve analysis. M3, M5 and M6 matched FIGO or performed less well. Compared to FIGO, most (excluding LR M4 and MLP M5) had significant discordance in patient classification (McNemar's test P < .05); 55-112 undertreated, 46-206 overtreated. Statistical modelling yielded only small gains over FIGO performance, arising through recategorisation of treatment-resistant patients, with a significant proportion of under/overtreatment as the available data have been used a priori to allocate primary chemotherapy. Streamlining FIGO should now be the focus.     

Bone Microarchitecture Phenotypes Identified in Older Adults Are Associated With Different Levels of Osteoporotic Fracture Risk

Prevalence of osteoporosis is more than 50% in older adults, yet current clinical methods for diagnosis that rely on areal bone mineral density (aBMD) fail to detect most individuals who have a fragility fracture. Bone fragility can manifest in different forms, and a “one-size-fits-all” approach to diagnosis and management of osteoporosis may not be suitable. High-resolution peripheral quantitative computed tomography (HR-pQCT) provides additive information by capturing information about volumetric density and microarchitecture, but interpretation is challenging because of the complex interactions between the numerous properties measured. In this study, we propose that there are common combinations of bone properties, referred to as phenotypes, that are predisposed to different levels of fracture risk. Using HR-pQCT data from a multinational cohort (n = 5873, 71% female) between 40 and 96 years of age, we employed fuzzy c-means clustering, an unsupervised machine-learning method, to identify phenotypes of bone microarchitecture. Three clusters were identified, and using partial correlation analysis of HR-pQCT parameters, we characterized the clusters as low density, low volume, and healthy bone phenotypes. Most males were associated with the healthy bone phenotype, whereas females were more often associated with the low volume or low density bone phenotypes. Each phenotype had a significantly different cumulative hazard of major osteoporotic fracture (MOF) and of any incident osteoporotic fracture (p < 0.05). After adjustment for covariates (cohort, sex, and age), the low density followed by the low volume phenotype had the highest association with MOF (hazard ratio = 2.96 and 2.35, respectively), and significant associations were maintained when additionally adjusted for femoral neck aBMD (hazard ratio = 1.69 and 1.90, respectively). Further, within each phenotype, different imaging biomarkers of fracture were identified. These findings suggest that osteoporotic fracture risk is associated with bone phenotypes that capture key features of bone deterioration that are not distinguishable by aBMD. © 2021 American Society for Bone and Mineral Research (ASBMR).     

The Neurosteroid Allopregnanolone Is Reduced in Prefrontal Cortex in Alzheimer’s Disease

BACKGROUND: Few data are currently available investigating neurosteroids (NS) in Alzheimer's disease (AD). The NS allopregnanolone may be decreased in serum and plasma in patients with AD, but it is unclear if allopregnanolone is also reduced in brain. Because a number of NS exhibit neuroprotective effects and impact cognitive performance in rodent models, these molecules may be relevant to the pathophysiology of neurodegenerative disorders. We therefore investigated prefrontal cortex (PFC) NS levels in AD. METHODS: Neurosteroid levels (allopregnanolone, pregnenolone, dehydroepiandrosterone [DHEA]) were determined in postmortem PFC in 14 male subjects with AD and 15 cognitively intact male control subjects by gas chromatography/mass spectrometry preceded by high-performance liquid chromatography purification. RESULTS: Subjects with AD exhibit significant reductions in allopregnanolone compared with cognitively intact control subjects (median levels = 2.50 ng/g vs. 5.59 ng/g, respectively; p = .02). Allopregnanolone levels are inversely correlated with neuropathological disease stage (Braak), r = -.49, p = .007. Median DHEA levels are elevated in subjects with AD (p = .01). CONCLUSIONS: Subjects with AD demonstrate significant reductions in PFC allopregnanolone levels, a finding that may be relevant to neuropathological disease stage severity. Neurosteroids may have utility as candidate biomarkers in AD.     

Pituitary abnormalities in eating disorders: further evidence from MRI studies

1. The frequent occurrence of hypothalamo-pituitary dysfunction in patients with eating disorders as well as prior reports that nutritional and endocrine status influence pituitary morphology, led us to hypothesize that pituitary size and shape may be altered in patients with eating disorders. 2. Magnetic resonance imaging (MRI) does not use ionizing radiation and is currently one of the most feasible modalities available to study the pituitary gland in vivo. Using MRI, we have previously reported in a preliminary study that female patients with eating disorders had significantly smaller pituitary glands than controls. In addition MRI excluded any pituitary mass lesions. 3. In this report, we confirm our previous MRI findings and provide further evidence of pituitary abnormalities in an expanded sample of eating disorder patients. Preliminary data on pituitary volume estimates from MRI scans are provided for a subset of patients and controls.     

Optic nerve glioma and the management of optic nerve tumours in the young.

Thirty-one patients presenting as orbital optic nerve glioma have been reviewed with maximum follow-up of 14 years. Sixteen of these patients have been reported on previously and further follow-up is provided. Sixteen patients had a stable clinical course with little change over a period of up to 13.5 years. Neurofibromatosis was relatively common in this group (11/16). Fifteen patients had progressive enlargement of the tumour; the incidence of neurofibromatosis in this group was low (4/15). Eleven of these patients were explored neurosurgically and the optic nerve totally excised in 10 of them. The proximal cut end was normal in six patients and the chiasm has apparently remained free of tumour in all of them. We suggest a method of management of primary optic nerve tumours, both meningiomas and gliomas, in young patients.     

Differences in SLE disease activity between patients of Caucasian and South‐East Asian/Chinese background in an Australian hospital

Aim: We performed a semiprospective and retrospective review of all admissions to a single institution of systemic lupus erythematosus (SLE) patients, admitted due to active disease. The aim was to describe differences in disease activity as a cause of hospital admissions between patients originating from South‐East Asia/China (SAC) and Caucasians. Method: There were 210 patients admitted for active disease, with a total of 567 admissions for active SLE over a 16‐year period. Allowing for patients who had left our database, there was a total of 3415 patient years of observation. Results: Patients from SAC with a flare requiring admission presented earlier in their disease course and with more active disease than did Caucasians (median SLE Disease Activity Index 13 vs. 8, P= 0.002). They had longer inpatient stays (7 vs. 5 days P = 0.03). There was a trend to higher rates of re‐presentation to hospital for flare (59% in SAC patients vs. 41% in Caucasians, P = 0.09) with more subsequent admissions (3 vs. 2 P = 0.06) despite a shorter period of observation. Conclusions: South‐East Asian/Chinese were more likely to be diagnosed with class III/IV glomerulonephritis and require cyclophosphamide both at presentation and subsequent admissions. More patients from SAC were readmitted to hospital for severe central nervous system disease after their first hospital admission. In this population, lupus patients had more severe flares and more frequently required admission for these than Caucasians.     

Altered excitatory and inhibitory amino acid receptor binding in hippocampus of patients with temporal lobe epilepsy.

We examined binding to excitatory amino acid and inhibitory amino acid receptors in frozen hippocampal sections prepared from surgical specimens resected from 8 individuals with medically refractory temporal lobe epilepsy. The excitatory receptors studied included N-methyl-D-aspartate (NMDA), strychnine-insensitive glycine, phencyclidine, and quisqualate. The inhibitory receptors studied were gamma-aminobutyric acid type A (GABAA) and benzodiazepine. Excitatory and inhibitory amino acid receptor binding were differentially altered in the patients with temporal lobe epilepsy in comparison to 8 age-comparable autopsy control subjects, and changes in receptor binding were regionally selective in four areas. Binding to phencyclidine receptors associated with the NMDA channel was reduced by 35 to 70% in all regions in the hippocampi of the patients. In contrast, binding to the NMDA recognition site and its associated glycine modulatory site was elevated by 20 to 110% in the cornu ammonis (CA) 1 area and dentate gyrus of the hippocampus of the patients. Binding to these sites was unaffected in area CA4. Binding to the quisqualate-type excitatory amino acid receptor was unchanged in all regions except the stratum lacunosum moleculare CA1, where it was increased by 63%. GABAA and benzodiazepine receptor binding was reduced by 20 to 60% in CA1 and CA4, but unchanged in dentate gyrus. The data indicate that excitatory and inhibitory amino acid receptors are altered in the hippocampus of patients with temporal lobe epilepsy.