Epidemiological analysis to identify predictors of X-linked hypophosphatemia (XLH) diagnosis in an Italian pediatric population: the EPIX project.

PURPOSE: X-linked hypophosphatemia (XLH) is a rare multi-systemic disease characterized by low plasma phosphate levels. The aim of this study was to investigate the annual XLH prevalence and internally evaluate predictive algorithms' application performance for the early diagnosis of XLH. METHODS: The PediaNet database, containing data on more than 400,000 children aged up to 14 years, was used to identify a cohort of XLH patients, which were matched with up to 10 controls by date of birth and gender. The annual prevalence of XLH cases per 100,000 patients registered in PediaNet database was estimated. To identify possible predictors associated with XLH diagnosis, a logistic regression model and two machine learning algorithms were applied. Predictive analyses were separately carried out including patients with at least 1 or 2 years of database history in PediaNet. RESULTS: Among 431,021 patients registered in the PediaNet database between 2007-2020, a total of 12 cases were identified with a mean annual prevalence of 1.78 cases per 100,000 patients registered in PediaNet database. Overall, 8 cases and 60 matched controls were included in the analysis. The random forest algorithm achieved the highest area under the receiver operating characteristic curve (AUC) value both in the one-year prior ID (AUC = 0.99, 95% CI = 0.99-1.00) and the two-year prior ID (AUC = 1.00, 95% CI = 1.00-1.00) analysis. Overall, the XLH predictors selected by the three predictive methods were: the number of vitamin D prescriptions, the number of recorded diagnoses of acute respiratory infections, the number of prescriptions of antihistamine for systemic use, the number of prescriptions of X-ray of the lower limbs and pelvis and the number of allergology visits. CONCLUSION: Findings showed that data-driven machine learning models may play a prominent role for the prediction of the diagnosis of rare diseases such as XLH.

BRAF-AXL-PD-L1 Signaling Axis as a Possible Biological Marker for RAI Treatment in the Thyroid Cancer ATA Intermediate Risk Category.

The use of radioiodine therapy (RIT) is debated in intermediate-risk differentiated thyroid cancer (DTC) patients. The understanding of the molecular mechanisms involved in the pathogenesis of DTC can be useful to refine patient selection for RIT. We analyzed the mutational status of BRAF, RAS, TERT, PIK3 and RET, and the expression of PD-L1 (as a CPS score), the NIS and AXL genes and the tumor-infiltrating lymphocytes (TIL, as the CD4/CD8 ratio), in the tumor tissue in a cohort of forty-six ATA intermediate-risk patients, homogeneously treated with surgery and RIT. We found a significant correlation between BRAF mutations and a less than excellent (LER, according to 2015 ATA classification) response to RIT treatment (p = 0.001), higher expression of the AXL gene (p = 0.007), lower expression of NIS (p = 0.045) and higher expression of PD-L1 (p = 0.004). Moreover, the LER patient group had a significantly higher level of AXL (p = 0.0003), a lower level of NIS (p = 0.0004) and a higher PD-L1 level (p = 0.0001) in comparison to patients having an excellent response to RIT. We also found a significant direct correlation between the AXL level and PD-L1 expression (p < 0.0001) and a significant inverse correlation between AXL and NIS expression and TILs (p = 0.0009 and p = 0.028, respectively). These data suggest that BRAF mutations and AXL expression are involved in LER among DTC patients and in the higher expression of PD-L1 and CD8, becoming new possible biomarkers to personalize RIT in the ATA intermediate-risk group, as well as the use of higher radioiodine activity or other possible therapies.

Persistent severe visual field impairment is associated with obesity and tumour invasiveness, but not with pituitary dysfunction, in patients with craniopharyngioma.

PURPOSE: Craniopharyngiomas (CP) are benign tumours of the sellar region. Hypopituitarism, visual deficits, hypothalamic damage with consequent obesity and related increased cardiovascular risk, are complications due to the tumour itself or secondary to treatment strategy. We retrospectively correlated visual field status with clinical, neuroradiological, histopathological features and management strategy, in a single-centre cohort of patients with CP. METHODS: Thirty-four patients (16 M; median age 27.2 ± 21.8 yrs) with CP were included. We evaluated visual field status, assessed by means of standard automated perimetry and expressed as mean deviation (MD), at last follow-up visit (median 14 ± 11.7 yrs). MD has been correlated with clinical, radiological, histological data and treatment modalities. RESULTS: In univariate analysis worst eye MD was significantly associated with panhypopituitarism (p 0.010). In multivariable linear regression, panhypopituitarism (p 0.008), CP recurrence (p 0.020) and DI (p 0.004) were found to be the main independent predictors of a worse visual field outcome. When stratifying patients according to the degree of visual field impairment (MD < -12 dB Vs MD > -12 dB), the main independent predictors of worse visual field outcome were older age at diagnosis (p 0.010), CP histological subtype (p 0.004), invasiveness (p 0.04), CP recurrence (p 0.035), DI (p 0.002) and weight at last follow-up (p 0.012). CONCLUSION: In CP patients the long-term ophthalmological impairment is frequent, especially at older age, and strictly related to tumour invasiveness and recurrence, and associated to pituitary disfunction and obesity.

Trabecular bone score, bone marrow fat and vertebral fractures in cushing syndrome.

OBJECTIVE: Prediction of fragility fractures in Cushing syndrome (CS) is a challenge since dual energy X-ray absorptiometry (DXA) measurement of bone mineral density (BMD) does not capture all the alterations in bone microstructure induced by glucocorticoid excess. In this study we investigated the relationship between trabecular bone score (TBS), bone marrow fat (BMF) and vertebral fractures (VFs) in endogenous CS. DESIGN: Cross-sectional. METHODS: Thirty subjects (7 M and 23 F, mean age 44.8 ± 13.4 yrs, range: 25-71) with active hypercortisolism were evaluated for VFs by quantitative morphometry, BMD and TBS by lumbar spine DXA and BMF by single-voxel magnetic resonance spectroscopy of vertebral body of L3. RESULTS: Subjects with VFs (17 cases; 56.7%) had higher BMF (P = 0.014) and lower BMD T-score (P = 0.012) and TBS (P = 0.004) as compared to those without VFs. Prevalence of VFs resulted to be significantly higher in individuals with impaired TBS as compared to those with normal TBS (77.8% vs. 25.0%; P = 0.008). Among patients with VFs, only 6 (35.3%) had either osteoporosis or "low BMD for age". In logistic regression analysis, impaired TBS maintained the significant association with VFs [odds ratio (OR) 6.60, 95% C.I. 1.07-40.61; P = 0.042] independently of BMF (OR 1.03, 95% C.I. 0.99-1.08; P = 0.152). CONCLUSIONS: TBS might be more accurate than BMF in identifying subjects with active CS and skeletal fragility at risk of VFs. SIGNIFICANCE STATEMENT: Excess in glucocorticoids is associated with alterations in bone remodeling and metabolism, leading to fragility fractures regardless of bone mineral density, making more challenging for the clinician the identification of high-risk population and the definition of preventing strategies. In this context, instrumental parameters suggestive of bone quality alterations and predictive of increased fracture risk are needed. In this study, we found CS patients to have bone quality alterations as indicated by the decreased trabecular bone score and increased bone marrow fat, as measured by DEXA and MRI respectively. Both parameters were associated with high risk of VFs, and were inversely correlated, although TBS seems to be more accurate than BMF in fractures prediction in this clinical setting.

Carcinoid Syndrome: Preclinical Models and Future Therapeutic Strategies.

Carcinoid syndrome represents a debilitating paraneoplastic disease, caused by the secretion of several substances, occurring in about 10-40% of patients with well-differentiated neuroendocrine tumors (NETs). The main signs and symptoms associated with carcinoid syndrome are flushing, diarrhea, hypotension, tachycardia, bronchoconstriction, venous telangiectasia, dyspnea and fibrotic complications (mesenteric and retroperitoneal fibrosis, and carcinoid heart disease). Although there are several drugs available for the treatment of carcinoid syndrome, the lack of therapeutic response, poor tolerance or resistance to drugs are often reported. Preclinical models are indispensable tools for investigating the pathogenesis, mechanisms for tumor progression and new therapeutic approaches for cancer. This paper provides a state-of-the-art overview of in vitro and in vivo models in NETs with carcinoid syndrome, highlighting the future developments and therapeutic approaches in this field.

Methylome Analysis in Nonfunctioning and GH-Secreting Pituitary Adenomas.

Pituitary adenomas (PAs), usually benign lesions, can sometimes present with "aggressive" features (rapid growth, local invasiveness, scarce response to conventional treatments). Despite the fact that a few genetic alterations have been associated to this clinical behavior, the role of epigenetic modifications, mainly methylation and miRNAs activity, is now opening new frontiers in this field. We evaluated the methylation profile of 21 PA (11 GH-omas, 10 nonfunctioning tumors-NFPAs) samples from TNS surgery and 5 normal pituitaries, collected at our neurosurgery between 2015 and 2017. DNA was extracted and sequenced, selecting 184,841 target regions. Moreover, methylation profiles were correlated with demographic, radiological, and clinicopathological features. NFPAs showed higher methylation levels vs. GH-omas, with 178 differentially methylated regions (DMRs) mainly consisting of noncoding and intronic sequences, and mostly localized in the open sea regions. We also found three hypermethylated genes (C7orf50, GNG7, and BAHCC1) involved in tumorigenesis processes and potentially influencing pituitary tumor pathophysiology. Among the clinicopathological features, only the maximum diameter resulted significantly higher in NFPAs. Our data provide further evidence of the complex epigenetic background of pituitary tumors. In line with the current literature, we confirmed a significant prevalence of hypermethylation in NFPAs vs. GH-omas, whose pathophysiological consequence is yet to be defined.

Shrinkage of a pituitary metastasis of melanoma induced by pembrolizumab: a case report.

BACKGROUND: Pituitary metastases are rare, often deriving from lung or breast cancer owing to the upper vena cava proximity. Pituitary metastases can manifest with signs and symptoms of pituitary tumors, consequent to mass effect (headache, visual impairment) and/or hormonal alterations (hyperprolactinemia, hypopituitarism, and diabetes insipidus). Immune checkpoint inhibitors burst immunity against tumors, significantly increasing patients' survival, but their autoimmune side effects frequently involve the skin, the gastrointestinal tract, and the endocrine glands (pituitary, thyroid, pancreas). CASE PRESENTATION: A 77-year-old Caucasian man had undergone trans-nasal sphenoidal surgery for a nonsecreting pituitary macroadenoma in 2001, without remnant or endocrine deficits. In 2016, he was operated for a shoulder melanoma. In February 2018, imaging evaluation demonstrated metastases in lung, liver, and femur. Therefore, treatment with pembrolizumab (anti-programmed death 1) was scheduled in May 2018, but, before starting this therapy, a brain computed tomography performed for a sudden loss of consciousness detected a sellar mass of 17 × 12 mm, which extended to the pituitary stalk and compressed the optic chiasma. Focused magnetic resonance imaging confirmed the size and characteristics of the lesion, while emergency evaluation of the hormonal profile demonstrated an impairment of adrenal and thyroid function. The pituitary lesion demonstrated a remarkable shrinkage (8 × 6 mm), which was confirmed by subsequent imaging evaluations. CONCLUSIONS: This is the first case reporting on effectiveness of immune checkpoint inhibitors in a patient with pituitary metastasis from a melanoma.