TGF-ß mRNA levels in circulating extracellular vesicles are associated with response to anti-PD1 treatment in metastatic melanoma.

Introduction: Immune checkpoint inhibitors (ICIs) represent the standard therapy for metastatic melanoma. However, a few patients do not respond to ICIs and reliable predictive biomarkers are needed. Methods: This pilot study investigates the association between mRNA levels of programmed cell death-1 (PD-1) ligand 1 (PD-L1), interferon-gamma (IFN-γ), and transforming growth factor-ß (TGF-ß) in circulating extracellular vesicles (EVs) and survival in 30 patients with metastatic melanoma treated with first line anti-PD-1 antibodies. Blood samples were collected at baseline and RNA extracted from EVs; the RNA levels of PD-L1, IFN-γ, and TGF-ß were analysed by digital droplet PCR (ddPCR). A biomarker-radiomic correlation analysis was performed in a subset of patients. Results: Patients with high TGF-ß expression (cut-off fractional abundance [FA] >0.19) at baseline had longer median progression-free survival (8.4 vs. 1.8 months; p = 0.006) and overall survival (17.9 vs. 2.63 months; p = 0.0009). Moreover, radiomic analysis demonstrated that patients with high TGF-ß expression at baseline had smaller lesions (2.41 ± 3.27 mL vs. 42.79 ± 101.08 mL, p < 0.001) and higher dissimilarity (12.01 ± 28.23 vs. 5.65 ± 8.4; p = 0.018). Discussion: These results provide evidence that high TGF-ß expression in EVs is associated with a better response to immunotherapy. Further investigation on a larger patient population is needed to validate the predictive power of this potential biomarker of response to ICIs.

Glandular involvement in primary Sjögren's syndrome patients with interstitial lung disease-onset and sicca-onset, a single centre cross-sectional study.

OBJECTIVES: Primary Sjögren's syndrome (pSS) is an autoimmune exocrinopathy classically presenting with sicca symptoms. Nonetheless, disease onset with extraglandular manifestations, including interstitial lung disease (ILD), is increasingly reported. However, studies investigating pSS patients presenting with ILD (pSS-ILD) are limited.Aim of this study was to better characterise the phenotype of pSS patients presenting with ILD in comparison to pSS patients with classicsicca-onset. We especially investigated whether the two groups differed in glandular involvement comparing functional, imaging andhistologic findings, as well as patient reported outcome (PRO). METHODS: Consecutive newly diagnosed pSS patients, all fulfilling the ACR/EULAR 2016 criteria, were included in this cross-sectional study from September 2016 to October 2021. Presence of ILD at pSS diagnosis was defined based on clinical findings, imaging assessment and pulmonary function tests (PFT). In addition to functional tests, a minor salivary gland biopsy was performed in all cases, recording number of foci, focus score (FS) and GC-like structures. Salivary glands ultrasonography (SGUS) was graded using the OMERACT semiquantitative scoring system (0-3) based on parenchyma inhomogeneity. PRO including ESSPRI, OHIP and OSSDI were collected.Extraglandular clinical features and biological abnormalities included in the ESSDAI were recorded. Data were expressed as mean±SD for continuous variables and as absolute frequencies and percentages for categorical variables. Chi-Square test and Mann-Whitney U-test and ANOVA were performed for comparisons of categorical variables and continuous variables, respectively. RESULTS: We included 178 newly diagnosed pSS patients (F:M=158:20). ILD was the first pSS manifestation in 11 (6%) cases, 8 F and 3 M, with a median time from ILD onset to pSS diagnosis of 2 years (25-75 IQ 1-4.5). Of the 11 pSS-ILD patients, HRCT pattern was defined as NSIP in 4, UIP in 4, NSIP+OP in 2 and LIP in 1 patient. Dyspnoea on exertion or chronic cough were reported by 7/11 (63.6%) patients.In comparison to sicca-onset patients, pSS-ILD patients presented an older age at diagnosis (55±13 vs. 70±7, p= 0.001) and a higher ESSDAI (3.9±4.7 vs. 12.3±4.3, p=0.001), driven by the pulmonary domain. Regarding glandular involvement, pSS-ILD patients reported milder xeropthalmia (VAS 5.8±3.1 vs. 2.8±3.5, p=0.002) and significative lower scores in OSDI (35.6±24.9 vs. 15.3±22.9, p=0.04) and OHIP (4.8±4.4 vs. 1.4±3.8, p=0.04), despite no significant differences observed between the two groups in ocular tests and unstimulated salivary flow rate. With respect to histology, no significant differences were found in number of foci, FS and GC-like structures. We observed a significantly different distribution of the SGUS OMERACT score in the two groups: none of pSS-ILD patients presented a SGUS OMERACT score ≥2 in the submandibular glands (SG), in contrast to 41/132 (31.1%) of the patients in the classical sicca-onset group (p=0.03). Finally, no significant differences were observed between the two groups with respect to non-pulmonary extraglandular manifestations, serologic features and other biological parameters. CONCLUSIONS: ILD-onset pSS patients represent an atypical phenotypic subset, with less pronounced sialadenitis structural changes in salivary glands, and with sicca symptoms probably overshadowed by the respiratory disease.

Computed Tomography-assessed Skeletal Muscle Index and Skeletal Muscle Radiation Attenuation in Patients With Ovarian Cancer Treated With Primary Surgery Followed by Platinum-based Chemotherapy: A Single-center Italian Study.

AIM: To assess the prognostic relevance of baseline and post-treatment skeletal muscle index (SMI) and skeletal muscle radiation attenuation (SMRA) at the level of third lumbar vertebra in patients with ovarian cancer who underwent primary surgery and platinum-based chemotherapy. PATIENTS AND METHODS: This retrospective investigation analyzed 134 patients who underwent staging computed tomography, surgery, chemotherapy and post-treatment computed tomography. RESULTS: At univariate analysis, stage (p<0.0001), histotype (p=0.01), residual disease (p<0.0001) and treatment response (p<0.0001) correlated with progression-free survival (PFS), whereas age (p=0.004), stage (p=0.006), residual disease (p<0.0001) and treatment response (p<0.0001) were associated with overall survival (OS). Neither baseline nor post-treatment SMI and SMRA had prognostic relevance. At multivariate analysis, residual disease and treatment response correlated with PFS (p<0.0001 and p<0.0001) and OS (p=0.007 and p<0.0001), whilst age was an independent prognostic variable for OS (p=0.02). CONCLUSION: Baseline and post-treatment SMI and SMRA did not correlate with patient outcome in this clinical setting.

Pulp chamber features, prevalence of abscesses, disease severity, and PHEX mutation in X-linked hypophosphatemic rickets.

INTRODUCTION: Rickets, growth failure, and recurrent periapical abscesses with fistulae are main signs in patients with X-linked hypophosphatemic rickets (XLH). Prevalence of abscesses, pulp chamber features, biochemical findings, disease severity, and PHEX gene mutation were examined. MATERIALS AND METHODS: Pulp chambers size, shape, and morphology were assessed by orthopantomography in XLH patients (n = 24, age 5.8 ± 1.6 years) and in sex and age-matched healthy controls (n = 23, age 6.2 ± 1.4 years). XLH patients received conventional treatment (3.5 ± 1.9 years). Pulp chamber features were assessed in teeth of primary dentition and in the permanent left mandibular first molar and compared with those of controls. Rickets severity score was assessed at wrist, knee, and ankle. RESULTS: The mean pulp chamber area/tooth area ratio, mean pulp chamber height/pulp chamber width ratio, and prominence of pulp horns into the tooth crown in primary and secondary molars were significantly higher in patients than in controls and in patients suffered abscesses than in patients without abscesses. Sixteen patients (67%) had a history of abscesses; incisors were affected more than canines and molars. Severity of rickets and mean serum parathyroid hormone (PTH) levels were significantly higher, and mean serum 1,25-dihydroxyvitamin D [1,25(OH)2D] levels significantly lower in patients suffered abscesses than in patients without abscesses. PHEX gene mutations were not correlated with dental phenotype and disease severity. CONCLUSION: Enlarged pulp chambers with altered shape and morphology affected the majority of XLH patients predisposing to recurrent periapical abscesses with fistulae. Dental phenotype was associated with severity of rickets, high serum PTH, and low serum 1,25(OH)2D levels.

Pediatric bronchiectasis: correlation of HRCT, ventilation and perfusion scintigraphy, and pulmonary function testing.

Bronchiectasis in children, although occurring with diminished frequency, continues as a major challenge for the pediatric pulmonologist. The method of choice for the diagnosis of the condition is high-resolution computed tomography (HRCT). The aim of the present study was to correlate the relationship(s) of HRCT, lung function, ventilation lung scintigraphy (VLS), and perfusion lung scintigraphy (PLS) in children with bronchiectasis. Sixteen children ranging in age from 4-18 years with clinical and chest X-ray evidence of bronchiectasis were enrolled in the study. The degree of bronchiectasis was assessed by HRCT scores, decrease in attenuation on expiratory scans, VLS, and PLS. HRCT scores for bronchiectasis and decreased lung attenuation showed a strong correlation with PLS (rho = 0.82; P < 0.001) and with VLS (rho = 0.72; P < 0.01). There was a moderate negative correlation between FEV(1) and HRCT bronchiectasis scores (rho = -0.53; P = 0.02), decreased lung attenuation score (rho = -0.64; P = 0.007), and atelectasis score (rho = -0.54; P = 0.03). In conclusion, HRCT provides a complete and precise assessment of children with bronchiectasis. Ventilation/perfusion scans and lung functions are additive tools to understand the complexity of the disease process and to improve diagnosis and therapeutic strategies.