Background: Identifying response markers is highly needed to guide the treatment strategy in patients with metastatic melanoma. Methods: A retrospective study was carried out in patients with unresectable/metastatic melanoma (stage IIIb–IV), treated with anti-PD-1 in the first line setting, to better explore the role and the timing of neutrophil/lymphocyte ratio (NLR) as potential biomarker of response. The relationship of NLR with inflammation-immune mediators and the underlying negative effect of raising NLR during immunotherapy, have been investigated with transcriptomic gene analysis. Results: The results confirmed previous findings that a high baseline NLR is associated with a poorer prognosis and with higher serum level of lactate dehydrogenase (LDH), regardless of the presence of brain metastases. The transcriptomic analysis showed that high baseline NLR is associated with a characteristic gene signature CCNA1, LDHA and IL18R1, which correlates with inflammation and tumorigenesis. Conversely, low baseline NLR is associated with the signature CD3, SH2D1A, ZAP70 and CD45RA, linked to the immune-activation. The genes positively associated with NLR (CD39 (ENTPD1), PTEN, MYD88, MMP9 and LDH) are involved in processes of immunosuppression, inflammation and tumor-promoting activity. Increased expression of CD39 correlated with TGFβ₂, a marker of the N2 neutrophils with immunosuppressive activity. Conclusions: These results suggest that increasing NLR is associated with an increased neutrophil population, with polarization to the N2 phenotype, and this process may be the basis for the negatively prognostic role of NLR.

Resistance biomarkers are needed to identify patients with advanced melanoma obtaining a response to ICI treatment and developing resistance later. We searched a combination of molecular signatures of response to ICIs in patients with metastatic melanoma. In a retrospective study on patients with metastatic melanoma treated with an anti-PD-1 agent carried out at Istituto Nazionale Tumori—IRCCS—Fondazione “G. Pascale”, Naples, Italy. We integrated a whole proteome profiling of metastatic tissue with targeted transcriptomics. To assess the prognosis of patients according to groups of low and high risk, we used PFS and OS as outcomes. To identify the proteins and mRNAs gene signatures associated with the patient’s response groups, the discriminant analysis for sparse data performed via partial least squares procedure was performed. Tissue samples from 22 patients were analyzed. A combined protein and gene signature associated with poorer response to ICI immunotherapy in terms of PFS and OS was identified. The PFS and OS Kaplan–Meier curves were significantly better for patients with high expression of the protein signature compared to patients with low expression of the protein signature and who were high-risk (Protein: HR = 0.023, 95% CI: 0.003–0.213; p < 0.0001. Gene: HR = 0.053, 95% CI: 0.011–0.260; p < 0.0001). The Kaplan–Meier curves showed that patients with low-risk gene signatures had better PFS (HR = 0 0.221, 95% CI: 0.071–0.68; p = 0.007) and OS (HR = 0.186, 95% CI: 0.05–0.695; p = 0.005). The proteomic and transcriptomic combined analysis was significantly associated with the outcomes of the anti-PD-1 treatment with a better predictive value compared to a single signature. All the patients with low expression of protein and gene signatures had progression within 6 months of treatment (median PFS = 3 months, 95% CI: 2–3), with a significant difference vs. the low-risk group (median PFS = not reached; p < 0.0001), and significantly poorer survival (OS = 9 months, 95% CI: 5–9) compared to patients with high expression of protein and gene signatures (median OS = not reached; p < 0.0001). We propose a combined proteomic and transcriptomic signature, including genes involved in pro-tumorigenic pathways, thereby identifying patients with reduced probability of response to immunotherapy with ICIs for metastatic melanoma.

In the analysis of the difference in the distribution and profiles of the equitable and sustainable well-being, the territorial dimension is a fundamental reading-key for local policies since it allows the areas of advantage or relative deprivation to emerge more accurately. Specifically, in Italy the provincial level coincides with the administrative area of metropolitan cities, which are the subject of growing attention from European and national policies. The BES 2018 report by Italian National Institute of Statistics (ISTAT) has confirmed that from 2015 an improvement in many areas of well-being has been marked, even if territorial differences remain stable both in levels and dynamics. These differences appear in some cases as real structural differences between the North and South of Italy. Then, the measures of equitable and sustainable well-being in the territories allow, in various degrees, to deepen and specify this situation employing synthetic measures of well-being. In this work, we propose a statistical methodology focused on the simultaneous partial least squares structural equation modeling and simultaneous K-means clustering to obtain a composite indicator of Italian well-being and at the same time a classification of Italian territorial micro-areas by means of the just updated provincial data about BES 2018. In this way, the territorial differences of well-being can be more reliably and more exactly defined on the basis of the relationships among all elementary indicators and domains proposed in the analysis of well-being by ISTAT.

Background: Rheumatoid Arthritis (RA) is a systemic and chronic autoimmune disease with inflammation at the synovial joints. The purposes of this study were to evaluate the correlation between serological variables and temporomandibular disorders (TMDs) in patients diagnosed with RA, evaluated through diagnostic criteria for temporomandibular disorders (DC/TMD), and to check the influence of comorbidities on the different TMD signs and symptoms, or any serological variables. Methods: This observational cohort research study included seventeen patients affected by RA. The comorbidities and some variables from the initial serological analyses were collected from the clinical rheumatological charts. Then, the presence of any of the following TMD signs/symptoms, temporal myalgia, temporomandibular joint arthralgia, click or crepitus, was evaluated through the symptom questionnaire of the DC/TMD during clinical evaluation following the DC/TMD examination form. Results: Rheumatoid factor (RF), anticitrullinated protein antibodies (ACPA), and anti-nuclear antibody (ANA) positivity were present in 82.4%, 52.9%, and 41.2% of patients, respectively. Indicators of tissue inflammation were evaluated with median values of 21 mm/h for erythrocyte sedimentation rate (ESR) and 0.50 mg/dL for C-reactive protein (CRP). The RA patients presented comorbidities such as hypertension in 70.6% and diabetes in 23.5%. Negative ACPA had a significant association with myalgia (p = 0.03), and positive ANA was significantly associated with crepitus (p = 0.05). Conclusion: ANA and ACPA evaluation can be considered predictive serological tests associated with specific TMDs. Conversely, no influence of any comorbidities was found between different TMD signs and symptoms, or any serological variables.