Ipilimumab (IPI) blocks CTLA-4 immune checkpoint resulting in T cell activation and enhanced antitumor immunity. IPI improves overall survival (OS) in 22% of patients with metastatic melanoma (MM). ...We investigated the association of CTLA-4 single nucleotide variants (SNVs) with best overall response (BOR) to IPI and OS in a cohort of 173 MM patients. Patients were genotyped for six CTLA-4 SNVs (-1661A>G, -1577G>A, -658C>T, -319C>T, +49A>G, and CT60G>A). We assessed the association between SNVs and BOR through multinomial logistic regression (MLR) and the prognostic effect of SNVs on OS through Kaplan-Meier method. Both -1577G>A and CT60G>A SNVs were found significantly associated with BOR. In particular, the proportion of responders was higher in G/G genotype while that of stable patients was higher in A/A genotype. The frequency of patients experiencing progression was similar in all genotypes. MLR evidenced a strong downward trend in the probability of responsiveness/progression, in comparison to disease stability, as a function of the allele A "dose" (0, 1, or 2) in both SNVs with reductions of about 70% (G/A vs G/G) and about 95% (A/A vs G/G). Moreover, -1577G/G and CT60G/G genotypes were associated with long-term OS, the surviving patients being at 3 years 29.8 and 30.8%, respectively, as compared to 12.9 and 14.4% of surviving patients carrying -1577G/A and CT60G/A, respectively. MM patients carrying -1577G/G or CT60G/G genotypes may benefit from IPI treatment in terms of BOR and long-term OS. These CTLA-4 SNVs may serve as potential biomarkers predictive of favorable outcome in this subset of patients.
Previous studies have reported an association between sun exposure and improved cutaneous melanoma (CM) survival. We analysed the association of UV exposure with prognostic factors and outcome in a ...large melanoma cohort.
A questionnaire was given to 289 (42%) CM patients at diagnosis (Group 1) and to 402 CM patients (58%) during follow-up (Group 2). Analyses were carried out to investigate the associations between sun exposure and melanoma prognostic factors and survival.
Holidays in the sun two years before CM diagnosis were significantly associated with lower Breslow thickness (p=0.003), after multiple adjustment. Number of weeks of sunny holidays was also significantly and inversely associated with thickness in a dose-dependent manner (p=0.007). However when stratifying by gender this association was found only among women (p=0.0004) the risk of CM recurrence in both sexes was significantly lower in patients (n=271) who had holidays in the sun after diagnosis, after multiple adjustment including education: HR=0.30 (95%CI:0.10-0.87; p=0.03) conclusions: Holidays in the sun were associated with thinner melanomas in women and reduced rates of relapse in both sexes. However, these results do not prove a direct causal effect of sun exposure on survival since other confounding factors, such as vitamin D serum levels and socio-economic status, may play a role. Other factors in sun seeking individuals may also possibly affect these results.
Secretory immunoglobulin A (SIgA) represents a first line of defense against mucosal pathogens by limiting their entrance. By using different strains of
Salmonella typhimurium that target the two ...mechanisms of bacterial entry (microfold cell M cell- or dendritic cell-mediated), we demonstrated here that the distribution of bacteria after oral infection directed the type of induced immune response. M cell-penetrating invasive, but not noninvasive,
S. typhimurium was found in large numbers in Peyer's patches (PPs), leading to the activation of immune cells and the release of fecal IgA. In contrast, both strains of bacteria were equally capable of reaching the mesenteric lymph node and the spleen and inducing IgG responses. These data suggest that PPs are absolutely required for the initiation of an IgA response to
Salmonella, whereas they are dispensable for a systemic response. This compartmentalization could allow the fast generation of both mucosal and systemic acquired immunity to pathogens.
Lung cancer (LC) remains a disease with poor prognosis despite recent advances in treatments. Here, we aimed at summarizing the current scientific evidence on whether quitting smoking at or around ...diagnosis has a beneficial effect on the survival of LC patients.
We searched MEDLINE and EMBASE for articles published until 31st October, 2021, that quantified the impact on LC patients’ survival of quitting smoking at or around diagnosis or during treatment. Study-specific data were pooled into summary relative risk (SRR) and corresponding 95% confidence intervals (CI) using random effect meta-analysis models.
Twenty-one articles published between 1980 and 2021 were included, which encompassed a total of over 10,000 LC patients. There was substantial variability across studies in terms of design, patients’ characteristics, treatments received, criteria used to define smoking status (quitters or continued), and duration of follow-up. Quitting smoking at or around diagnosis was significantly associated with improved overall survival (SRR 0.71, 95% CI 0.64–0.80), consistently among patients with non-small cell LC (SRR 0.77, 95% CI 0.66–0.90, n studies = 8), small cell LC (SRR 0.75, 95% CI 0.57–0.99, n studies = 4), or LC of both or unspecified histological type (SRR 0.81, 95% CI 0.68–0.96, n studies = 6).
Quitting smoking at or around diagnosis is associated with a beneficial effect on the survival of LC patients. Treating physicians should educate LC patients about the benefits of quitting smoking even after diagnosis and provide them with the necessary smoking cessation support.
Cancer‐related inflammation may play an important role in disease progression and patient outcome, and could be easily monitored through indirect parameters routinely evaluated at diagnosis. Here, we ...investigated if peripheral blood cells and the ratios of neutrophils to lymphocytes (NLR) and of lymphocytes to monocytes (LMR) as surrogate markers of cancer related inflammation are associated with disease progression and survival of melanoma patients at any stage of the disease. Records of 1,182 melanoma patients included in an Institutional tumor registry in the period 2000–2010, were reviewed. Among them, 584 patients with a cutaneous or unknown primary melanoma and available pre‐operative blood tests were analyzed. Survival was estimated with the Kaplan–Meier method, and analyzed using Log‐rank test, Cox regression and multivariate Cox proportional hazard models. We found that patients presenting with distant metastases had higher leukocytes, neutrophils and monocytes, and lower lymphocytes compared to Stage I–III patients. Furthermore, at a single‐patient level, hematological profiles changed on disease progression from regional to distant metastatic, with significantly increased circulating leukocytes, neutrophils and monocytes, and decreased lymphocytes. Peripheral blood cell counts were not associated with survival of patients with a localized or regionally metastasized melanoma. Instead, in Stage IV patients, leukocytes (p = 0.001), neutrophils (p = 0.0002), monocytes (p = 0.002), NLR (p < 0.0001) and LMR (p = 0.005) were all significantly associated with survival, independently of other known prognostic factors. These results suggest that cellular components of peripheral blood do count for survival of patients with advanced melanoma.
What's new?
Inflammation plays a role in all aspects of tumorigenesis and progression, to the extent that for certain malignancies peripheral blood markers of systemic inflammation can potentially predict patient outcome. In this analysis of melanoma patients in various stages of disease, the presence of distant metastases was found to be associated with changes in blood cell counts, specifically in absolute cell numbers and relative frequencies. In Stage IV patients, a distinct hematological profile, characterized by elevations in monocytes and in neutrophil‐to‐lymphocyte ratios, was strongly linked to increased risk of mortality, independent of existing established predictors of patient outcome.
CTLA-4 blockade by means of ipilimumab (IPI) potentiates the immune response and improves overall survival (OS) in a minority of metastatic melanoma (MM) patients. We investigated the role of soluble ...CTLA-4 (sCTLA-4) as a possible biomarker for identifying this subset of patients. sCTLA-4 levels were analyzed at baseline in sera from 113 IPI-treated MM patients by ELISA, and the median value (200 pg/ml) was used to create two equally sized subgroups. Associations of sCTLA-4 with best overall response (BOR) to IPI and immune-related adverse events (irAEs) were evaluated through logistic regression. Kaplan–Meier and Cox regression methods were used to analyze OS. A remarkable association between sCTLA-4 levels and BOR was found. Specifically, the proportion of patients with sCTLA-4 > 200 pg/ml in irSD or irPD (immune-related stable or progressive disease) was, respectively, 80% (OR = 0.23; 95%CL = 0.03–1.88) and 89% (OR = 0.11; 95%CL = 0.02–0.71) and was lower than that observed among patients in irCR/irPR (immune-related complete/partial response). sCTLA-4 levels increased during IPI treatment, since the proportion of patients showing sCTLA > 200 pg/ml after 3 cycles was 4 times higher (OR = 4.41, 95%CL = 1.02–19.1) than that after 1 cycle. Moreover, a significantly lower death rate was estimated for patients with sCTLA-4 > 200 pg/ml (HR = 0.61, 95%CL = 0.39–0.98). Higher baseline sCTLA-4 levels were also associated with the onset of any irAE (
p
value = 0.029), in particular irAEs of the digestive tract (
p
value = 0.041). In conclusion, our results suggest that high sCTLA-4 serum levels might predict favorable clinical outcome and higher risk of irAEs in IPI-treated MM patients.
Background and aim: Over the last decades, the incidence of melanoma has been steadily growing, with 4.2% of the population worldwide affected by cutaneous melanoma (CM) in 2020 and with a higher ...incidence and mortality in men than in women. We investigated both the risk factors for CM development and the prognostic and predictive factors for survival, stratifying for both sex and gender. Methods: We conducted a systematic review of studies indexed in PUB-MED, EMBASE, and Scopus until 4 February 2021. We included reviews, meta-analyses, and pooled analyses investigating differences between women and men in CM risk factors and in prognostic and predictive factors for CM survival. Data synthesis: Twenty-four studies were included, and relevant data extracted. Of these, 13 studies concerned potential risk factors, six concerned predictive factors, and five addressed prognostic factors of melanoma. Discussion: The systematic review revealed no significant differences in genetic predisposition to CM between males and females, while there appear to be several gender disparities regarding CM risk factors, partly attributable to different lifestyles and behavioral habits between men and women. There is currently no clear evidence of whether the mutational landscapes of CM differ by sex/gender. Prognosis is justified by a complex combination of phenotypes and immune functions, while reported differences between genders in predicting the effectiveness of new treatments are inconsistent. Overall, the results emerging from the literature reveal the importance of considering the sex/gender variable in all studies and pave the way for including it towards precision medicine. Conclusions: Men and women differ genetically, biologically, and by social construct. Our systematic review shows that, although fundamental, the variable sex/gender is not among the ones collected and analyzed.
Background
A polygenic inheritance involving high, medium and low penetrance genes has been suggested for melanoma susceptibility in adults, but genetic information is scarce for paediatric patients.
...Objective
We aim to analyse the major high and intermediate melanoma risk genes, CDKN2A, CDK4, POT1, MITF and MC1R, in a large multicentre cohort of Italian children and adolescents in order to explore the genetic context of paediatric melanoma and to reveal potential differences in heritability between children and adolescents.
Methods
One‐hundred‐twenty‐three patients (<21 years) from nine Italian centres were analysed for the CDKN2A, CDK4, POT1, MITF, and MC1R melanoma predisposing genes. The rate of gene variants was compared between sporadic, familial and multiple melanoma patients and between children and adolescents, and their association with clinico‐pathological characteristics was evaluated.
Results
Most patients carried MC1R variants (67%), while CDKN2A pathogenic variants were found in 9% of the cases, the MITF E318K in 2% of patients and none carried CDK4 or the POT1 S270N pathogenic variant. Sporadic melanoma patients significantly differed from familial and multiple cases for the young age at diagnosis, infrequent red hair colour, low number of nevi, low frequency of CDKN2A pathogenic variants and of the MC1R R160W variant. Melanoma in children (≤12 years) had more frequently spitzoid histotype, were located on the head/neck and upper limbs and had higher Breslow thickness. The MC1R V92M variant was more common in children than in adolescents. CDKN2A common polymorphisms and MC1R variants were associated with a high number of nevi.
Conclusion
Our results confirm the scarce involvement of the major high‐risk susceptibility genes in paediatric melanoma and suggest the implication of MC1R gene variants especially in the children population.
Linked Commentary: H. Helgadottir. J Eur Acad Dermatol Venereol 2022; 36: 167–168. https://doi.org/10.1111/jdv.17879.
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