[Amelanotic acral melanoma originating from the foot: a clinical case.]

We will present the case of a 75-year-old woman diagnosed with an amelanotic acral melanoma originating from the left foot relapsed to the lung and to muscular and subcutaneous tissues less than one year after the surgical treatment (pT4bN3c, AJCC 8th ed.) of the primary lesion. Treated with first-line encorafenib + binimetinib, the patient reported a complete response lasting 37 months and followed by a partial response, still ongoing after 19 months, to anti-PD-1 antibody second line therapy

IL-8, S100 and IL-10 as indipendent predictors of response and survival in melanoma-patients treated with immune checkpoint inhibitors: preliminary results of an observational prospective study

Background.The identification of factors influencing ICI efficacy in cancer pts and the elaboration of a prognostic score based on circulating biomarkers could optimize treatment selection and outcomes in metastatic melanoma treated with ICI. Matherials and methods. We performed an observational, prospective, translational, multicentric study, which involved 4 Italian centers and two pathologies (melanoma and NSCL) and was approved and, supported by Italian Ministry of Health and, by Veneto Institute of Oncology (RF- 2018-12367604 and IOV-IRCCS BIGID219SILE). The planned accrual was of 160 pts (80 advanced Mel and 80 advanced NSCLC) treated with ICI, according to the Agenzia Italiana del Farmaco (AIFA) authorization and reimbursement. Each patient signed a written informed consent, approved by the local Ethical Committees of all the participating centers. The primary endpoint of the study was to evaluate the association between circulating cytokines (IL-1b, Il-2, IL-4, IL-5, IL-6, IL-8, IL-10, TNFa, GM-CSF) and response to ICI (BOR). Secondary endpoint was the evaluation of the association between the same circulating cytokines and their variations and i) progression free survival (PFS), ii) overall survival (OS) and, iii) toxicity. Pts underwent a blood sample at baseline, before each of first 6 ICI cycles (T1-T6) and at each tumour assessment until disease progression (PD) or for maximum of 2 years. Anti-cancer immunotherapy was administered as per standard of care. Treatment response was evaluated according to RECIST 1.1 criteria and subjects with no progressive disease were considered with disease control (DC). Timing of tumour assessment was performed according to AIFA recommendations. Safety was recorded and graduated according NCI-CTCAE version 5.1. Biomarker levels are assessed by Lumine xMAP based technology using R&D High Sensitivity kits. Results.The results in the first 43 Mel pts enrolled (M:F 20:23, median age 71), showed that IL-6 and IL-8 serum level were significantly higher at baseline and at T2 for PD pts (Kruskal-Wallis test). The median relative increase (RI) from T1 of IL8 was 32% for PD pts and it was significantly higher than for pts with disease control (DC) (decrease of 11%). Likewise, IL-10 median RI was 104% for PD pts and of 41% for DC pts (p=0.002). Multiple logistic analysis confirmed higher T2-IL-8 (>34.22pg/ml) and IL-8-RI (>1%) as independent factors (accuracy 88.6%) associated with a lower probability of DC (odd ratio-OR-=0.02, 95%CI: 0.00─0.18 and OR= 0.06, 95%CI: 0.00─0.65 respectively). In multiple Cox regression: elevated T2-IL-8 (>36.98pg/ml, HR=7.89, 95% CI: 2.66─25.78), T2-IL-10 (>2.66pg/ml, HR=2.99, 95%CI: 1.09─8.49) and IL-8-RI (> 11%, HR=3.61, 95%CI: 1.27─13.81) were significantly associated with a worse PFS. Higher T2-IL-8 (>31.55pg/ml, HR=15.67, 95%CI: 3.54─107.19), IL8-RI (> 30%, HR=5.12, 95%CI: 1.57─19.50), and T2-S100 (>0.15μg/L, HR=14.35, 95%CI: 2.61─170.9) were significantly associated with shorter OS. Conclusions: T2-IL8 and IL8-RI were independently associated to PD, PFS and OS, S100 with OS, and T2-IL-10 with PFS. Conclusions and future perspectives. The accrual of planned patients (166, included NSCLC) has been completed in July 2022.The analyses in all patients are expected to increase the significance level and to allow the evaluation of the impact of all cytokines on activity, efficacy and, safety , The comparison between melanoma and NSCLC will permit to define whether the results are treatment or tumour related or both, and, to analyse if there is or not a gender effect in cytokines behaviour.Background.The identification of factors influencing ICI efficacy in cancer pts and the elaboration of a prognostic score based on circulating biomarkers could optimize treatment selection and outcomes in metastatic melanoma treated with ICI. Matherials and methods. We performed an observational, prospective, translational, multicentric study, which involved 4 Italian centers and two pathologies (melanoma and NSCL) and was approved and, supported by Italian Ministry of Health and, by Veneto Institute of Oncology (RF- 2018-12367604 and IOV-IRCCS BIGID219SILE). The planned accrual was of 160 pts (80 advanced Mel and 80 advanced NSCLC) treated with ICI, according to the Agenzia Italiana del Farmaco (AIFA) authorization and reimbursement. Each patient signed a written informed consent, approved by the local Ethical Committees of all the participating centers. The primary endpoint of the study was to evaluate the association between circulating cytokines (IL-1b, Il-2, IL-4, IL-5, IL-6, IL-8, IL-10, TNFa, GM-CSF) and response to ICI (BOR). Secondary endpoint was the evaluation of the association between the same circulating cytokines and their variations and i) progression free survival (PFS), ii) overall survival (OS) and, iii) toxicity. Pts underwent a blood sample at baseline, before each of first 6 ICI cycles (T1-T6) and at each tumour assessment until disease progression (PD) or for maximum of 2 years. Anti-cancer immunotherapy was administered as per standard of care. Treatment response was evaluated according to RECIST 1.1 criteria and subjects with no progressive disease were considered with disease control (DC). Timing of tumour assessment was performed according to AIFA recommendations. Safety was recorded and graduated according NCI-CTCAE version 5.1. Biomarker levels are assessed by Lumine xMAP based technology using R&D High Sensitivity kits. Results.The results in the first 43 Mel pts enrolled (M:F 20:23, median age 71), showed that IL-6 and IL-8 serum level were significantly higher at baseline and at T2 for PD pts (Kruskal-Wallis test). The median relative increase (RI) from T1 of IL8 was 32% for PD pts and it was significantly higher than for pts with disease control (DC) (decrease of 11%). Likewise, IL-10 median RI was 104% for PD pts and of 41% for DC pts (p=0.002). Multiple logistic analysis confirmed higher T2-IL-8 (>34.22pg/ml) and IL-8-RI (>1%) as independent factors (accuracy 88.6%) associated with a lower probability of DC (odd ratio-OR-=0.02, 95%CI: 0.00─0.18 and OR= 0.06, 95%CI: 0.00─0.65 respectively). In multiple Cox regression: elevated T2-IL-8 (>36.98pg/ml, HR=7.89, 95% CI: 2.66─25.78), T2-IL-10 (>2.66pg/ml, HR=2.99, 95%CI: 1.09─8.49) and IL-8-RI (> 11%, HR=3.61, 95%CI: 1.27─13.81) were significantly associated with a worse PFS. Higher T2-IL-8 (>31.55pg/ml, HR=15.67, 95%CI: 3.54─107.19), IL8-RI (> 30%, HR=5.12, 95%CI: 1.57─19.50), and T2-S100 (>0.15μg/L, HR=14.35, 95%CI: 2.61─170.9) were significantly associated with shorter OS. Conclusions: T2-IL8 and IL8-RI were independently associated to PD, PFS and OS, S100 with OS, and T2-IL-10 with PFS. Conclusions and future perspectives. The accrual of planned patients (166, included NSCLC) has been completed in July 2022.The analyses in all patients are expected to increase the significance level and to allow the evaluation of the impact of all cytokines on activity, efficacy and, safety , The comparison between melanoma and NSCLC will permit to define whether the results are treatment or tumour related or both, and, to analyse if there is or not a gender effect in cytokines behaviour

Total metabolic tumor volume by 18F-FDG PET/CT for the prediction of outcome in patients with non-small cell lung cancer

Objective Metabolic tumor volume (MTV) and total lesion glycolysis (TLG) are imaging parameters derived from 18F-FDG PET/CT that have been proposed for risk stratification of cancer patients. The aim of our study was to test whether these whole-body volumetric imaging parameters may predict outcome in patients with non-small cell lung cancer (NSCLC). Methods Sixty-five patients (45 men, 20 women; mean age ± SD, 65 ± 12 years), with histologically proven NSCLC who had undergone 18F-FDG PET/CT scan before any therapy, were included in the study. Imaging parameters including SUVmax, SUVmean, total MTV (MTVTOT) and whole-body TLG (TLGWB) were determined. Univariate and multivariate analyses of clinical and imaging variables were performed using Cox proportional hazards regression. Survival analysis was performed using Kaplan–Meier method and log-rank tests. Results A total of 298 lesions were analyzed including 65 primary tumors, 114 metastatic lymph nodes and 119 distant metastases. MTVTOT and TLGWB could be determined in 276 lesions. Mean value of MTVTOT was 81.83 ml ± 14.63 ml (SE) whereas mean value of TLGWB was 459.88 g ± 77.02 g (SE). Univariate analysis showed that, among the variables tested, primary tumor diameter (p = 0.0470), MTV of primary tumor (p = 0.0299), stage (p 54.7 g (p 9.5 ml (p < 0.0001). Similar results were obtained in a subgroup of 43 patients with advanced disease (stages III and IV). Conclusions Whole-body PET-based volumetric imaging parameters are able to predict outcome in NSCLC patients

Investigating the Retained Inhibitory Effect of Cobimetinib against p.P124L Mutated MEK1: A Combined Liquid Biopsy and in Silico Approach

Simple Summary This work focuses on the peculiar contribution made by molecular dynamics simulation and in silico tools, in the choice of an effective second line therapy for a BRAF-mutated melanoma patient who developed resistance to the undergoing targeted therapy with BRAF/MEK inhibitors. Among the MEK inhibitors, we identified a drug alternative to trametinib, able to block the target even in the presence of a damaging mutation, and supported these findings, gathered by an in silico approach, with a liquid biopsy tracking of the response to treatment. The evolution of the disease, before and after the therapy change, was followed by analysis of the circulating tumor DNA and circulating melanoma cells. The systemic treatment of metastatic melanoma has radically changed, due to an improvement in the understanding of its genetic landscape and the advent of targeted therapy. However, the response to BRAF/MEK inhibitors is transitory, and big efforts were made to identify the mechanisms underlying the resistance. We exploited a combined approach, encompassing liquid biopsy analysis and molecular dynamics simulation, for tracking tumor evolution, and in parallel defining the best treatment option. The samples at different time points were collected from a BRAF-mutant melanoma patient who developed an early resistance to dabrafenib/trametinib. The analysis of the circulating tumor DNA (ctDNA) identified the MEK1 p.P124L mutation that confers resistance to trametinib. With an in silico modeling, we identified cobimetinib as an alternative MEK inhibitor, and consequently suggested a therapy switch to vemurafenib/cobimetinib. The patient response was followed by ctDNA tracking and circulating melanoma cell (CMC) count. The cobimetinib administration led to an important reduction in the BRAF p.V600E and MEK1 p.P124L allele fractions and in the CMC number, features suggestive of a putative response. In summary, this study emphasizes the usefulness of a liquid biopsy-based approach combined with in silico simulation, to track real-time tumor evolution while assessing the best treatment option

Total metabolic tumor volume by 18F-FDG PET/CT for the prediction of outcome in patients with non-small cell lung cancer

Objective Metabolic tumor volume (MTV) and total lesion glycolysis (TLG) are imaging parameters derived from 18F-FDG PET/CT that have been proposed for risk stratification of cancer patients. The aim of our study was to test whether these whole-body volumetric imaging parameters may predict outcome in patients with non-small cell lung cancer (NSCLC). Methods Sixty-five patients (45 men, 20 women; mean age +/- SD, 65 +/- 12 years), with histologically proven NSCLC who had undergone 18F-FDG PET/CT scan before any therapy, were included in the study. Imaging parameters including SUVmax, SUVmean, total MTV (MTVTOT) and whole-body TLG (TLG(WB)) were determined. Univariate and multivariate analyses of clinical and imaging variables were performed using Cox proportional hazards regression. Survival analysis was performed using Kaplan-Meier method and log-rank tests. Results A total of 298 lesions were analyzed including 65 primary tumors, 114 metastatic lymph nodes and 119 distant metastases. MTVTOT and TLG(WB) could be determined in 276 lesions. Mean value of MTVTOT was 81.83 ml +/- 14.63 ml (SE) whereas mean value of TLG(WB) was 459.88 g +/- 77.02 g (SE). Univariate analysis showed that, among the variables tested, primary tumor diameter (p = 0.0470), MTV of primary tumor (p = 0.0299), stage (p 54.7 g (p 9.5 ml (p < 0.0001). Similar results were obtained in a subgroup of 43 patients with advanced disease (stages III and IV). Conclusions Whole-body PET-based volumetric imaging parameters are able to predict outcome in NSCLC patients

Overexpression of DNAJC12 predicts poor response to neoadjuvant concurrent chemoradiotherapy in patients with rectal cancer

[[abstract]]Genes associated with protein folding have been found to have certain prognostic significance in a subset of cancers. The aim of this study is to evaluate the clinical impact of DNAJC12 expression in patients with rectal cancers receiving neoadjuvant concurrent chemoradiotherapy (CCRT) followed by surgery. Through data mining from a public transcriptomic dataset of rectal cancer focusing on genes associated with protein folding, we found that DNAJC12, a member of the HSP40/DNAJ family, was the most significant such gene correlated with the CCRT response. We further evaluated the expression of DNAJC12 by immunohistochemistry in the pre-treatment tumor specimens from 172 patients with rectal cancers. From this set, we statistically analyzed the association of DNAJC12 expression with various clinicopathological factors, tumor regression grade, overall survival (OS), disease-free survival (DFS) and local recurrence-free survival (LRFS). High expression of DNAJC12 was significantly associated with advanced pre- and post-treatment tumor status (. P<. 0.001), advanced pre- and post-treatment nodal status (. P<. 0.001), increased vascular invasion (. P=. 0.015), increased perineural invasion (. P=. 0.023) and lower tumor regression grade (. P=. 0.009). More importantly, high expression of DNAJC12 was found to be correlated with poor prognosis for OS (. P=. 0.0012), DFS (. P<. 0.0001) and LRFS (. P=. 0.0001). In multivariate analysis, DNAJC12 overexpression still emerged as an independent prognosticator for shorter OS (. P=. 0.040), DFS (. P<. 0.001) and LRFS (. P=. 0.016). The data indicate that DNAJC12 overexpression acts as a negative predictive factor for the response to neoadjuvant CCRT and was significantly associated with shorter survival in patients with rectal cancers receiving neoadjuvant CCRT followed by surgery

MOESM1 of Sex and interleukin-6 are prognostic factors for autoimmune toxicity following treatment with anti-CTLA4 blockade

Additional file 1. Model validation. The scatter plot represents the validation of the predicted risk of toxicity model built with bootstrap analysis with gender and interleukin-6 baseline blood concentrations. However limited by the small sample, the validation result is satisfactory; an ideal line at 45° that would represent a perfect match between observations and predictions, and the validation scatter plot has a very limited dispersion

TRK Protein Expression in Merkel Cell Carcinoma Is Not Caused by <i>NTRK</i> Fusions

Merkel cell carcinoma (MCC) is a rare and aggressive cutaneous malignant tumor with neuroendocrine differentiation, with a rapidly growing incidence rate, high risk of recurrence, and aggressive behavior. The available therapeutic options for advanced disease are limited and there is a pressing need for new treatments. Tumors harboring fusions involving one of the neurotrophin receptor tyrosine kinase (NTRK) genes are now actionable with targeted inhibitors. NTRK-fused genes have been identified in neuroendocrine tumors of other sites; thus, a series of 76 MCCs were firstly analyzed with pan-TRK immunohistochemistry and the positive ones with real-time RT-PCR, RNA-based NGS, and FISH to detect the eventual underlying gene fusion. Despite 34 MCCs showing pan-TRK expression, NTRK fusions were not found in any cases. As in other tumors with neural differentiation, TRK expression seems to be physiological and not caused by gene fusions