ErbB3 Phosphorylation as Central Event in Adaptive Resistance to Targeted Therapy in Metastatic Melanoma. Early Detection in CTCs during Therapy and Insights into Regulation by Autocrine Neuregulin

In recent years the introduction of target therapies with BRAF and MEK inhibitors (MAPKi) and of immunotherapy with anti-CTLA-4 and anti-PD-1 monoclonal antibodies have dramatically improved survival of metastatic melanoma patients. Despite these changes drug resistance remains a major hurdle. Several mechanisms are at the basis of drug resistance. Particular attention has been devoted over the last years to unravel mechanisms at the basis of adaptive/non genetic resistance occurring in BRAF mutated melanomas upon treatment with to MAPKi. In this paper we focus on the involvement of activation of ErbB3 receptor following early exposure of melanoma cells to BRAF or MEK inhibitors, and the following induction of PI3K/AKT pathway. Although different mechanisms have been invoked in the past at the basis of this activation we show here with a combination of approaches that autocrine production of neuregulin by melanoma cells is a major factor responsible for ErbB3 phosphorylation and downstream AKT activation. Interestingly the kinetic of neuregulin production and of the ensuing ErbB3 phosphorylation is different in different melanoma cell lines which underscores the high degree of tumor heterogeneity. Moreover, heterogeneity is further highlighted by the evidence that in different cell lines neuregulin upregulation can occur at the transcriptional or at the post-transcritpional level. Finally we complement our study by showing with a liquid biopsy assay that circulating tumor cells (CTCs) from melanoma patients undergo upregulation of ErbB3 phosphorylation in vivo shortly after initiation of therapy

The role of 3D echocardiographic imaging in the differential diagnosis of an atypical left atrial myxoma

We describe a case of a left atrial myxoma atypical for its anatomical features and site of attachment. Although an initial multimodality imaging was performed, the diagnosis of myxoma was possible only by three dimensional echocardiography (3DE) which was able to identify the pedicle and the attachment at the base of the interatrial septum, close to the origin of right inferior pulmonary vein. In fact the 3DE can electronically section the structures and obtain unique planes useful in visualizing correctly the anatomical features of the myxomas and as a result, it facilitates the surgical decision planning. Even the anatomical appearance was uncommon at surgery and the diagnosis could be confirmed only by pathology.  This case highlights the diagnostic ability of the 3DE in similar challenging scenarios.

The role of diabetes in metastatic melanoma patients treated with nivolumab plus relatlimab

Background The combination of nivolumab + relatlimab is superior to nivolumab alone in the treatment of naive patients and has activity in PD-1 refractory melanoma. We had previously observed a reduced expression of LAG3 in melanoma tissue from patients with type 2 diabetes. Method To evaluate the impact of diabetes on oncological outcomes of patients with advanced melanoma treated with nivolumab plus the LAG3 inhibitor relatlimab we performed a retrospective multicenter study. Results Overall, 129 patients were included: 88 without diabetes before the treatment, 37 who were diagnosed with type 2 diabetes before the start of treatment, and 4 without diabetes before treatment who developed immune checkpoint inhibitor-induced diabetes (ICI-DM). PFS was 21.71 months (95% CI: 15.61–27.81) in patients without diabetes, 10.23 months (95% CI: 5.81–14.66) in patients with type 2 diabetes, and 50.85 months (95% CI: 23.04–78.65) in patients who developed ICI-DM. OS was 37.94 months (95% CI: 31.02–44.85) in patients without diabetes, 22.12 months (95% CI: 14.41–29.85) in those with type 2 diabetes and 57.64 months (95% CI: 42.29–72.99) in those who developed ICI-DM. Multivariate analysis showed that the presence of diabetes and LDH was correlated with OS and PFS. The mean OS was 64.63 months in subjects with low levels of glucose ( 1.5) had a worse prognosis than those whose glucose level had not increased. This result was observed also in subgroups treated either in first line or further lines. Patients who developed ICI-DM during the study period had better outcomes than the overall population and patients without diabetes. Conclusions LAG3 inhibition for treating metastatic or unresectable melanoma has a reduced efficacy in patients with type 2 diabetes, possibly due to a low expression of LAG3 in tumor tissue. Higher level evidence should be obtained

MMP-9 as a Candidate Marker of Response to BRAF Inhibitors in Melanoma Patients With BRAFV600E Mutation Detected in Circulating-Free DNA

The BRAFV600E mutation is associated with melanoma development and its detection in circulating-free DNA cannot be observed in all melanoma patients harboring this mutation in tumor specimens. Beside the circulating-free DNA BRAFV600E mutation, other markers of therapeutic response should be identified. Matrix metalloproteinase-9 (MMP-9) could be one of them as its role as indicator of invasiveness in melanoma have been explored. In this study, MMP-9 was evaluated in melanoma cells after treatment with dabrafenib. In vitro data were validated in 26 melanoma patients, of which 14 treated with BRAF inhibitor alone and 12 treated with both BRAF and MEK inhibitors, by ELISA assay and droplet digital PCR for measuring MMP-9 serum levels and circulating-free DNA BRAFV600E mutation, respectively. Statistical analyses were performed to evaluate the prognostic significance of MMP-9, progression-free survival (PFS) and overall survival (OS) according to the BRAFV600E mutation and MMP-9 levels. The performed analyses showed that MMP-9 and pEKR1-2 were statistically down-regulated in melanoma cells after treatment with dabrafenib. Circulating-free DNA BRAFV600E mutation was detected in 11 out of 26 melanoma patients showing higher levels of MMP-9 compared to those with undetectable BRAFV600E mutation. Furthermore, higher levels of MMP-9 and circulating-free DNA BRAFV600E mutation were associated with lower PFS and OS. Finally, the monitoring of therapy showed that MMP-9 significantly decreased at T1 and T2, but not at T-last, for the patients with detectable circulating-free DNA BRAFV600E mutation. In conclusion, high levels of MMP-9 and circulating-free DNA BRAFV600E mutation are associated with poor PFS and OS. MMP-9 may represent a promising indicator of response to BRAF inhibitors in combination with the detection of BRAFV600E mutation

Sequential immunotherapy and targeted therapy for metastatic BRAF V600 mutated melanoma: 4-year survival and biomarkers evaluation from the phase II SECOMBIT trial

No prospective data were available prior to 2021 to inform selection between combination BRAF and MEK inhibition versus dual blockade of programmed cell death protein-1 (PD-1) and cytotoxic T lymphocyte antigen-4 (CTLA-4) as first-line treatment options for BRAFV600-mutant melanoma. SECOMBIT (NCT02631447) was a randomized, three-arm, noncomparative phase II trial in which patients were randomized to one of two sequences with immunotherapy or targeted therapy first, with a third arm in which an 8-week induction course of targeted therapy followed by a planned switch to immunotherapy was the first treatment. BRAF/MEK inhibitors were encorafenib plus binimetinib and checkpoint inhibitors ipilimumab plus nivolumab. Primary outcome of overall survival was previously reported, demonstrating improved survival with immunotherapy administered until progression and followed by BRAF/MEK inhibition. Here we report 4-year survival outcomes, confirming long-term benefit with first-line immunotherapy. We also describe preliminary results of predefined biomarkers analyses that identify a trend toward improved 4-year overall survival and total progression-free survival in patients with loss-of-function mutations affecting JAK or low baseline levels of serum interferon gamma (IFNy). These long-term survival outcomes confirm immunotherapy as the preferred first-line treatment approach for most patients with BRAFV600-mutant metastatic melanoma, and the biomarker analyses are hypothesis-generating for future investigations of predictors of durable benefit with dual checkpoint blockade and targeted therapy

Civiltà della Campania. Anno III, n. 4 (gennaio-marzo 1976)

A. III, n. 4 (gennaio-marzo 1976): Ricordo di Alfonso, P. 3 ; A. Gatto, Un sodalizio d’arte sotto lo stesso cielo, P. 4 ; R. Causa, Itinerari nell’arte catalana, P. 12 ; B. Gatta, Un altro inglese che ama Garibaldi, P. 18 ; A. Garzya, Napoli e Bisanzio, P. 26 ; S. Ferraretti, Il grande Archivio Napoletano, P. 32 ; B.G., L’Abate Galiani tra Napoli e Parigi, P. 34 ; M. Stefanile, Campania a tavola, P. 36 ; D. Rea, Pulcinella: il mistero di una maschera, P. 44 ; L. Compagnone, Il piccolo teatro di Raffaele Petra, P. 56 ; V. Ricciuti, Quando il cinema si chiamava Napoli, P. 58 ; R. Cantarella, C’era una volta una piccola città, P. 62 ; E. Mallardo, La cattedrale di Avellino, P. 66 ; V. Gramignazzi-Serrone, S. Guglielmo al Goleto, P. 70 ; F. de Ciuceis, I fasti del San Carlo, P. 78 ; L. Orsini, Faito una selva nel cielo, P. 82 ; S. Ferraro, Archeologia a Sorrento, P. 86 ; G. Blasi, Un parco negli Alburni, P. 88 ; D. Lanzara, Il convento di Ischia, P. 92 ; Notiziario, P. 93

[Cardiac sympathetic innervation imaging with myocardial MIBG scintigraphy]. FT Studio dell'innervazione cardiaca mediante scintigrafia miocardica con MIBG.

Metaiodobenzylguanidine (MIBG) was developed initially as a tracer for oncological imaging; when labeled with 123 I or 131 I, it may detect APUDomas, such as pheochromocytomas and paragangliomas. In the last years, MIBG has found an important role also in neurology and cardiology, as cardiac innervation tracer. Actually, MIBG cardiac imaging is a universally accepted method to estimate cardiac sympathetic innervations. This review covers the role of MIBG cardiac imaging in Parkinson disease and parkinsonisms, from the pathophysiological premises for cardiac denervation to new emerging data

Soluble CD73 as biomarker in patients with metastatic melanoma patients treated with nivolumab

Background: Nivolumab is an anti-PD1 checkpoint inhibitor active in patients with advanced melanoma and as adjuvant therapy in high-risk metastatic melanoma patients. Methods: In this single-center retrospective analysis, we investigated the CD73 enzyme activity in patients with metastatic melanoma stage IV and its correlation with the response to nivolumab. The soluble CD73 (sCD73) enzyme activity was measured in the serum of 37 melanoma patients before receiving nivolumab and the Harrel's C index was used to find the best cut-off for this biomarker. The multivariate Cox proportional hazard model was used to evaluate the prognostic value of CD73 enzyme activity for survival and progression-free survival. Results: Our results show that high levels of sCD73 enzyme activity were significantly associated with poor overall survival and progression-free survival in patients with metastatic melanoma. The median progression-free survival was 2.6months [95% confidence interval (CI) 1.9-3.3] in patients with high sCD73 enzyme activity (>27.8pmol/min/mg protein), and 14.2months (95% CI 4.6-23.8) in patients with lower CD73 enzyme activity, when patients were follow-up for a median of 24months range. The median overall survival was not reached in patients with low sCD73 activity (<27.8pmol/min/mg protein) compared with 6.1months (95% CI 0-14.8) in patients with higher sCD73 activity. In multivariate analyses, the sCD73 enzyme activity emerged as the strongest prognostic factor for overall survival and progression-free survival. Elevated basal levels of sCD73 enzyme activity, before starting nivolumab treatment, were associated with lower response rates to therapy. Conclusions: We observed a significant association between the activity of sCD73 in the blood and clinical outcomes in patients with metastatic melanoma stage IV, receiving nivolumab. Although our results need to be confirmed and validated, we suggest that sCD73 might be used as serologic prognostic biomarker. Potentially evaluating sCD73 enzyme activity in the peripheral blood before treatment could help to estimate the response to nivolumab