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By applying robust control the decision maker wants to make good decisions when his model is only a good approximation of the true one. Such decisions are said to be robust to model misspecification. In this paper it is shown that the application of the usual robust control framework in discrete time problems is associated with some interesting, if not unexpected, results. Results that have far reaching consequences when robust control is applied sequentially, say every year in fiscal policy or every quarter (month) in monetary policy. This is true when unstructured uncertainty à la Hansen and Sargent is used, both in the case of a “probabilistically sophisticated” and a non- “probabilistically sophisticated” decision maker, or when uncertainty is related to unknown structural parameters of the model.

Non-melanoma skin cancers (NMSCs) include basal cell carcinoma (BCC), squamous cell carcinoma (SCC) and Merkel cell carcinoma (MCC). These neoplasms are highly diverse in their clinical presentation, as well as in their biological evolution. While the deregulation of the Hedgehog pathway is commonly observed in BCC, SCC and MCC are characterized by a strikingly elevated mutational and neoantigen burden. As result of our improved understanding of the biology of non-melanoma skin cancers, innovative treatment options including inhibitors of the Hedgehog pathway and immunotherapeutic agents have been recently investigated against these malignancies, leading to their approval by regulatory authorities. Herein, we review the most relevant biological and clinical features of NMSC, focusing on innovative treatment approaches.

By applying robust control, the decision maker wants to make good decisions when his model is only a good approximation of the true one. Such decisions are said to be robust to model misspecification. In this paper it is shown that, in many situations relevant in economics, a decision maker applying robust control implicitly assumes that today’s worst-case adverse shock is serially uncorrelated with tomorrow’s worst-case adverse shock. Then, further investigation is needed to see how strong is the ‘immunization against uncertainty’ provided by these popular frameworks.

Over the last decades, the concept of precision medicine has dramatically renewed the field of medical oncology; the introduction of patient-tailored therapies has significantly improved all measurable outcomes. Liquid biopsy is a revolutionary technique that is opening previously unexpected perspectives. It consists of the detection and isolation of circulating tumor cells, circulating tumor DNA and exosomes, as a source of genomic and proteomic information in patients with cancer. Many technical hurdles have been resolved thanks to newly developed techniques and next-generation sequencing analyses, allowing a broad application of liquid biopsy in a wide range of settings. Initially correlated to prognosis, liquid biopsy data are now being studied for cancer diagnosis, hopefully including screenings, and most importantly for the prediction of response or resistance to given treatments. In particular, the identification of specific mutations in target genes can aid in therapeutic decisions, both in the appropriateness of treatment and in the advanced identification of secondary resistance, aiming to early diagnose disease progression. Still application is far from reality but ongoing research is leading the way to a new era in oncology. This review summarizes the main techniques and applications of liquid biopsy in cancer.

BackgroundConcomitant medications, such as steroids, proton pump inhibitors (PPI) and antibiotics, might affect clinical outcomes with immune checkpoint inhibitors.MethodsWe conducted a multicenter observational retrospective study aimed at evaluating the impact of concomitant medications on clinical outcomes, by weighing their associations with baseline clinical characteristics (including performance status, burden of disease and body mass index) and the underlying causes for their prescription. This analysis included consecutive stage IV patients with cancer, who underwent treatment with single agent antiprogrammed death-1/programmed death ligand-1 (PD-1/PD-L1) with standard doses and schedules at the medical oncology departments of 20 Italian institutions. Each medication taken at the immunotherapy initiation was screened and collected into key categories as follows: corticosteroids, antibiotics, gastric acid suppressants (including proton pump inhibitors - PPIs), statins and other lipid-lowering agents, aspirin, anticoagulants, non-steroidal anti-inflammatory drugs (NSAIDs), ACE inhibitors/Angiotensin II receptor blockers, calcium antagonists, β-blockers, metformin and other oral antidiabetics, opioids.ResultsFrom June 2014 to March 2020, 1012 patients were included in the analysis. Primary tumors were: non-small cell lung cancer (52.2%), melanoma (26%), renal cell carcinoma (18.3%) and others (3.6%). Baseline statins (HR 1.60 (95% CI 1.14 to 2.25), p=0.0064), aspirin (HR 1.47 (95% CI 1.04 to 2.08, p=0.0267) and β-blockers (HR 1.76 (95% CI 1.16 to 2.69), p=0.0080) were confirmed to be independently related to an increased objective response rate. Patients receiving cancer-related steroids (HR 1.72 (95% CI 1.43 to 2.07), p<0.0001), prophylactic systemic antibiotics (HR 1.85 (95% CI 1.23 to 2.78), p=0.0030), prophylactic gastric acid suppressants (HR 1.29 (95% CI 1.09 to 1.53), p=0.0021), PPIs (HR 1.26 (95% CI 1.07 to 1.48), p=0.0050), anticoagulants (HR 1.43 (95% CI: 1.16 to 1.77), p=0.0007) and opioids (HR 1.71 (95% CI 1.28 to 2.28), p=0.0002) were confirmed to have a significantly higher risk of disease progression. Patients receiving cancer-related steroids (HR 2.16 (95% CI 1.76 to 2.65), p<0.0001), prophylactic systemic antibiotics (HR 1.93 (95% CI 1.25 to 2.98), p=0.0030), prophylactic gastric acid suppressants (HR 1.29 (95% CI 1.06 to 1.57), p=0.0091), PPI (HR 1.26 (95% CI 1.04 to 1.52), p=0.0172), anticoagulants (HR 1.45 (95% CI 1.14 to 1.84), p=0.0024) and opioids (HR 1.53 (95% CI 1.11 to 2.11), p=0.0098) were confirmed to have a significantly higher risk of death.ConclusionWe confirmed the association between baseline steroids administered for cancer-related indication, systemic antibiotics, PPIs and worse clinical outcomes with PD-1/PD-L1 checkpoint inhibitors, which can be assumed to have immune-modulating detrimental effects.

Purpose of ReviewSummarize the writings published in the last years on the management and novel therapies of mucosal melanoma (MM).Recent FindingsNew research has demonstrated a difference between MM and cutaneous melanoma (CM) in their genomic and molecular landscapes, explaining the response's heterogeneity. Immunotherapy and targeted therapy have limited benefit, but novel therapies are rapidly expanding.SummaryMM is aggressive cancer occurring in gastrointestinal, respiratory, or urogenital mucosa; whose incidence is greater in the Asian population. The etiology and pathogenesis remain unclear since UV exposure is not a proven risk factor as in cutaneous melanoma. In contrast to CM, lesions on the mucosal surface are less likely to be recognized early; therefore, the disease is diagnosed in an advanced stage. Clinical manifestations, such as bleeding or pain, can help to detect this tumor, although the prognosis remains unfavorable with an overall 5-year survival rate of less than 20%. The mutational landscape of MM includes mutations of BRAF and NRAS, as well as mutations in the c-KIT/CD117 gene (in 50% of patients), thus limiting therapeutic interventions to immunotherapy. However, clinical studies show less responsiveness to immunotherapy compared to CM, therefore novel therapeutic strategies targeting new molecules are needed to improve the survival of patients with MM.

Molecular alterations of the Ataxia-telangiectasia (AT) gene are frequently detected in breast cancer (BC), with an incidence ranging up to 40%. The mutated form, the Ataxia-telangiectasia mutated (ATM) gene, is involved in cell cycle control, apoptosis, oxidative stress, and telomere maintenance, and its role as a risk factor for cancer development is well established. Recent studies have confirmed that some variants of ATM are associated with an increased risk of BC development and a worse prognosis. Thus, many patients harboring ATM mutations develop intermediate- and high-grade disease, and there is a higher rate of lymph node metastatic involvement. The evidence concerning a correlation of ATM gene mutations and the efficacy of therapeutic strategies in BC management are controversial. In fact, ATM mutations may sensitize cancer cells to platinum-derived drugs, as BRCA1/2 mutations do, whereas their implications in objective responses to hormonal therapy or target-based agents are not well defined. Herein, we conducted a review of the role of ATM gene mutations in BC development, prognosis, and different treatment strategies.

Background Bone metastases occur rarely in patients suffering from malignant melanoma, although their onset severely worsens both prognosis and quality of life. Extracellular vesicles (EVs) including exosomes (Exos) are active players in melanoma progression involved in the formation of the pre-metastatic niche. Methods Trans-well assays explored the basal migratory and invasive potential of four melanoma cell lines and investigated their different propensity to be attracted toward the bone. Exosomes were purified from cell supernatants by ultracentrifugation and explored in their ability to influence the bone tropism of melanoma cells. The molecular machinery activated during this process was investigated by RT-PCR, droplet digital-PCR, flow-cytometry and Western blot, while loss of function studies with dedicated siRNAs defined the single contribute of CXCR4 and CXCR7 molecules. Results Melanoma cells revealed a variable propensity to be attracted toward bone fragments. Gene profiling of both osteotropic and not-osteotropic cells did not show a different expression of those genes notoriously correlated to chemotaxis and bone metastasis. However, bone conditioned medium significantly increased CXCR4 , CXCR7 and PTHrP expression solely to osteotropic cells, while their Exos were able to revert the original poor bone tropism of not-osteotropic cells through CXCR7 up-regulation. Silencing experiments also demonstrated that membrane expression of CXCR7 is required by melanoma cells to promote their chemotaxis toward SDF-1 gradients. Conclusions Our data correlated the osteotropism of melanoma cells to the activation of the SDF-1/CXCR4/CXCR7 axis following the exposition of tumor cells to bone-derived soluble factors. Also, we demonstrated in vitro that tumor-derived Exos can reprogram the innate osteotropism of melanoma cells by up-regulating membrane CXCR7. These results may have a potential translation to future identification of druggable targets for the treatment of skeletal metastases from malignant melanoma.

Immune checkpoint inhibitors (ICIs) have improved the prognosis of patients with cutaneous melanoma. Immunotherapy (IT) is generally well tolerated, but an increasing area of investigation concerns the optimal treatment duration of anti-programmed cell death-1 (anti-PD1) regimens to limit the immune-related adverse events in patients who obtained a clinical response. Another point of interest is the impact of the early discontinuation of ICIs on the maintenance of response in terms of survival in patients developing grade 3–4 adverse events that mostly occur in those receiving the combo-IT. Currently, we are still far from having final conclusions on these topics and, thus, the present review aims to describe the recent data about the optimal treatment duration and the maintenance of response in the case of early discontinuation. In this context, we include data on the real life of patients from our Medical Oncology Center who discontinued anti-PD1 after at least a stable disease or those interrupting the combo-IT due to adverse events.

Extracellular Vesicles (EVs) are emerging as pivotal elements in cancer. Many studies have focused on the role of Small- (S)-EVs but in recent years Large-(L)-EVs have progressively gained increasing interest due to their peculiar content and functions. Tumor-derived L-EVs carry a lot of oncogenic proteins, nucleic acids and lipids to recipient cells and are involved in the reshaping of the tumor microenvironment as well as in the metabolic rewiring and the promotion of the pro-metastatic attitude of cancer cells. Several techniques have been developed for the isolation of L-EVs and commercial kits are also available for efficient and easy recovery of these vesicles. Also, the improvement in DNA sequencing and “omics sciences” profoundly changed the way to analyze and explore the molecular content of L-EVs, thus providing novel and potentially useful cancer biomarkers. Herein, we review the most recent findings concerning the role of L-EVs in cancer and discuss their possible use in oncology as “liquid biopsy” tools as compared to the other classes of EVs.