Pancreatic ductal adenocarcinoma (PDAC) is a deadly disease, whose main molecular trait is the MAPK pathway activation due to KRAS mutation, which is present in 90% of cases. The genetic landscape of KRAS wild type PDAC can be divided into three categories. The first is represented by tumors with an activated MAPK pathway due to BRAF mutation that occur in up to 4% of cases. The second includes tumors with microsatellite instability (MSI) due to defective DNA mismatch repair (dMMR), which occurs in about 2% of cases, also featuring a high tumor mutational burden. The third category is represented by tumors with kinase fusion genes, which marks about 4% of cases. While therapeutic molecular targeting of KRAS is an unresolved challenge, KRAS-wild type PDACs have potential options for tailored treatments, including BRAF antagonists and MAPK inhibitors for the first group, immunotherapy with anti-PD-1/PD-L1 agents for the MSI/dMMR group, and kinase inhibitors for the third group. This calls for a complementation of the histological diagnosis of PDAC with a routine determination of KRAS followed by a comprehensive molecular profiling of KRAS-negative cases.
Mutations of the proto-oncogene KRAS are the most frequent gain-of-function alterations found in cancer. KRAS is mutated in about 30% of all human tumors, but it could reach more than 90% in certain cancer types such as pancreatic adenocarcinoma. Although historically considered to be undruggable, a particular KRAS mutation, the G12C variant, has recently emerged as an actionable alteration especially in non-small cell lung cancer (NSCLC). KRASG12C and pan-KRAS inhibitors are being tested in clinical trials and have recently shown promising activity. Due to the difficulties in direct targeting of KRAS, other approaches are being explored. The inhibition of target upstream activators or downstream effectors of KRAS pathway has shown to be moderately effective given the evidence of emerging mechanisms of resistance. Various synthetic lethal partners of KRAS have recently being identified and the inhibition of some of those might prove to be successful in the future. The study of escape mechanisms to KRAS inhibition could support the utility of combination strategies in overcoming intrinsic and adaptive resistance and enhancing clinical benefit of KRASG12C inhibitors. Considering the role of the microenvironment in influencing tumor initiation and promotion, the immune tumor niche of KRAS mutant tumors has been deeply explored and characterized for its unique immunosuppressive skewing. However, a number of aspects remains to be fully understood, and modulating this tumor niche might revert the immunoresistance of KRAS mutant tumors. Synergistic associations of KRASG12C and immune checkpoint inhibitors are being tested.
Cancer and obesity are the two major epidemics of the 21st century. Pancreatic ductal adenocarcinoma (PDAC) is one of the leading causes of death, with a five-year overall survival rate of only 8%. Its incidence and mortality have increased in recent years, and this cancer type is expected to be among the top five leading causes of cancer-related death by 2030 in the United States (US). In the last three decades, the prevalence of overweight people has boosted with a consequent increase in obesity-related diseases. Considerable epidemiologic evidence correlates overweight and obese conditions to an increased risk of several types of cancer, including PDAC. Besides being a risk factor for multiple metabolic disorders, the tumor-promoting effects of obesity occur at the local level via inflammatory mediators that are associated with adipose inflammation and metabolic or hormones mediators and microbiota dysbiosis. Although an excess of body mass index (BMI) represents the second most modifiable risk factor for PDAC with an increased cancer related-death of more than 20–40%, still little is known about the molecular mechanisms that underlie this strong association. In this review, we focused on the role of obesity as a preventable risk factor of PDAC, discussing the molecular mechanisms linking obesity to cancer initiation and progression. Moreover, we highlighted the role of obesity in defining chemoresistance, showing how a high BMI can actually reduce response to chemotherapy.
Background: On February 23rd, the 1st case of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection was diagnosed at the University Hospital Trust of Verona, Italy. On March 13th, the Oncology Section was converted into a 22-inpatient bed coronavirus disease (COVID) Unit, and we reshaped our organisation to face the SARS-CoV-2 epidemic, while maintaining oncological activities. Methods: We tracked down (i) volumes of oncological activities (January 1st -March 31st, 2020 versus the same period of 2019), (ii) patients' and caregivers' perception and (iii) SARS-CoV-2 infection rate in oncology health professionals and SARS-CoV-2 infection erelated hospital admissions of "active"' oncological patients. Results: As compared with the same trimester in 2019, the overall reduction in total numbers of inpatient admissions, chemotherapy administrations and specialist visits in JanuaryeMarch 2020 was 8%, 6% and 3%, respectively; based on the weekly average of daily accesses, reduction in some of the oncological activities became statistically significant from week 11. The overall acceptance of adopted measures, as measured by targeted questionnaires administered to a sample of 241 outpatients, was high (>70%). Overall, 8 of 85 oncology health professionals tested positive for SARS-CoV-2 infection (all but one employed in the COVID Unit, no hospital admissions and no treatment required); among 471 patients admitted for SARS-CoV-2 infection, 7 had an "active"' oncological disease (2 died of infection-related complications). Conclusions: A slight, but statistically significant reduction in oncology activity was registered during the SARS-CoV-2 epidemic peak in Verona, Italy. Organisational and protective measures adopted appear to have contributed to keep infections in both oncological patients and health professionals to a minimum.
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