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Genetic alterations in CRC have shown a negative predictive and prognostic role in specific target therapies. The onset of immunotherapy has also undergone remarkable therapeutic innovation, although limited to a small subgroup of patients, the MSI-H/dMMR, which represents only 5% of CRC. Research is moving forward to identify whether other biomarkers can predict response to ICIs, despite various limitations regarding expression and identification methods. For this purpose, TMB, LAG3, and PD-L1 expression have been retrospectively evaluated in several solid tumors establishing the rationale to design clinical trials with concurrent inhibition of LAG3 and PD-1 results in a significant advantage in PFS and OS in advanced melanoma patients. Based on these data, there are clinical trials ongoing in the CRC as well. This review aims to highlight what is already known about genetic mutations and genomic alterations in CRC, their inhibition with targeted therapies and immune checkpoints inhibitors, and new findings useful to future treatment strategies. [ABSTRACT FROM AUTHOR]

Background: The liver is one of the most frequent sites of metastases in rectal cancer. This study aimed to evaluate how the development of synchronous or metachronous liver metastasis and overall survival are impacted by baseline liver steatosis and chemotherapy-induced liver damage in rectal cancer patients.Methods: Patients diagnosed with stage II to IV rectal cancer between 2010 and 2016 in our province with suitable baseline CT scan were included. Data on cancer diagnosis, staging, therapy, outcomes and liver function were collected. CT scans were retrospectively reviewed to assess baseline steatosis (liver density < 48 HU and/or liver-to-spleen ratio < 1.1). Among patients without baseline steatosis and treated with neoadjuvant chemotherapy, chemotherapy-induced liver damage was defined as steatosis appearance, ≥ 10% liver volume increase, or significant increase in liver function tests.Results: We included 283 stage II to IV rectal cancer patients with suitable CT scan (41% females; mean age 68 ± 14 years). Steatosis was present at baseline in 90 (31.8%) patients, synchronous liver metastasis in 42 (15%) patients and metachronous liver metastasis in 26 (11%); 152 (54%) deaths were registered. The prevalence of synchronous liver metastasis was higher in patients with steatosis (19% vs 13%), while the incidence of metachronous liver metastasis was similar. After correcting for age, sex, stage, and year of diagnosis, steatosis was not associated with metachronous liver metastasis nor with overall survival. In a small analysis of 63 patients without baseline steatosis and treated with neoadjuvant chemotherapy, chemotherapy-induced liver damage was associated with higher incidence of metachronous liver metastasis and worse survival, results which need to be confirmed by larger studies.Conclusions: Our data suggest that rectal cancer patients with steatosis had a similar occurrence of metastases during follow-up, even if the burden of liver metastases at diagnosis was slightly higher, compatible with chance. [ABSTRACT FROM AUTHOR]

Current treatment for acute myeloid leukemia (AML) is less than optimal, but increased understanding of disease pathobiology and genomics has led to clinical investigation of novel targeted therapies and rational combinations. Targeting the cyclin-dependent kinase 9 (CDK9) pathway, which is dysregulated in AML, is an attractive approach. Inhibition of CDK9 leads to downregulation of cell survival genes regulated by super enhancers such as MCL-1, MYC, and cyclin D1. As CDK9 inhibitors are nonselective, predictive biomarkers that may help identify patients most likely to respond to CDK9 inhibitors are now being utilized, with the goal of improving efficacy and safety. [ABSTRACT FROM AUTHOR]

Rhabdomyolysis is defined as dissolution of striped muscle characterized by leakage of intracellular muscle components into the circulation, which can ultimately lead to renal failure with a possible fatal outcome. This is an uncommon side effect of trabectedin which is used in second-line therapy of metastatic sarcoma after anthracycline and ifosfamide failure. Here, we describe a case of reversible rhabdomyolysis in a male patient with recurrent metastatic synovial sarcoma of the hand, with marked 18F-FDG uptake into his skeletal muscles, after 4 cycles of trabectedin, and who at the same time was taking an alternative medicine (bioflavonoids) suspected of triggering this adverse event. [ABSTRACT FROM AUTHOR]

Background: FOLFOXIRI (fluorouracil, leucovorin, oxaliplatin, and irinotecan) plus bevacizumab has shown to be one of the therapeutic regimens in first line with the highest activity in patients (pts.) with metastatic colorectal cancer (mCRC) unselected for biomolecular alterations. Generally, tumors co-opt the programmed death-1/ligand 1 (PD-1/PD-L1) signaling pathway as one key mechanism to evade immune surveillance. As today, anti-PD-1 monoclonal antibodies are FDA approved only for DNA mismatch repair deficient/microsatellite instability-high (MMRd/MSI-H), which represent only about 5% among all mCRC. Nowadays, there are no data demonstrating anti PD-1 activity in proficient and stable disease (MMRp/MSS). A different target in mCRC is also the Vascular Endothelial Growth Factor A (VEGF-A), which acts on endothelial cells to stimulate angiogenesis. VEGF-A inhibition with bevacizumab has shown to increase the immune cell infiltration, providing a solid rationale for combining VEGF targeted agents with immune checkpoint inhibitors. Based on these evidences, we explore the combination of triplet chemotherapy (FOLFOXIRI) with bevacizumab and nivolumab in pts. with mCRC RAS/BRAF mutant regardless of microsatellite status.Methods/design: This is a prospective, open-label, multicentric phase II trial where pts. with mCRC RAS/BRAF mutated, in first line will receive nivolumab in combination with FOLFOXIRI/bevacizumab every 2 weeks for 8 cycles followed by maintenance with bevacizumab plus nivolumab every 2 weeks. Bevacizumab will be administered intravenously at dose of 5 mg/kg every 2 weeks and nivolumab intravenously as a flat dose of 240 mg every 2 weeks. The primary endpoint is the overall response rate (ORR). This study hypothesis is that the treatment is able to improve the ORR from 66 to 80%. Secondary endpoints include OS, safety, time to progression, duration of response. Collateral translational studies evaluate the i) tumor mutational burden, and ii) genetic alterations by circulating free DNA (cfDNA) obtained from plasma samples. The trial is open to enrollment, 9 of planned 70 pts. have been enrolled.Trial Registration: NIVACOR is registered at ClinicalTrials.gov: NCT04072198 , August 28, 2019. [ABSTRACT FROM AUTHOR]

Background: Deleterious polymorphisms in the gene encoding DPD (DPYD) may result in severe reduction of DPD enzymatic activity that causes life-threatening toxicities when the standard dose of fluorouracil is used. The best panel of single-nucleotide polymorphism (SNPs) of DPYD is not well defined.Methods: In 2011, we began screening DPYD*2A in patients candidate for fluoropyrimidine-based chemotherapy. We planned a case-control study with all cases of DPYD*2A wild type who developed toxicity ≥G3 and with a cohort of patients who did not present severe toxicities. Then, we tested the additional SNPs: c.2846A>T, c.1679T>G, c.2194G>A.Results: From 2011 to 2016, we screened 1827 patients for DPD deficiency; of those, 31 subjects (1.7%) showed DPYD*2A SNP. We selected 146 subjects who developed severe toxicities (Cases) and 220 patients who experienced no or mild toxicities (Controls); 53 patients carried one of the additional SNPs: 35 subjects (66%) fell into the Cases and 18 (34%) into the Controls (p < 0.0001). c.2194G>A was the most frequent SNP (12.5%) and showed a correlation with neutropenia. We confirmed that c.2846A>T and c.1679T>G were related to various toxicities.Conclusions: The additional DPYD polymorphisms could enhance the prevention of fluoropyrimidine toxicity. c.2194G>A is the most frequent polymorphism and it was found to be associated with neutropenia. [ABSTRACT FROM AUTHOR]

Simple Summary: Research suggests that lengthening the prognosis in cancer patients (which is certainly a positive thing) requires greater attention to be paid to the onset of other pathologies. The increase in cardiovascular mortality in cancer patients (due to both exposure to risk factors and the side effects of cytotoxic drugs) requires greater collaboration between oncologists and cardiologists, and the integration of shared follow-up paths. Particular attention to the follow-up of cancer patients can reduce this risk: in the present study, patients presented an excessive risk of cardiovascular mortality only in the first two years from cancer diagnosis. The present research describes 25 years of cardiovascular mortality in a cohort of patients in Northern Italy. The study included patients with malignant cancer enrolled in the period of 1996–2019, and describes cardiovascular and cancer mortality in relation to sex, age, year of diagnosis, months of survivorship, tumor site, and standardized mortality ratio (SMR). Out of 67,173 patients, 38,272 deaths (57.7%) were recorded: 4466 from cardiovascular disease (CVD) (6.6%), and 28,579 (42.6%) from cancer. The proportion of CVD death increased from 4.5% in the first two years after diagnosis, to 7.3% after more than 10 years, while the proportion of deaths from cancer decreased from 70.5% to 9.4%. The CVD SMR comparing cancer patients with the general population was 0.87 (95% CI: 0.82–0.92) in 1996–1999, rising to 0.95 (95% CI: 0.84–1.08) in 2015–2019, without differences in terms of sex or age. The risk of dying from CVD was higher compared with the general population (SMR 1.31; 95% CI: 1.24–1.39) only in the first two years after diagnosis. The trend over time underscored that CVD deaths increased in patients with breast, bladder, prostate, and colorectal cancers, and, in the more recent period, for kidney cancer and melanoma patients. Our data confirmed that cardiovascular mortality is an important issue in the modern management of cancer patients, suggesting the need for an extensive interdisciplinary approach. [ABSTRACT FROM AUTHOR]

Simple Summary: Diffuse liver diseases have a high incidence among the general population and even higher in patients with a solid cancer. Since many patients with a solid tumor die of liver metastases, the aim of this systematic review of the literature was to explore the correlation between diffuse liver diseases and the risk of having liver metastases at diagnosis or during follow-up. To summarize the results of included studies, a meta-analysis was also conducted. The results of our systematic review should encourage the research community to further investigate the complex relationship between the liver's microscopic environment and metastases, which may also affect prognosis and response to therapy. This systematic review with meta-analysis aimed to assess the effect of diffuse liver diseases (DLD) on the risk of synchronous (S-) or metachronous (M-) liver metastases (LMs) in patients with solid neoplasms. Relevant databases were searched for systematic reviews and cross-sectional or cohort studies published since 1990 comparing the risk of LMs in patients with and without DLD (steatosis, viral hepatitis, cirrhosis, fibrosis) in non-liver solid cancer patients. Outcomes were prevalence of S-LMs, cumulative risk of M-LMs and LM-free survival. Risk of bias (ROB) was assessed using the Newcastle-Ottawa Scale. We report the pooled relative risks (RR) for S-LMs and hazard ratios (HR) for M-LMs. Subgroup analyses included DLD, primary site and continent. Nineteen studies were included (n = 37,591 patients), the majority on colorectal cancer. ROB appraisal results were mixed. Patients with DLD had a lower risk of S-LMs (RR 0.50, 95% CI 0.34–0.76), with a higher effect for cirrhosis and a slightly higher risk of M-LMs (HR 1.11 95% CI, 1.03–1.19), despite a lower risk of M-LMs in patients with vs without viral hepatitis (HR 0.57, 95% CI 0.40–0.82). There may have been a publication bias in favor of studies reporting a lower risk for patients with DLD. DLD are protective against S-LMs and slightly protective against M-LMs for viral hepatitis only. [ABSTRACT FROM AUTHOR]

In the coronavirus disease (COVID-19) pandemic, cancer patients could be a high-risk group due to their immunosuppressed status; therefore, data on cancer patients must be available in order to consider the most adequate strategy of care. We carried out a cohort study on the risk of hospitalization for COVID-19, oncological history, and outcomes on COVID-19 infected cancer patients admitted to the Hospital of Reggio Emilia. Between 1 February and 3 April 2020, a total of 1226 COVID-19 infected patients were hospitalized. The number of cancer patients hospitalized with COVID-19 infection was 138 (11.3%). The median age was slightly higher in patients with cancers than in those without (76.5 vs. 73.0). The risk of intensive care unit (ICU) admission (10.1% vs. 6.7%; RR 1.23, 95% Confidence Interval (CI) 0.63–2.41) and risk of death (34.1% vs. 26.0%; RR 1.07, 95% CI 0.61–1.71) were similar in cancer and non-cancer patients. In the cancer patients group, 89/138 (64.5%) patients had a time interval >5 years between the diagnosis of the tumor and hospitalization. Male gender, age > 74 years, metastatic disease, bladder cancer, and cardiovascular disease were associated with mortality risk in cancer patients. In the Reggio Emilia Study, the incidence of hospitalization for COVID-19 in people with previous diagnosis of cancer is similar to that in the general population (standardized incidence ratio 98; 95% CI 73–131), and it does not appear to have a more severe course or a higher mortality rate than patients without cancer. The phase II of the COVID-19 epidemic in cancer patients needs a strategy to reduce the likelihood of infection and identify the vulnerable population, both in patients with active antineoplastic treatment and in survivors with frequently different coexisting medical conditions. [ABSTRACT FROM AUTHOR]