KRAS mutations are one of the most frequent oncogenic mutations of all human cancers, being more prevalent in pancreatic, colorectal, and lung cancers. Intensive efforts have been encouraged in order to understand the effect of KRAS mutations, not only on tumor cells but also on the dynamic network composed by the tumor microenvironment (TME). The relevance of the TME in cancer biology has been increasing due to its impact on the modulation of cancer cell activities, which can dictate the success of tumor progression. Here, we aimed to clarify the pro- and anti-inflammatory role of KRAS mutations over the TME, detailing the context and the signaling pathways involved. In this review, we expect to open new avenues for investigating the potential of KRAS mutations on inflammatory TME modulation, opening a different vision of therapeutic combined approaches to overcome KRAS-associated therapy inefficacy and resistance in cancer.

KRAS, one of the RAS protein family members, plays an important role in autophagy and apoptosis, through the regulation of several downstream effectors. In cancer cells, KRAS mutations confer the constitutive activation of this oncogene, stimulating cell proliferation, inducing autophagy, suppressing apoptosis, altering cell metabolism, changing cell motility and invasion and modulating the tumor microenvironment. In order to inhibit apoptosis, these oncogenic mutations were reported to upregulate anti-apoptotic proteins, including Bcl-xL and survivin, and to downregulate proteins related to apoptosis induction, including thymine-DNA glycosylase (TDG) and tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL). In addition, KRAS mutations are known to induce autophagy in order to promote cell survival and tumor progression through MAPK and PI3K regulation. Thus, these mutations confer resistance to anti-cancer drug treatment and, consequently, result in poor prognosis. Several therapies have been developed in order to overcome KRAS-induced cell death resistance and the downstream signaling pathways blockade, especially by combining MAPK and PI3K inhibitors, which demonstrated promising results. Understanding the involvement of KRAS mutations in apoptosis and autophagy regulation, might bring new avenues to the discovery of therapeutic approaches for CRCs harboring KRAS mutations.

Background The platelet-to-lymphocyte ratio (PLR) index has recently been a focus of investigation as a reliable marker of inflammation, being shown to have a good accuracy upon predicting endoscopic remission in patients with colonic Crohn’s Disease (CD). We aimed to evaluate and validate the discriminative power of PLR index in patients with small bowel CD. Methods Single center study including patients with isolated small bowel CD (L1 ± L4 disease according to Montreal classification) undergoing small bowel capsule endoscopy (SBCE) for assessment of endoscopic activity. CD endoscopic activity was classified according to the Lewis score (LS) value. Complete blood count, C-reactive protein and fecal calprotectin values were collected within 1 month of SBCE. A retrospective sample was used for initial assessment of PLR index performance, followed by a prospective 2-years application on a distinct sample. Results The initial sample included 49 and the validation sample 48 patients, both groups being age- and gender-matched. On the initial cohort, PLR index presented a positive moderate correlation with LS (k=0.597; p<0.001), which was stronger than the one found with fecal calprotectin (k=0.525; p=0.001) or C-reactive protein (k=0.321; p=0.029). PLR index presented an excellent accuracy for predicting patients with a moderate-to-severe endoscopic activity (AUC=0.91; 95%CI=0.82-0.99; p<0.001), and a good accuracy for prediction of mucosal healing (AUC=0.74; 95%CI=0.60-0.89; p=0.007). These results were confirmed on the prospective validation cohort, as the correlation of LS with PLR index (k=0.631; p<0.001) was further stronger than with fecal calprotectin (k=0.355; p=0.040) and C-reactive protein (k=0.183; p=0.219). The accuracy of PLR index was confirmed to be excellent for moderate-to-severe endoscopic activity (AUC=0.87; 95%CI=0.76-0.98; p<0.001) and good for mucosal healing (AUC=0.74; 95%CI=0.59-0.87; p<0.001). Conclusion PLR index demonstrated an excellent acuity in predicting moderate-to-severe disease and good acuity in predicting mucosal healing in patients with small bowel CD, with both associations confirmed on a prospective validation cohort. Our findings establish this index as a promising and easy-to-apply tool for non-invasive and regular follow-up of patients with small bowel CD.

Background Contrary to the Simple Endoscopic Score for Crohn’s Disease (SES-CD), Modified Multiplier SES-CD (MM-SES-CD) is a new endoscopic severity assessment tool that was able to predict one-year endoscopic remission in patients with Crohn’s Disease (CD) on active therapy. Unlike SES-CD, MM-SES-CD accounts for the number of segments affected and the different prognostic weight of individual SES-CD parameters according to disease location. Nevertheless, there is scarce information regarding its relationship with laboratorial parameters, namely C-reactive protein (CRP) and fecal calprotectin (FC). We aimed to analyze the association between MM-SES-CD and these laboratorial parameters. Methods Retrospective cohort-study including all ileocolonoscopies performed in adult CD patients between January 2020 and October 2022 with CRP (mg/dL) and FC (ug/g) collected within one month. Patients with previous intestinal surgery or inadequate bowel preparation were excluded. MM-SES-CD, ranging from 0 to 130.5, was calculated and different severity categories were defined as follows: remission (<14), mild (≥14 to <31), moderate (≥31 to <45), and severe (≥45). MM-SES-CD values were correlated and compared, according to severity categories, with laboratorial biomarkers. Results A total of 272 ileocolonoscopies from 218 CD patients were included, most females (54.1%) with a mean age of 41 years old. Most patients were A2 (72.8%), L1 (51.1%) and B1 (73.9%), according to Montreal classification. Median MM-SES-CD, CRP and FC was 12.0, 2.9 and 222.0, respectively. Despite MM-SES-CD values correlated weakly with CRP (r=0.376, P<0.001) and moderately with FC (r=0.531, P<0.001), patients with endoscopic remission had significantly lower median CRP (2.9 vs 7.7, P<0.001) and FC (128 vs 587, P<0.001) than patients with active disease. Additionally, median CRP (2.9 vs 6.0 vs 16.0 vs 30.7, P<0.001), and median FC (128 vs 531 vs 637 vs 877, P<0.001) were significantly different between MM-SES-CD severity categories (remission vs mild vs moderate vs severe), respectively. CRP and FC optimal cut-offs for endoscopic remission were 8.5 mg/dL (Sensitivity 74.7%, Specificity 43.6%, negative predictive value (NPV) 77.4%, positive predictive value (PPV) 40.0%) and 471.5 ug/g (Sensitivity 62.6%, Specificity 87.3%, NPV 82.3%, PPV 71.3%), respectively. Conclusion To the best of our knowledge, this is the first study reporting an association between CRP and FC and increasing degrees of disease activity assessed by MM-SES-CD. A CRP <8.5 mg/dL and a FC <471.5 ug/g are suggested as cut-offs associated with endoscopic remission.

Background The endoscopic Mayo score (MS) is the most frequent score used for the evaluation of inflammatory activity in Ulcerative Colitis (UC), varying from 0 to 3 points. Recently the DUBLIN score (DS) emerged, which varies from 0 to 9 points and results from the product of the MS and the disease extent, according to Montreal classification, E1-E3. In this study we aimed to evaluate and compare the predictive ability of MS and DS for long term treatment failure. Methods A retrospective and unicentric study was conducted, including patients with left-sided or extensive UC, asymptomatic and without the need for steroid therapy or therapy changes in the 6 months prior to undergoing total colonoscopy with calculation of MS and DS. Treatment failure was evaluated, defined by the need for therapy changes and/or hospitalization because of disease exacerbation, over a follow-up period of a minimum of 24 months and a maximum of 84 months. Results A total of 204 patients were included, 104 (51%) females and with a mean age at diagnosis of 36.4±12.7 years. In the initial evaluation, 48 (23.5%) were being treated with anti-TNFα medication. The mean values of MS were 1.0±1.1 points and of DS were 2.2±2.6 points. During follow-up, 32 (15.7%) patients experienced treatment failure and patients initially treated with anti-TNFα medication had 2.3 times higher risk of treatment failure (p=0.042). MS values (AUC 0.809; p<0.001; with sensitivity of 0.938 and specificity of 0.529 for values equal or superior to 1) and DS values (AUC 0.789; p<0.001; with sensitivity of 0.844 and specificity of 0.581 for values equal or superior to 2) had good discriminative abilities in predicting treatment failure. There were no statistically significant differences in the discriminative ability between both scores (p=0.340). Conclusion MS and DS had good discriminative abilities in predicting treatment failure. However, the integration of the disease extent in the DS as a complement of MS in the evaluation of UC was not associated with a higher predictive ability of long term treatment failure.

Background In 2022, the Simplified Endoscopic Mucosal Assessment for Crohn’s Disease (SEMA-CD) was created and internally validated, aiming to simplify endoscopic activity assessment in ileocolonoscopies for CD. This score was shown to be easier and faster to apply than previously used Simple Endoscopic Score for CD (SES-CD). In our investigation, we aimed to apply this score on a European population and to assess if its prognostic value was the same as SES-CD. Methods Longitudinal study of consecutive CD patients undergoing ileocolonoscopy for assessment of endoscopic activity. Patients with previous ileocecal resection were excluded. CD endoscopic activity was classified according to both SES-CD and SEMA-CD. A minimum follow-up period of 12 months was required. Treatment escalation, hospitalization and bowel resection were assessed during the follow-up period. Results The initial sample included 265 patients, with 61 being excluded for having previous ileocecal surgery. Final sample included 204 patients, 113 (54.9%) female, with a mean age of 43±14 years. SEMA-CD had a nearly-perfect correlation with SES-CD (r=0.998; p<0.001). SEMA-CD performed similarly to SES-CD in predicting treatment escalation (AUC=0.905 vs AUC=0.908), bowel resection (AUC=0.517 vs AUC=0.516), and hospitalization (AUC=0.605 vs AUC=0.610) (p>0.05). Optimal SEMA-CD cut-off predicting treatment escalation during the subsequent year was a SEMA-CD ≥2 (sensitivity 88%; specificity 86%). Conclusion In our sample, SEMA-CD perfectly correlated with SES-CD, having similar performances in predicting treatment escalation, surgery and hospitalization in CD patients. We first defined a SEMA-CD ≥2 as a possible guide to treatment escalation. Our study confirms SEMA-CD as a potentially helpful tool in CD patients’ follow-up.

Background Anti-tumour necrosis factor-α (anti-TNF-α) therapy is an effective treatment for Crohn’s disease (CD). However, treatment failure is common. Our aim was to identify predictors of anti-TNF-α therapy failure. Methods Retrospective single-center study including anti-TNF-α naïve patients with CD, who started on intravenous infliximab, between January 2019 and December 2021. Biochemical parameters included erythrocyte sedimentation rate(ESR), c-reactive protein(CRP), faecal calprotectin, infliximab serum concentrations and antibodies to infliximab(ATI). Anti-TNF-α therapy failure was defined as ATI development at 6 or 12 months, absence of clinical response at 6 months, absence of clinical remission or objective response at 12 months. Clinical response was defined as reduction in Harvey-Bradshaw index(HBI) of≥3points comparing with initial value or HBI<5points if initial HBI≥7points and clinical remission as HBI≤4points. Objective response was assessed by endoscopic studies (improvement of mucosal inflammation and absence of deep ulcerations) or imaging (improvement in bowel wall thickness, inflammatory fat, mural blood flow and hyper-enhancement). Results Totally 53 CD patients were included, 49.1%treated with combination of anti-TNF-α and immunomodulatory therapy. Anti-TNF-α therapy failure occurred in 21 patients(39.6%). At 6 months, ATI development occurred in 6 patients(11.3%) and absence of clinical response in 9(17.0%). At 12 months, absence of clinical remission was seen in 13.6% of patients and absence of objective response in 27.0%. At 6 months, ATI development was significantly higher in patients with lower infliximab serum concentrations at week 14 (with ATI 5.9±3.2 vs without 14.3±7.7, p<0.001). Additionally, ATI development was significantly higher in patients with a higher initial value of ESR (with ATI median 35 vs without median 13, p=0.045). The infliximab serum concentrations at week 14 (AUC 0.828;p=0.009; sensitivity 0.833, specificity 0.404 for values≤11.6) and the initial value of ESR (AUC 0.754;p=0.045; sensitivity 0.833, specificity 0.468 for values≥15) had very good and good discriminative capacity, respectively, in predicting ATI development. No statistically significant differences were found in initial values of CRP and faecal calprotectin. The other definers of anti-TNF-α therapy failure were not associated with the combination with immunomodulatory therapy, infliximab serum concentrations at week 14 or initial values of biochemical parameters. Conclusion Infliximab serum concentration after induction is the most important factor in ATI development, influencing treatment response, regardless of the combination with immunomodulatory therapy. Higher initial value of ESR can also predict the development of ATI.