Impact of RAS mutation subtype on clinical outcome-a cross-entity comparison of patients with advanced non-small cell lung cancer and colorectal cancer.

Mutated RAS onco-proteins are key drivers across many cancers. The distribution of somatic RAS mutations varies between cancer entities. Retrospective analyses have associated some RAS mutations with distinct clinical outcomes. However, the clinical impact of the full spectrum of RAS mutations in their disease contextuality remains to be defined. To improve upon this situation, we studied genomically and clinically annotated, prospectively recruited cohorts of patients with RAS-mutated metastatic lung cancer and colorectal cancer. Mutational spectra were compared with predictions derived from analyzing the mutagenic impact at the genome level for each entity. Interestingly, we found concordance of predicted signatures with those actually observed in our patients. Thus, composition of the functionally active RAS mutational subtypes is primarily determined by the mutagenic context. Most RAS mutations seemed dominant oncogenic drivers with entity-dependent clinical outcomes. RAS comutations were enriched in tumors harboring class 2/3 BRAF mutations, highlighting the functional dependency of some mutated BRAF isoforms on RAS. With our dataset, we established a probabilistic model for cross-entity comparison of the prognostic impact of specific RAS mutational subtypes. The resulting prognostic clusters showed largely consistent clinical categorizations in both entities. This suggests mutant subtype-specific functional properties leading to similar clinical effects. A notable exception is KRAS G12C, which imparted an adverse prognosis only in colorectal cancer. Our findings provide a framework for risk stratification of specific RAS mutations across several cancer entities, which is required to guide the analysis of clinical findings in patients treated with direct RAS inhibitors or agents targeting downstream pathways.

Changes of Intestinal Microflora in Patients with Rheumatoid Arthritis during Fasting or a Mediterranean Diet.

BACKGROUND: therapeutic dietary interventions are effective treatments for rheumatoid arthritis (RA). The mechanisms to affect inflammation and clinical outcome in rheumatoid arthritis are only partly understood. Alterations in intestinal microflora are believed to be associated with disease activity in RA. AIM: to evaluate changes in short-chain fatty acid (SCFA) profiles and clinical outcome in RA during medical fasting or mediterranean diet. METHODS: Fifty consecutive in-patients from an Integrative Medicine Department were included in a prospective observational, non-randomised, clinical trial. Patients underwent a 7-day fasting (MF) therapy or a Mediterranean diet (MD) as part of a multimodal therapeutic treatment approach. RESULTS: the mean Disease Activity Score (DAS-28) significantly decreased in both groups (p < 0.001) from 5.7 ± 0.9 to 4.1 ± 1.3 in the MF and from 5.4 ± 1.4 to 4.5 ± 1.3 in the MG group, with no significant difference between the groups (p = 0.115). VAS showed a consecutive decrease of pain in both study groups which was significantly higher in the fasting group on day 7 (p = 0.049). No significant differences between the study groups were found in the profile of total-fatty acids (p = 0.069), butyrate (p = 0.611) and propionate (p = 0.419). Measurement of acetate, however, showed significant differences (p = 0.044) with an increase from 17,4 ± 9.8 µmol/g to 21,4 ± 16.4 µmol/g in MF compared to a decrease from 15,2 ± 10.4 µmol/g to 13,8 ± 9.3 µmol/g in MD. There was no significant correlation between dietary induced changes of SCFA and changes of disease activity. CONCLUSION: alterations in SCFA were found in terms of significant changes to increased acetate levels in the fasting group. A correlation between changes of SCFA from intestinal microflora and disease activity in RA could not be revealed. Further studies are needed in the field of dietary inducible changes of the intestinal microflora in patients with RA.