Assessing the Performance of a Novel Stool-Based Microbiome Test That Predicts Response to First Line Immune Checkpoint Inhibitors in Multiple Cancer Types.

The intestinal microbiome is by now an undebatable key player in the clinical outcome of ICI therapies. However, no microbiome profiling method to aid therapy decision is yet validated. We conducted a multi-centric study in patients with stage III/IV melanoma, NSCLC, or RCC receiving ICI treatment. The stool microbiome profile of 63 patients was analyzed with BiomeOne®, a microbiome-based algorithm that anticipates whether a patient will achieve clinical benefit with ICIs prior to therapy initiation. Classification of patient samples as Rs and NRs was achieved with a sensitivity of 81% and a specificity of 50% in this validation cohort. An ICI-favorable response was characterized by an intestinal microbiome rich in bacteria such as Oscillospira sp., Clostridia UCG-014, Lachnospiraceae UCG-010 sp., Prevotella copri, and a decrease in Sutterella sp., Lactobacillales, and Streptococcus sp. Patients who developed immune-related adverse events (irAEs) had an overall increased microbial diversity and richness, and a stool microbiome depleted in Agathobacter. When compared with the programmed death-ligand 1 (PD-L1) expression test in the subcohort of NSCLC patients (n = 38), BiomeOne® exhibited a numerically higher sensitivity (78.6%) in identifying responders when compared with the PD-L1 test (67.9%). This study provides an evaluation of BiomeOne®, the first microbiome-based test for prediction of ICI response, to achieve market authorization. Validation with further indications and expansion to other microbiome-based interventions will be essential to bring microbiome-based diagnostics into standard clinical practice.

Circulating microRNAs as molecular biomarkers for lung adenocarcinoma.

BACKGROUND: The potential of microRNAs (miRNAs) as molecular tumor biomarkers for early diagnosis and prognosis in lung cancer is still unclear. OBJECTIVE: To analyze expression of miRNAs in A549 lung adenocarcinoma (LUAD) cells and in primary, non-malignant bronchial epithelial (BE) cells from healthy donors. To analyze the most prominently deregulated miRNAs in plasma samples of LUAD patients and healthy donors. MATERIALS AND METHODS: The expression of 752 miRNAs in LUAD and BE cells was assessed by RT-qPCR with mean-centering restricted normalization. The relative plasma levels of 18 miRNAs in LUAD patients and healthy donors were analyzed using RT-qPCR and normalized to miR-191-5p and miR-16-3p. Putative interactions between miRNAs and their target genes were investigated in silico. RESULTS: Out of 752 miRNAs, 37 miRNAs were significantly deregulated in A549 cells compared to BE cells. MiR-15b-3p, miR-148a-3p, miR-193b-3p, and miR-195-5p were significantly deregulated in plasma samples of LUAD patients compared to donors. The target genes of those four miRNAs are involved in essential mechanisms in cancer development and progression. CONCLUSIONS: There are substantial differences between cancer and control miRNA expression in vitro and in plasma samples of LUAD patients compared to healthy donors. Four deregulated miRNAs are promising as a diagnostic biomarker for adenocarcinoma of the lung.

Does short-term vitamin C reduce cardiovascular risk in type 2 diabetes?

OBJECTIVE: Vitamin C is a powerful antioxidant that is potentially useful in the prevention of atherosclerosis in diabetic individuals. However, the mechanism(s) of vitamin C's anti-atherosclerotic effects in vivo are unresolved, and clinical trials in nondiabetic individuals have yielded conflicting results. Therefore, we performed 32 studies in a randomized, crossover, dose-response trial in 8 volunteers with type 2 diabetes to determine the effects of vitamin C on serum vitamin C levels, lipids, inflammation, and coagulation. METHODS: Well-controlled, type 2 volunteers received, in randomized order for 2-week periods, each of the following: 1) no supplemental vitamin C, 2) low-dose vitamin C (250 mg/day), 3) medium-dose vitamin C (500 mg/day), and 4) high-dose vitamin C (1,000 mg/day). A high-caloric content lunch was ingested during each study arm to enhance oxidative stress. Serum vitamin C levels and atherosclerotic risk factors including lipids and markers of oxidative stress, inflammation, and hypercoagulation were determined. RESULTS: Serum vitamin C levels increased significantly at all dosages. In addition, the high-caloric content meal resulted in acute elevations of glucose, insulin, and triglycerides for several hours postmeal. However, no significant effect of vitamin C was observed on lipid parameters or any of the surrogate markers of oxidative stress, inflammation, or hypercoagulability. CONCLUSION: Our study suggests that if vitamin C does have anti-atherosclerotic effects in diabetes, it does not exert them through the traditional pathways identifiable by established surrogate markers of cardiovascular risk.

The response of gamma vitamin E to varying dosages of alpha vitamin E plus vitamin C.

Vitamin E has been studied extensively in the prevention of atherosclerosis. Cross-sectional population studies as well as randomized controlled intervention trials have demonstrated conflicting results. A recent meta-analysis of these trials has emphasized the ineffectiveness of vitamin E in atherosclerosis prevention, with a possibility of harm at higher dosages. However, vitamin E has several isomers, with the alpha form being available via dietary supplements and the gamma form being available via dietary foodstuffs. The gamma form of vitamin E demonstrates several superior properties (such as trapping reactive nitrogen species and detoxifying nitrogen dioxide) compared with alpha vitamin E. All clinical trials have used the alpha isomer, with little concern that this isomer of vitamin E may actually suppress the gamma isomer of vitamin E. We undertook a dose-response study in volunteers with type 2 diabetes mellitus to include all the dosages of alpha vitamin E that have been used in cardiovascular prevention trials to determine the effect of alpha vitamin E on gamma vitamin E. We also assessed the effect of alpha vitamin E on several traditional markers of atherosclerotic risk. We added vitamin C to the vitamin E because several clinical trials included this vitamin to enhance the antioxidant effects of alpha vitamin E. Volunteers received, in randomized order for a 2-week period, one of the following vitamin dosage arms: (1) no vitamins, (2) low-dose supplemental vitamins E plus C, (3) medium-dose supplemental vitamins E plus C, and (4) high-dose supplemental vitamins E plus C. Blood levels of both alpha and gamma vitamin E were measured as well as surrogate markers of oxidative stress, hypercoagulation, and inflammation during a high-fat atherogenic meal (to increase the ambient oxidative stress level during the study). The results demonstrate that alpha vitamin E levels increased in proportion to the dose administered. However, at every dose of alpha vitamin E, gamma vitamin E concentration was significantly suppressed. No beneficial changes in surrogate markers of atherosclerosis were observed, consistent with the negative results of prospective clinical trials using alpha vitamin E. Our results suggest that all prospective cardiovascular clinical trials that used vitamin E supplementation actually suppressed the beneficial antioxidant gamma isomer of vitamin E. No beneficial effects on several potential cardiovascular risk factors were observed, even when the vitamin E was supplemented with vitamin C. If a standardized preparation of gamma vitamin E (without the alpha isomer) becomes available, the effects of gamma vitamin E on atherosclerotic risk will warrant additional studies.

Vitamin E in humans: an explanation of clinical trial failure.

OBJECTIVE: To describe the potential benefits and hazards of vitamin E supplementation and present a rational basis for understanding the conflicting results among randomized clinical trials, epidemiologic investigations, and animal studies on the use of vitamin E to prevent atherosclerosis. METHODS: We conducted a retrospective review of the pertinent literature found in PubMed from 1981 through August 2005. The published data are analyzed and summarized. RESULTS: The possible factors implicated for failure of vitamin E therapy include the following: (1) the inclusion of patients without biochemical evidence of increased oxidative stress, (2) the relatively short duration of treatment, (3) the use of suboptimal dosages of vitamin E, (4) the suppression of gamma-tocopherol by alpha-tocopherol, (5) the use of vitamin E supplementation without the concurrent use of vitamin C, (6) the lack of inclusion of biochemical markers of oxidative stress and markers of vascular response, (7) the inappropriate administration of vitamins relative to meal ingestion, and (8) the poor patient compliance and the lack of monitoring of vitamin E levels. CONCLUSION: Large, randomized clinical trials have not yet substantiated a beneficial effect of use of vitamin E to reduce atherosclerotic risk in humans, despite demonstration of antioxidant effects in vitro and in animals. Only in subsets of patients at high risk for atherosclerosis has a beneficial effect been suggested. Before additional large, randomized clinical trials of vitamin E are performed, the specific biologic and surrogate marker effects of vitamin E in each target population must be defined more carefully. This approach will save resources, minimize untoward side effects, and identify the patients who will benefit the most.