Tumor immunosurveillance plays a major role in melanoma, prompting the development of immunotherapy strategies. The gut microbiota composition, influencing peripheral and tumoral immune tonus, earned ...its credentials among predictors of survival in melanoma. The MIND-DC phase III trial (NCT02993315) randomized (2:1 ratio) 148 patients with stage IIIB/C melanoma to adjuvant treatment with autologous natural dendritic cell (nDC) or placebo (PL). Overall, 144 patients collected serum and stool samples before and after 2 bimonthly injections to perform metabolomics (MB) and metagenomics (MG) as prespecified exploratory analysis. Clinical outcomes are reported separately. Here we show that different microbes were associated with prognosis, with the health-related Faecalibacterium prausnitzii standing out as the main beneficial taxon for no recurrence at 2 years (p = 0.008 at baseline, nDC arm). Therapy coincided with major MB perturbations (acylcarnitines, carboxylic and fatty acids). Despite randomization, nDC arm exhibited MG and MB bias at baseline: relative under-representation of F. prausnitzii, and perturbations of primary biliary acids (BA). F. prausnitzii anticorrelated with BA, medium- and long-chain acylcarnitines. Combined, these MG and MB biomarkers markedly determined prognosis. Altogether, the host-microbial interaction may play a role in localized melanoma. We value systematic MG and MB profiling in randomized trials to avoid baseline differences attributed to host-microbe interactions.
Abstract Tumor immunosurveillance plays a major role in melanoma, prompting the development of immunotherapy strategies. The gut microbiota composition, influencing peripheral and tumoral immune ...tonus, earned its credentials among predictors of survival in melanoma. The MIND-DC phase III trial (NCT02993315) randomized (2:1 ratio) 148 patients with stage IIIB/C melanoma to adjuvant treatment with autologous natural dendritic cell (nDC) or placebo (PL). Overall, 144 patients collected serum and stool samples before and after 2 bimonthly injections to perform metabolomics (MB) and metagenomics (MG) as prespecified exploratory analysis. Clinical outcomes are reported separately. Here we show that different microbes were associated with prognosis, with the health-related Faecalibacterium prausnitzii standing out as the main beneficial taxon for no recurrence at 2 years ( p = 0.008 at baseline, nDC arm). Therapy coincided with major MB perturbations (acylcarnitines, carboxylic and fatty acids). Despite randomization, nDC arm exhibited MG and MB bias at baseline: relative under-representation of F. prausnitzii , and perturbations of primary biliary acids (BA). F. prausnitzii anticorrelated with BA, medium- and long-chain acylcarnitines. Combined, these MG and MB biomarkers markedly determined prognosis. Altogether, the host-microbial interaction may play a role in localized melanoma. We value systematic MG and MB profiling in randomized trials to avoid baseline differences attributed to host-microbe interactions.
BackgroundAdulthood cancer results from (epi)genomic cellular changes associated with chronic inflammatory processes and maladaptive immune responses. Identifying sensors of health to disease ...transition culminating in early carcinogenesis beyond cell autonomous cues is an unmet medical need. A holistic view might help defining a high-risk model based on functional biomarkers amenable to personalized screening interventions and interceptive measures.MethodsWe conducted a prospective omics-based translational research study (PREVALUNG trial, NCT03976804) in 508 smokers with cardiovascular disease (CVD) aimed at predicting the 17 tobacco-associated cancers beyond the NLST, NELSON, PLCOm2012 screening scores. After inclusion, patients were scheduled for a low-dose chest CT-scan, and blood and feces samples were collected concomitantly. PREVALUNG omics-based sensors of health to disease transition included analytes related to inflammation, immunity, metabolism, metagenome, gut barrier, plasma proteomics, and clonal hematopoiesis. To validate our hypotheses, we investigated a Li-Fraumeni cohort of TP53 germline mutation carriers (LIFSCREEN trial, NCT01464086), and performed the same omics assessment on biological sample taken before cancer detection.ResultsWe could estimate cancer risk of CVD patients based on 33 soluble markers and 2 clinical risk factors, with an AUC of 0.78 (0.67; 0.79). To challenge this model of inflammation-related cancer, we investigated a Li-Fraumeni cohort of TP53 germline mutation carriers who have a significantly increased lifetime cancer risk affecting multiple organ sites. Here, 13 soluble markers and 8 clinical risk factors predicted cancer with an AUC of 0.82 (0.66; 0.91). The functional pathways shared by both cohorts paving the way to carcinogenesis include the neutrophil/lymphocyte ratio, Th2 immunity (CCL24, CCL26, IL-4/IL-4R, IL-5, CCL11, CCL22, CD163, IL-33/ST2), inflammasome activation (IL-1b, IL-1R2, IL-1RN), gut barrier permeability (IL-33/ST2, CD14/LBP, MAdCAM-1, CCL25), cholesterol and biliary salt circuitries, tryptophan and vitamin B3 metabolism, polyamines and ketogenesis.ConclusionsThese two studies suggest that health to cancer transition results from coordinated and cumulative pathological failures of the meta-organism, amenable to biologically-guided prophylactic measures beyond life style changes.AcknowledgementsMF, LZ and GK are supported by the SEERAVE Foundation, the European Union’s Horizon Europe research and innovation programme under grant agreement number No 101095604 project acronym: PREVALUNG-EU, project title: Personalized lung cancer risk assessment leading to stratified Interception. LIFSCREEN (NCT01464086) is funded by the French Ligue Contre le Cancer.Trial RegistrationPrevalence of Lung Cancer (PREVALUNG) study was approved according the French Jardé law; the study is referenced at the French ‘Agence Nationale de Sécurité du Médicament et des Produits de Santé’ (reference ID RCB: 2019-A00262-55) and registered on clinicaltrial.gov (NCT03976804).LIFSCREEN (ClinicalTrials.gov Identifier: NCT01464086).Ethics ApprovalPrevalence of Lung Cancer (PREVALUNG) study was approved according the French Jardé law; the study is referenced at the French ‘Agence Nationale de Sécurité du Médicament et des Produits de Santé’ (reference ID RCB: 2019-A00262-55) and registered on clinicaltrial.gov (NCT03976804).LIFSCREEN (ClinicalTrials.gov Identifier: NCT01464086).
Gastroesophageal reflux disease is a common comorbidity in idiopathic pulmonary fibrosis (IPF) and may contribute to its progression. Anti-acid therapy, such as proton pump inhibitors (PPIs), has ...been considered as a potential treatment option for IPF. The evidence for this treatment comes from several observational studies affected by time-related bias.
Is use of PPIs in patients with IPF associated with a reduction in all-cause mortality, respiratory-related mortality, and respiratory-related hospitalization?
We used the UK Clinical Practice Research Datalink to identify a cohort of patients diagnosed with IPF between 2003 and 2016. The prevalent new-user cohort design was used to match patients initiating PPIs with non-users using time-conditional propensity scores, with follow-up until death or end of observation. Cox models were used to estimate hazard ratios (HR) and 95% CIs of death and of a respiratory-related hospitalization, correcting for informative censoring by inverse probability weighting.
There were 1,852 PPI users who were matched to 1,852 non-users identified among the cohort of patients with IPF, with a median survival of 2.8 years (mortality rate, 26.7 per 100 per year). The HR of all-cause mortality with PPI use was 1.07 (95% CI, 0.94-1.22), relative to non-use. For respiratory-related mortality, the HR was 1.10 (95% CI, 0.94-1.28) and 1.00 (95% CI, 0.86-1.16) for respiratory-related hospitalizations.
PPI use was not associated with lower mortality or hospitalization incidence in this large study conducted among patients with IPF within a real-world setting of clinical practice and designed to avoid the time-related biases affecting previous studies. PPIs may not be as beneficial in treating IPF as suggested by some studies and conditionally recommended in treatment guidelines.
Abstract Aim Non‐randomized studies on bariatric surgery have reported large reductions in mortality within 6‐12 months after surgery compared with non‐surgical patients. It is unclear whether these ...findings are the result of bias. Study Design and Setting We searched PubMed to identify all non‐randomized studies investigating the effect of bariatric surgery on all‐cause mortality compared with non‐surgical patients. We assessed these studies for potential confounding and time‐related biases. We conducted bias analyses to quantify the effect of these biases. Results We identified 21 cohort studies that met our inclusion criteria. Among those, 11 were affected by immortal time bias resulting from the misclassification or exclusion of relevant follow‐up time. Five studies were subject to potential confounding bias because of a lack of adjustment for body mass index (BMI). All studies used an inadequate comparator group that lacked indications for bariatric surgery. Bias analyses to correct for potential confounding from BMI shifted the effect estimates towards the null reported hazard ratio (HR): 0.78 vs. bias‐adjusted HR: 0.92. Bias analyses to correct for the presence of immortal time also shifted the effect estimates towards the null (adjustment for 2‐year wait time: reported HR: 0.57 vs. bias‐adjusted HR: 0.81). Conclusion Several important sources of bias were identified in non‐randomized studies of the effectiveness of bariatric surgery versus non‐surgical comparators on mortality. Future studies should ensure that confounding by BMI is accounted for, considering the choice of the comparator group, and that the design or analysis avoids immortal time bias from the misclassification or exclusion.
Gastroesophageal reflux disease is a common comorbidity in idiopathic pulmonary fibrosis (IPF) and may contribute to its progression. Anti-acid therapy, such as proton pump inhibitors (PPIs), has ...been considered as a potential treatment option for IPF. The evidence for this treatment comes from several observational studies affected by time-related bias.
Is use of PPIs in patients with IPF associated with a reduction in all-cause mortality, respiratory-related mortality, and respiratory-related hospitalization?
We used the UK Clinical Practice Research Datalink to identify a cohort of patients diagnosed with IPF between 2003 and 2016. The prevalent new-user cohort design was used to match patients initiating PPIs with non-users using time-conditional propensity scores, with follow-up until death or end of observation. Cox models were used to estimate hazard ratios (HR) and 95% CIs of death and of a respiratory-related hospitalization, correcting for informative censoring by inverse probability weighting.
There were 1,852 PPI users who were matched to 1,852 non-users identified among the cohort of patients with IPF, with a median survival of 2.8 years (mortality rate, 26.7 per 100 per year). The HR of all-cause mortality with PPI use was 1.07 (95% CI, 0.94-1.22), relative to non-use. For respiratory-related mortality, the HR was 1.10 (95% CI, 0.94-1.28) and 1.00 (95% CI, 0.86-1.16) for respiratory-related hospitalizations.
PPI use was not associated with lower mortality or hospitalization incidence in this large study conducted among patients with IPF within a real-world setting of clinical practice and designed to avoid the time-related biases affecting previous studies. PPIs may not be as beneficial in treating IPF as suggested by some studies and conditionally recommended in treatment guidelines.
The ability of four experienced clinicians to predict short-term outcome (serum creatinine level at 1 year) and long-term outcome (renal insufficiency) was evaluated in 87 patients with lupus ...nephritis. The correlational agreement and the accuracy of their predictions were contrasted with the actual outcomes observed and with statistically generated prognostic regression models. In contrast to previously published data, all four clinicians predicted both short-term outcomes (P < 0.001) and long-term outcomes (P < 0.02) well. The clinicians' predictions approximated that of a statistically generated computer model for both agreement and accuracy for renal function at 1 year. The four clinicians identified nearly identical clinical variables as important in determining prognosis. Provision of biopsy data to the clinicians improved short-term and long-term prediction slightly. The value of the statistical models was 'validated' by demonstrating that three of the four clinical variables identified by the models, but not by the clinicians, could enhance clinical prediction (P < 0.05). In addition, the extent of tubulo-interstitial involvement on biopsy, a predictor that has recently received increased attention, could improve the long-term clinical predictions of all four clinicians (P < 0.05).
