Use of ctDNA in early breast cancer: analytical validity and clinical potential.

Circulating free tumor DNA (ctDNA) analysis is gaining popularity in precision oncology, particularly in metastatic breast cancer, as it provides non-invasive, real-time tumor information to complement tissue biopsies, allowing for tailored treatment strategies and improved patient selection in clinical trials. Its use in early breast cancer has been limited so far, due to the relatively low sensitivity of available techniques in a setting characterized by lower levels of ctDNA shedding. However, advances in sequencing and bioinformatics, as well as the use of methylome profiles, have led to an increasing interest in the application of ctDNA analysis in early breast cancer, from screening to curative treatment evaluation and minimal residual disease (MRD) detection. With multiple prospective clinical trials in this setting, ctDNA evaluation may become useful in clinical practice. This article reviews the data regarding the analytical validity of the currently available tests for ctDNA detection and the clinical potential of ctDNA analysis in early breast cancer.

The conundrum of breast cancer and microbiome - A comprehensive review of the current evidence.

Disturbance of the microbial balance of a habitat can have detrimental effects on the health of the individual and, in addition, polymorphic microbiomes were recently suggested as emerging cancer hallmarks. Modern sequencing and metagenomics techniques have allowed characterization of intratumoral microbiome composition even in tissues such as the breast. We conducted a comprehensive literature review on different aspects related to the microbial landscape of the breast tissue and breast tumors, as well as its relation to systemic therapy. Emerging data suggest varying microbiome composition intratumorally compared to the normal breast tissue and other tumor types. Differences in the microbes present in normal breast and cancerous lesions of the breast have also been described, as well as potential correlation between microbiome composition and breast cancer subtype and stage. The interplay between gut and breast microbiome is not well understood although bacterial allocation through mesenteric lymph nodes has been suggested as a possible pathway. Moreover, gut bacteria with estrogen metabolizing properties are of special interest in the context of breast cancer and available knowledge and reported studies are hereby described. The relationship of gut microbiome and cancer therapy is another aspect of interest and available data are presented. Notwithstanding, the field of microbiome in the context of breast cancer is starting to evolve and a number of questions arise, with the gut-breast-cancer therapy axis in the center.

High rates of long-term progression in HIV-1-positive elite controllers.

INTRODUCTION: Elite controllers (EC) are a rare group of HIV-1-positive individuals who suppress viral loads (VL) to undetectable levels with elevated CD4 T-cell counts in the absence of ART. While rates of short- and mid-term progression have been described in these patients, few studies have focused on their long-term outcome This study aims to describe the virological and immunological behaviour in a cohort of elite controllers followed up for a median of 17 years in the University Hospital, and to identify factors that may be related to disease progression. METHODS: We conducted a descriptive, prospective and single-centre study of all HIV-positive adults recorded in the University Hospital database who met the definition criteria for EC. EC were defined as patients having two consecutive undetectable VL without ART for at least one year. Patients were followed from baseline up to December 2019, to the development of a progression event (loss of VL control, CD4+ T cell decline, AIDS or death) or to the censoring date (lost to follow-up or initiation of ART). Predictive models of progression were calculated. RESULTS: Fifty-nine EC were identified with a median follow-up of 17 years contributing 1033 PYFU. The median (95% CI) time duration from HIV-1 diagnosis to disease progression was four (1.7 to 6.3) years. Forty-nine (83%) presented progression to the composite end-point, 44 (74.6%) lost viral control, 39 (66.1%) lost immunological control, two developed AIDS and two died. Only 10 patients (16.9%) did not show progression of any kind. Independent predictors of virological progression were sexual risk of HIV-1 acquisition and VL blips during the first year of follow-up (baseline). The only independent predictor detected for progression to a composite end-point was VL blips during the first year of follow-up (baseline). CONCLUSIONS: The rate of long-term progression in EC was very high. Only a minority of patients did not show clinical progression after a median of 17 years of follow-up. These results should be taken in account when considering EC as a model of HIV-1 remission.

Clinical benefit and cost of breakthrough cancer drugs approved by the US Food and Drug Administration.

BACKGROUND: The clinical benefit and pricing of breakthrough-designated cancer drugs are uncertain. This study compares the magnitude of the clinical benefit and monthly price of new and supplemental breakthrough-designated and non-breakthrough-designated cancer drug approvals. METHODS: A cross-sectional cohort comprised approvals of cancer drugs for solid tumors from July 2012 to December 2017. For each indication, the clinical benefit from the pivotal trials was scored via validated frameworks: the American Society of Clinical Oncology Value Framework (ASCO-VF), the American Society of Clinical Oncology Cancer Research Committee (ASCO-CRC), the European Society for Medical Oncology Magnitude of Clinical Benefit Scale (ESMO-MCBS), and the National Comprehensive Cancer Network (NCCN) Evidence Blocks. A high clinical benefit was defined as scores ≥ 45 for the ASCO-VF, overall survival gains ≥ 2.5 months or progression-free survival gains ≥ 3 months for all cancer types for the ASCO-CRC criteria, a grade of A or B for trials of curative intent and a grade of 4 or 5 for trials of noncurative intent for the ESMO-MCBS, and scores of 4 and 5 and a combined score ≥ 16 for the NCCN Evidence Blocks. Monthly Medicare drug prices were calculated with Medicare prices and DrugAbacus. RESULTS: This study identified 106 trials supporting approval of 52 drugs for 96 indications. Forty percent of these indications received the breakthrough designation. Among the included trials, 33 (43%), 46 (73%), 35 (34%), and 67 (69%) met the thresholds established by the ASCO-VF, ASCO-CRC, ESMO-MCBS, and NCCN, respectively. In the metastatic setting, there were higher odds of clinically meaningful grades in trials supporting breakthrough drugs with the ASCO-VF (odds ratio [OR], 3.69; P = .022) and the NCCN Evidence Blocks (OR, 5.80; P = .003) but not with the ASCO-CRC (OR, 3.54; P = .11) or version 1.1 (v1.1) of the ESMO-MCBS (OR, 1.22; P = .70). The median costs of breakthrough therapy drugs were significantly higher than those of nonbreakthrough therapies (P = .001). CONCLUSIONS: In advanced solid cancers, drugs that received the breakthrough therapy designation were more likely than nonbreakthrough therapy drugs to be scored as providing a high clinical benefit with the ASCO-VF and the NCCN Evidence Blocks but not with the ESMO-MCBS v1.1 or the ASCO-CRC scale.

Microvasculature Recovery by Angiogenesis After Myocardial Infarction.

Advances in early reperfusion therapies focused on the revascularization of the ischemic tissues, in the last decades, lead to reduced mortality in acute myocardial infarction (MI) patients. However, a large proportion of patients show inadequate myocardial perfusion because of dysfunction of the microcirculation. The high prevalence of microvascular dysfunction after reperfusion therapies and the negative prognostic of this procedure justify the search for therapeutic strategies that aim to restore the microvascular network. It is well known that the size of the initial infarct, the duration of ischemia and the efficiency of reperfusion determine myocardial tissue damage and cardiomyocyte loss after myocardial infarction. Therefore any advancement on the mechanisms that induce the repair process of microvascular dysfunction after reperfused MI is of great interest. Here, we will review the different proteins and cells known to participate in angiogenesis induction post-MI and we will also discuss the potential pharmacological and cellular processes that promote the recovery of microvasculature by angiogenesis stimulation after MI.

Silybum marianum provides cardioprotection and limits adverse remodeling post-myocardial infarction by mitigating oxidative stress and reactive fibrosis.

AIMS: Milk thistle (Silybum marianum; SM) is an herb commonly used for hepatoprotection with antioxidant and antifibrotic properties. We investigated in pigs the cardiac effects of SM intake during the acute phase of myocardial infarction (MI) and remodeling period post-MI. METHODS: Study-1 tested the effect of SM use on the acute phase of MI. Hence, animals were distributed to a control group or to receive SM prior infarction (1.5 h ischemia). Animals were sacrificed after 2.5 h of reperfusion. Study-2 tested the effect of SM use in the cardiac remodeling phase. Accordingly, animals received for 10 d diet ±â€¯SM prior MI and followed the same regime for 3 weeks and then sacrificed. Study-3 tested the effect of SM in a non-infarcted heart; therefore, animals received for 10 d diet ±â€¯SM and then sacrificed. RESULTS: Animals taking SM before MI showed a reduction in cardiac damage (decreased oxidative damage, ROS production and xanthine oxidase levels; preserved mitochondrial function; and increased myocardial salvage; p < 0.05) versus controls. Animals that remained on chronic SM intake post-MI improved left ventricular remodeling. This was associated with the attenuation of the TGFß1/TßRs/SMAD2/3 signaling, lower myofibroblast transdifferentiation and collagen content in the border zone (p < 0.05 vs. all other groups). Cardiac contractility improved in animals taking SM (p < 0.05 vs. post-MI-control). No changes in cardiac function or fibrosis were detected in animals on SM but without MI. CONCLUSION: Intake of SM protects the heart against the deleterious effects of an MI and favors cardiac healing. These benefits may be attributed to the antioxidant and antifibrotic properties of SM.