Abstract
Background
The incidence of non-AIDS defining cancer (NADC) is higher in people living with HIV (PLWH) than in the general population, and it is already one of the leading causes of death in ...the HIV-infected population. It is estimated that the situation will be aggravated by the progressive aging of PLWH. Early diagnosis through intensive cancer screening may improve the ability for therapeutic interventions and could be critical in reducing mortality, but it might also increase expenditure and harms associated with adverse events. The aim of this study is to evaluate an enhanced screening program for early diagnosis of cancer in PLWH compared to standard practice. The specific objectives are (1) to compare the frequency of cancer diagnosed at an early stage, (2) to analyze safety of the enhanced program: adverse events and unnecessary interventions, (3) to analyze the cost-utility of the program, and (4) to estimate the overall and site-specific incidence of NADC in PLWH.
Methods
We will conduct a multicenter, non-blinded, randomized, controlled trial, comparing two parallel arms: conventional vs enhanced screening. Data will be recorded in an electronic data collection notebook. Conventional intervention group will follow the standard of care screening in the participating centers, according to the European AIDS Clinical Society recommendations, and the enhanced intervention group will follow an expanded screening aimed to early detection of lung, liver, anal, cervical, breast, prostate, colorectal, and skin cancer. The trial will be conducted within the framework of the Spanish AIDS Research Network Cohort (CoRIS).
Discussion
The trial will evaluate the efficacy, safety, and efficiency of an enhanced screening program for the early diagnosis of cancer in HIV patients compared to standard of care practice. The information provided will be relevant since there are currently no studies on expanded cancer screening strategies in patients with HIV, and available data estimating cost effectiveness or cost-utility of such as programs are scarce. An enhanced program for NADC screening in patients with HIV could lead to early diagnosis and improve the prognosis of these patients, with an acceptable rate of unnecessary interventions, but it is critical to demonstrate that the benefits clearly outweigh the harms, before the strategy could be implemented.
Trial registration
ClinicalTrials.gov
NCT04735445. Registered on 25 June 2019
The relationship between host microRNAs (miRNA), viral control and immune response has not yet been elucidated in the field of HIV. The aim of this study was to assess the differential miRNA profile ...in CD8+ T-cells between HIV-infected individuals who differ in terms of viral replication control and immune response.
miRNA profile from resting and CD3/CD28-stimulated CD8+ T-cells from uninfected individuals (HIV-, n = 11), Elite Controllers (EC, n = 15), Viremic Controllers (VC, n = 15), Viremic Progressors (VP, n = 13) and HIV-infected patients on therapy (ART, n = 14) was assessed using Affymetrix miRNA 3.1 arrays. After background correction, quantile normalization and median polish summarization, normalized data were fit to a linear model. The analysis comprised: resting samples between groups; stimulated samples between groups; and stimulated versus resting samples within each group. Enrichment analyses of the putative target genes were perfomed using bioinformatic algorithms.
A downregulated miRNA pattern was observed when resting samples from all infected groups were compared to HIV-. A miRNA downregulation was also observed when stimulated samples from EC, ART and HIV- groups were compared to VP, being hsa-miR-4492 the most downregulated. Although a preferential miRNA downregulation was observed when stimulated samples were compared to the respective resting samples, VP presented a differential miRNA expression pattern. In fact, hsa-miR-155 and hsa-miR-181a were downregulated in VP whereas in the other groups, either an upregulation or no differences were observed after stimulation, respectively. Overall, functional enrichment analysis revealed that the predicted target genes were involved in signal transduction pathways, metabolic regulation, apoptosis, and immune response.
Resting CD8+ T-cells do not exhibit a differential miRNA expression between HIV-infected individuals but they do differ from non-infected individuals. Moreover, a specific miRNA pattern is present in stimulated CD8+ T-cells from VP which could reflect a detrimental pattern in terms of CD8+ T-cell immune response.
Se presentaron ponencias desarrolladas en la ciudad de Bogotá, Medellín, Manizales, Huila, Campina Grande (Brasil). A su vez los ponentes eran futuros docentes, docentes en ejercicio, estudiantes de ...maestría y doctorado. Provenientes de universidades como Universidad Pedagógica Nacional, Universidad Surcolombiana, Universidad Nacional de Medellín, Universidad de Antioquia, Universidad de Caldas y Universidad Distrital Francisco José de Caldas y de la Escuela pedagógica Experimental.
Outcomes of people living with HIV (PLWH) developing non-AIDS events (NAEs) remain poorly defined. We aimed to classify NAEs according to severity, and to describe clinical outcomes and prognostic ...factors after NAE occurrence using data from CoRIS, a large Spanish HIV cohort from 2004 to 2013.
Prospective multicenter cohort study.
Using a multistate approach we estimated 3 transition probabilities: from alive and NAE-free to alive and NAE-experienced ("NAE development"); from alive and NAE-experienced to death ("Death after NAE"); and from alive and NAE-free to death ("Death without NAE"). We analyzed the effect of different covariates, including demographic, immunologic and virologic data, on death or NAE development, based on estimates of hazard ratios (HR). We focused on the transition "Death after NAE".
8,789 PLWH were followed-up until death, cohort censoring or loss to follow-up. 792 first incident NAEs occurred in 9.01% PLWH (incidence rate 28.76; 95% confidence interval CI, 26.80-30.84, per 1000 patient-years). 112 (14.14%) NAE-experienced PLWH and 240 (2.73%) NAE-free PLWH died. Adjusted HR for the transition "Death after NAE" was 12.1 (95%CI, 4.90-29.89). There was a graded increase in the adjusted HRs for mortality according to NAE severity category: HR (95%CI), 4.02 (2.45-6.57) for intermediate-severity; and 9.85 (5.45-17.81) for serious NAEs compared to low-severity NAEs. Male sex (HR 2.04; 95% CI, 1.11-3.84), age>50 years (1.78, 1.08-2.94), hepatitis C-coinfection (2.52, 1.38-4.61), lower CD4 cell count at cohort entry (HR 2.49; 95%CI 1.20-5.14 for CD4 cell count below 200 and HR 2.16; 95%CI 1.01-4.66 for CD4 cell count between 200-350, both compared to CD4 cell count higher than 500) and concomitant CD4<200 cells/mL (2.22, 1.42-3.44) were associated with death after NAE. CD4 count and HIV-1 RNA at engagement, previous AIDS and hepatitis C-coinfection predicted mortality in NAE-free persons.
NAEs, including low-severity events, increase prominently the risk for mortality in PLWH. Prognostic factors differ between NAE-experienced and NAE-free persons. These findings should be taken into account in the clinical management of PLWH developing NAEs and may permit more targeted prevention efforts.
The inhibitors of mammalian target of rapamycin (mTOR) have documented antitumor activity via disruption of various signaling pathways leading to impaired cellular growth, proliferation, and ...survival. In preclinical studies, mTOR inhibitors use in combination with hormonal therapy has shown promising results in overcoming endocrine resistance in breast cancer cells. The role of everolimus in breast cancer was established in the Breast Cancer Trial of Oral Everolimus-2 (BOLERO-2) trial in combination with exemestane for patients with advanced metastatic hormone receptor-positive (HR+) breast cancer, who relapsed after initial hormonal manipulation. The study met its primary endpoint of significant improvement in progression free survival (PFS) with a median time to progression of 6.9 months in the combination group versus 2.8 months in exemestane group. Favorable improvements in PFS were reported across all patient subgroups regardless of age, Eastern Cooperative Oncology Group performance status, number of prior therapies, and presence of visceral metastases. Adverse events were mostly mild to moderate in severity and consistent with the known safety profile of everolimus. Major toxicities reported include stomatitis, non-infectious pneumonitis, and hyperglycemia. The purpose of this review is to discuss the role of everolimus as a valuable component in advanced metastatic breast cancer and delineate current strategies to prevent and manage the most common toxicities associated with this combination regimen.
Clostridium difficile infection (CDI) is characterized by a high delayed and unrelated mortality. Predicting delayed mortality in CDI patients could allow the implementation of interventions that ...could reduce these events. A prospective multicentric study was carried out to investigate prognostic factors associated with mortality. It was based on a cohort (July 2015 to February 2016) of 295 patients presenting with CDI. Logistic regression was used and the model was calibrated using the Hosmer-Lemeshow test.
The mortality rate at 75 days in our series was 18%. Age (>65 years), comorbidity (defined by heart failure, diabetes mellitus with any organ lesion, renal failure, active neoplasia or immunosuppression) and fecal incontinence at clinical presentation were associated with delayed (75-day) mortality. When present, each of the aforementioned variables added one point to the score. Mortalities with 0, 1, 2 and 3 points were 0%, 9.4%, 18.5% and 38.2%, respectively. The area under the ROC curve was 0.743, and the Hosmer-Lemeshow goodness-of-fit test p value was 0.875. Therefore, the prediction of high delayed mortality in CDI patients by our scoring system could promote measures for increasing survival in suitable cases.
•CDI patients present a high, non-infection related, delayed mortality.•Age, comorbidity and fecal incontinence at diagnosis are related to patient outcome.•A scoring system based on these variables may predict mortality.•Preventive measures could eventually be implemented to improve patient prognoses.
OBJECTIVE:
To report the serial development of oral mucositis following infusion of bevacizumab in a young woman with a malignant brain tumor and history of cutaneous psoriasis.
CASE SUMMARY:
A ...29-year-old woman with a history of active cutaneous psoriasis and a malignant glioneuronal tumor was treated with bevacizumab for 2.5 years. With each infusion of bevacizumab, she developed oral mucositis within 36 hours. She received temozolomide as part of concurrent therapy with radiation and as maintenance therapy; it was discontinued after continuous therapy for 1.5 years. Bevacizumab 10 mg/kg was added after 7 cycles of maintenance temozolomide, as the tumor had minimal response and evidence of increased perfusion with angiogenesis on imaging studies. All medication, including temozolomide, was evaluated and eventually discontinued, with the exception of bevacizumab, which remained the drug suspected of causing the mucositis.
DISCUSSION:
Oral mucositis is a frequent adverse effect of cytotoxic chemotherapy, but has not been reported with bevacizumab. The Naranjo probability scale indicated a probable adverse drug reaction. This likely indicates that bevacizumab is one of many drugs known to induce exacerbation of psoriatic disease. We speculate that oral mucositis developed as bevacizumab-induced generation of proinflammatory cytokines within the vascular endothelium, leading to mucosal damage and ulceration. In addition, interruption of reparative angiogenic pathways with bevacizumab likely contributed to the severity of mucositis.
CONCLUSIONS:
Clinicians should be aware that bevacizumab can potentially exacerbate psoriatic disease.
Breast cancer is the leading cause of cancer in women. In recent years, there has been immense drug discovery and development in the field of breast cancer. Most recently, the role of vascular ...endothelial growth factor has moved to the treatment forefront with bevacizumab immersed into the literature as well as the media. Bevacizumab, a vascular endothelial growth factor inhibitor FDA approved for the treatment of other cancers, was first studied in metastatic breast cancer. Its use in human epidermal growth factor receptor 2–negative metastatic breast cancer ultimately failed to show an improvement in overall survival in landmark trials (E2100, AVADO, RIBBON-1 and RIBBON-2) despite its positive impact on progression-free survival. The role is yet to be determined in triple negative breast cancer as well as in the adjuvant and neoadjuvant settings. Trends begin to emerge as bevacizumab is combined with other chemotherapeutic drugs in terms of toxicities. The addition of bevacizumab is associated with an increase in the dose-limiting toxicities of the drugs combined in the regimen. As previous literature suggest, hypertension and proteinuria were also seen with the addition of bevacizumab, both of which are known adverse events. Lastly, there is a trend towards increased incidence of heart failure when bevacizumab is combined with another cardiotoxic medication, doxorubicin. This toxicity has been shown to be reversible in the majority of the cases and has a low incidence in the currently published literature.
Abstract
Colitis-Associated Colorectal Cancer (CAC) is triggered by chronic inflammation. Macrophage migration inhibitory factor (MIF) is a pro-inflammatory cytokine promoting angiogenesis, ...metastasis, proliferation and survival in malignant cells. When MIF binds to CXCR2 and CXCR4 attracts macrophages and T cells, respectively. As MIF promotes inflammation and recruit immune cells, we investigated the role of MIF in murine model of CAC. Mif−/− and WT BALB/c mice received intraperitoneally azoxymethane and later were exposed to 3 cycles of Dextran Sodium Sulfate (DSS, 2%) in drinking water. After the first DSS cycle WT mice received a synthetic MIF’s inhibitor (CPSI-156). All mice were killed 68 days after CAC induction. Greater burden of tumors were observed in both Mif−/− (25.38±1.772) and CPSI-156-treated mice (18.83±2.43) compared to CAC-WT mice (13.00±1.862). Tumors from Mif−/− mice were histologically-identified as more aggressive. Lower percentages of tumor-associated macrophages were found in both, Mif−/− (0.6577 ± 0.117) and CPSI-156-treated mice (1.2 ± 0.14) compared to CAC-WT mice (2.044±0.39). Similar percentage of T-cells was observed in all groups. RT-PCR of tumors was performed, relative expression (RE) was compared to β-actin gene. CAC-WT mice increased T-regs (foxp3 RE= 0.49), M2 (arginase-1 RE=1.53) and IL-10 (il-10 RE=0.52) and reduces expression of IL-17 (il-17 RE=3.14). Conversely, CAC-Mif−/− mice developed higher IL-17 (il-17 RE=17.15) and lower foxp3 (RE=0.32), arginase-1 (RE=1.12) and il-10 (RE=0.47) expression. Our results suggest that MIF plays a role in regulating the tumor microenvironment attracting macrophages at the tumor site, condition that may favor antitumor responses.
In this study, we used proton-localized spectroscopy ((1) H-MRS) for the acquisition of the neurochemical profile longitudinally in a novel rat model of human wild-type alpha-synuclein (α-syn) ...over-expression. Our goal was to find out if the increased α-syn load in this model could be linked to changes in metabolites in the frontal cortex. Animals injected with AAV vectors encoding for human α-syn formed the experimental group, whereas green fluorescent protein expressing animals were used as the vector-treated control group and a third group of uninjected animals were used as naïve controls. Data were acquired at 2, 4, and 8 month time points. Nineteen metabolites were quantified in the MR spectra using LCModel software. On the basis of 92 spectra, we evaluated any potential gender effect and found that lactate (Lac) levels were lower in males compared to females, while the opposite was observed for ascorbate (Asc). Next, we assessed the effect of age and found increased levels of GABA, Tau, and GPC+PCho. Finally, we analyzed the effect of treatment and found that Lac levels (p = 0.005) were specifically lower in the α-syn group compared to the green fluorescent protein and control groups. In addition, Asc levels (p = 0.05) were increased in the vector-injected groups, whereas glucose levels remained unchanged. This study indicates that the metabolic switch between glucose-lactate could be detectable in vivo and might be modulated by Asc. No concomitant changes were found in markers of neuronal integrity (e.g., N-acetylaspartate) consistent with the fact that α-syn over-expression in cortical neurons did not result in neurodegeneration in this model. We acquired the neurochemical profile longitudinally in a rat model of human wild-type alpha-synuclein (α-syn) over-expression in cortical neurons. We found that Lactate levels were reduced in the α-syn group compared to the control groups and Ascorbate levels were increased in the vector-injected groups. No changes were found in markers of neuronal integrity consistent with the fact that α-syn over-expression did not result in frank neurodegeneration.
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