Metabolic stress in obesity induces endothelial inflammation and activation, which initiates adipose tissue inflammation, insulin resistance, and cardiovascular diseases. However, the mechanisms ...underlying endothelial inflammation induction are not completely understood. Stimulator of interferon genes (STING) is an important molecule in immunity and inflammation. In the present study, we sought to determine the role of STING in palmitic acid-induced endothelial activation/inflammation.
In cultured endothelial cells, palmitic acid treatment activated STING, as indicated by its perinuclear translocation and binding to interferon regulatory factor 3 (IRF3), leading to IRF3 phosphorylation and nuclear translocation. The activated IRF3 bound to the promoter of ICAM-1 (intercellular adhesion molecule 1) and induced ICAM-1 expression and monocyte-endothelial cell adhesion. When analyzing the upstream signaling, we found that palmitic acid activated STING by inducing mitochondrial damage. Palmitic acid treatment caused mitochondrial damage and leakage of mitochondrial DNA into the cytosol. Through the cytosolic DNA sensor cGAS (cyclic GMP-AMP synthase), the mitochondrial damage and leaked cytosolic mitochondrial DNA activated the STING-IRF3 pathway and increased ICAM-1 expression. In mice with diet-induced obesity, the STING-IRF3 pathway was activated in adipose tissue. However, STING deficiency (
) partially prevented diet-induced adipose tissue inflammation, obesity, insulin resistance, and glucose intolerance.
The mitochondrial damage-cGAS-STING-IRF3 pathway is critically involved in metabolic stress-induced endothelial inflammation. STING may be a potential therapeutic target for preventing cardiovascular diseases and insulin resistance in obese individuals.
Given recent advances in screening mammography and adjuvant therapy (treatment), quantifying their separate and combined effects on US breast cancer mortality reductions by molecular subtype could ...guide future decisions to reduce disease burden.
To evaluate the contributions associated with screening and treatment to breast cancer mortality reductions by molecular subtype based on estrogen-receptor (ER) and human epidermal growth factor receptor 2 (ERBB2, formerly HER2 or HER2/neu).
Six Cancer Intervention and Surveillance Network (CISNET) models simulated US breast cancer mortality from 2000 to 2012 using national data on plain-film and digital mammography patterns and performance, dissemination and efficacy of ER/ERBB2-specific treatment, and competing mortality. Multiple US birth cohorts were simulated.
Screening mammography and treatment.
The models compared age-adjusted, overall, and ER/ERBB2-specific breast cancer mortality rates from 2000 to 2012 for women aged 30 to 79 years relative to the estimated mortality rate in the absence of screening and treatment (baseline rate); mortality reductions were apportioned to screening and treatment.
In 2000, the estimated reduction in overall breast cancer mortality rate was 37% (model range, 27%-42%) relative to the estimated baseline rate in 2000 of 64 deaths (model range, 56-73) per 100 000 women: 44% (model range, 35%-60%) of this reduction was associated with screening and 56% (model range, 40%-65%) with treatment. In 2012, the estimated reduction in overall breast cancer mortality rate was 49% (model range, 39%-58%) relative to the estimated baseline rate in 2012 of 63 deaths (model range, 54-73) per 100 000 women: 37% (model range, 26%-51%) of this reduction was associated with screening and 63% (model range, 49%-74%) with treatment. Of the 63% associated with treatment, 31% (model range, 22%-37%) was associated with chemotherapy, 27% (model range, 18%-36%) with hormone therapy, and 4% (model range, 1%-6%) with trastuzumab. The estimated relative contributions associated with screening vs treatment varied by molecular subtype: for ER+/ERBB2-, 36% (model range, 24%-50%) vs 64% (model range, 50%-76%); for ER+/ERBB2+, 31% (model range, 23%-41%) vs 69% (model range, 59%-77%); for ER-/ERBB2+, 40% (model range, 34%-47%) vs 60% (model range, 53%-66%); and for ER-/ERBB2-, 48% (model range, 38%-57%) vs 52% (model range, 44%-62%).
In this simulation modeling study that projected trends in breast cancer mortality rates among US women, decreases in overall breast cancer mortality from 2000 to 2012 were associated with advances in screening and in adjuvant therapy, although the associations varied by breast cancer molecular subtype.
Abstract Background Pericardial effusion (PE) is common in cancer patients, but the optimal therapeutic approach is not well defined. Percutaneous pericardiocentesis is less invasive than surgery, ...but its long-term effectiveness and safety have not been well documented. Objectives The goal of this study was to evaluate outcomes of cancer patients undergoing percutaneous pericardiocentesis for PE and assess the procedure’s safety in patients with thrombocytopenia. Methods Cancer patients who underwent percutaneous pericardiocentesis for PE between November 2009 and October 2014 at the MD Anderson Cancer Center were included. Procedure-related complications, effusion recurrence rate, and overall survival were analyzed. Results Of 1,645 cancer patients referred for PE, 212 (13%) underwent percutaneous pericardiocentesis. The procedure was successful in 99% of the cases, and there were no procedure-related deaths. Four patients had major procedure-related bleeding that did not vary by platelet count <50,000/μl or ≥50,000/μl (p = 0.1281). Patients with catheter drainage for 3 to 5 days had the lowest recurrence rate (10%). Median overall survival was 143 days; older age (i.e., >65 years), lung cancer, platelet count <20,000/μl, and malignant pericardial fluid were independently associated with poor prognosis. Lung cancer patients with proven malignant effusions had a significantly shorter median 1-year survival compared with those with nonmalignant effusions (16.2% vs. 49.0%, respectively; log-rank test p = 0.0101). A similar difference in 1-year survival was not observed in patients with breast cancer (40.2% vs. 40.0%; log-rank test p = 0.4170). Conclusions Percutaneous pericardiocentesis with extended catheter drainage was safe and effective as the primary treatment for PE in cancer patients, including in those with thrombocytopenia. Malignant PE significantly shortened the survival outcome of patients with lung cancer but not those with breast cancer.
To determine the impact of RAS mutation status on the traditional clinical score (t-CS) to predict survival after resection of colorectal liver metastases (CLM).
The t-CS relies on the following ...factors: primary tumor nodal status, disease-free interval, number and size of CLM, and carcinoembryonic antigen level. We hypothesized that the addition of RAS mutation status could create a modified clinical score (m-CS) that would outperform the t-CS.
Patients who underwent resection of CLM from 2005 through 2013 and had RAS mutation status and t-CS factors available were included. Multivariate analysis was used to identify prognostic factors to include in the m-CS. Log-rank survival analyses were used to compare the t-CS and the m-CS. The m-CS was validated in an international multicenter cohort of 608 patients.
A total of 564 patients were eligible for analysis. RAS mutation was detected in 205 (36.3%) of patients. On multivariate analysis, RAS mutation was associated with poor overall survival, as were positive primary tumor lymph node status and diameter of the largest liver metastasis >50 mm. Each factor was assigned 1 point to produce a m-CS. The m-CS accurately stratified patients by overall and recurrence-free survival in both the initial patient series and validation cohort, whereas the t-CS did not.
Modifying the t-CS by replacing disease-free interval, number of metastases, and CEA level with RAS mutation status produced an m-CS that outperformed the t-CS. The m-CS is therefore a simple validated tool that predicts survival after resection of CLM.
Background. Each year, the US Influenza Vaccine Effectiveness Network examines the effectiveness of influenza vaccines in preventing medically attended acute respiratory illnesses caused by ...influenza. Methods. Patients with acute respiratory illnesses of ≤7 days' duration were enrolled at ambulatory care facilities in 5 communities. Specimens were collected and tested for influenza by real-time reverse-transcriptase polymerase chain reaction. Receipt of influenza vaccine was defined based on documented evidence of vaccination in medical records or immunization registries. Vaccine effectiveness was estimated in adjusted logistic regression models by comparing the vaccination coverage in those who tested positive for influenza with those who tested negative. Results. The 2011–2012 season was mild and peaked late, with circulation of both type A viruses and both lineages of type B. Overall adjusted vaccine effectiveness was 47% (95% confidence interval CI, 36–56) in preventing medically attended influenza; vaccine effectiveness was 65% (95% CI, 44–79) against type A (H1N1) pdm09 but only 39% (95% CI, 23–52) against type A (H3N2). Estimates of vaccine effectiveness against both type B lineages were similar (overall, 58%; 95% CI, 35–73). An apparent negative effect of prior year vaccination on current year effectiveness estimates was noted, particularly for A (H3N2) outcomes. Conclusions. Vaccine effectiveness in the 2011–2012 season was modest overall, with lower effectiveness against the predominant A (H3N2) virus. This may be related to antigenic drift, but past history of vaccination might also play a role.
Circulating lymphocytes are exquisitely sensitive to radiation exposure, even to low scattered doses which can vary drastically between radiation modalities. We compared the relative risk of ...radiation-induced lymphopenia between intensity modulated radiation therapy (IMRT) or proton beam therapy (PBT) in esophageal cancer (EC) patients undergoing neoadjuvant chemoradiation therapy (nCRT).
EC patients treated with IMRT and PBT were propensity matched based on key clinical variables. Treatment-associated lymphopenia was graded using CTCAE v.4.0. Using matched cohorts, univariate and multivariable multiple logistic regression was used to identify factors associated with increased risk of grade 4 lymphopenia as well as characterize their relative contributions.
Among the 480 patients treated with nCRT, 136 IMRT patients were propensity score matched with 136 PBT patients. In the matched groups, a greater proportion of the IMRT patients (55/136, 40.4%) developed grade 4 lymphopenia during nCRT compared with the PBT patients (24/136, 17.6%, P < 0.0001). On multivariable analysis, PBT was significantly associated with a reduction in grade 4 lymphopenia risk (odds ratio, 0.29; 95% confidence interval, 0.16–0.52; P < 0.0001).
PBT is associated with significant risk reduction in grade 4 lymphopenia during nCRT in esophageal cancer.
Background Oral mucositis (OM) in patients receiving cancer therapy is thus far not well managed with standard approaches. We aimed to assess the safety and effectiveness of methylene blue (MB) oral ...rinse for OM pain in patients receiving cancer therapy. Methods In this randomized, single-blind phase 2 clinical trial, patients were randomized to one of four arms: MB 0.025%+conventional therapy (CTx) (n = 15), MB 0.05%+CTx (n = 14), MB 0.1%+CTx (n = 15), or CTx alone (n = 16). Intervention groups received MB oral rinse every 6 h for 2 days with outcomes measured at days 1-2; safety was evaluated up to 30 days. The primary outcome measured change in the pain numeric rating scale (0-10) from baseline to day 2. Secondary outcome measured change in oral function burden scores from baseline to day 2, World Health Organization OM grades, morphine equivalent daily doses, and adverse events. The trial was registered with ClinicalTrials.gov ID: NCT03469284. Results Sixty patients (mean age 43, range 22-62 years) completed the study. Compared with those who received CTx alone, those who received MB had a significant reduction of pain scores at day 2 of treatment (mean + or - SD); 0.025%: 5.2 + or - 2.9, 0.05%: 4.5 + or - 2.9, 0.1%: 5.15 + or - 2.6) and reduction of oral function burden scores (0.025%: 2.5 + or - 1.55, 0.05%: 2.8 + or - 1.7, 0.1%: 2.9 + or - 1.60). No serious adverse events were noted, but eight patients reported burning sensation of the oral cavity with the first dose, and this caused one patient to discontinue therapy. Conclusions MB oral rinse showed significant pain reduction and improved oral functioning with minimal adverse effects. Trial registration ClinicalTrials.gov ID: NCT03469284. Keywords: Oral mucositis, Cancer therapy, Methylene blue Oral Rinse
Introduction
The role of modified radical mastectomy (MRM) in patients with de novo stage IV inflammatory breast cancer (IBC) remains controversial. We evaluated the impact of MRM on outcomes in this ...population.
Methods
Ninety-seven women presenting with stage IV IBC were identified in an institutional database (2007–2016) and were stratified by receipt of MRM or no surgery (non-MRM). Demographic, clinicopathologic, and treatment factors were compared. Local–regional recurrence patterns were described and survival analyses were conducted.
Results
All patients initially received chemotherapy. Fifty-two patients (53.6%) underwent MRM; 47 received post-mastectomy radiation. Differences between the non-MRM and MRM groups included tumor receptor subtypes (hormone receptor-positive HR+/human epidermal growth factor receptor 2-positive HER2+: 4.4% vs. 19.2%; HR+/HER2-negative HER2−: 31.1% vs. 44.2%; HR-negative HR−/HER2+: 24.4% vs. 15.4%; and HR−/HER2−: 40.0% vs. 21.2%;
p
= 0.03), number of metastatic sites (3 vs. 2;
p
= 0.01), and clinical partial/complete response to chemotherapy (13.3% vs. 75.0%;
p
< 0.001). Of the 47 patients who completed trimodality therapy, 6 (12.8%) had a local–regional recurrence. Median overall survival (OS) was 19 months in the non-MRM group and 58 months in the MRM group (
p
< 0.001). On multivariable analysis, clinical N3 disease (hazard ratio 2.16, 95% confidence interval CI 1.07–4.37;
p
= 0.03) as well as tumor subtypes HR+/HER2− (hazard ratio 4.98, 95% CI 1.15–21.47;
p
= 0.03) and HR−/HER2− (hazard ratio 7.18, 95% CI 1.66–31.07;
p
= 0.008) were associated with decreased OS. Partial/complete response of distant disease to chemotherapy (hazard ratio 0.43, 95% CI 0.24–0.77;
p
= 0.005) and receipt of MRM (hazard ratio 0.52, 95% CI 0.29–0.93;
p
= 0.03) were independently associated with improved OS.
Conclusions
In our retrospective study, MRM in de novo stage IV IBC patients is an independent factor associated with improved OS. Our findings strongly support the need for prospective randomized trials evaluating possible survival benefits of MRM in de novo stage IV IBC patients.
Inflammatory breast cancer (IBC) is a clinically distinct and highly aggressive form of breast cancer with rapid onset and a strong propensity to metastasize. The molecular mechanisms underlying the ...aggressiveness and metastatic propensity of IBC are largely unknown. Herein, we report that decorin (DCN), a small leucine-rich extracellular matrix proteoglycan, is downregulated in tumors from patients with IBC. Overexpression of DCN in IBC cells markedly decreased migration, invasion, and cancer stem cells in vitro and inhibited tumor growth and metastasis in IBC xenograft mouse models. Mechanistically, DCN functioned as a suppressor of invasion and tumor growth in IBC by destabilizing E-cadherin and inhibiting EGFR/ERK signaling. DCN physically binds E-cadherin in IBC cells and accelerates its degradation through an autophagy-linked lysosomal pathway. We established that DCN inhibits tumorigenesis and metastasis in IBC cells by negatively regulating the E-cadherin/EGFR/ERK axis. Our findings offer a potential therapeutic strategy for IBC, and provide a novel mechanism for IBC pathobiology.
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