Uncategorized – Page 17680 – 1stOncology™: Cancer Intelligence Service

Patient-reported pain and other quality of life domains as prognostic factors for survival in a phase III clinical trial of patients with advanced breast cancer.

Patient-reported outcomes have been associated with survival in numerous studies across cancer types, including breast cancer. However, the Brief Pain Inventory-Short Form (BPI-SF) and the Rotterdam Symptom Checklist (RSCL) have rarely been investigated in this regard in breast cancer.
Here we describe a post hoc analysis of the prognostic effect of baseline scores of these instruments on survival in a phase III trial of patients with advanced breast cancer who received gemcitabine plus paclitaxel or paclitaxel alone after anthracycline-based adjuvant or neoadjuvant therapy. The variables for this analysis were baseline BPI-SF &quot;worst pain&quot; and BPI-SF &quot;pain interference&quot; scores, and four RSCL subscales (each transformed to 0-100). Univariate and multivariate Cox models were used, the latter in the presence of 11 demographic/clinical variables. Kaplan-Meier curves and log-rank tests were used to compare survival for patients by BPI-SF or RSCL scores.
Of 529 randomized patients, 286 provided BPI-SF data and 336 provided RSCL data at baseline. Univariate analyses identified BPI-SF worst pain and pain interference (both hazard ratios [HR], 1.07 for a 1-point increase; both p ≤ 0.0061) and three of four RSCL subscales [activity level, physical distress, and health-related quality of life (HRQOL) (HR, 0.86-0.91 for 10-point increase all p ≤ 0.0104)], to have significant prognostic effect for survival. BPI-SF worst pain (p = 0.0342) and RSCL activity level (p = 0.0004) were prognostic in the multivariate analysis. Median survival for patients categorized by BPI-SF worst pain score was 23.8 (n = 91), 17.9 (n = 94) and 14.6 (n = 94) months for scores 0, 1-4, and 5-10, respectively (log-rank p = 0.0065). Median survival was 23.8 and 14.6 months for patients (n = 330) with above- and below-median RSCL activity level scores respectively (log-rank p &lt; 0.0001).
Pretreatment BPI-SF worst pain and RSCL activity scores provide distinct prognostic information for survival in patients receiving paclitaxel or gemcitabine plus paclitaxel for advanced breast cancer even after controlling for multiple demographic and clinical factors.
Clinicaltrials.gov, NCT00006459 .

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Chemotherapy induces expression and release of heparanase leading to changes associated with an aggressive tumor phenotype.

High heparanase expression is associated with enhanced tumor growth, angiogenesis, and metastasis in many types of cancer. However, the mechanisms driving high heparanase expression are not fully understood. In the present study, we discovered that drugs used in the treatment of myeloma upregulate heparanase expression. Frontline anti-myeloma drugs, bortezomib and carfilzomib activate the nuclear factor-kappa B (NF-κB) pathway to trigger heparanase expression in tumor cells. Blocking the NF-κB pathway diminished this chemotherapy-induced upregulation of heparanase expression. Activated NF-κB signaling was also found to drive high heparanase expression in drug resistant myeloma cell lines. In addition to enhancing heparanase expression, chemotherapy also caused release of heparanase by tumor cells into the conditioned medium. This soluble heparanase was taken up by macrophages and triggered an increase in TNF-α production. Heparanase is also taken up by tumor cells where it induced expression of HGF, VEGF and MMP-9 and activated ERK and Akt signaling pathways. These changes induced by heparanase are known to be associated with the promotion of an aggressive tumor phenotype. Importantly, the heparanase inhibitor Roneparstat diminished the uptake and the downstream effects of soluble heparanase. Together, these discoveries reveal a novel mechanism whereby chemotherapy upregulates heparanase, a known promoter of myeloma growth, and suggest that therapeutic targeting of heparanase during anti-cancer therapy may improve patient outcome.
Copyright © 2015. Published by Elsevier B.V.

TIGIT Enhances Antigen-Specific Th2 Recall Responses and Allergic Disease.

T cell Ig and ITIM domain receptor (TIGIT), expressed on T, NK, and regulatory T cells, is known as an inhibitory molecule that limits autoimmunity, antiviral and antitumor immunity. In this report, we demonstrate that TIGIT enhances Th2 immunity. TIGIT expression was upregulated in activated Th2 cells from mice with experimental allergic disease and in Th2 polarization cultures. In addition, its high-affinity ligand CD155 was upregulated in mediastinal lymph node dendritic cells from allergic mice. In an in vitro setting, we observed thatTigitexpression in Th2 cells and its interaction with CD155 expressed in dendritic cells were important during the development of Th2 responses. In addition, blockade of TIGIT inhibited Th2, but had no effect on either Th1 or Th17 polarization. In vivo blockade of TIGIT suppressed hallmarks of allergic airway disease, such as lung eosinophilia, goblet cell hyperplasia, Ag-specific Th2 responses, and IgE production, and reduced numbers of T follicular helper and effector Th2 cells. Thus, TIGIT is critical for Th2 immunity and can be used as a therapeutic target, especially in light of recent findings showing TIGIT locus hypomethylation in T cells from pediatric patients with allergic asthma.
Copyright © 2016 by The American Association of Immunologists, Inc.

Activated platelet-T-cell conjugates in peripheral blood of patients with HIV infection: coupling coagulation/inflammation and T cells.

Despite successfully suppressed viremia by treatment, patients with high levels of biomarkers of coagulation/inflammation are at an increased risk of developing non-AIDS defining serious illnesses such as cardiovascular diseases. Thus, there is a relationship between persistent immune activation and coagulation/inflammation, although the mechanisms are poorly understood. Platelets play an important role in this process. Although interactions between platelets and elements of the innate immune system, such as monocytes, are well described, little is known about the interaction between platelets and the adaptive immune system.
We investigated the interaction of a component of the coagulation system, platelets, and the adaptive immune system T cells.
Healthy controls and combination antiretroviral therapy (cART)-treated HIV-infected patients with viral loads of less than 40 copies/ml for more than 15 months were analysed for platelet-T-cell conjugate formation.
Platelets can form conjugates with T cells and were preferentially seen in CD4 and CD8 T-cell subsets with more differentiated phenotypes [memory, memory/effector and terminal effector memory (TEM)]. Compared with healthy controls, these conjugates in patients with HIV infection were more frequent, more often composed of activated platelets (CD42bCD62P), and were significantly associated with the D-dimer serum levels.
These data support a model in which platelet-T-cell conjugates may play a critical role in the fast recruitment of antigen-experienced T cells to the place of injury. This mechanism can contribute in maintaining a state of coagulation/inflammation observed in these patients contributing to the pathology of the disease.

Prognostic impact of KRAS mutant type and MET amplification in metastatic and recurrent gastric cancer patients treated with first-line S-1 plus cisplatin chemotherapy.

Receptor tyrosine kinase (RTK)-related genes, including HER2, EGFR, MET, FGFR2 and KRAS, are target molecules that are clinically beneficial in gastric cancer (GC). We investigated the correlation between RTK-related genes and the curative effect of first-line S-1 plus cisplatin (SP) combination chemotherapy in metastatic and recurrent GC. We enrolled 150 patients with histopathologically confirmed metastatic and recurrent GC treated with SP. KRAS mutation was detected using direct sequencing. DNA copy number was measured by real-time PCR. Formalin-fixed paraffin-embedded specimens were examined immunohistochemically for HER2, EGFR, FGFR2 and MET. Among 144 patients, KRAS mutation was detected in five (3.5%) at codon 12 and one (0.7%) at codon 13. FGFR2, EGFR, HER2, MET and KRAS gene amplification was suggested in 4.4%, 5.9%, 9%, 3.7% and 10.3% of patients, respectively. KRAS mutation, but not KRAS amplification, was associated with significantly shorter overall and progression-free survival. MET membranous overexpression was associated with a significantly higher tumor response. MET amplification was associated with significantly shorter overall survival. We show for the first time that KRAS mutation and MET amplification are promising predictive markers in metastatic and recurrent GC patients treated with SP. KRAS status may be a useful prognostic marker in patients treated with SP.

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Category: Uncategorized

Patient-reported pain and other quality of life domains as prognostic factors for survival in a phase III clinical trial of patients with advanced breast cancer.

Chemotherapy induces expression and release of heparanase leading to changes associated with an aggressive tumor phenotype.

TIGIT Enhances Antigen-Specific Th2 Recall Responses and Allergic Disease.

Activated platelet-T-cell conjugates in peripheral blood of patients with HIV infection: coupling coagulation/inflammation and T cells.

Prognostic impact of KRAS mutant type and MET amplification in metastatic and recurrent gastric cancer patients treated with first-line S-1 plus cisplatin chemotherapy.