Aspirin improves outcome in high risk prostate cancer patients treated with radiation therapy

Purpose High-risk prostate cancer (PC) has poor outcomes due to therapeutic resistance to conventional treatments, which include prostatectomy, radiation, and hormone therapy. Previous studies suggest that anticoagulant (AC) use may improve treatment outcomes in PC patients. We hypothesized that AC therapy confers a freedom from biochemical failure (FFBF) and overall survival (OS) benefit when administered with radiotherapy in patients with high-risk PC.Materials and Methods Analysis was performed on 74 high-risk PC patients who were treated with radiotherapy from 2005 to 2008 at UT Southwestern. Of these patients, 43 were on AC including aspirin (95.6%), clopidogrel (17.8%), warfarin (20%), and multiple ACs (31.1%). Associations between AC use and FFBF, OS, distant metastasis, and toxicity were analyzed.Results Median follow-up was 56.6 mo for all patients. For patients taking any AC compared with no AC, there was improved FFBF at 5 years of 80% vs. 62% (P = 0.003), and for aspirin the FFBF was 84% vs. 65% (P = 0.008). Aspirin use was also associated with reduced rates of distant metastases at 5 years (12.2% vs. 26.7%, P = 0.039). On subset analysis of patients with Gleason score (GS) 9–10 histology, aspirin resulted in improved 5-year OS (88% vs. 37%, P = 0.032), which remained significant on multivariable analysis (P < 0.05).Conclusions AC use was associated with a FFBF benefit in high-risk PC which translated into an OS benefit in the highest risk PC patients with GS 9–10, who are most likely to experience mortality from PC. This hypothesis-generating result suggests AC use may represent an opportunity to augment current therapy.     

Experience With Afatinib in Patients With Non‐Small Cell Lung Cancer Progressing After Clinical Benefit From Gefitinib and Erlotinib

Background.

Afatinib, an irreversible ErbB family blocker, demonstrated superiority to chemotherapy as first-line treatment in patients with EGFR-mutated non-small cell lung cancer (NSCLC). Afatinib is also active in patients progressing on EGFR tyrosine kinase inhibitors (EGFR-TKIs). We report the results of a large cohort of NSCLC patients receiving afatinib within a compassionate-use program (CUP).

Patients and Methods.

Patients with advanced NSCLC progressing after one line or more of chemotherapy and one line or more of EGFR-TKI treatment with either an EGFR mutation or documented clinical benefit were enrolled. Data collection was not monitored or verified by central review. The intention of this CUP was to provide controlled preregistration access to afatinib for patients with life-threatening diseases and no other treatment option.

Results.

From May 2010 to October 2013, 573 patients (65% female; median age: 64 years [range: 28–89 years]) were enrolled, with strong participation of community oncologists. Comorbidities were allowed, including second malignancies in 11% of patients. EGFR mutation status was available in 391 patients (72%), and 83% tested mutation positive. Median time to treatment failure (TTF) of 541 patients treated with afatinib was 3.7 months (range: 0.0 to >29.0 months). Median TTF was 4.0 and 2.7 months in patients with adenocarcinomas and squamous cell carcinomas, respectively, and 4.6 months in patients with EGFR-mutated NSCLC. Adverse events were generally manageable.

Conclusion.

Afatinib was able to be given in a real-world setting to heavily pretreated patients with EGFR-mutated or EGFR-TKI-sensitive NSCLC. Acknowledging the constraints of data collection in a CUP, afatinib appears to be safe and to confer some clinical benefit in this population.     

The Force Cone Method Applied to Explain Hidden Whirls in Tribology

In tribologically loaded materials, folding instabilities and vortices lead to the formation of complex internal structures. This is true for geological as well as nanoscopic contacts. Classically, these structures have been described by Kelvin–Helmholtz instabilities or shear localization. We here introduce an alternative explanation based on an intuitive approach referred to as the force cone method. It is considered how whirls are situated near forces acting on a free surface of an elastic or elastoplastic solid. The force cone results are supplemented by finite element simulations. Depending on the direction of the acting force, one or two whirls are predicted by the simplified force cone method. In 3D, there is always a ring shaped whirl present. These modelling findings were tested in simple model experiments. The results qualitatively match the predictions and whirl formation was found. The force cone method and the experiments may seem trivial, but they are an ideal tool to intuitively understand the presence of whirls within a solid under a tribological load. The position of these whirls was found at the predicted places and the force cone method allows a direct approach to understand the complex processes in the otherwise buried interfaces of tribologically loaded materials.     

Targeting by cmHsp70.1-antibody coated and survivin miRNA plasmid loaded nanoparticles to radiosensitize glioblastoma cells

Nanoparticles (NP) as carriers for anti-cancer drugs have shown great promise. Specific targeting of NP to malignant cells, however, remains an unsolved problem. Conjugation of antibodies specific for tumor membrane antigens to NP represents one approach to improve specificity and to increase therapeutic efficacy. In the present study, for the first time a novel membrane heat shock protein (Hsp70)-specific antibody (cmHsp70.1) was coupled to human serum albumin (HSA) NP, loaded with microRNA (miRNA) plasmids to target the inhibitor of apoptosis protein survivin. The physicochemical properties of monodisperse miRNA-loaded NP showed a diameter of 180 nm to 220 nm, a plasmid incorporation of more than 95% and a surface binding capacity of the antibody of 70–80%. Antibody-conjugated NP displayed an increased cellular uptake in U87MG and LN229 glioblastoma cells compared to isotype control antibody, PEG-coupled controls and peripheral blood lymphocytes (PBL). Survivin expression was significantly reduced in cells treated with the Hsp70-miRNA-NP as compared to non-conjugated NP. Hsp70-miRNA-NP enhanced radiation-induced increase in caspase 3/7 activity and decrease in clonogenic cell survival. In summary, cmHsp70.1 miRNA-NP comprise an enhanced tumor cell uptake and increased therapeutic efficacy of radiation therapy in vitro and provide the basis for the development of antibody-based advanced carrier systems for a tumor cell specific targeting.     

Soluble serum Klotho levels in healthy subjects. Comparison of two different immunoassays

Objective

Soluble serum Klotho is a new biomarker linked to chronic kidney disease, cardiovascular disease and diabetes. This study describes the evaluation and comparison of two different immunoassays and establishment of assay specific reference intervals in adults.

Design and methods

Serum Klotho concentrations were determined in 120 healthy adults aged 19–66 years. Blood samples were collected, and stored sera were assayed for Klotho according to age and gender. In addition several other clinical and laboratory characteristics were determined in the cohort and compared to the levels of serum Klotho.

Results

Serum Klotho levels were significantly higher in time-resolved fluorescence immunoassay (TRF) compared to an ELISA (IBL) and no correlation was found between the assays. No signal was obtained in either assay when the standard curve was switched between the two different immunoassays. The median serum Klotho concentration using TRF was 61 ng/mL (2.5–97.5% reference limits; 11–181 ng/mL) for males and 99 ng/mL (2.5–97.5% reference limits; 19–316 ng/mL) for females while the ELISA gave a mean value of 472 pg/mL (2.5–97.5% reference limits; 204–741 pg/mL) with no difference between genders. Concentrations of serum Klotho were independently associated with estimated glomerular filtration rate (eGFR) and body weight using TRF whereas serum Klotho concentrations were associated with age using the ELISA.

Conclusion

Comparison of two different immunoassays for serum Klotho indicate, that the protein exists in human beings in different forms which may function as independent factors and whose role and potential value as biomarkers needs to be evaluated separately. Reference intervals specific for the different forms recognized by the different assays were calculated in this study.     

Flow‐mediated vasodilatation: variation and interrelationships with plasma lipids and lipoproteins

Objective. Endothelial dysfunction is a critical, prerequisite step in atherosclerosis, and may be evaluated by flow‐mediated vasodilatation (FMD). The objective of this study was to examine interrelationships between FMD and plasma lipids and lipoproteins, and to determine the between‐operator and within‐subject variability associated with this technique. Material and methods. FMD, plasma lipids and lipoproteins, including small dense LDL (sdLDL), were measured twice in 40 healthy volunteers, 4 weeks apart. Interrelationships between mean FMD responses and plasma lipids and lipoproteins were examined by correlation analysis. FMD measurements were taken by two independent operators, allowing determination of between‐operator variability. Within‐subject variability was determined by obtaining two measurements, 4 weeks apart, in every subject, and carried out by the same operator. Results. FMD was inversely related to plasma triglycerides (r = ?0.47, p = 0.002), total cholesterol/HDL cholesterol (r = ?0.35, p = 0.03) and apolipoprotein B (r = ?0.36, p = 0.02), but not to other plasma lipids and lipoproteins. When measuring variation in FMD, the following results were found: Between operators (SD = 4.0?FMD%) and within subjects (SD = 2.9?FMD%). Conclusions. The associations between FMD, plasma triglycerides and apoB provide evidence supporting a role for triglyceride‐rich lipoproteins in endothelial dysfunction.     

Characteristics of the respiratory mechanical and muscle function of competitive breath-hold divers

Competitive breath-hold divers (BHD) employ glossopharyngeal insufflation (GI) to increase intrapulmonary oxygen stores and prevent the lungs from dangerous compressions at great depths. Glossopharyngeal insufflation is associated with inflation of the lungs beyond total lung capacity (TLC). It is currently unknown whether GI transiently over-distends the lungs or adversely affects lung elastic properties in the long-term. Resting lung function, ventilatory drive, muscle strength, and lung compliance were measured in eight BHD who performed GI since 5.5 (range 2–6) years on average, eight scuba divers, and eight control subjects. In five BHD subsequent measures of static lung compliance (Cstat) were obtained after 1 and 3 min following GI. Breath-hold divers had higher than predicted ventilatory flows and volumes and did not differ from control groups with regard to gas transfer, inspiratory muscle strength, and lung compliance. A blunted response to CO₂ was obtained in BHD as compared to control groups. Upon GI there was an increase in mean vital capacity (VC_GI) by 1.75 ± 0.85 (SD) L compared to baseline (p < 0.001). In five BHD Cstat raised from 3.7 (range 2.9–6.8) L/kPa at baseline to 8.1 (range 3.4–21.2) L/kPa after maximal GI and thereafter gradually decreased to 5.6 (range 3.3–8.1) L/kPa after 1 min and 4.2 (range 2.7–6.6) L/kPa after 3 min (p < 0.01). We conclude that in experienced BHD there is a transient alteration in lung elastic recoil. Resting lung function did not reveal a pattern indicative of altered lung ventilatory or muscle function.