Radioprotective effect of amifostine on cells from cancer prone patients and healthy individuals studied by the G2 and PCC assays

Purpose: To investigate whether amifostine is effective at reducing the yield of chromatid breaks when present during G₂‐phase irradiation of human normal cells and cells from cancer prone patients, as well as to study the mechanisms underlying the radioprotective effect of amifostine.

Materials and methods: G₂ chromosomal radiosensitivity in the presence or absence of amifostine was studied in healthy donors, cancer patients, ataxia‐telangietasia (A‐T) patients and five human lymphoblastoid cell lines with genes predisposing to cancer. The yield of chromatid breaks following γ‐irradiation in G₂ phase was obtained at the subsequent metaphase using the G₂ assay. For scoring chromatid damage directly in G₂ or G₀ phase, premature chromosome condensation was used.

Results: When amifostine was present during irradiation, the mean yield of radiation‐induced chromatid breaks as visualized by the G₂ assay was significantly reduced in healthy donors (t‐test, p=0.001), in cells from cancer patients (p=0.001) and in cell lines from patients with genes predisposing to cancer (p=0.01) except ATM^?/? (0.1<p<0.2). However, when chromatid breaks were scored directly in G₂ or G₀ phase using premature chromosome condensation, the presence of amifostine did not affect the yields obtained.

Conclusion: Amifostine reduces the mean yield of chromatid breaks in normal cells and in cells from cancer prone patients when present during G₂ irradiation. Although the precise mechanisms of radioprotection caused by amifostine remain unclear, the results obtained using premature chromosome condensation reveal that amifostine does not act on cells only as a free radical scavenger and as a repair enhancer of DNA damage.     

Measurement of body fat by dual-energy X-ray absorptiometry and bioimpedance analysis in men with prostate cancer

OBJECTIVE: The aims of this study were to determine the percentage of body fat (%BF) by dual-energy x-ray absorptiometry (DXA) and bioelectrical impedance analysis (BIA) using a standard adult equation and BIA using a standard geriatric equation in a population of older men with prostate cancer and to compare the results from these different methods. METHODS: We conducted a cross-sectional study in 38 men with locally advanced, node-positive, or recurrent prostate cancer and no history of androgen-deprivation therapy. Body composition was evaluated by DXA with the use of a Hologic 4500A densitometer and BIA. BIA %BF was calculated by using standard equations developed for adult and geriatric populations. RESULTS: %BF by DXA, BIA with the standard adult equation, BIA with the standard geriatric equation, and BIA with the age-appropriate equation were 26.7 +/- 5.3%, 22.5 +/- 5.6%, 38.2 +/- 6.9%, and 35.4 +/- 9.6%, respectively. There were statistically significant differences between %BF by DXA and all BIA estimates. By using the methods described by Bland and Altman (Lancet 1986;1(8476):307), the standard adult equation showed the least bias and variability. CONCLUSIONS: In this group of men with prostate cancer, BIA with the standard adult equation provided a reasonable estimate of %BF compared with DXA, although the differences were statistically significant. BIA with the standard geriatric equation, however, markedly overestimated %BF compared with DXA, even when its use was restricted to elderly men.     

Association of rectal toxicity with thermal dose parameters in treatment of locally advanced prostate cancer with radiation and hyperthermia

PURPOSE: Although hyperthermia has been used for more than two decades in the treatment of pelvic tumors, little is known about the potential impact of heat on rectal toxicity when combined with other treatment modalities. Because rectal toxicity is a concern with radiation and may be exacerbated by hyperthermia, definition of the association of thermal dose parameters with rectal toxicity is important. In this report, we correlate rectal toxicity with thermal dose parameters for patients treated with hyperthermia and radiation for prostate cancer. METHODS AND MATERIALS: Thirty patients with T2b-T3b disease (1992 American Joint Committee On Cancer criteria) enrolled in a Phase II study of external beam radiation +/- androgen-suppressive therapy with two transrectal ultrasound hyperthermia treatments were assessed for rectal toxicity. Prostatic and anterior rectal wall temperatures were monitored for all treatments. Rectal wall temperatures were limited to 40 degrees C in 19 patients, 41 degrees C in 3 patients, and 42 degrees C in 8 patients. Logistic regression was used to estimate the log hazard of developing National Cancer Institute Common Toxicity Criteria Grade 2 toxicity based on temperature parameters. The following were calculated: hazard ratios, 95% confidence intervals, p values for statistical significance of each parameter, and proportion of variability explained for each parameter. RESULTS: Gastrointestinal toxicity was limited to Grade 2. The rate of acute Grade 2 proctitis was greater for patients with an allowable rectal wall temperature of >40 degrees C. In this group, 7 of 11 patients experienced acute Grade 2 proctitis, as opposed to 3 of 19 patients in the group with rectal wall temperatures limited to 40 degrees C (p = 0.004). Preliminary assessment of long-term toxicity revealed no differences in toxicity. Hazard ratios for acute Grade 2 proctitis for allowable rectal wall temperature, average rectal wall Tmax, and average prostate Tmax were 9.33 (p = 0.01), 3.66 (p = 0.03), and 2.29 (p = 0.08), respectively. A model combining these three parameters explained 48.6% of the variability among groups. CONCLUSION: Rectal toxicity correlates with maximum allowable rectal wall temperature, average rectal wall Tmax, and average prostate Tmax for patients undergoing transrectal ultrasound hyperthermia combined with radiation for treatment of advanced clinically localized prostate cancer. Further definition of this association of thermal dose parameters with rectal toxicity in treatment of pelvic malignancies with hyperthermia should advance the goal of delivering thermal therapy in an effective yet safe manner.     

The Patterns of Non-vitamin K Antagonist Oral Anticoagulants (NOACs) Use in Patients with Atrial Fibrillation in Seven Balkan Countries: a Report from the BALKAN-AF Survey

Introduction

Data on management of atrial fibrillation (AF) in the Balkan Region are scarce. To capture the patterns in AF management in contemporary clinical practice in the Balkan countries a prospective survey was conducted between December 2014 and February 2015, and we report results pertinent to the use of non-vitamin K antagonist oral anticoagulants (NOACs).

Methods

A 14-week prospective, multicenter survey of consecutive AF patients seen by cardiologists or internal medicine specialists was conducted in Albania, Bosnia and Herzegovina, Bulgaria, Croatia, Montenegro, Romania, and Serbia (a total of about 50 million inhabitants).

Results

Of 2712 enrolled patients, 2663 (98.2%) had complete data relevant to oral anticoagulant (OAC) use (mean age 69.1 ± 10.9 years, female 44.6%). Overall, OAC was used in 1960 patients (73.6%) of whom 338 (17.2%) received NOACs. Malignancy [odds ratio (OR), 95% confidence interval (CI) 2.06, 1.20–3.56], rhythm control (OR 1.64, 1.25–2.16), and treatment by cardiologists were independent predictors of NOAC use (OR 2.32, 1.51–3.54) [all p < 0.01)], whilst heart failure and valvular disease were negatively associated with NOAC use (both p < 0.01). Individual stroke and bleeding risk were not significantly associated with NOAC use on multivariate analysis.

Conclusions

NOACs are increasingly used in AF patients in the Balkan Region, but NOAC use is predominantly guided by factors other than evidence-based decision-making (e.g., drug availability on the market or reimbursement policy). Efforts are needed to establish an evidence-based approach to OAC selection and to facilitate the optimal use of OAC, thus improving the outcomes in AF patients in this large region.

     

Comparison of dengue-1 virus envelope glycoprotein gene sequences from French Polynesia

Dengue (DEN) is the leading arboviral infection of humans, with 100 million cases annually in the tropical areas of the world. The recent severe DEN-1 epidemic in French Polynesia in 2001, with an incidence rate of 16% and more than 45% of the cases with dengue hemorrhagic fever/dengue shock syndrome among 1,400 hospitalized children and eight fatalities, led us to study this new circulating strain. The entire envelope (E) gene of two French Polynesian DEN-1 virus isolates from the two epidemics of 1988-1989 (FP89) and 2001 (FP01) were sequenced and compared with 29 published DEN-1 virus E gene sequences. Phylogenetic relationships showed that the FP89 strain belonged to genotype V and the FP01 strain to genotype IV based on studies on the same region of DEN-1 virus genome (1,485 nucleotides). The recent dengue epidemic in French Polynesia in 2001 was probably due to the introduction of a new DEN-1 virus from Southeast Asia, since the minimum nucleotide divergence was 3.3% with A88, the Indonesian strain isolated in 1988 in Jakarta.     

Interferon lambda1/IL‐29 and inorganic polyphosphate are novel regulators of neutrophil‐driven thromboinflammation

Neutrophils and neutrophil‐released meshwork structures termed neutrophil extracellular traps (NETs) are major mediators of thromboinflammation and emerging targets for therapy, yet the mechanisms and pathways that control the role of neutrophils in thromboinflammation remain poorly understood. Here, we explored the role of IFN‐λ1/IL‐29, a major antiviral cytokine recently shown to suppress the neutrophil migratory capacity, in prothrombotic and proNETotic functions of neutrophils. In an ex vivo human experimental setting of acute ST‐segment elevation myocardial infarction (STEMI), we show that IFN‐λ1/IL‐29 hinders NET release and diminishes the amount of cytoplasmic TF in neutrophils. Since platelet–neutrophil interaction plays a major role in NET‐induced thromboinflammation, we further studied how IFN‐λ1/IL‐29 may interrupt this interaction. In this context, we identified inorganic polyphosphate (polyP) as a platelet‐derived NET inducer in STEMI. In arterial STEMI thrombi, polyP was present in platelets and in close proximity to NET remnants. PolyP release from activated platelets was dependent on thrombin present in infarcted artery plasma, resulting in NET formation by promoting mTOR inhibition and autophagy induction. The effect of polyP on mTOR inhibition was counteracted by IFN‐λ1/IL‐29 treatment, leading to inhibition of NET formation. Consistently, we show in an in vivo model of FeCl₃‐induced arterial thrombosis that IFN‐λ2/IL‐28A exerts strong antithrombotic potential. Taken together, these findings reveal a novel function of IFN‐λ1/IL‐29 in the suppression of thromboinflammation. Copyright © 2017 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.     

Failure of Intracardiac Pacing After Fatal Propafenone Overdose: A Case Report

Background

Propafenone is a sodium-channel blocker, class IC antiarrhythmic drug, frequently used to manage supraventricular dysrhythmias, especially atrial fibrillation. We report a self mono-intoxication with propafenone.

The moderating role of job resources in the relationship between job demands and interleukin‐6 in an Italian healthcare organization

In this study we examined the association between job demands (JD), job resources (JR), and serum levels of a possible biomarker of stress, the pro‐inflammatory cytokine interleukin‐6 (IL‐6). According to the buffer hypothesis of the Job Demands‐Resources (JD‐R) model, we expected that job resources—defined as job autonomy and social support from supervisor—might buffer the relationship between job demands, defined as emotional demands and interpersonal conflict with colleagues, and IL‐6. Data from 119 employees in an Italian public healthcare organization (acute care hospital) were analyzed using multiple regression. In predicting IL‐6, the interactions between emotional demands and JR and between interpersonal conflict with colleagues and job autonomy (but not social support) were significant, after controlling for the effect of age and gender. The association between JD and IL‐6 was stronger for individuals with low levels of JR, so that levels of IL‐6 were highest when JD were high and JR were low. Overall, these results are consistent with the buffer hypothesis of the JD‐R model and also extend previous research, showing that the exposure to stressful situations at work, measured as high JD and low JR, is associated with higher levels of IL‐6 in hospital employees.     

Phase II study of low dose and high dose conjugated estrogen for androgen independent prostate cancer

PURPOSE: Although estrogens have known antitumor activity in androgen independent prostate cancer, the best studied agent, diethylstilbestrol, is no longer commercially available in the United States. We tested 2 doses of the conjugated estrogen Premarin(R) in patients with androgen independent prostate cancer to determine the efficacy and safety of this widely available medication. MATERIALS AND METHODS: A total of 45 patients with progressive androgen independent prostate cancer were randomly assigned to receive Premarin 1.25 mg once (17) or 3 times (28) daily. Warfarin 1 mg daily was administered to all patients to minimize risk of thromboembolism. Low dose prophylactic breast irradiation was administered to most patients. RESULTS: Of the patients receiving high dose Premarin 25% achieved a 50% or greater reduction in prostate specific antigen. No patients treated with low dose Premarin reached a 50% reduction in prostate specific antigen. After 3 months of treatment, 11 patients (39.3%) on the high dose arm and 6 patients (35.3%) on the low dose arm showed no signs of progression. Three patients (6.7%) had a thromboembolic event. No significant gynecomastia was noted. A significant difference in dehydroepiandrosterone sulfate levels was detected between those who did and did not respond to Premarin (p = 0.03). CONCLUSIONS: High dose Premarin resulted in prostate specific antigen decreases of 50% or greater in 25% of patients with androgen independent prostate cancer. More than a third of patients receiving high or low dose Premarin maintained stable disease for at least 3 months. With concurrent warfarin 1 mg treatment, 6.7% experienced thromboembolic complications. Premarin 1.25 mg 3 times daily is a reasonable therapeutic option for patients with androgen independent disease.     

A phase II trial of doxorubicin and gemcitabine in renal cell carcinoma with sarcomatoid features: ECOG 8802

Sarcomatoid features can arise in renal cell carcinoma of any subtype and are associated with a poor prognosis. Doxorubicin and gemcitabine in a limited series showed activity in aggressive renal tumors and we wished to formally assess the combination in patients with renal cell carcinoma specifically containing sarcomatoid features. The Eastern Cooperative Oncology Group (ECOG) conducted a phase II trial of doxorubicin 50 mg/m² IV push and gemcitabine 1,500 mg/m² IV over 30 min every 2 weeks in 39 patients with locally advanced or metastatic renal cell carcinoma with sarcomatoid features. Ten patients (26%) had grade 3 toxicity, and four patients (11%) had grade 4 toxicities. Although most toxicity was from myelosuppression, one patient died on study from cardiac dysfunction after a cumulative dose of 450 mg/m² doxorubicin. Six (16%) patients experienced responses (5 partial responses and 1 complete response), and ten (26%) patients had stable disease. In addition, another patient had an unconfirmed partial response and an additional patient experienced over 50% decrease in her tumor burden after an initial progression. The median overall survival was 8.8 months, and the median progression-free survival was 3.5 months. We conclude that the combination of doxorubicin and gemcitabine, inactive in patients with mostly clear cell histology, demonstrated responses in patients with RCC with sarcomatoid features. We acknowledge the toxicity of this combination but note that limited treatment options exist for this aggressive histology. Only through prospective multicenter trials with comprehensive central pathology review will better treatment options be identified.