PTX Treatment of Colon Cancer: Mode of Action Based on Tumor Marker and Cytokine Kinetics.

BACKGROUND/AIM: Cancer progression is associated with significant cachexia-induced weight loss and stomatitis. Pentoxifylline (PTX) is a drug shown to have beneficial anti-inflammatory effects in cancer patients, mainly through anti-TNFα mechanisms. This study determined the PTX effects and mode of action on weight-loss, stomatitis, and survival in colon cancer patients treated with chemotherapy, examining the kinetics of tumor markers and cytokine levels. PATIENTS AND METHODS: Forty patients with metastatic colon cancer receiving chemotherapy, were randomized in this study. Seventeen patients were assigned to the treatment group - 8 received a full PTX dose (400 mg TID) and 9 a reduced dose (200 mg TID). Results were compared to 23 untreated, control patients. Blood analysis of tumor markers (CEA and TPS), inflammatory cytokines (IL-1ß, IL-6, IL-8, TNFα, TNF-R), CRP and sIL-2R, were performed. Additionally, clinical parameters were assessed. RESULTS: Patients treated with PTX (full/reduced doses), gained significant weight, and experienced a reduction in stomatitis, resulting in multiple beneficial effects, including improved life quality. Significant reductions in CRP, sIL-2R, and inflammatory cytokine levels, correlated to increases in weight and a reduction in stomatitis. A similar pattern was observed in tumor marker levels, where decreasing levels were correlated with weight gain and reduction in inflammatory cytokine levels. CONCLUSION: Colon cancer patients receiving PTX with chemotherapy, experienced weight gain and reduced stomatitis occurrence. Beneficial PTX effects were correlated to significant decreases in patient inflammatory cytokines and tumor marker levels, probably due to PTX mode of action.

Effect of irradiation on cytokine production in cancer patients.

BACKGROUND: Irradiation, which affects cytokine secretion, is used to treat cancer patients. Cytokine levels have correlations to disease parameters, serving as biomarkers for patients. We aim to explore the effect of irradiation on cytokine production both in vitro (using lymphocytes from healthy donors) and in vivo (using serum levels of head and neck cancer patients following irradiation) and correlating them to mucositis severity/need for percutaneous endoscopic gastroscopy (PEG) tube installation. METHODS: Cytokine production by cultured lymphocytes from healthy donors, in vitro, following irradiation of 5 or 10 Gy. In addition, blood from 23 patients with head and neck cancers, irradiated by 60-72G in vivo, were assessed for inflammatory cytokines (tumor necrosis factor (TNF)α, interleukin (IL)-6, IL-8, IL-18), the anti-inflammatory cytokine IL-10, and the general marker sIL-2R. Following radiation, selected patients who were developing mucositis were treated by PEG tube installation. Changes in cytokine levels were studied as predictive biomarkers of response to therapy/PEG tube installation. Cytokine production levels were measured using ELISAs kits. RESULTS: Irradiation decreased the levels of all tested cytokines, most notably IL-6 and IL-8, proportional to irradiation dose. In patients, increases in cytokine levels, correlated with mucositis severity and potentially the need for PEG tube installation. CONCLUSIONS: Irradiation decreased the levels of all cytokines of healthy lymphocytes in a dose-dependent manner, especially those of IL-6 and IL-8. This study shows a correlation between high and increasing levels of inflammatory cytokines, sIL-2R, plus radiation toxicity and the need for PEG. The reduction of cytokine levels after radiotherapy predicts that PEG will not be required. Thus, our study shows that cytokine changes are predictive biomarkers in head and neck cancer patients.

sIL-2R- an Immuno-biomarker for Prediction of Metastases in Uveal Melanoma.

BACKGROUND/AIM: Uveal melanoma (UM) is the most common primary intraocular malignancy in adults. High serum levels of soluble IL-2 receptor (sIL-2R) have been reported in acute inflammations and metastatic cancers. This study evaluated the potential of high/increasing sIL-2R levels in predicting metastases. PATIENTS AND METHODS: The study included a total of 1,546 sera samples of subjects from three groups: 119 healthy controls (73 subjects), 566 UM 10 year (10y) disease-free (DF) (220 patients), 861 metastatic UM (268 patients). Patients were followed-up biannually with liver ultrasound and liver function tests for the presence of metastases (Mets). Blood samples to measure the levels of sIL-2R were obtained at the time of primary diagnosis, soon after initial treatment (enucleation, brachytherapy), every 6 months, 10 years from diagnosis, at Mets confirmation by CT, and after additional treatments. RESULTS: Significantly higher sIL-2R levels were detected in the Mets patients compared to healthy controls and 10y DF patients. Compared to the upper limit of the normal levels of sIL-2R, 1,000 U/ml, its levels in metastatic UM were 61%, 25% in 10y DF UM, and 6.25% in the controls. High levels of sIL-2R in metastatic patients, decreased significantly post treatments. Individual kinetics of markers, indicated similar trends of sIL-2R compared to osteopontin and S-Protein 100, predicting metastases, which were confirmed on liver imaging. CONCLUSION: Significantly higher sIL-2R levels were evident in all UM patients with Mets. Significant increases in sIL-2R levels on serial evaluations indicated and predicted UM Mets, enabling earlier treatment of Mets, to improve survival.

Effect of pentoxifylline on colon cancer patients treated with chemotherapy (Part I).

BACKGROUND: Cancer progression is associated with significant systemic clinical manifestations including cachexia induced weight loss and anorexia. Pentoxifylline (PTX) is a drug that has been shown to have multiple beneficial effects in cancer patients through its anti-inflammatory properties. MAIN OBJECTIVE: To evaluate PTX effects on colon cancer patients treated with chemotherapy. PATIENTS AND METHODS: Forty metastatic colon cancer patients receiving chemotherapy were enrolled in this randomized study. 17 patients were treated with a full dose of PTX (400 mg TID), 9 patients with a reduced dose PTX (200 mg TID) and 23 served as controls (no PTX). RESULTS: Follow-up evaluations of patients included the following: physical examination; leukopenia determination; weight determination; stomatitis determination; and survival rate. Patients treated with PTX (both full and reduced doses), experienced a significant increase in weight and a reduction in stomatitis relative to the control group. Treatment with PTX also significantly increased patient survival rate. All patients treated with PTX, had a median overall survival (OS) rate of 20.4 months as compared to 13.2 months in the control group. CONCLUSIONS: PTX treatment of colon cancer patients, in addition to chemotherapy, significantly improved survival rates, induced weight gain and reduced stomatitis occurrence -all important parameters of cachexia.

Clinical Applicability of the Proliferation Marker Thymidine Kinase 1 in Head and Neck Cancer Patients.

BACKGROUND/AIM: Prognostic factors serve as a vital tool in the treatment of patients with head and neck cancer (HNC). The aim of this study was to evaluate the clinical potential of Thymidine-kinase-1 (TK1) marker in the prognosis of HNC patients. PATIENTS AND METHODS: We evaluated 366 blood samples from 278 HNC patients and 88 healthy controls, using an ELISA assay. Correlations of TK1 levels with disease stage, lymph node involvement and response to radiation therapy, were determined. RESULTS: In HNC patients, TK1 levels were significantly higher compared to healthy controls. Significantly higher TK1 levels were demonstrated in node positive cases and in advanced disease stages compared to node negative and early disease stages. Levels were higher prior to radiation and decreased significantly thereafter, in patients responding to treatment. Increasing levels of TK1 post-radiation were indicative of recurrence or of non-response to treatment, while decreasing levels indicated a positive response. CONCLUSION: TK1 is a tumor marker in HNC patients with the ability to assess response to therapy. High or increasing levels correlated to a poor prognosis, whereas low levels correlated to an overall increased survival.

Non-invasive Detection of Bladder Cancer by UBC Rapid Test, Ultrasonography and Cytology.

BACKGROUND/AIM: There is a need to diagnose early bladder cancer by non-invasive tests. This study aimed to explore the clinical value of three non-invasive methods, UBC Rapid, ultrasound (US), and urine cytology, separately and in combination, for the primary diagnosis and surveillance of bladder-cancer. PATIENTS AND METHODS: Urine samples were obtained from 106 patients who presented with symptoms of bladder cancer and patients followed-up after transurethral resection of bladder tumors (TURB). Each patient underwent US, cystoscopy, cytology and UBC Rapid test. The sensitivity and specificity of all methods and combinations were calculated and related to cystoscopy and biopsy. RESULTS: Voided urine samples assayed with UBC Rapid and cytology yielded a sensitivity and specificity of 58.3% and 75.9%, and 57.1% and 98.0%, respectively and for US 76.2% and 98.1%. The combination of all three methods resulted in a sensitivity and specificity of 95.8% and 67.3%, and the combination of UBC Rapid and US, gave a sensitivity of 91.3%, and a specificity of 72.2%, The combination of UBC Rapid and cytology yielded a sensitivity and specificity of 84.6% and 71.2%. CONCLUSION: Combined use of UBC Rapid, US and cytology improved the sensitivity of bladder cancer detection.

The Use of Immunotherapy to Treat Metastatic Breast Cancer.

This article reviews the principal attempts of immune-modulation or immune therapy in metastatic breast cancer. It considers their rationale and reports on results from the relevant key clinical trials. Immune-modulatory or immune-stimulating cytokines used alone or combined with conventional therapies is among the principal approaches of immune manipulation in breast cancer. As this issue has recently been reviewed by us, the aim of the current article is to discuss our updated and unpublished data on this topic. Overall survival in luminal (28 patients) and non-luminal (9 patients) molecular subtypes is 91 and 59 months respectively that is about two and half or three times longer than expected. Thereafter, we focus on monoclonal antibodies (mAb) based-therapies including novel strategies to overcome resistance to anti-HER2 mAb. The main vaccine platforms in different molecular subtypes and immune therapies in triple negative metastatic breast cancer (m-TNBC) are discussed in the last sections. Some phase III investigations have already changed the current clinical practice. In fact, pertuzumab plus trastuzumab and docetaxel is the recommended first line regimen in HER2 positive locally recurrent or metastatic breast cancer and bevacizumab plus paclitaxel or docetaxel is a reasonable option for m-TNBC. In some other observational or phase I/II studies on first-line trastuzumab plus chemotherapy and hormonal therapy and in that on HER2 peptide/protein vaccines promising although preliminary findings have been reported to be further validated. In the remaining studies, results were disappointing. In the future, finding new predictive biomarkers and exploring more suitable synergizing combinations, time and dose-dependent-scheduled sequences of currently and further investigated immunological approaches are main challenges.

An individual reference limit of the serum CEA-TPA-CA 15-3 tumor marker panel in the surveillance of asymptomatic women following surgery for primary breast cancer.

PURPOSE: The purpose of this study was to evaluate the combined measurement of serum CEA, TPA, and CA 15-3, using an individual reference limit (IRL), for predicting distant metastases in asymptomatic women following a diagnosis of primary breast cancer. METHODS: A total of 231 patients were followed up for a mean of 5.5±1.6 years. An IRL for defining critical changes (CCs) in marker levels was used as a warning signal of pending distant metastases. RESULTS: Sensitivity, specificity, and accuracy of the combined CEA-TPA-CA 15-3 marker panel for predicting patient outcome were 95.2%, 97.8%, and 97.9%, respectively. In all, 19 (8.3%) patients relapsed with a mean lead time to radiological evidence of metastases of 11.7±13.8 months. CONCLUSION: We concluded that the combined measurement of CA 15-3, CEA, and TPA using an IRL for determining the CC in markers levels is an accurate strategy for predicting outcome during postoperative monitoring of asymptomatic breast cancer patients. Whether the early prediction of metastasis and subsequent administration of therapy impacts on patient outcome should now be the objective of a prospective clinical trial. The marker panel described here could serve as the basis for such a trial.

The relationship between serum cytokine levels and degree of psychosis in patients with schizophrenia.

Several observations indicate that cytokine concentrations might also relate to the severity of the psychosis. In this study we assessed whether inflammatory and anti-inflammatory cytokine concentrations are associated with the degree of the psychotic manifestations. A group of 41 patients with schizophrenia suffering from an acute psychosis leading to hospitalization in a psychiatric ward were assessed for the intensity of their psychotic manifestations by the PANSS score. Serum IL-2R, IL-6, IL-8, IL-10 were analyzed by commercial ELISA kits. These patients were compared to controls without schizophrenia. At the univariate analysis, statistically significant elevated levels of the cytokines IL-6, IL-2R and IL-8 were detected in the sera of the patients with schizophrenia compared to controls. At the multivariate analysis, statistically significance held only for IL-2R concentration. Furthermore, positive correlation was found between symptom severity as measured by the PANSS and IL-6 levels as well as IL-2R levels. In Conclusion, our data indicate that elevated serum concentrations of IL-6, IL-8 and IL-2R are associated with severe clinical symptoms measured by the total, general, negative and positive scores of the PANSS scale.

Exploring the potential of mucin 13 (MUC13) as a biomarker for carcinomas and other diseases.

BACKGROUND: Mucin 13 (MUC13) is a cell surface glycoprotein aberrantly expressed in a variety of epithelial carcinomas. Thus far, the role of MUC13 in various diseases remains elusive. To the best of our knowledge, this is the first study to examine the potential of MUC13 as a serum biomarker in a variety of carcinomas and other conditions. METHODS: We developed a recombinant MUC13 protein, mouse monoclonal antibodies and enzyme immunoassay (ELISA) for MUC13. We used this assay to measure MUC13 levels in the supernatants of cancer cell lines and a large cohort of serum samples from healthy and diseased individuals. RESULTS: MUC13 is secreted from cancer cell lines, with highest levels found in ovarian cancer cell lines. MUC13 levels in human sera were significantly increased in patients with renal failure and 20%-30% of patients with ovarian, liver, lung and other cancers. MUC13 was also elevated in 70% of patients with active cutaneous melanoma, but not uveal melanoma. Furthermore, we identified significant MUC13 elevations in the serum of patients with vasculitis (ANCA-positive) autoantibodies, but not in those with inflammatory bowel disease. CONCLUSIONS: Serum MUC13 is frequently elevated not only in a variety of malignant cases but also in some benign pathologies, thus appearing to be a non-specific disease biomarker. Nonetheless, serum MUC13 is clearly highly elevated in some carcinoma patients, and its relationship with tumor progression in this context warrant further research. Future studies that examine the correlation between serum MUC13 levels to stage of cancer could elucidate prognostic potential.

[SERUM CYTOKINE CONCENTRATIONS ASSOCIATION WITH THE SEVERITY OF SYMPTOMS IN MAJOR DEPRESSION].

BACKGROUND: Mounting data are indicating that major depression is related to diverse functions of the immune system. Several observations indicate that cytokine concentrations might also relate to the intensity of depressive manifestations. In this study we assessed whether inflammatory and anti-inflammatory cytokine concentrations are associated with the intensity of the depressive features in a cohort of patients with major depression and in healthy normal controls. METHODS: A group of 25 patients with major depression all suffering from an acute deterioration of their mental status and all hospitalized in a psychiatric ward were assessed for the intensity of their depressive manifestations according to the Hamilton rating scale for depression and by the clinical global impression scale (CGI). In parallel, concentrations of serum IL-2R, IL-6, IL-8, IL-10 were analyzed by commercial ELISA kits. As comparators, a group of 25 healthy controls was analyzed. RESULTS: The levels of IL-6 were higher among patients with depression. A high degree of correlation was found between the scores measured by the Hamilton and CGI scales by which the intensity of depressive symptoms were ranked. Interestingly, within the group of patients with depression a negative correlation was detected between the IL-6 concentrations and the CGI scores while a positive correlation was found between the IL-10 concentration and IL-6 concentration. CONCLUSIONS: Our data indicate that the patients with depression differ from healthy individuals by their cytokine profile. Within this group of patients depressive features have a specific pattern and linkage to inflammatory and anti-inflammatory scores.

The Diagnostic and Prognostic Value of sIL-2R as an Immune Biomarker in Head and Neck Cancers.

BACKGROUND/AIM: Head and neck cancer (HNC) patients are usually diagnosed with advanced disease and multimodality therapies are required, as well as prognostic biomarkers to predict their response and assess survival. In this study, we aimed to evaluate the ability and clinical significance of the immune biomarker sIL-2R in HNC patients, to assess therapy response and prognosis. MATERIALS AND METHODS: We evaluated 328 blood samples from 145 head and neck cancer patients (HNC) from several subgroups: 84 larynx carcinomas pre- and 39 post-therapy, 46 oral cavity carcinomas pre- and 29 post-therapy, 12 nasopharynx carcinomas, 16 parotid and other salivary gland carcinoma patients. The control group included 45 healthy subjects. Serum sIL-2R levels were evaluated by ELISA assays and correlated to disease stage, lymph nodes, response to therapy, survival and cancer differentiation. RESULTS: Significantly higher sIL-2R levels were recorded in all HNC patients, as opposed to controls, in advanced versus early-stage disease that decreased following therapy. sIL-2R distinguished best, in comparison to other tumor markers, between HNC patients and controls. Survival was strongly associated to lower sIL-2R levels in patients entering the study. CONCLUSION: sIL-2R is a sensitive immune marker for HNC patients. Its levels correlate to disease stage, assess response to therapy and are predictive of recurrence or better survival. We suggest, therefore, using sIL-2R as a reliable prognostic marker in HNC patients as a single marker, or in a combined panel of biomarkers.

Assessing Response to New Treatments and Prognosis in Melanoma Patients, by the Biomarker S-100ß.

BACKGROUND/AIM: Malignant melanoma incidence is increasing over the last years, while mortality is strongly decreasing due to improved early detection, close monitoring of patients including disease biomarkers as well as introduction of new therapies. The aim of the present study was to evaluate biomarkers, mainly S-100ß in melanoma patients, regarding its ability to assess treatment response, especially to new immunotherapies (anti-BRAF, ipilimumab, anti-PD-1) and evaluation of prognosis of those patients. PATIENTS AND METHODS: We evaluated both retrospectively and prospectively 137 malignant melanoma patients. Blood biomarker levels were evaluated by conventional ELISA assays. Correlations of marker levels to disease stage, metastases, response to new immunotherapies and survival, were performed. RESULTS: Serum levels of biomarkers, mainly S-100ß, were significantly higher in all patients before various therapies were applied (5.1+0.7 µg/L) and decreased thereafter (1.3+0.4 µg/L). Significantly higher levels of S-100ß were demonstrated in advanced disease including metastases, (5.95+0.62 µg/L) as opposed to early disease (0.32+0.06 µg/L) and NED patients (0.18+0.03 µg/L). When comparing melanoma deceased patients who had extremely high levels of S-100ß, (2.2+0.45 µg/L) we showed significantly lower levels in alive patients (0.26+0.02 µg/L) and certainly in normal controls (0.07+0.02 µg/L). In individual patients, kinetic evaluations showed earlier response to therapy, or recurrence and non-response, as shown only later by CT evaluations. CONCLUSION: S-100ß can serve as a useful biomarker for the assessment of treatment response and prognosis, especially after using new immunological treatments, such as anti-BRAF, ipilimumab or anti-PD1 in malignant melanoma patients. Additional biomarkers, such as LDH, ß2M and TK may also serve as part of a biomarkers panel, for improved detection of recurrence and metastasis of melanoma patients.

The Diagnostic and Prognostic Value of Tumor Markers (CEA, SCC, CYFRA 21-1, TPS) in Head and Neck Cancer Patients.

BACKGROUND/AIM: Establishing prognostic factors is very important in the management of cancer patients. Our aim was to evaluate the clinical significance of a panel of tumor markers, including CEA (Carcino Embryonic Antigen), SCC (Squamous Cell Carcinoma Antigen), TPS (Tissue Polypeptide Specific Antigen) and CYFRA 21-1 in head and neck cancer patients, for assessing treatment response and prognosis of patients. PATIENTS AND METHODS: We evaluated 312 blood samples from 143 head and neck cancer patients, from several sub-groups: 82 Larynx Carcinoma pre- and 38 post-therapy, 46 Oral Cavity pre and 29 post-therapy, 12 nasopharynx, 16 parotid and other salivary gland patients. Blood tumor markers levels were evaluated by conventional ELISA assays. Correlations of marker levels to stage of disease, lymph node involvement and therapy, were performed. RESULTS: Serum levels of all four tumor markers were higher before therapy and decreased thereafter in all patients. The decrease in TPS level following therapy was significant (p=0.03). Significantly higher levels of TPS and similarly higher levels of the other tumor markers were demonstrated in advanced disease (stages III and IV) patients, as opposed to early disease (stages I and II) patients (p=0.012). Node positive patients had significantly higher TPS levels as compared to node negative (p=0.02). The same trend was shown by the other markers as well, but did not reach statistical significance. TPS was best correlated to survival of patients; those having low levels had the best clinical outcome and longer survival. CONCLUSION: CEA, SCC, TPS and CYFRA 21-1 can all serve as useful tumor markers in HNC patients. They assessed response to therapy and were prognostic for recurrence. TPS proved to be the most sensitive predictor of advanced disease and poor prognosis.

Thymidine kinase levels correlate with prognosis in aggressive lymphoma and can discriminate patients with a clinical suspicion of indolent to aggressive transformation.

Serum levels of thymidine kinase 1 (TK1), an enzyme involved in the G1-S phase of the cell cycle, have been previously shown to correlate with the prognosis of lymphoid malignancies. We hypothesized that TK1 levels will be higher in aggressive, compared to indolent lymphoproliferative, malignancies and this may serve as a marker of transformation from an indolent to aggressive disease. We analyzed serum from 182 patients and correlated the findings with the type of malignancy and prognosis; we further compared the TK1 levels of 31 patients with a proven transformation and 34 patients with clinically suspected transformation that was eventually deferred. The mean TK1 levels of patients with indolent and aggressive disease was 18.9±3.3 and 39.8±3.3 U/l respectively (p<0.001). Among patients with aggressive disease, low TK1 levels correlated with improved survival (p=0.008). TK1 levels >16.6 U/l predicted transformation from indolent to aggressive disease (sensitivity of 95%, specificity of 76%, negative predictive value (NPV) of 96% and positive predictive value (PPV) of 69%). A regression analysis showed that only TK1 levels were significant (relative risk (RR)=1.03 for each unit, confidence interval (CI)=1-1.05; p=0.015) for diagnosing a true transformation. In conclusion, TK levels are useful in assessing prognosis, especially in aggressive lymphoproliferative diseases. Moreover, TK levels are adequate in discriminating cases of indolent lymphoma that transformed to an aggressive disease from patients with no proven transformations. This tool provides the clinician a novel method to distinguish between symptomatic patients utilizing a simple test and may lessen the need for aggressive or invasive measures of investigation.

Validation of new cancer biomarkers: a position statement from the European group on tumor markers.

BACKGROUND: Biomarkers are playing increasingly important roles in the detection and management of patients with cancer. Despite an enormous number of publications on cancer biomarkers, few of these biomarkers are in widespread clinical use. CONTENT: In this review, we discuss the key steps in advancing a newly discovered cancer candidate biomarker from pilot studies to clinical application. Four main steps are necessary for a biomarker to reach the clinic: analytical validation of the biomarker assay, clinical validation of the biomarker test, demonstration of clinical value from performance of the biomarker test, and regulatory approval. In addition to these 4 steps, all biomarker studies should be reported in a detailed and transparent manner, using previously published checklists and guidelines. Finally, all biomarker studies relating to demonstration of clinical value should be registered before initiation of the study. SUMMARY: Application of the methodology outlined above should result in a more efficient and effective approach to the development of cancer biomarkers as well as the reporting of cancer biomarker studies. With rigorous application, all stakeholders, and especially patients, would be expected to benefit.

Myocardial Dysfunction in Severe Sepsis and Septic Shock: No Correlation With Inflammatory Cytokines in Real-life Clinical Setting.

BACKGROUND: In vitro studies suggested that circulating inflammatory cytokines cause septic myocardial dysfunction. However, no in vivo clinical study has investigated whether serum inflammatory cytokine concentrations correlate with septic myocardial dysfunction. METHODS: Repeated echocardiograms and concurrent serum inflammatory cytokines (IL-1ß, IL-6, IL-8, IL-10, IL-18, tumor necrosis factor-α, and monocyte chemoattractant protein-1) and cardiac biomarkers (high-sensitivity [hs] troponin-T and N-terminal pro-B-type natriuretic peptide [NT-proBNP]) were examined in 105 patients with severe sepsis and septic shock. Cytokines and biomarkers were tested for correlations with systolic and diastolic dysfunction, sepsis severity, and mortality. RESULTS: Systolic dysfunction defined as reduced left ventricular ejection fraction (LVEF) < 50% or < 55% and diastolic dysfunction defined as e'-wave < 8 cm/s on tissue-Doppler imaging (TDI) or E/e'-ratio were found in 13 (12%), 24 (23%), 53 (50%), and 26 (25%) patients, respectively. Forty-four patients (42%) died in-hospital. All cytokines, except IL-1, correlated with Sequential Organ Failure Assessment and APACHE (Acute Physiology and Chronic Health Evaluation) II scores, and all cytokines predicted mortality. IL-10 and IL-18 independently predicted mortality among cytokines (OR = 3.1 and 28.3, P = .006 and < 0.0001). However, none of the cytokines correlated with LVEF, end-diastolic volume index (EDVI), stroke-volume index (SVI), or s'-wave and e'-wave velocities on TDI (Pearson linear and Spearman rank [ρ] nonlinear correlations). Similarly, no differences were found in cytokine concentrations between patients dichotomized to high vs low LVEF, EDVI, SVI, s'-wave, or e'-wave (Mann-Whitney U tests). In contrast, NT-proBNP strongly correlated with both reduced LVEF and reduced e'-wave velocity, and hs-troponin-T correlated mainly with reduced e'-wave. CONCLUSIONS: Unlike cardiac biomarkers, none of the measured inflammatory cytokines correlates with systolic or diastolic myocardial dysfunction in severe sepsis or septic shock.

Vitamin D inflammatory cytokines and coronary events: a comprehensive review.

Myocardial infarction (MI) is the most common cause of cardiac injury in the Western world. Cardiac injury activates innate immune mechanisms initiating an inflammatory reaction. Inflammatory cytokines and vascular cell adhesion molecules (VCAM) promote adhesive interactions between leukocytes and endothelial cells, resulting in the transmigration of inflammatory cells into the site of injury. Low vitamin D levels are associated with higher prevalence of cardiovascular risk factors and a higher risk of MI. In this paper, we examine the effects of short-term vitamin D supplementation on inflammatory cytokine levels after an acute coronary syndrome. We recruited patients arriving to the hospital with an acute MI. All patients received optimal medical therapy and underwent a coronary catheterization. Half of the patients were randomly selected and treated with a daily supplement of vitamin D (4,000 IU) for 5 days. A short course of treatment with vitamin D effectively attenuated the increase in circulating levels of inflammatory cytokines after an acute coronary event. Control group patients had increased cytokine and cellular adhesion molecules serum concentrations after 5 days, while the vitamin D-treated group had an attenuated elevation or a reduction of these parameters. There were significant differences in VCAM-1 levels, C-reactive protein, and interleukin-6. There were trends toward significance in interleukin-8 levels. There were no significant differences in circulating levels of intercellular adhesion molecule 1, E-selectin, vascular endothelial growth factor, and tumor necrosis factor-α. These findings provide information on the anti-inflammatory effects of vitamin D on the vascular system and suggest mechanisms that mediate some of its cardioprotective properties. There is place for further studies involving prolonged vitamin D treatment in patients suffering from ischemic heart disease.

Design of tumor biomarker-monitoring trials: a proposal by the European Group on Tumor Markers.

A major application of tumor biomarkers is in serial monitoring of cancer patients, but there are no published guidelines on how to evaluate biomarkers for this purpose. The European Group on Tumor Markers has convened a multidisciplinary panel of scientists to develop guidance on the design of such monitoring trials. The panel proposes a 4-phase model for biomarker-monitoring trials analogous to that in use for the investigation of new drugs. In phase I, biomarker kinetics and correlation with tumor burden are assessed. Phase II evaluates the ability of the biomarker to identify, exclude, and/or predict a change in disease status. In phase III, the effectiveness of tumor biomarker-guided intervention is assessed by measuring patient outcome in randomized trials. Phase IV consists of an audit of the long-term effects after biomarker monitoring has been included into standard patient care. Systematic well-designed evaluations of biomarkers for monitoring may provide a stronger evidence base that might enable their earlier use in evaluating responses to cancer therapy.