Decrease of Interleukin-2 secretion is a new independent prognostic factor associated with poor survival in patients with small-cell lung cancer

Background: We have previously shown that suppression of Interleukin-2(IL-2) secretion was mediated by transforming growth factor (TGF) 1secreted by small-cell lung cancer (SCLC) tumor cells. We have also shown thatIL-2 secretion was significantly impaired in patients with SCLC at the timeof diagnosis. Reconstitution of cytokine secretion correlated with reductionof tumor load. These data suggested that the immune system was suppressed bythe tumor. To address the clinical relevance of cytokine suppression in SCLC,we investigated the correlation of the level of IL-2 secretion with survival.Patients and methods: The significance of correlations between singleparameters in the test groups was calculated by using the linear regressionanalysis, the Wilcoxon rank sum test and the exact test according to Fisher.Using the Kaplan–Meier method, the log-rank test and the Cox-regressionmodel, we analysed the relation of IL-2 secretion in whole blood cell culturesfrom 52 patients with SCLC at the time of diagnosis to established prognosticfactors relevant for survival in SCLC.Results: Impairment of IL-2 secretion significantly correlates to survivalin SCLC (P = 0.004). Further univariate and multivariate analysis showed thatthis prognostic factor is independent from other factors of prognosticrelevance in SCLC, namely stage of disease, neurone specific enolase (NSE),lactate dehydrogenase (LDH), age, and sex. More important, the prognosticvalue of IL-2 secretion is comparable to the most predominant prognosticfactors for survival in SCLC identified so far. In the final model of the coxregression analysis, the P-value for IL-2 secretion in relation to stage ofdisease was 0.012 and 0.019, respectively.Conclusions: IL-2 secretion at the time of diagnosis represents anindependent prognostic factor for survival in SCLC. Although its prognosticvalue has to be confirmed in a larger group of patients, our resultsdemonstrate that IL-2 secretion may play an important role in diagnosis andtreatment of SCLC. Moreover, in contrast to other prognostic factors,impairment of IL-2 secretion may help to understand immunosuppression in SCLCand, thus, important elements of the pathogenesis of this disease.     

High rate of isolated right ventricular dysfunction in patients with non-significant CT pulmonary angiography

Background

Right ventricular (RV) dysfunction and pulmonary hypertension (PH) are commonly unrecognized in the emergency department (ED), but are associated with poor outcomes. Prior research has found a 30% prevalence of isolated RV dysfunction in ED patients after non-significant computed tomographic pulmonary angiography (CTPA). We aimed to prospectively define the prevalence of RV dysfunction and/or PH in short of breath ED patients, and assess outcomes.

17β-Estradiol and estrogen receptor α protect right ventricular function in pulmonary hypertension via BMPR2 and apelin

Women with pulmonary arterial hypertension (PAH) exhibit better right ventricular (RV) function and survival than men; however, the underlying mechanisms are unknown. We hypothesized that 17β-estradiol (E2), through estrogen receptor α (ER-α), attenuates PAH-induced RV failure (RVF) by upregulating the procontractile and prosurvival peptide apelin via a BMPR2-dependent mechanism. We found that ER-α and apelin expression were decreased in RV homogenates from patients with RVF and from rats with maladaptive (but not adaptive) RV remodeling. RV cardiomyocyte apelin abundance increased in vivo or in vitro after treatment with E2 or ER-α agonist. Studies employing ER-α–null or ER-β–null mice, ER-α loss-of-function mutant rats, or siRNA demonstrated that ER-α is necessary for E2 to upregulate RV apelin. E2 and ER-α increased BMPR2 in pulmonary hypertension RVs and in isolated RV cardiomyocytes, associated with ER-α binding to the Bmpr2 promoter. BMPR2 is required for E2-mediated increases in apelin abundance, and both BMPR2 and apelin are necessary for E2 to exert RV-protective effects. E2 or ER-α agonist rescued monocrotaline pulmonary hypertension and restored RV apelin and BMPR2. We identified what we believe to be a novel cardioprotective E2/ER-α/BMPR2/apelin axis in the RV. Harnessing this axis may lead to novel RV-targeted therapies for PAH patients of either sex.     

Prognostic significance of cytokine modulation in non-small cell lung cancer

Increased production of immunosuppressive interleukin-10 (IL-10) by non-small cell lung cancer (NSCLC) and increased serum IL-10 concentrations in NSCLC-patients have recently been correlated to reduced survival. We earlier demonstrated suppression of IL-2 secretion in whole blood cell cultures of NSCLC-patients. We now analyzed the influence of IL-2 secretion on survival in NSCLC-patients and the influence of IL-10 on IL-2 secretion. The correlation of the IL-2 producing ability of whole blood cells in response to PHA in 90 NSCLC-patients at the time of diagnosis to survival was calculated by Crit-level, the Kaplan-Meier method and the log-rank test. With a cut-off value of IL-2 production of 1,100 pg/ml by whole blood cells the difference in survival was significant with a p-value of 0.014. In the group with high and low IL-2, median survival was 14.1 and 9.7 months, respectively. In the subgroup of 33 surgically-treated patients the difference in survival was significant with a p-value of 0.011. In 14 patients with surgical resection of the tumor and high IL-2 at diagnosis and 19 patients with surgical resection, but low IL-2 at diagnosis, median survival was 86.2 and 11.3 months, respectively. Secretion of IL-2 in whole blood cell cultures from healthy individuals was inhibited in a dose-dependent manner upon addition of IL-10. Taken together, suppression of IL-2 secretion has prognostic significance for survival of NSCLC-patients and may be mediated by tumor-derived IL-10.     

Vitamin E succinate is a potent novel antineoplastic agent with high selectivity and cooperativity with tumor necrosis factor-related apoptosis-inducing ligand (Apo2 ligand) in vivo.

Alpha-tocopheryl succinate (alpha-TOS), a redox-inactive analogue of vitamin E, is a strong inducer of apoptosis, whereas alpha-tocopherol (alpha-TOH) lacks apoptogenic activity (J. Neuzil et al., FASEB J., 15: 403-415, 2001). Here we investigated the possible antineoplastic activities of alpha-TOH and alpha-TOS and further explored the potential of alpha-TOS as an antitumor agent. Using nude mice with colon cancer xenografts, we found that alpha-TOH exerted modest antitumor activity and acted by inhibiting tumor cell proliferation. In contrast, alpha-TOS showed a more profound antitumor effect, at both the level of inhibition of proliferation and induction of tumor cell apoptosis. alpha-TOS was nontoxic to normal cells and tissues, triggered apoptosis in p53(-/-) and p21(Waf1/Cip1(-/-)) cancer cells, and exerted a cooperative proapoptotic activity with tumor necrosis factor-related apoptosis-inducing ligand (Apo2 ligand) due to differences in proapoptotic signaling. Finally, alpha-TOS cooperated with tumor necrosis factor-related apoptosis-inducing ligand in suppression of tumor growth in vivo. Vitamin E succinate is thus a potent and highly specific anticancer agent and/or adjuvant of considerable therapeutic potential.     

Wechseloperationen von Kniegelenksendoprothesen

Thirty-one revisions for aseptic or septic loosening of knee arthroplasty have been performed between 1983 and 1995. In 18 cases we had loosening of uni- or bicondylar prosthesis and in 13 cases a tricompartimental revision arthroplasty. With an average of 53 months (1,5 to 13 years) after the last operation 21 patients could be examined. Main reasons for failure of uni- and bicondylar prosthesis were as well a proceeding of the arthritis in other compartments, instability, incorrect alignment and other reasons depending on the surgical technique. We found similar reasons in aseptic loosening of total knee arthroplasties including wrong choice of non-constrained condylar prosthesis. Seven cases of late infection affected semiconstrained prosthesis. Two of the reimplantations in a 2-stage procedure failed. Using the Insall-Score in the follow-up the patients reached 71,9 points in the knee score and 58.9 points in the functional score. Patients with former aseptic loosening reached better results than these with septic loosening. 38% were absolutely painfree, 14% complained about permanent pain. Unlimited walking was found 5 times, none of the examined persons was unable to walk. Main problems in revision surgery concern reconstruction of a good alignment and the management of bone loss.     

Strahlenwirkungen

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Strahlenwirkungen

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