Adoptive Immunotherapy with Interleukin-2 and Interferon-alpha in Metastatic Renal Cell Cancer

Approximately one half of all newly diagnosed cancer patients will die of metastatic disease despite the application of the best available treatment consisting of surgery, radiation therapy and chemotherapy. Attempts to develop new approaches for the treatment of metastatic cancer by stimulating immune host defences against the tumor have received substantial attention. Initially most efforts to develop immunotherapies have involved nonspecific stimulation of the immune system with unspecific immunostimulants such as Bacille Calmette Guerin or Corynebacterium parvum. However, clinical trials have been disappointing and this immunotherapeutic approach has been abandoned. An alternative approach is that of adoptive immunotherapy, which is defined as the transfer of immunologic reagents or immune cells with antitumor reactivity to the tumor bearing host

Pulmonary arterial wall distensibility assessed by intravascular ultrasound in children with congenital heart disease: an indicator for pulmonary vascular disease?

BACKGROUND: Both pulmonary hypertension and pulmonary overflow are associated with functional and structural changes of the pulmonary arterial wall. Current techniques to evaluate the pulmonary vasculature neglect the pulsatile nature of pulmonary flow. STUDY OBJECTIVES: To determine whether the dynamic properties of the pulmonary arterial wall are altered in patients with abnormal pulmonary hemodynamics due to congenital heart defects, and whether these changes are associated with the progression of pulmonary vascular disease (PVD). PATIENTS AND METHODS: In 43 children with PVD due to congenital heart defects and 12 control subjects, pulmonary arterial pulsatility (the relative increase in vessel area during the cardiac cycle) and distensibility (the inverse of the stress/strain elastic modulus) were determined with intravascular ultrasound. Results were correlated with clinical and hemodynamic parameters. RESULTS: Pulsatility correlated with pulmonary pulse pressure (p < 0.001), pulmonary-to-systemic vascular resistance ratio (PVR/SVR) [p = 0.001], and hemoglobin concentration (p = 0.01). However, when corrected for these variables, pulsatility did not differ between patients and control subjects. In contrast, arterial wall distensibility decreased with the severity of PVD and correlated independently with pulmonary-to-systemic arterial pressure ratio (p < 0.001) and PVR/SVR (p = 0.03), and with hemoglobin concentration (p < 0.01). Adjusted for hemodynamic variables, distensibility was still decreased in patients with PVD compared to control subjects. CONCLUSIONS: These results demonstrate that pulmonary arterial wall distensibility is progressively decreased in PVD; moreover, this decreased distensibility is, in part, related to increased distending pressure as a result of pulmonary hypertension but also, in part, to stiffening of the arterial wall during the disease process. Arterial wall distensibility may be of additional value in the evaluation of pulmonary vasculature and ventricular workload

The Photometric and Kinematic Structure of Face-On Disk Galaxies. I. Sample Definition, H-alpha Integral Field Spectroscopy, and HI Line-Widths

We present a survey of the photometric and kinematic properties of 39 nearby, nearly face-on disk galaxies. Our approach exploits echelle-resolution integral-field spectroscopy of the H-alpha regions, obtained with DensePak on the WIYN 3.5m telescope Bench Spectrograph. This data is complemented by HI line-profiles observed with the Nancay radio telescope for 25 of these sample galaxies. Twelve additional line-widths are available for sample galaxies from the literature. In this paper, we introduce the goals of this survey, define the sample selection algorithm, and amass the integral field spectroscopic data and HI line-widths. We establish spatially-integrated H-alpha line-widths for the sample. We test the veracity of these spatially-integrated line profiles by convolving narrow-band imaging data with velocity field information for one of the sample galaxies, PGC 38268, and also by comparing to HI line profiles. We find HI and H-alpha line profiles to be similar in width but different in shape, indicating we are observing different spatial distributions of ionized and neutral gas in largely axisymmetric systems with flat outer rotation-curves. We also find vertical velocity dispersions of the ionized disk gas within several disk scale-lengths have a median value of 18 km/s and an 80% range of 12-26 km/s. This is only a factor of ~2 larger than what is observed for neutral atomic and molecular gas. With standard assumptions for intrinsic and thermal broadening for H-alpha, this translates into a factor of three range in turbulent velocities, between 8 and 25 km/s.Comment: 29 pages, 20 figures; accepted for publication in ApJ Supplement Serie

THE MULTILAYER CHARACTERISTICS OF THE LIFE SUPPORT NETWORK FOR THE SENIOR CITIZEN IN NOTO PENINSULA EARTHQUAKE SUFFERING VILLAGE, TOUGE : Mainly on analysis of the investigation about the care advanced age household required in 2009

textabstractIn a phase II study, 27 patients with metastatic breast cancer were treated with oral etoposide as second-line chemotherapy at a dose of 50 mg/m2/day for 21 days, which courses were repeated every 4 weeks. Twenty-one patients were evaluable for response, and twenty-five for toxicity. In two (10%) patients a partial response was observed with a duration of 60 and 122 weeks respectively, and seven patients (33%) showed stable disease. Gastrointestinal toxicity was usually mild, though relatively frequent. Anemia grade II and III was observed in 20% of all courses (< 10% of all measurements), and leukopenia grade III and IV was observed in 22% of all courses (< 10% of all measurements). There was one toxic death. Reviewing the literature we calculated a response rate of intravenous etoposide treatment of 8% in 276 patients with metastatic breast cancer from 7 studies (response rates ranging between 0-14%), while (chronic) oral treatment caused a response rate of 19% in 145 patients from 8 different studies (response rates ranging between 0-35%)

Serum amino acids, biopterin and neopterin during long-term immunotherapy with interferon-alpha in high-risk melanoma patients

Abstract Immunotherapy with interferon-alpha (IFN-a) induces neuropsychiatric side effects, most notably depression. One of the presumed pathophysiological mechanisms is an effect on tryptophan metabolism. As tryptophan is the precursor of serotonin, decreased availability of tryptophan to the central nervous system could result in serotonin deficiency. Tetrahydrobiopterin (BH ) is a cofactor for one of the enzymes synthesizing serotonin. We conducted an exploratory 4 ( ) study into the serum concentrations of large neutral amino acids (AA), biopterin (BIOP) and neopterin (NEOP), of 67 patients with high-risk melanoma, who were either treated with two different doses of IFN-a or were part of an observation-only control group. We found evidence for IFN-a to decrease concentrations of all AA except phenylalanine. The decrease in tryptophan concentration was most prominent and consistent. These changes persisted throughout a year of maintenance treatment. Concentrations of NEOP rose sharply, whereas, those of BIOP did not change. Except for the increase in NEOP and the increase in the ratio between phenylalanine (PHE) and tyrosine (TYR), no support for derangement in BH metabolism was found. The increase in the ratio between PHE and 4 ( ) TYR suggests inhibition of the enzyme phenylalanine hydroxylase. Patients with IFN-a induced anxiety and depression had higher pretreatment concentrations of NEOP. Changes in tryptophan metabolism may play a role in the pathophysiology of the neuropsychiatric side effects of IFN-a, and further research into the predictive potential of NEOP is warranted.

Tc17 CD8+ T-cells accumulate in murine atherosclerotic lesions, but do not contribute to early atherosclerosis development

Aims CD8+ T cells can differentiate into subpopulations that are characterized by a specific cytokine profile, such as the Tc17 population that produces interleukin-17. The role of this CD8+ T-cell subset in atherosclerosis remains elusive. In this study, we therefore investigated the contribution of Tc17 cells to the development of atherosclerosis. Methods and results Flow cytometry analysis of atherosclerotic lesions from apolipoprotein E-deficient mice revealed a pronounced increase in RORγt+CD8+ T cells compared to the spleen, indicating a lesion-specific increase in Tc17 cells. To study whether and how the Tc17 subset affects atherosclerosis, we performed an adoptive transfer of Tc17 cells or undifferentiated Tc0 cells into CD8−/− low-density lipoprotein receptor-deficient mice fed a Western-type diet. Using flow cytometry, we showed that Tc17 cells retained a high level of interleukin-17A production in vivo. Moreover, Tc17 cells produced lower levels of interferon-γ than their Tc0 counterparts. Analysis of the aortic root revealed that the transfer of Tc17 cells did not increase atherosclerotic lesion size, in contrast to Tc0-treated mice. Conclusion These findings demonstrate a lesion-localized increase in Tc17 cells in an atherosclerotic mouse model. Tc17 cells appeared to be non-atherogenic, in contrast to their Tc0 counterpart

Nitric oxide production and monoamine oxidase activity in cancer patients during interferon-α therapy

Both increased and decreased nitric oxide (NO) synthesis have been reported in patients treated with interferon-α (IFN-α). Animal studies showed that IFN-α administration results in increased levels of biogenic amines, subsequent activation of monoamine oxidases (MAOs), and finally in a change in NO production due to the H2O2 generated by MAOs. We examined the potential relationship between NO production in plasma and MAO-B activity in platelets of 43 cancer patients during 8 weeks of treatment with IFN-α. NO synthesis was quantitated by measuring both the ratio of citrulline and arginine (CIT/ARG-ratio) and total nitrite/nitrate (NOx) levels. Compared to baseline, MAO activity and NOx increased, while the CIT/ARG-ratio decreased. No associations were found between NOx, MAO and CIT/ARG-ratio. Only few associations were observed between changes in the biochemical parameters and changes in psychopathology induced by IFN-α, of which the association between changes in CIT and lassitude was the most consistent. The results suggest that peripheral NO production and MAO activity are unrelated to each other, and that peripheral changes in these biochemical parameters induced by IFN-α are unlikely to contribute to definite psychiatric disturbance

Vemurafenib plus cobimetinib in unresectable stage IIIc or stage IV melanoma

Background: In patients with BRAFV600 mutated unresectable stage IIIc or metastatic melanoma, molecular targeted therapy with combined BRAF/MEK-inhibitor vemurafenib plus cobimetinib has shown a significantly improved progression-free survival and overall survival compared to treatment with vemurafenib alone. Nevertheless, the majority of BRAFV600 mutation-positive melanoma patients will eventually develop resistance to treatment. Molecular imaging with 18F-Fluorodeoxyglucose (18F-FDG) PET has been used to monitor response to vemurafenib in some BRAFV600 mutated metastatic melanoma patients, showing a rapid decline of 18F-FDG uptake within 2 weeks following treatment. Furthermore, preliminary results suggest that metabolic alterations might predict the development of resistance to treatment. 18F-Fluoro-3'-deoxy-3'L-fluorothymidine (18F-FLT), a PET-tracer visualizing proliferation, might be more suitable to predict response or resistance to therapy than 18F-FDG. Methods: This phase II, open-label, multicenter study evaluates whether metabolic response to treatment with vemurafenib plus cobimetinib in the first 7 weeks as assessed by 18F-FDG/18F-FLT PET can predict progression-free survival and whether early changes in 18F-FDG/18F-FLT can be used for early detection of treatment response compared to standard response assessment with RECISTv1.1 ceCT at 7 weeks. Ninety patients with BRAFV600E/K mutated unresectable stage IIIc/IV melanoma will be included. Prior to and during treatment all patients will undergo 18F-FDG PET/CT and in 25 patients additional 18F-FLT PET/CT is performed. Histopathological tumor characterization is assessed in a subset of 40 patients to unravel mechanisms of resistance. Furthermore, in all patients, blood samples are taken for pharmacokinetic analysis of vemurafenib/cobimetinib. Outcomes are correlated with PET/CT-imaging and therapy response.