BACKGROUND:
Interferon alfa is a conservative and widely used alternative to bone marrow transplantation in treatment of patients with early chronic myeloid leukemia (CML). A meta-analysis was conducted to develop a reliable prognostic scoring system for estimation of survival of patients with CML treated with interferon alfa.

METHODS:
Patients treated in prospective studies, including major randomized trials, were separated into learning and validation samples. Cox regression analysis and the minimum P-value approach were used to identify prognostic factors for patient survival and to discover groups in the learning sample with the greatest differences in survival. These findings were then validated by applying the new scoring system to patients in the validation sample.

RESULTS:
We collected data on 1573 patients who were participants in 14 studies involving 12 institutions; 1303 patients (learning sample, n = 981; validation sample, n = 322) were eligible for inclusion in this analysis, and their median survival time was 69 months (range, 1-117 months). Because two previously described prognostic scoring systems failed to discriminate risk groups satisfactorily, we developed a new scoring system that utilizes the following covariates: age, spleen size, blast count, platelet count, eosinophil count, and basophil count. Among 908 patients with complete data in the learning sample, three distinct risk groups were identified (median survival times of 98 months [n = 369; 40.6%], 65 months [n = 406; 44.7%], or 42 months [n = 133;14.6%]; two-sided logrank test, P< or =.0001). The ability of the new scoring system to discriminate these risk groups was confirmed by analysis of 285 patients with complete data in the validation sample (two-sided logrank test, P = .0002).

CONCLUSIONS:
A new prognostic scoring system for estimating survival of patients with CML treated with interferon alfa has been developed and validated through use of a large dataset.

A new prognostic score for survival of patients with chronic myeloid leukemia treated with interferon alfa. Writing Committee for the Collaborative CML Prognostic Factors Project Group.

An evidence-based analysis of the effect of busulfan, hydroxyurea, interferon, and allogeneic bone marrow transplantation in treating the chronic phase of chronic myeloid leukemia: Developed for the American Society of Hematology

The accumulated knowledge about the organization and function of the human immune system contributes to a better understanding of the pathogenesis of most diverse disorders and is opening new avenues for therapeutic regimens. To gain further insight into the complex interactions within the components of the immune system, it has become increasingly necessary to develop rapid and simple methods to monitor the status of the immune system in patients. The determination of neopterin concentrations in human body fluids allows to investigate sensitively the cell-mediated immune status to be investigated with considerable sensitivity. In recent years it was shown that production and release of neopterin is inducible in human monocytes/macrophages by interferon gamma. Increased neopterin levels indicate endogenous formation of gamma interferon, and monitoring of neopterin levels therefore permits the activation status of the cell-mediated immune system to be examined. Neopterin concentrations in serum and in urine increase in parallel to the clinical course of infections with viruses, intracellular bacteria, and parasites. In patients with human immunodeficiency virus infection neopterin concentration in serum and urine is a significant predictor of disease progression, the statistical power being similar to CD4+ T-cell numbers. In patients with autoimmune disorders, neopterin levels correlate with the extent and the activity of the disease. Neopterin concentrations are also sensitive indicators of immunological complications in allograft recipients. In certain malignant diseases neopterin concentrations correlate with the stage of the disease and bear prognostic information. Results of neopterin measurements agree with the important role that the cellular immune system plays in these disorders.

The role of neopterin as a monitor of cellular immune activation in transplantation, inflammatory, infectious, and malignant diseases.

https://www.kidney-international.org/article/S0085-2538(15)57636-9/pdf

Dialysis-related amyloidosis

The observation of aerobic glycolysis by tumor cells in 1924 by Otto Warburg, and subsequent innovation of imaging glucose uptake by tumors in patients with PET-CT, has incited a renewed interest in the altered metabolism of tumors. As tumors grow in situ, a fraction of it is further away from their blood supply, leading to decreased oxygen concentrations (hypoxia), which induces the hypoxia response pathways of HIF1α, mTOR, and UPR. In normal tissues, these responses mitigate hypoxic stress and induce neoangiogenesis. In tumors, these pathways are dysregulated and lead to decreased perfusion and exacerbation of hypoxia as a result of immature and chaotic blood vessels. Hypoxia selects for a glycolytic phenotype and resultant acidification of the tumor microenvironment, facilitated by upregulation of proton transporters. Acidification selects for enhanced metastatic potential and reduced drug efficacy through ion trapping. In this review, we provide a comprehensive summary of preclinical and clinical drugs under development for targeting aerobic glycolysis, acidosis, hypoxia and hypoxia response pathways. Hypoxia and acidosis can be manipulated, providing further therapeutic benefit for cancers that feature these common phenotypes.

/pdf/targeting-the-metabolic-microenvironment-of-tumors-3bqug4nvnp.pdf

Targeting the Metabolic Microenvironment of Tumors

The object of this study was to investigate the effects of different single doses of recombinant interferon-γ (rIFN-γ) on white blood cell counts, differential blood counts, and the relative composition of T-cell subsets in the peripheral blood of cancer patients. Sixteen patients suffering from metastasizing renal cell carcinoma received 10, 100, or 500 μg of rIFN-γ three times at weekly intervals. After a therapy-free interval of 2 weeks, the next dose level was applied. The order of dose levels was assigned randomly to each patient. White blood cells, differential blood counts, and the number of Leu1, Leu3, Leu2a, Leu7, and HLA DR+ cells were measured immediately before and at 4, 24, 48, 72, 96, and 168 h after the administration of single doses of rIFN-γ. Results indicated that white blood cells were transiently removed from the blood circulation after administration of IFN-γ. Monocytes, HLA DR+ cells, and Leu7+ cells were reduced to below 50% of pretreatment values 4 h after application of t...

Acute Effects of Single Doses of Recombinant Interferon-γ on Blood Cell Counts and Lymphocyte Subsets in Patients with Advanced Renal Cell Cancer

Treatment of chronic myelogenous leukemia with interferon alfa-2c : response rate and toxicity in a phase II multicenter study

The effect of different doses of recombinant human tumor necrosis factor-α (rTNF-α) on serum levels of neopterin, β-2-microglobulin and interferon-γ (IFN-γ) was investigated in tumor patients. Twel...

Enhanced Serum Levels of β-2-Microglobulin, Neopterin, and Interferon-γ in Patients Treated with Recombinant Tumor Necrosis Factor-α

Minimal interferon-alpha doses for hairy cell leukemia [letter; comment]

Interferons (IFNs) comprise a heterogenous group of cytokines with pleiotropic activities. The mode of action of IFNs in human disease is still poorly understood. In particular it is not established whether IFNs exert their antineoplastic activity by direct interaction with tumor cells or indirectly by enhancing host antitumor responses. Nor is it known which biological features of a tumor and which host factors determine the sensitivity of malignant diseases to IFN therapy. In order to select IFN-α-sensitive tumor patients we have chosen Philadelphia chromosome- (Ph1)-positive chronic myelocytic leukemia (CML) as a model disease.

Strategies for Optimizing Cytokine Treatment of Malignancies: Determination of Interferon Sensitivity in Chronic Myelocytic Leukemia*

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