Vitamin D and Its Metabolites Status before and during Chemotherapy in Caucasian Breast Cancer Patients.

BACKGROUND: The predictive role of vitamin D (VD) in breast cancer (BC) patients' survival is still being investigated. This paper aims to evaluate the changes in VD metabolites during chemotherapy (CTH) and the predictive role of VD status in Caucasian BC patients treated with CTH. METHODS: Vitamin D and its metabolites were assessed with reference LC-MS/MS methodology in 98 consecutive BC patients starting CHT, after 3 and 6 months, and compared to the control group. RESULTS: The frequency of VD deficiency in BC patients was greater than in the control group (56.1% vs. 37.2%). After 6 months of CTH, the number of VD-deficient BC patients slightly increased to 60%. The concentrations of VD active forms [25(OH)D2, 25(OH)D3], and catabolites [24,25(OH)2D3 and 3-epi-25(OH)D3] decreased after 3 and 6 months of CTH compared to the baseline values. Strong positive correlations between concentrations of 3-epi-25(OH)D3 and 25(OH)D in both groups were found. Similar correlations were also observed between 24,25(OH)2D3 and 25(OH)D levels. Kaplan-Meier survival analysis showed significantly longer survival in BC patients without deficiency (>20 ng/mL) at baseline (HR = 2.44 (95% CI 1.07-5.59), p = 0.026). CONCLUSIONS: (1) Our data provide further evidence that BC patients before CTH are more VD-deficient than the general population and this deficiency increases further during CTH treatment, as observed using the reference LC-MS methodology. (2) Presented results show that VD catabolism is not affected in BC patients. (3) The poorer survival in VD-deficient BP patients supports the importance of VD supplementation in BC patients with 25(OH)D levels below 20 ng/mL.

Mechanisms of immune modulation in the tumor microenvironment and implications for targeted therapy.

The efficacy of cancer therapies is limited to a great extent by immunosuppressive mechanisms within the tumor microenvironment (TME). Numerous immune escape mechanisms have been identified. These include not only processes associated with tumor, immune or stromal cells, but also humoral, metabolic, genetic and epigenetic factors within the TME. The identification of immune escape mechanisms has enabled the development of small molecules, nanomedicines, immune checkpoint inhibitors, adoptive cell and epigenetic therapies that can reprogram the TME and shift the host immune response towards promoting an antitumor effect. These approaches have translated into series of breakthroughs in cancer therapies, some of which have already been implemented in clinical practice. In the present article the authors provide an overview of some of the most important mechanisms of immunosuppression within the TME and the implications for targeted therapies against different cancers.

Intracellular DNA sensing by neutrophils and amplification of the innate immune response.

As the first responders, neutrophils lead the innate immune response to infectious pathogens and inflammation inducing agents. The well-established pathogen neutralizing strategies employed by neutrophils are phagocytosis, the action of microbicide granules, the production of ROS, and the secretion of neutrophil extracellular traps (NETs). Only recently, the ability of neutrophils to sense and respond to pathogen-associated molecular patterns is being appreciated. This review brings together the current information about the intracellular recognition of DNA by neutrophils and proposes models of signal amplification in immune response. Finally, the clinical relevance of DNA sensing by neutrophils in infectious and non-infectious diseases including malignancy are also discussed.

The Value of Prolactin, a Panel of Cytokines, and the Soluble Human Epidermal Growth Factor Receptor 2 in the Prediction of Rapid Progression and Shorter Survival during Palliative Chemotherapy of Colorectal Cancer Patients.

The prediction of colorectal cancer (CRC) response to palliative chemotherapy (CTH) is still difficult. Patients at a higher risk of progression may benefit from more aggressive treatment. This study assessed the predictive value of prolactin (PRL) and a panel of cytokines, chemokines, and growth factors for the risk of rapid progression in CRC patients starting palliative CTH. This study included 51 CRC patients initiating palliative CTH with up to 5-year follow-up, divided into rapid and non-rapid progressors. Serum samples were collected before CTH for assessment of a large panel of cytokines, chemokines, growth factors, and PRL via a multiplex method. Rapid progressors (N = 19) were characterized by increased baseline values of IL-8 and IP10 but decreased PRL levels. In addition, PRL below 18.2 ng/mL was a strong predictor of weight loss during CTH. Grade 3 (HR = 2.97; 95%CI: 1.48-5.98) and PRL level (HR = 0.96; 95%CI: 0.91-1.01) were independent risk factors of progression. We showed that CRC rapid progressors are characterized by decreased baseline PRL levels. In addition, increased baseline levels of IP-10, sHER-2, IL-6, and IL-8 may be associated with longer survival; however, larger studies are needed to confirm their predictive role in CRC patients.

Predictive Role of Soluble IL-6R, TNF-R1/2, and Cell Adhesion Molecules Serum Levels in the Preoperative and Adjuvant Therapy in Women with Nonmetastatic Breast Cancer: A Preliminary Study.

Soluble cell adhesion molecules (sCAMs) are involved in the development of neoplastic diseases. sCAMs can block lymphocytes and promote angiogenesis and migration of breast cancer (BC) cells. Interleukin 6 (IL-6) and tumor necrosis factor α (TNF-α) enhance metastatic potential via upregulation of CAMs. We assessed soluble interleukin-6 receptor subunit alpha (IL-6Ra), TNF-R1, TNF-R2, E-selectin, P-selectin, VCAM-1, ICAM-1, and EpCAM in 89 women with stage I-III BC and 28 healthy women. Blood samples were obtained at the beginning of neoadjuvant/induction (N = 49) or adjuvant treatment (N = 40), and after 2 months. Surgery revealed complete response in 29.4% of patients, partial response in 67%, and stable disease in 5.9%. Achieving a pathological response was 4 times greater for baseline levels of sIL-6Ra >5.63 ng/mL [odds ratio (OR) = 4.1, 95% confidence interval (CI): 0.8-20.4, P = 0.08] and more than 6 times for soluble tumor necrosis factor receptor 1 (sTNF-R1) ≥ 0.97 ng/mL (OR = 6.2, 95% CI: 1.2-32.3, P < 0.05). Compared with the control group, serum sP-selectin, soluble epithelial cell adhesion molecule (sEpCAM), and sTNF-R2 concentrations were significantly higher in patients who started adjuvant therapy (P < 0.05) and preoperative therapy (P < 0.01). Baseline serum sIL-6Ra concentrations were significantly higher in patients before surgery than in patients after tumor resection (P < 0.05), independent of the follow-up time. The baseline serum soluble receptors of IL-6 (sIL-6R) and TNF-α (sTNF-R1) concentrations have a predictive value for preoperative therapy in patients with BC.

The Predictive Role of Serum Levels of Soluble Cell Adhesion Molecules (sCAMs) in the Therapy of Advanced Breast Cancer-A Single-Centre Study.

Background and Objectives: Soluble cell adhesion molecules (sCAMs) play a significant role in the metastatic potential of breast cancer (BC). They might block lymphocytes and promote angiogenesis and migration of cancer cells. We assessed the usefulness of sCAMs in the prognosis and monitoring of the progression of advanced BC. Materials and Methods: We assessed soluble E-selectin, P-selectin, VCAM-1, ICAM-1, EpCAM, IL-6Ra, TNF-R1, and TNF-R2 in 39 women with aBC. Blood samples were obtained at the beginning of the treatment and after 2 months. Results: The median progression-free survival (PFS) was 9 months, and overall survival (OS) was 27 months. The higher levels of sICAM-1 (HR = 2.60, p = 0.06) and lower levels of sEpCAM (HR = 2.72, p < 0.05) were associated with faster progression of aBC. High levels of sEpCAM through the follow-up period were significantly associated with a lower risk of progression (HR = 0.40, p < 0.01). We found the independent predictive value of higher than median sICAM-1 levels for PFS (HR = 2.07, p = 0.08) and of sVCAM-1 levels for OS (HR = 2.59, p < 0.05). Conclusions: Our data support the predictive value of sICAM-1 and sVCAM-1 and suggest that they could become markers for tailoring new therapies in aBC. sEpCAM level could be used as an early indicator of response to the therapy.

Systemic Interleukins' Profile in Early and Advanced Colorectal Cancer.

Tumor microenvironment (TME) is characterized by mutual interactions of the tumor, stromal and immune cells. Early and advanced colorectal tumors differ in structure and present altered serum cytokine levels. Mutual crosstalk among TME infiltrating cells may shift the balance into immune suppressive or pro-inflammatory, antitumor response this way influencing patients' prognosis. Cancer-related inflammation affects all the body and this way, the systemic level of cytokines could reflect TME processes. Despite numerous studies, it is still not known how systemic cytokines levels change during colorectal cancer (CRC) tumor development. Better understanding tumor microenvironment processes could help in planning therapeutic interventions and more accurate patient prognosis. To contribute to the comprehension of these processes within TME, we reviewed cytokines levels from clinical trials in early and advanced colorectal cancer. Presented data were analyzed in the context of experimental studies and studies analyzing tumor infiltration with immune cells. The review summarizes clinical data of cytokines secreted by tumor microenvironment cells: lymphocytes T helper 1 (Th1), lymphocytes T helper 2 (Th2), lymphocytes T helper 17 (Th17), regulatory T cells (Treg cells), regulatory T cells (Breg cells), M1/M2 macrophages, N1/N2 neutrophils, myeloid-derived suppressor cells (MDSC), dendritic cells (DC), innate lymphoid cells (ILC) natural killer (NK) cells and tumor cells.

Serum cytokine profile as a potential prognostic tool in colorectal cancer patients - one center study.

AIM: Comparison of 14 cytokines levels between a control group and prospectively enrolled CRC patients to confirm their significance in CRC development. We tested if a model based on 14 cytokines levels could predict prognosis in Caucasian CRC patients treated with 5-FU based chemotherapy. BACKGROUND: Novel prognostic tools in colorectal cancer (CRC) are necessary to optimize treatment, reduce toxicity and chemotherapy (CHT) costs. MATERIALS AND METHODS: We assessed prognostic significance of 14 cytokines: IL-1 beta, IL-1RA, IL-2, IL-4, IL-5, IL-6, IL-7, IL-8, IL-9, IL-10, IL12p70, IL-13, IL-17A in 75 prospectively enrolled CRC patients before initiation of palliative or adjuvant CHT and in 22 control subjects. Readings were taken using the Bio-Plex 200 System. Response to treatment was assessed after 6 months from initiation of CHT. The treated group was divided depending on the response into a progressors (death, progression of disease) and non-progressors group (stable disease, partial response, complete response). RESULTS: We found that increased concentration of IL-8 was a negative prognostic factor in the whole group and palliative subgroup, whereas increased level of IL-10, IL-7, and IL-12p70 was a negative predictor in the adjuvant group CHT. CONCLUSIONS: We proposed a statistical model based on circulating cytokine levels, showing a good prognostic value in prediction of the response to CHT (AUC = 0.956). The model, including combined IL-2, IL-8, IL-10 and IL-13 levels, established in the whole treated group, should be validated in larger trials.

Increased serum levels of Galectin-9 in patients with chronic lymphocytic leukemia.

Chronic lymphocytic leukemia (CLL) is the most common type of leukemia in adults. Despite improvements in treatment, CLL is still considered an incurable disease. The aim of the present study was to evaluate galectin-1, -3 and -9 (Gal-1, -3 and -9) and Gal-3 binding protein (Gal-3BP) as prognostic and predictive factors in patients with CLL. Serum concentrations of Gal-1, -3 and -9 and Gal-3BP were measured in 48 patients with CLL and 30 control patients, using multiplex bead arrays. In patients with CLL, galectin concentrations were assessed prior to, during and following treatment. In patients with CLL who were untreated, galectin concentrations were measured twice with a 6-month interval. The serum level of Gal-9 was significantly increased (P<0.0001) in patients with CLL compared with the control group, and was associated with the clinical stage according to Binet classification, as well as poor cytogenetic and serum CLL prognostic factors. In addition, patients with CLL, who exhibited treatment failure, exhibited higher concentrations of Gal-9 (P=0.06) and Gal-3BP (P=0.009) at the end of the treatment when compared with patients under complete remission or stabilization of the disease. The serum level of Gal-3 was significantly decreased (P=0.012) in patients with CLL compared with the control group. These results suggest that Gal-9 is a potential prognostic factor in patients with CLL. The predictive value of Gal-9 requires further study in larger cohorts of patients.

[The role of inflammation in colon cancer pathogenesis]. / Rola zapalenia w patogenezie raka jelita grubego.

The results of the latest research more and more bind development of neoplasms with the chronic inflammation. Inflammatory process creates microenvironment promoting development of neoplasms; as a result, malignant process start to develop in places, where chronic inflammation proceeds or regeneration of tissues takes place. Inflammatory cells not only create suitable microenvironment for development of neoplasms, but also excrete number of cytokines and growth factors promoting survival of a neoplasmatic cell and avoiding its apoptosis, promoting neoangiogenesis and metastases formation. Moreover, cytokines and other pro-inflammatory factors modulate expression of genes important in cancerogenesis, they also activate NFκB-dependent signaling pathways, which favor neoplasmatic cells to avoid apoptosis. On the other hand, oxidative stress accompanying chronic inflammation may promote mutagenesis, enabling that way the neoplasm development. The same cells and metabolic pathways are engaged in inflammatory and neoplasmatic processes, and development of cancer may be a consequence of loss of control over tissue regeneration during resolution of chronic inflammation. The role of most important cells and metabolic pathways in inflammatory process, which may lead to colon cancer, was discussed in this paper.

C-C motif ligand 11 reduction in CLL patients serum after vitamin D supplementation.

BACKGROUND: Vitamin D (VD) deficiency results in a worse prognosis in patients with chronic lymphocytic leukemia (CLL) and may affect the production of cytokines. Nonetheless, there is the lack of studies dealing with VD supplementation and its impact on chemokines in CLL patients. AIM: The primary endpoint of our interventional study was to evaluate the effect of cholecalciferol supplementation on serum chemokines levels in CLL patients. MATERIALS AND METHODS: Eighteen subjects with CLL were enrolled for the study. Six-month-long cholecalciferol supplementation was performed in CLL patients with serum 25-OH-D3 levels below 30 ng/ml. Cytokines levels were assessed at the beginning of the study and after 6 months. Baseline measurements of cytokines were compared to those in apparently healthy controls. RESULTS: Increased levels of CCL2, CCL3, CCL4, CXCL8, CXCL10, TNFα, bFGF, G-CSF, and VEGF were found in CLL patients in comparison with the healthy controls. In the course of the VD supplementation a decrease in serum levels of chemokines CCL11, CCL3, and cytokine PDGF-BB was observed. The decrease of CCL11 was found in CLL patients on VD supplementation solely, whereas the decrease of CCL3 and PDGF-BB was observed in CLL subjects on both chemotherapy and VD supplementation. CONCLUSION: The VD supplementation may exert beneficial effect on chemokines levels in CLL patients with VD deficiency.