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.

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.

A survey across orbital lymphoma in Poland: Multicenter retrospective study of polish lymphoma research group (PLRG).

OBJECTIVE: To investigate the prevalence of histopathological subtypes, the clinical stage at presentation and treatment modalities in Polish patients with orbital lymphoma (OL) and to determine prognostic outcomes. METHODS: The retrospective study of 107 patients with OL treated in a 14-year period in Polish hematological centers. The analysis included histopathological subtype, disease clinical advancement, treatment modalities, progression-free survival (PFS), and overall survival (OS). RESULTS: The median patient age was 60 years (range 51-71). Mucosa-associated lymphoid tissue (MALT) lymphoma accounted for slightly more than half of all cases of orbital lymphoma (51%). The second most common subtype was diffuse large B-cell lymphoma (DLBCL) (29%). Primary orbital lymphoma was diagnosed in 48% of all patients. According to the Ann Arbor, localized stage IE of orbital lymphoma was diagnosed only in 39% of all patients. Systemic involvement was observed in more than half of all patients (52%). The median follow-up period was 30 months (range 0-160 months). Patients with non-MALT lymphoma had a significantly inferior PFS compared to patients with MALT lymphoma, (p = 0.047). Patients with primary orbital lymphoma had a superior PFS compared to patients with secondary orbital lymphoma [median PFS 104.5 months vs. 33.4 months], (p = 0.069). Younger patients with MALT lymphoma were characterized by superior PFS (median PFS not reached) compared to other studied subgroups of patients (older patients with MALT lymphoma, younger and older non-MALT lymphoma patients) with a median PFS of 30.5, 32.2, 32.6 months respectively (p = 0.039). Patients treated with chemotherapy alone had inferior PFS compared to patients treated with combined therapies (p = 0.034). The median PFS across patients who received chemotherapy alone was 23.7 months, whereas across other patients was 73.9 months. CONCLUSIONS: Secondary lymphoma accounts for more than half of the orbital lymphoma in Polish population. The advanced clinical stage of the disease (non-IE according to Ann Arbor) concerns two-thirds of the overall population of patients with orbital lymphomas and one-third of MALT lymphoma patients. The high incidence of advanced stages of orbital lymphoma may indicate the need for combined treatment. Combined orbital lymphoma treatment is associated with superior PFS compared to chemotherapy alone in overall population of patients with orbital lymphoma.

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.

Galectin Targeted Therapy in Oncology: Current Knowledge and Perspectives.

The incidence and mortality of cancer have increased over the past decades. Significant progress has been made in understanding the underpinnings of this disease and developing therapies. Despite this, cancer still remains a major therapeutic challenge. Current therapeutic research has targeted several aspects of the disease such as cancer development, growth, angiogenesis and metastases. Many molecular and cellular mechanisms remain unknown and current therapies have so far failed to meet their intended potential. Recent studies show that glycans, especially oligosaccharide chains, may play a role in carcinogenesis as recognition patterns for galectins. Galectins are members of the lectin family, which show high affinity for ß-galactosides. The galectin-glycan conjugate plays a fundamental role in metastasis, angiogenesis, tumor immunity, proliferation and apoptosis. Galectins' action is mediated by a structure containing at least one carbohydrate recognition domain (CRD). The potential prognostic value of galectins has been described in several neoplasms and helps clinicians predict disease outcome and determine therapeutic interventions. Currently, new therapeutic strategies involve the use of inhibitors such as competitive carbohydrates, small non-carbohydrate binding molecules and antibodies. This review outlines our current knowledge regarding the mechanism of action and potential therapy implications of galectins in cancer.

Exenatide modulates tumor-endothelial cell interactions in human ovarian cancer cells.

Diabetes and cancer are prevalent diseases whose incidence is increasing globally. Diabetic women have a moderate risk increase in ovarian cancer, suggested to be due to an interaction between these two disorders. Furthermore, patients manifesting both diseases have associated worse prognosis, reduced survival and shorter relapse-free survival. According to current recommendations, incretin drugs such as Exenatide, a synthetic analog of Exendin-4, and Liraglutide are used as therapy for the type 2 diabetes (T2D). We studied the effects of GLP-1 and Exendin-4 on migration, apoptosis and metalloproteinase production in two human ovarian cancer cells (SKOV-3 and CAOV-3). Exendin-4 inhibited migration and promoted apoptosis through caspase 3/7 activation. Exendin-4 also modulated the expression of key metalloproteinases (MMP-2 and MMP-9) and their inhibitors (TIMP-1 and TIMP-2). Vascular endothelial cells, which contribute to the formation and progression of metastasis, were also analyzed. TNF-α-stimulated endothelial cells from iliac artery after Exendin-4 treatment showed reduced production of adhesion molecules (ICAM-1 and VCAM-1). Additionally, incretin treatment inhibited activation of apoptosis in TNF-α-stimulated endothelial cells. In the same experiment, MMPs (MMP-1 and MMP-9), which are relevant for tumor development, were also reduced. Our study demonstrated that incretin drugs may reduce cancer cell proliferation and dissemination potential, hence limiting the risk of metastasis in epithelial ovarian cancer.

Efficacy and safety of vitamin D supplementation in patients with chronic lymphocytic leukemia.

BACKGROUND: Vitamin D (VD) deficiency in chronic lymphocytic leukemia (CLL) is associated with inferior prognosis, shorter time to treatment and worse overall survival. VD deficiency is the first potentially modifiable prognostic factor in CLL. Currently, however, there is a lack of studies concerning VD supplementation in CLL patients. AIM: To evaluate the efficacy and safety of VD supplementation in patients with CLL. METHODS: A 6-month interventional study was conducted in CLL patients with lower serum 25-OH-D3 concentrations (< 30 ng/ml) than currently recommended. Patients with VD insufficiency (20-30 ng/ml) received 2000 IU of cholecalciferol/day, patients with moderate deficiency (10-19.9 ng/ml) received 4000 IU/day, and patients with severe VD deficiency (<10 ng/ml) received 6000 IU/day. RESULTS: In the analyzed group of 13 CLL subjects, only 1 patient had a VD level within the optimal range (30-80 ng/ml), 7 had an insufficient concentration, 4 had moderate deficiency, and 1 had severe deficiency. Secondary hyperparathyroidism was diagnosed in 4 subjects. Cholecalciferol supplementation (mean dose of 3384 ± 1211 IU) was followed by a significant increase in 25-OH-D3 concentration (from 17.3 ± 5.8 to 41.4 ± 17.5 ng/ml; p<0.05) and decrease in PTH (p<0.05). Five patients did not achieve the recommended 25-OH-D3 concentration. Calcium level remained unchanged and no patients developed hypercalcemia. CONCLUSIONS: VD replenishment is safe and can be effectively achieved by means of the employed cholecalciferol dosage in the majority of patients. However, some subjects may require higher doses to obtain the optimal level and immune function.

[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.

[Galectins in hematological malignancies--role, functions and potential therapeutic targets]. / Galektyny w nowotworach hematologicznych--rola, funkcje i potencjalne mozliwosci wykorzystania w terapii.

Galectins are a family of lectins characterized by an affinity for ß-galactosides through the carbohydrate recognition domain (CRD). The extracellular and intracellular presence of Galectins has been described. Their activity and functions are mainly attributed to cell type. The tumor microenviroment is a complex milieu connected with immunosupression, angiogenesis and hypoxic compartments. The studies of interactions between Glycans-Lectins are highly advanced and promising. We are not able to explain the pathogenesis of many diseases only by protein-protein interactions, that is why in these studies is a chance to find a new therapeutic targets. Galectins play a fundametal functions in tumor growth and progression, angiogenesis, adhesion, tumor immune-escape. They are also active in inflammation, fibrosis, organogenesis and immunological functions. The most known Galectin is Gal-3. Depending on the localization Gal-3 may exhibit either pro-apoptotic or anti-apoptotic activity. This publication presents role of Galectins in hematological malignancies and shows potencial prognostoic value and new therapeutic possibilities.

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.

Osteoid Osteoma - Diagnostic and Therapeutic Difficulties. A. Single-centre Experience.

BACKGROUND: Osteoid osteoma is a primary, benign bone tumour. The characteristic clinical symptom is nocturnal pain at the tumour site that decreases or resolves completely with salicylates and non-steroidal antiinflammatory drugs (NSAIDs). The typical radiological features include a radiolucent area with an osteosclerotic rim. An unusual location or absence of visible abnormalities on conventional radiographs may pose a diagnostic challenge. MATERIAL AND METHODS: We report our clinical experience with osteoid osteoma in 15 patients, with special regard to diagnostic and therapeutic difficulties in two cases. RESULTS: All patients reported the characteristic pattern of nocturnal pain that was reduced or resolved after administration of aspirin or NSAIDs. A typical radiological appearance of osteoid osteoma was observed in 13 patients, with radiological studies showing no changes in two patients, who required extended imaging workup to establish the diagnosis. CONCLUSIONS: 1. Osteoid osteoma may be a diagnostic and therapeutic problem. 2. Lack of visible abnormalities on conventional radiographs in the presence of typical clinical symptoms does not rule out osteoid osteoma. 3. Bone scintigraphy and magnetic resonance imaging are helpful methods in the imaging of radiologically silent pathological lesions.

Assessment of risk factors for mortality in patients with cardiovascular disease and a history of treatment for malignancy.

BACKGROUND: Patients with advanced cancer after radio- and/or chemotherapy are increasingly commonly hospitalised in cardiology units due to coexisting cardiovascular diseases (CVD). A rational assessment of mortality risk is an important part of patient preparation for invasive cardiac procedures. One disadvantage of cardiac risk scores is the fact that malignancies are not taken into account. At present, accurate estimation of life expectancy is possible in up to 20% of patients with an advanced malignancy. AIM: To evaluate the effect of selected clinical parameters on survival of patients with CVD and coexisting lung or breast cancer after radio- and/or chemotherapy. An additional aim was to identify patients with a high probability of surviving a year in a good general clinical condition. METHODS: The study group involved 326 subjects with established CVD and lung cancer (small-cell or non-small-cell) or breast cancer who were selected from the group of 7818 patients receiving palliative care in the Palium hospice in Czestochowa, Poland, in 2008-2012. The obtained data were collected in a database and subjected to a statistical analysis. RESULTS: The strongest factors associated with an increased risk of death among patients with CVD and coexisting advanced lung or breast cancer after chemo- and/or radiotherapy were the type and stage of malignancy, functional status according to the ECOG classification, and the presence of cachexia. Other factors that had a significant effect on survival included higher severity of heart failure symptoms as evaluated by the New York Heart Association class, decreased left ventricular ejection fraction, presence of ischaemic heart disease, chronic obstructive pulmonary disease, fasting hyperglycaemia, and the severity of fatigue, nausea, and pain. When the effects of drug treatment on survival were analysed, significantly increased survival was observed in patients treated with angiotensin-converting enzyme inhibitors while diuretic and glucocorticosteroid use was associated with decreased survival. Among the evaluated groups of patients with CVD and advanced malignancy after radio- and/or chemotherapy, the highest probability of surviving a year in a relatively good general clinical condition was noted in patients with stage 3 breast cancer without cachexia, ischaemic heart disease and persistent somatic symptoms who were treated with tamoxifen, angiotensin-converting enzyme inhibitors and megestrol acetate. CONCLUSIONS: This is the first study that evaluated the combined effect of oncological and cardiovascular risk factors on survival of patients with CVD and coexisting cancer after radio- and/or chemotherapy treatment. When the three groups of cancer patients with different prognosis were compared, the study revealed varying effects of each factor depending on the underlying malignancy. The analysis confirmed the significance of the cumulative risk. The present study showed that malignancy-related prognostic factors are important in the context of cardiac evaluation and treatment of cancer patients. It also showed that further research is needed to clarify these issues.

[Vitamin D deficiency among women diagnosed with breast cancer and unclear benefits of vitamin supplementation]. / Niedobory witaminy D u kobiet z rakiem piersi i niepewne korzysci z jej suplementacji.

Breast cancer is the most common cancer in the world and also in Poland. Morbidity for breast cancer is increasing, but mortality rate is still on the same level. In Poland morbidity has increased almost two times during the last 30 years. Vitamin D deficiency in the general population is a common phenomenon, especially among obese and elder. It increases the risk of development and worsens the prognosis in breast cancer. In recent years, the role of vitamin D and its nuclear receptor (VDR) in cancer epidemiology, and its impact on the regulation of immune processes have raised interest. VDR acts as ligand-activated transcription factor. Recent studies suggest a role of vitamin D in the regulation of energy pathways in tumor cells. Another observation on vitamin D is its inhibitory effect on inflammation and regulation of glucose metabolism in neoplastic cell. This article explores the available literature on the effect of vitamin D supplementation in women with breast cancer, describes the potential regulatory vitamin D depend mechanisms occurring in the breast cancer. Due to the limited data on the efficacy and safety, the optimal dose of vitamin D in supplementation of patients with cancer breast has not been determined.

Laparoscopy-assisted percutaneous endoscopic gastrostomy enables enteral nutrition even in patients with distorted anatomy.

AIM: To analyzed whether laparoscopy-assisted percutaneous endoscopic gastrostomy (PEG) could be a valuable option for patients with complicated anatomy. METHODS: A retrospective analysis of twelve patients (seven females, five males; six children, six young adults; mean age 19.2 years) with cerebral palsy, spastic quadriparesis, severe kyphoscoliosis and interposed organs and who required enteral nutrition (EN) due to starvation was performed. For all patients, standard PEG placement was impossible due to distorted anatomy. All the patients qualified for the laparoscopy-assisted PEG procedure. RESULTS: In all twelve patients, the laparoscopy-assisted PEG was successful, and EN was introduced four to six hours after the PEG placement. There were no complications in the perioperative period, either technical or metabolic. All the patients were discharged from the hospital and were then effectively fed using bolus methods. CONCLUSION: Laparoscopy-assisted PEG should become the method of choice for gastrostomy tube placement and subsequent EN if PEG placement cannot be performed safely.

Activating killer immunoglobulin-like receptor incompatibilities enhance graft-versus-host disease and affect survival after allogeneic hematopoietic stem cell transplantation.

OBJECTIVES: Killer immunoglobulin-like receptors (KIRs) regulate function of natural killer (NK) cells and a subset of T cells. In this study, we prospectively evaluated the impact of donor and recipient activating KIR genes on outcome of allogeneic hematopoietic stem cell transplantation (alloHSCT) for patients with hematological malignancies. METHODS: One-hundred consecutive recipients of myeloablative transplantation and their donors were tested for KIR genotype as well as for immune reconstitution, including activating KIR expression on NK cells and T cells. RESULTS: In a multivariate analysis, mismatches of particular activating KIRs such that the patient was negative and the donor was positive (P-D+) resulted in increased risk of acute (KIR2DS1) and chronic (KIR2DS3) graft-versus-host disease (GVHD) as well as relapse (KIR2DS5). KIR2DS1 incompatibility in the same direction in the presence of HLA-C-group 2 ligand in recipient was associated with reduced overall (risk ratio, RR = 3.01; P = 0.01) and disease-free survival (RR = 2.92, P = 0.03). Activating mismatches in P-D+ direction resulted in decreased CD4+ : CD8+ T-cell ratio up to 1 yr after alloHSCT, as a consequence of decreased CD3+CD4+ number within the first 100 d and increased CD3+CD8+ number in later time-points. Among six evaluated patients, expression of activating KIRs on NK cells and T cells was particularly prominent for those developing intestinal GVHD. CONCLUSION: Our findings indicate that the presence of particular activating KIRs in donor with their absence in recipient enhances GVHD, which is not accompanied by graft-versus-leukemia effect. Evaluation of activating KIR genotype may allow optimization of both donor selection and transplantation procedure in order to avoid GVHD.

Outcome of HLA-matched related allogeneic hematopoietic stem cell transplantation for patients with acute leukemia in first complete remission treated in Eastern European centers. Better results in recent years.

The goal of this study was to analyze results and to determine factors affecting outcome of HLA-matched hematopoetic stem cells transplantation (MRD-HSCT) for patients with acute leukemia transplanted in first complete remission in Eastern European countries. Six hundred forty HSCT were performed between 1990 and 2006 for adults with acute myeloid (n = 459) and lymphoblastic (n = 181) leukemia. Two-year leukemia-free survival (LFS), nonrelapse mortality (NRM), and relapse incidence were 58 +/- 2%, 19 +/- 2%, and 23 +/- 2%, respectively. The cumulative incidence of NRM decreased from 22 +/- 2% for patients treated between 1990 and 2002 to 15 +/- 3% for transplantations performed between 2003 and 2006 (p = 0.02), despite increasing recipient age. In a multivariate analysis, time of HSCT affected both NRM and LFS. Among other prognostic factors, the use of TBI decreased relapse incidence and increased the LFS rate. We conclude that results of MRD-HSCT for acute leukemia in Eastern Europe improved over time as a consequence of decreased NRM. The use of TBI containing regimens appears advantagous.

Elastin metabolism is disrupted in patients after allogeneic hematopoietic stem cell transplantation (alloHSCT) for acute and chronic myeloid leukemia.

BACKGROUND: The potential role of elastin in patients with myeloid leukemia treated with hematopoietic stem cell transplantation (HSCT) has not been investigated so far. The objective of the study was to evaluate elastin metabolism before and at two time-points after HSCT. MATERIAL/METHODS: Forty patients (22 male and 18 female, median age: 34 years, range: 14-54) were included. The diagnoses were acute myeloid leukemia (AML, n=25) and chronic myeloid leukemia (CML, n=15). Busulfan and cyclophosphamide (4+2) were administered as conditioning. Graft-versus-host disease (GVHD) prophylaxis consisted of cyclosporine and methotrexate. Twenty-three patients experienced acute GVHD and 17 developed chronic GVHD. Plasma elastase activity (EA) and plasma elastin-derived peptide concentration (EDPc) were measured. RESULTS: There were statistically significant differences in EA before HSCT (1.3 U/ml) compared with day +30 (2.9 U/ml) and day +100 (3.2 U/ml) after HSCT (p<0.001 for both). EA was also higher in patients with chronic GVHD than in those who did not develop chronic GVHD. EDPc was significantly higher on days +30 (49.3 U/ml) and +100 (57.7 U/ml) after HSCT than on day -10 before HSCT (15.5 U/ml, p<0.001 for both). EDPc was significantly higher in patients with chronic GVHD. CONCLUSIONS: EA and EDPc were increased in patients after HSCT. If the role of elastase in the pathogenesis of GVHD is confirmed, it will be possible to apply inhibitors of elastases in the treatment of this condition in the near future.

Treosulfan and fludarabine low-toxicity conditioning for allogeneic haematopoietic stem cell transplantation in chronic myeloid leukaemia.

Allogeneic haematopoietic stem cell transplantation (alloHSCT) is the only treatment of proven long-term efficacy in chronic myeloid leukaemia (CML), although high non-relapse mortality (NRM) observed after conventional myeloablative conditioning limits its applicability. This phase II trial evaluated the efficacy and toxicity of a new preparative regimen consisting of treosulfan 3 x 14 g/m(2) and fludarabine 5 x 30 mg/m(2), in patients with CML in chronic phase. Among the 40 patients included, 18 received alloHSCT from a sibling and 22 from an unrelated donor. All patients engrafted with 92.5% of cases achieving complete donor chimaerism by day +100. All but one patient had achieved complete cytogenetic remission on day +100. Grade III or IV non-haematological toxicities included: neutropenic fever (10%), nausea/vomiting (10%), elevated liver enzymes (5%) and infection (2.5%). The incidence of grade II-IV acute graft-versus-host disease (GVHD) was 22.5% and extensive chronic GVHD, 14%. The 2-year probability of overall survival, leukaemia-free survival and NRM was 85%, 82.5% and 15% respectively. At 1 year post-transplant, 85% of survivors had a Karnofsky index of 100%. We concluded that treosulfan and fludarabine conditioning is a low-toxicity regimen with high anti-leukaemic potential that seems feasible in CML patients referred for alloHSCT.