Publications by authors named "Damir Nemet"

53 Publications

Sarcopenia among patients after allogeneic hematopoietic stem cell transplantation and the impact of chronic graft-versus-host disease.

J Cancer Res Clin Oncol 2020 Nov 7;146(11):2967-2978. Epub 2020 Jun 7.

Clinical Unit of Clinical Nutrition, Department of Internal Medicine, University Hospital Centre Zagreb, Zagreb, Croatia.

Purpose: This study investigated the frequency and characteristics of sarcopenia among patients after allogeneic hematopoietic stem cell transplantation (allo-HSCT) with a specific focus on the chronic graft-versus-host disease (cGVHD) population and its association with malnutrition, vitamin D and clinical characteristics.

Methods: We assessed sarcopenia, vitamin D levels, and nutritional status in 73 patients who underwent allo-HSCT, of which 45 were diagnosed with cGVHD. Sarcopenia was diagnosed according to the European Working Group on Sarcopenia in Older People (EWGSOP) criteria.

Results: Sarcopenia was diagnosed in 19.2% of patients after allo-HSCT with statistically no significant difference between cGVHD and non-cGVHD patients. The risk factor for sarcopenia was the male gender. Sarcopenia in allo-HSCT patients correlated strongly with malnutrition and with current corticosteroid treatment (p < 0.005). Among cGVHD patients sarcopenia additionally correlated strongly with the number of prior systemic immunosuppressive therapy lines (p < 0.005) and moderately with the intensity of immunosuppression, cGVHD severity global rating assessed by both the health care provider and the patient and joint and fascia cGVHD involvement (p < 0.05). Vitamin D deficiency was found in more than 54.8% of patients, but the correlation to sarcopenia was not found.

Conclusion: Sarcopenia was found to be common in long term survivors of allo-HSCT independently of the cGVHD diagnosis. Prospective longitudinal studies are needed for a better understanding of factors affecting the development of sarcopenia after allo-HSCT.
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http://dx.doi.org/10.1007/s00432-020-03280-0DOI Listing
November 2020

Myeloablative conditioning for allo-HSCT in pediatric ALL: FTBI or chemotherapy?-A multicenter EBMT-PDWP study.

Bone Marrow Transplant 2020 08 17;55(8):1540-1551. Epub 2020 Mar 17.

Division for Stem Cell Transplantation and Immunology, Department for Children and Adolescents, University Hospital, Goethe University Frankfurt, Frankfurt, Germany.

Although most children with acute lymphoblastic leukemia (ALL) receive fractionated total body irradiation (FTBI) as myeloablative conditioning (MAC) for allogeneic hematopoietic stem cell transplantation (allo-HSCT), it is an important matter of debate if chemotherapy can effectively replace FTBI. To compare outcomes after FTBI versus chemotherapy-based conditioning (CC), we performed a retrospective EBMT registry study. Children aged 2-18 years after MAC for first allo-HSCT of bone marrow (BM) or peripheral blood stem cells (PBSC) from matched-related (MRD) or unrelated donors (UD) in first (CR1) or second remission (CR2) between 2000 and 2012 were included. Propensity score weighting was used to control pretreatment imbalances of the observed variables. 3.054 patients were analyzed. CR1 (1.498): median follow-up (FU) after FTBI (1.285) and CC (213) was 6.8 and 6.1 years. Survivals were not significantly different. CR2 (1.556): median FU after FTBI (1.345) and CC (211) was 6.2 years. Outcomes after FTBI were superior as compared with CC with regard to overall survival (OS), leukemia-free survival (LFS), relapse incidence (RI), and nonrelapse mortality (NRM). However, we must emphasize the preliminary character of the results of this retrospective "real-world-practice" study. These findings will be prospectively assessed in the ALL SCTped 2012 FORUM trial.
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http://dx.doi.org/10.1038/s41409-020-0854-0DOI Listing
August 2020

Influence of Blood Count, Cardiovascular Risks, Inherited Thrombophilia, and JAK2 V617F Burden Allele on Type of Thrombosis in Patients With Philadelphia Chromosome Negative Myeloproliferative Neoplasms.

Clin Lymphoma Myeloma Leuk 2019 01 10;19(1):53-63. Epub 2018 Sep 10.

School of Medicine, University of Zagreb, Zagreb, Croatia; Center for Medical Experts, Zagreb, Croatia.

Introduction: Thrombosis is the most common complication in Philadelphia chromosome negative (Ph-) myeloproliferative neoplasms patients.

Patients And Methods: In a cohort of 258 Ph- myeloproliferative neoplasm patients, the difference between patients with and without thrombosis was analyzed according to genetic thrombophilia factors, JAK2 V617F status and burden allele, blood count, cardiovascular risk factors and age. Patients were also divided in polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis (PMF) subgroups as well as by the type of thrombosis.

Results: Analysis of cardiovascular risk factors regarding arterial thrombosis showed that PV patients with thrombosis had higher incidence of diabetes (P = .030), ET patients more often had hypertension (P = .003) and hyperlipidemia (P = .005), while PMF patients had hyperlipidemia (P = .046) and at least one cardiovascular risk factor (P = .044). Moreover, leukocytes > 18 × 10/L and V617F burden allele > 25.7% were statistically significantly different in PV patients (P = .019 and borderline significant at P = .055, respectively), while in ET patients leukocytes > 9.2 × 10/L (P < .001) and age at diagnosis of > 55 years were statistically significantly different (P = .002). PMF patients with V617F burden allele ≤ 34.8% were more prone to thrombosis (P = .032). When comparing patients with and without venous thrombosis, cutoff value of V617F burden allele > 90.4% was significant for PV patients with thrombosis (P = .036), as was > 56.7% for PMF patients with thrombosis (P = .046). Platelets ≤ 536 × 10/L and age at diagnosis > 54 years showed statistically significant difference for ET patients with thrombosis (P = .015 and P = .041, respectively).

Conclusion: On the basis of our results, a new scoring system for thrombosis risk in PV could be made, while PMF prognostic model may be expanded for better recognition of potential thrombotic risk factors.
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http://dx.doi.org/10.1016/j.clml.2018.08.020DOI Listing
January 2019

Guidelines for Diagnosis and Treatment of Chronic Lymphocytic Leukemia. Krohem B-Cll 2017.

Acta Clin Croat 2018 Mar;57(1):190-215

Dubrava University Hospital, School of Medicine, University of Zagreb, Zagreb, Croatia.

Recent developments in the diagnosis and treatment of chronic lymphocytic leukemia (B-CLL) have led to change of approach in clinical practice. New treatments have been approved based on the results of randomized multicenter trials for first line and for salvage therapy, and the results of numerous ongoing clinical trials are permanently providing new answers and further refining of therapeutic strategies. This is paralleled by substantial increase in understanding the disease genetics due to major advances in the next generation sequencing (NGS) technology. We define current position of the Croatian Cooperative Group for Hematologic Disease on diagnosis and treatment of CLL in the transition from chemo-immunotherapy paradigm into a new one that is based on new diagnostic stratification and unprecedented therapeutic results of B-cell receptor inhibitors (BRI) and Bcl-2 antagonists. This is a rapidly evolving field as a great number of ongoing clinical trials con-stantly accumulate and provide new knowledge. We believe that novel therapy research including genomic diagnosis is likely to offer new options that will eventually lead to time limited therapies without chemotherapy and more effective clinical care for B-CLL based on individualized precision medicine.
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http://dx.doi.org/10.20471/acc.2018.57.01.27DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6400341PMC
March 2018

Multiple Myeloma Treatment in Real-world Clinical Practice: Results of a Prospective, Multinational, Noninterventional Study.

Clin Lymphoma Myeloma Leuk 2018 10 25;18(10):e401-e419. Epub 2018 Jun 25.

Myeloma Unit, Division of Hematology, Città della Salute e della Scienza, University of Torino, Turin, Italy.

Background: The present prospective, multinational, noninterventional study aimed to document and describe real-world treatment regimens and disease progression in multiple myeloma (MM) patients.

Patients And Methods: Adult patients initiating any new MM therapy from October 2010 to October 2012 were eligible. A multistage patient/site recruitment model was applied to minimize the selection bias; enrollment was stratified by country, region, and practice type. The patient medical and disease features, treatment history, and remission status were recorded at baseline, and prospective data on treatment, efficacy, and safety were collected electronically every 3 months.

Results: A total of 2358 patients were enrolled. Of these patients, 775 and 1583 did and did not undergo stem cell transplantation (SCT) at any time during treatment, respectively. Of the patients in the SCT and non-SCT groups, 49%, 21%, 14%, and 15% and 57%, 20%, 12% and 10% were enrolled at treatment line 1, 2, 3, and ≥ 4, respectively. In the SCT and non-SCT groups, 45% and 54% of the patients had received bortezomib-based therapy without thalidomide/lenalidomide, 12% and 18% had received thalidomide/lenalidomide-based therapy without bortezomib, and 30% and 4% had received bortezomib plus thalidomide/lenalidomide-based therapy as frontline treatment, respectively. The corresponding proportions of SCT and non-SCT patients in lines 2, 3, and ≥ 4 were 45% and 37%, 30% and 37%, and 12% and 3%, 33% and 27%, 35% and 32%, and 8% and 2%, and 27% and 27%, 27% and 23%, and 6% and 4%, respectively. In the SCT and non-SCT patients, the overall response rate was 86% to 97% and 64% to 85% in line 1, 74% to 78% and 59% to 68% in line 2, 55% to 83% and 48% to 60% in line 3, and 49% to 65% and 36% and 45% in line 4, respectively, for regimens that included bortezomib and/or thalidomide/lenalidomide.

Conclusion: The results of our prospective study have revealed great diversity in the treatment regimens used to manage MM in real-life practice. This diversity was linked to factors such as novel agent accessibility and evolving treatment recommendations. Our results provide insight into associated clinical benefits.
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http://dx.doi.org/10.1016/j.clml.2018.06.018DOI Listing
October 2018

Autologous blood as a source of platelet gel for the effective and safe treatment of oral chronic graft-versus-host disease.

Transfusion 2018 06 14;58(6):1494-1499. Epub 2018 Mar 14.

National Cancer Institute, Center for Cancer Research, NIH, Bethesda, Maryland.

Background: Oral chronic graft-versus-host disease (cGvHD) impairs oral function and patients' quality of life. Some lesions are refractory to local and systemic immunosuppressive therapy, and new therapeutic modalities are required. The aim of the study was to assess the efficacy and safety of topical application of autologous platelet gel (PG) in patients with oral cGvHD.

Study Design And Methods: PG was prepared from autologous blood and applied on ulcerous lesions using an automated system. The oral cGvHD was assessed using the 273-point Oral Mucositis Rating Scale (OMRS) prior and after completion of the PG treatment. The overall response to treatment of particular topography expressed as the total score on OMRS was compared to total score on National Institutes of Health cGvHD Oral Mucosal Score (NIH OMS). The pain intensity was measured by the Numeric Pain Rating Scale (NRS).

Results: In five patients, 12 autologous blood collections were performed; median 3 (range 1-3) per patient, and 26 PG applications were performed; median 6 (range 2-8) per patient. PG applications reduced lesions in oral cGvHD: median OMRS total score was reduced for 43.2% (range 9.6%-47.3%), and median NIH OMS total score for 27.3% (range 20.0%-50.0%) from baseline values. Median of pain intensity reduction on NRS scale was 57.1% (range 50%-100%). No side effects were observed.

Conclusion: Application of autologous PG in oral cGvHD showed as an efficient and safe treatment option for patients who do not respond to standard local treatment.
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http://dx.doi.org/10.1111/trf.14594DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6786782PMC
June 2018

Extensive Deep Venous Thrombosis in a Young Male Patient as the First Manifestation of a Rare Venous Anomaly - Inferior Vena Cava Duplication: Case Report.

Acta Clin Croat 2017 Jun;56(2):338-343

Division of Hematology, Department of Internal Medicine, Zagreb University Hospital Center; School of Medicine, University of Zagreb, Zagreb; School of Medicine, Josip Juraj Strossmayer University of Osijek, Osijek.

Although venous thromboembolism (VTE) including deep venous thrombosis (DVT) and pulmonary embolism is a major health problem in the world, it is an infrequent disease among young people. It is always mandatory to look at the underlying conditions for VTE, and in young patients, inherited prothrombotic factors should also be evaluated, especially in case of unprovoked VTE. Anomalies of inferior vena cava (IVC) are very rare in the general population. In this case report we describe rare occurrence of extensive DVT in a young male patient with rare anomaly of IVC - duplication of IVC - as a predisposition factor for DVT. Physicians need to be reminded of the IVC anomalies that should be considered in young patients with idiopathic DVT of lower extremity, which may require extended anticoagulant treatment.
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http://dx.doi.org/10.20471/acc.2017.56.02.19DOI Listing
June 2017

Role of Plasmapheresis in the Management of Acute Kidney Injury in Patients With Multiple Myeloma: Should We Abandon It?

Ther Apher Dial 2018 Feb 14;22(1):79-86. Epub 2017 Dec 14.

Department of Nephrology, Hypertension, Dialysis and Transplantation, University Hospital Centre Zagreb, Zagreb, Croatia.

The aim of the current study was to determine whether plasmapheresis in combination with chemotherapy could significantly remove free light chains (FLC) in multiple myeloma (MM) patients with acute kidney injury (AKI) and therefore improve renal recovery and patient survival. During the study period, 29 patients with MM and AKI presented to our unit and were treated with two different therapy modalities (plasmapheresis with chemotherapy or bortezomib). At the end of treatment, a significant decrease of FLCs was present in the group treated with plasmapheresis compared to the bortezomib group. Patients treated with plasmapheresis had similar survival compared to patients treated with bortezomib. There was a significantly higher decrease of FLCs and longer survival in patients treated with three or more plasmapheresis sessions than in patients treated with two plasmapheresis sessions. Plasmapheresis therapy still remains a useful and effective method in the treatment of AKI in MM patients. Plasmapheresis significantly reduces FLCs compared to bortezomib especially with higher number of plasma exchange sessions but it must be combined with other chemotherapy agents in order to prolong renal recovery and therefore patient survival.
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http://dx.doi.org/10.1111/1744-9987.12606DOI Listing
February 2018

High dose chemotherapy and autologous stem cell transplantation in nodular lymphocyte-predominant Hodgkin lymphoma: A retrospective study by the European society for blood and marrow transplantation-lymphoma working party.

Am J Hematol 2018 01 9;93(1):40-46. Epub 2017 Nov 9.

Lymphoma Working Party, EBMT, Paris, France.

Whilst autologous stem cell transplantation (auto-SCT) is considered standard of care for relapsed/refractory classical Hodgkin lymphoma, the role of auto-SCT in nodular lymphocyte-predominant Hodgkin lymphoma (NLPHL) is not well defined due to limited data. We report the first study on auto-SCT for NLPHL with a larger cohort. Eligible for this retrospective registry study were patients reported to the EBMT between 2003 and 2013, aged 18 or older with relapsed/refractory NLPHL who underwent first auto-SCT with disease chemosensitive to salvage therapy. NLPHL transformed to diffuse large B cell lymphoma were excluded. Sixty patients (83% male; median age 40 years) met the eligibility criteria. The median time between diagnosis and transplant was 21 months (IQR 13-58), and the median number of prior treatment lines was 2 (range 1-5), including rituximab in 63% of the patients. At auto-SCT, 62% of the patients were in complete remission (CR) and 38% in partial remission. Seventy-two percent of the patients received BEAM as high-dose therapy. With a median follow-up of 56 months (range 3-105), 5-year progression-free and overall survival (OS) were 66% and 87%, respectively. Univariate comparisons considering age, time from diagnosis to transplant, prior chemotherapy lines, and prior rituximab use failed to identify significant predictors for any survival endpoint except for being in CR at the time of auto-SCT (vs PR, P = .049) for OS. Auto-SCT in patients with relapsed/refractory NLPHL who are sensitive to salvage therapy gives excellent disease control and long-term survival independent of the time interval between diagnosis and transplant.
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http://dx.doi.org/10.1002/ajh.24927DOI Listing
January 2018

Gut Colonization by Multidrug-Resistant Gram-Negative Bacteria Is an Independent Risk Factor for Development of Intestinal Acute Graft-versus-Host Disease.

Biol Blood Marrow Transplant 2017 07 5;23(7):1221-1222. Epub 2017 Apr 5.

School of Medicine, University of Zagreb, Zagreb, Croatia; Department of Hematology, University Hospital Centre Zagreb, Zagreb, Croatia.

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http://dx.doi.org/10.1016/j.bbmt.2017.03.025DOI Listing
July 2017

[GUIDELINES FOR DIAGNOSIS AND TREATMENT OF PATIENTS WITH MYELODYSPLASTIC SYNDROME].

Lijec Vjesn 2017 Jan-Feb;139(1-2):1-11

Myelodysplastic syndrome Working Group of the Croatian Cooperative Group for Hematologic Diseases (CROHEM), Referral center of the Ministry of Health of the Republic of Croatia for diagnostics and treatment of MDS, as well as the Croatian Society for Haematology of the Croatian Medical Association have made Croatian guidelines for diagnosis and treatment of myelodysplastic syndrome (MDS). MDS is a heterogeneous group of clonal hematopoietic stem cell disorders characterized by ineffective hematopoiesis, dysplasia, cytopenia and risk of transformation to acute myeloid leukemia (AML). Diagnosis is based on morphological characteristics of hematopoietic cells supplemented with the cytogenetic analysis and bone marrow flow cytometry. Due to great differences in the natural course of the disease, i.e. time to progression to AML and the expected time of survival several scoring systems have been developed to determine the disease risk. The treatment of patients with MDS is based on the risk factors of the disease as well as the individual risk of treatment.
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January 2019

The impact of KIR2DS4 gene on clinical outcome after hematopoietic stem cell transplantation.

Hum Immunol 2017 Feb 18;78(2):95-102. Epub 2016 Dec 18.

Tissue Typing Centre, Clinical Department for Transfusion Medicine and Transplantation Biology, University Hospital Centre Zagreb, Zagreb, Croatia. Electronic address:

Killer cell immunoglobulin-like receptors (KIR) are a family of inhibitory/activating receptors expressed on NK cells. Interactions of KIR receptors with KIR ligands have been shown to modify hematopoietic stem cell transplantation (HSCT) outcome. The aim of this research was to determine the KIR2DS4 allele variants distribution among 111 patients with different hematological malignancy who underwent HSCT and their donors, and to evaluate KIR2DS4 alleles' impact on HSCT outcome. The KIR gene frequency analysis showed a significantly higher incidence of full-length KIR2DS4 alleles among patients. The impact of KIR2DS4 alleles on transplantation outcomes revealed that donors' full-length KIR2DS4 alleles is associated with lower overall survival rates, higher risk of GVHD and higher relapse incidence. The expression of full-length KIR2DS4 allele variants may contribute to a worse clinical outcome after HSCT. KIR typing for KIR2DS4 could be used as an additional criterion for selecting suitable donors in cases when more than one HLA identical donor is identified for a specific patient.
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http://dx.doi.org/10.1016/j.humimm.2016.11.010DOI Listing
February 2017

Autologous stem cell transplantation for adult acute myelocytic leukemia in first remission-Better outcomes after busulfan and melphalan compared with busulfan and cyclophosphamide: A retrospective study from the Acute Leukemia Working Party of the European Society for Blood and Marrow Transplantation (EBMT).

Cancer 2017 03 1;123(5):824-831. Epub 2016 Dec 1.

EBMT Office, INSERM Unit 938, St. Antoine Public Assistance Hospital, Pierre and Marie Curie University, Paris, France.

Background: Autologous stem cell transplantation (ASCT) for adult acute myelogenous leukemia (AML) is a valid therapeutic option for patients with good-risk and intermediate-risk disease. The authors used the registry of the European Society for Blood and Marrow Transplantation to compare combined busulfan and melphalan (BUMEL) with combined busulfan and cyclophosphamide (BUCY) before transplantation.

Methods: From 2005 to 2013, 853 patients with available cytogenetics underwent ASCT in first remission, including 257 after receiving BUMEL and 596 after receiving BUCY. The proportion of patients with good-risk AML was lower in those who received BUMEL (14% vs 20%; P = .02). More patients who received BUMEL underwent autograft in molecular remission (89% vs 78%; P = .02). Three years after transplantation, the relapse incidence (RI) was 48.7%, the leukemia-free survival (LFS) rate was 47.7%, the overall survival (OS) rate was 66.2%, and the nonrelapse mortality (NRM) rate was 3.6%.

Results: Patients who underwent an autograft after receiving BUMEL fared better than those who underwent an autograft after receiving BUCY with a lower RI (39.5% vs 52.2%; hazard ratio [HR], 0.65; 95% confidence interval [CI], 0.49-0.87; P = .003) a better LFS (55.4% vs 44.6%; HR, 0.69; 95% CI, 0.53-0.89; P = .005), and a better OS (73.8% vs 63%; HR, 0.62; 95% CI, 0.47-0.82; P = .0007). There was no difference in the NRM rate (BUMEL vs BUCY, 4.5% vs 3.2%, respectively). Among 74 patients in the BUMEL group and 187 in the BUCY group who underwent autograft in molecular remission, the RI was 30% versus 51%, respectively (univariate analysis; P = .01), and the LFS rate was 66% versus 47%, respectively (univariate analysis; P = .03).

Conclusions: In patients with AML in first complete remission who undergo ASCT, the BUMEL combination is a better preparative regimen. Cancer 2017;123:824-31. © 2016 American Cancer Society.
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http://dx.doi.org/10.1002/cncr.30400DOI Listing
March 2017

The effect of HLA allele and haplotype polymorphisms on donor matching in hematopoietic stem cell transplantation - Croatian experience.

Hum Immunol 2016 Dec 15;77(12):1120-1127. Epub 2016 Oct 15.

Tissue Typing Centre, Department of Transfusion Medicine and Transplantation Biology, University Hospital Centre Zagreb, Zagreb, Croatia.

The knowledge of HLA characteristics of a patient's population helps to predict the probability of finding a MUD. The study included 170 transplanted patients for whom a search for a MUD in BMDW was performed and a sample of 4000 volunteer unrelated donors from the Croatian Bone Marrow Donor Registry (CBMDR). Patients and their MUDs were typed for HLA-A, -B, -C, -DRB1, and -DQB1 loci using PCR-SSO and PCR-SSP methods while donors were typed for HLA-A, -B, -C, and -DRB1 loci using the PCR-SSO method. A comparison of allele frequencies at tested HLA loci between patients and donors from CBMDR did not reveal significant differences. The majority of patients (117, 68.8%) had a 10/10 MUD, 45 (26.5%) patients had a 9/10 MUD and eight (4.7%) patients had an 8/10 MUD. The highest number of mismatches (MM) was present at HLA-DRB1 (19; 31.1%). The presence of DRB1*11 and DRB1*04 allelic groups among patients caused allelic MMs at HLA-DRB1 in most cases. The presence of an infrequent HLA-B∼C haplotype resulted in the HLA-C MM at antigen level in the majority of cases. The present study clarified HLA factors that cause difficulties in searching for a 10/10 MUD for Croatian patients.
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http://dx.doi.org/10.1016/j.humimm.2016.10.004DOI Listing
December 2016

Joint and fascial chronic graft-vs-host disease: correlations with clinical and laboratory parameters.

Croat Med J 2016 Jun;57(3):266-75

Tamara Vukić, Department of Rehabilitation and Orthopeadic Aids, University Hospital Center Zagreb, Božidarevićeva 11, 10000 Zagreb, Croatia,

Aim: To determine if there are correlations between joint and fascial chronic graft-vs-host disease (cGVHD) with clinical findings, laboratory parameters, and measures of functional capacity.

Methods: 29 patients were diagnosed with cGVHD based on National Institutes of Health (NIH) Consensus Criteria at the University Hospital Centre Zagreb from October 2013 to October 2015. Physical examination, including functional measures such as 2-minute walk test and hand grip strength, as well as laboratory tests were performed. The relationship between these evaluations and the severity of joint and fascial cGVHD was tested by logistical regression analysis.

Results: 12 of 29 patients (41.3%) had joint and fascial cGVHD diagnosed according to NIH Consensus Criteria. There was a significant positive correlation of joint and fascial cGVHD and skin cGVHD (P<0.001), serum C3 complement level (P=0.045), and leukocytes (P=0.032). There was a significant negative correlation between 2-minute walk test (P=0.016), percentage of cytotoxic T cells CD3+/CD8+ (P=0.022), serum albumin (P=0.047), and Karnofsky score (P<0.001). Binary logistic regression model found that a significant predictor for joint and fascial cGVHD was cGVHD skin involvement (odds ratio, 7.79; 95 confidence interval 1.87-32.56; P=0.005).

Conclusion: Joint and fascial cGVHD manifestations correlated with multiple laboratory measurements, clinical features, and cGVHD skin involvement, which was a significant predictor for joint and fascial cGVHD.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4937232PMC
http://dx.doi.org/10.3325/cmj.2016.57.266DOI Listing
June 2016

Glycoprotein YKL-40: a novel biomarker of chronic graft-vs-host disease activity and severity?

Croat Med J 2016 Jun;57(3):239-46

Nadira Duraković, University Hospital Centre Zagreb, Dept of Internal Medicine, Division of Hematology, Kišpatićeva 12, 10000 Zagreb, Croatia,

Aim: To investigate whether increased YKL-40 levels positively correlate with graft-vs-host disease (cGVHD) activity and severity and if YKL-40 could serve as a disease biomarker.

Methods: This case-control study was conducted at the University Hospital Centre Zagreb from July 2013 to October 2015. 56 patients treated with hematopoietic stem cell transplantation (HSCT) were included: 35 patients with cGVHD and 21 without cGVHD. There was no difference between groups in age, sex, median time from transplant to study enrollment, intensity of conditioning, type of donor, or source of stem cells. Blood samples were collected at study enrollment and YKL-40 levels were measured with ELISA. Disease activity was estimated using Clinician's Impression of Activity and Intensity of Immunosuppression scales and disease severity using Global National Institutes of Health (NIH) score.

Results: YKL-40 levels were significantly higher in cGVHD patients than in controls (P=0.003). The difference remained significant when patients with myelofibrosis were excluded from the analysis (P=0.017). YKL-40 level significantly positively correlated with disease severity (P<0.001; correlation coefficient 0.455), and activity estimated using Clinician's Impression of Activity (P=0.016; correlation coefficient 0.412) but not using Intensity of Immunosuppression (P=0.085; correlation coefficient 0.296).

Conclusion: YKL-40 could be considered a biomarker of cGVHD severity and activity. However, validation in a larger group of patients is warranted, as well as longitudinal testing of YKL-40 levels in patients at risk of developing cGVHD.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4937225PMC
http://dx.doi.org/10.3325/cmj.2016.57.239DOI Listing
June 2016

High frequency of cutaneous manifestations including vitiligo and alopecia areata in a prospective cohort of patients with chronic graft-vs-host disease.

Croat Med J 2016 Jun;57(3):229-38

Romana Čeović, Department of Dermatology and Venereology, University of Zagreb School of Medicine and University Hospital Centre Zagreb, Šalata 4, HR-10000 Zagreb, Croatia,

Aim: To determine the frequency and the characteristics of cutaneous manifestations, especially vitiligo and alopecia areata, in patients with chronic graft-vs-host disease (cGVHD).

Methods: 50 patients with cGVHD were prospectively enrolled in the observational study protocol and evaluated by an experienced dermatologist. The evaluation was focused on the clinical spectrum of skin and adnexal involvement, and the cutaneous GVHD score was determined according to National Institutes of Health (NIH) Consensus criteria. The presence of vitiligo, alopecia, xerosis, nail changes, and dyspigmentation was also assessed.

Results: Out of 50 cGVHD patients, 28 (56%) had skin involvement, and 27 of them (96%) had hypo and/or hyperpigmentations. 11 patients (39%) had a mild cutaneous NIH cGVHD score, 22% moderate, and 39% severe. 15 (30%) patients had nail changes and 10 (20%) had vitiligo or alopecia areata. Univariate analysis showed that patients with vitiligo/alopecia areata received more lines of prior systemic immunosuppressive therapy (P=0.043), had lower Karnofsky performance status (P=0.028), and had a higher B-cell number (P=0.005), platelet count (P=0.022), and total protein (P=0.024). Vitiligo and alopecia areata were associated with higher NIH skin score (P=0.001), higher intensity of immunosuppressive treatment (P=0.020), and total body irradiation conditioning (P=0.040). Multivariate regression model showed that patients with higher NIH skin scoring were 3.67 times more likely to have alopecia and/or vitiligo (odds ratio 3.67; 95% confidence interval 1.26-10.73), controlled for all other factors in the model (age at study entry, number of B-cells, platelet count, and global NIH score).

Conclusion: These data indicate that vitiligo and alopecia areata occur more frequently in cGVHD than previously reported.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4937222PMC
http://dx.doi.org/10.3325/cmj.2016.57.229DOI Listing
June 2016

Comparison of Branded and Generic Imatinib Plasma Concentrations in Patients With Chronic Myelogenous Leukemia: Unicentric Study.

Clin Lymphoma Myeloma Leuk 2016 08 5;16(8):472-6. Epub 2016 May 5.

Department of Internal Medicine, Hematology Division, University Hospital Center Zagreb, Zagreb, Croatia; Department of Internal Medicine, University of Zagreb School of Medicine, Zagreb, Croatia.

Introduction: For over a decade, imatinib has been the first-line treatment of Philadelphia chromosome-positive chronic myeloid leukemia (CML). Doubts on the bioequivalence and bioavailability of emerging generic compounds have been expressed. Adequate imatinib plasma concentration ([IPC] ≥1000 μmol/L) is associated with a better chance of optimal treatment response in patients with CML. In this study, we compared the achieved IPCs between the branded compound and its 2 generic forms.

Patients And Methods: IPCs were compared in 24 consecutive patients with CML in the first chronic phase who changed from branded to generic imatinib. The median age was 49 years (range, 22-76 years). Fifteen of them were male. Six patients were switched to Neopax, 13 to Imakrebin, and 5 patients received both generics consecutively. All compounds were used in an equivalent dose of 400 mg orally once daily for at least 1 month before plasma concentrations were measured. High-performance liquid chromatography was used to determine imatinib plasma concentration from a specimen collected 21 to 24 hours after the last dose.

Results: The median IPC achieved with branded imatinib was 1454 μmol/L (range, 485-2707 μmol/L) with 18 patients (75%) having IPC ≥ 1000 μmol/L. For Neopax and Imakrebin, median IPCs were 1717 μmol/L (range, 1249-3630 μmol/L) and 1458 μmol/L (range, 707-880 μmol/L), respectively, with 11 of 11 (100%) and 16 of 18 (89%) patients having IPC ≥ 1000 μmol/L. No significant difference in measured IPCs between all 3 compounds was found (P > .257).

Conclusion: When taken at equivalent doses, imatinib generics are bioequivalent and comparable in clinical efficacy and have the potential for substantial savings in the treatment cost for CML.
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http://dx.doi.org/10.1016/j.clml.2016.04.003DOI Listing
August 2016

High-dose ifosfamide and mitoxantrone (HDIM) in patients with relapsed or refractory Hodgkin's lymphoma.

Ann Hematol 2016 Jun 22;95(7):1129-36. Epub 2016 Apr 22.

Division of Hematology, Department of Internal Medicine, University Hospital Centre Zagreb, Kišpatićeva 12, 10000, Zagreb, Croatia.

Relapsed/refractory Hodgkin's lymphoma (HL) is treated with salvage chemotherapy and autologous stem cell transplantation (ASCT). Optimal chemotherapy is unknown. We retrospectively analyzed outcomes of 58 patients treated with 2 cycles of high-dose ifosfamide and mitoxantrone (HDIM). HDIM consisted of ifosfamide 5 g/m(2)/day and MESNA 5 g/m(2)/day in continuous 24-h infusion (days 1 and 2), MESNA 2.5 g/m(2) over 12 h (day 3), and mitoxantrone 20 mg/m(2) (day 1) administered every 2 weeks. Stem cells were collected after the first cycle. Responding patients proceeded to ASCT. Toxicity was acceptable. Stem cell mobilization was successful in 96 % of patients. Overall response rate was 74 % (89 % in relapsing and 45 % in refractory patients) with 31 % complete remissions. After a median follow-up of 54 months, 5-year event-free survival was 56 % (69 % for relapsing and 35 % for refractory patients), and 5-year overall survival was 67 % (73 % for relapsing and 55 % for refractory patients). Significant adverse prognostic factors were refractoriness to previous therapy and HDIM failure. No differences in outcomes were noted between patients with early and late relapses or between complete and partial responders. HDIM is a well-tolerated and effective regimen for relapsed and refractory HL with excellent stem cell mobilizing properties. Patients failing HDIM may still benefit from other salvage options.
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http://dx.doi.org/10.1007/s00277-016-2676-0DOI Listing
June 2016

Which questionnaires should we use to evaluate quality of life in patients with chronic graft-vs-host disease?

Croat Med J 2016 Feb;57(1):6-15

Zinaida Perić, Department of Internal Medicine, University of Zagreb, School of Medicine, Zagreb, Croatia,

Aim: To investigate the ability of two standard quality of life (QOL) questionnaires - The Short Form (36-item) Health Survey (SF-36) and The European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 (EORTC QLQ C30) to evaluate QOL in patients with chronic graft-vs-host disease (cGVHD) graded according to National Institutes of Health (NIH) consensus criteria.

Methods: In this cross-sectional study, QOL was assessed in patients who underwent allogeneic stem cell transplantation (allo-SCT) at the University Hospital Centre Zagreb and were alive and in complete remission for more than one year after allo-SCT.

Results: The study included 58 patients, 38 patients with cGVHD and 20 controls, patients without cGVHD. Patients with cGVHD scored according to the NIH criteria had significantly lower scores of global health status and lower QOL on all SF-36 subscales and most of QLQ C30 functional subscales (P<0.050 for all comparisons). Furthermore, patients with active cGVHD had significantly lower QOL scores than patients with inactive cGVHD, and this difference was most evident in physical functioning subscale of SF-36 (P=0.0007) and social functioning subscale of QLQ C30 (P=0.009).

Conclusion: cGVHD scored according to the NIH criteria is correlated with patient-reported QOL, particularly in the physical domains as detected by SF-36. QLQ C30 questionnaire adds more information on social functioning and should be used as a valuable tool in the evaluation of social domains in cGVHD patients.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4800326PMC
http://dx.doi.org/10.3325/cmj.2016.57.6DOI Listing
February 2016

Chronic graft-vs-host disease in 2016: a major challenge and an opportunity.

Croat Med J 2016 Feb;57(1):1-3

Dražen Pulanić, Division of Hematology, Department of Internal Medicine, University Hospital Center Zagreb, Zagreb, Croatia,

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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4800321PMC
http://dx.doi.org/10.3325/cmj.2016.57.1DOI Listing
February 2016

Potential of glycosylation research in graft versus host disease after allogeneic hematopoietic stem cell transplantation.

Biochim Biophys Acta 2016 Aug 26;1860(8):1615-22. Epub 2016 Feb 26.

Graft-versus-Host and Autoimmunity Section, Experimental Transplantation and Immunology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.

Background: Glycans, complex oligosaccharides, are directly involved in almost every biological process, have a fundamental role in the immune system, and are probably involved in nearly every human disease. However, glycosylation has been greatly ignored in the area of allogeneic hematopoietic stem cell transplantation (alloHSCT) and graft versus host disease (GVHD). Both acute and chronic GVHD are multisystemic debilitating immunological disturbances arising after alloHSCT.

Scope Of Review: In this paper, we review the glycosylation research already done in the field of alloHSCT and GVHD and evaluate further potential of glycan analysis in GVHD by looking into resembling inflammatory and autoimmune conditions.

Major Conclusions: Glycan research could bring significant improvement in alloHSCT procedure with reduction in following complications, such as GVHD. Identifying glycan patterns that induce self-tolerance and the ones that cause the auto- and allo-immune response could lead to innovative and tissue-specific immunomodulative therapy instead of the current immunosuppressive treatment, enabling preservation of the graft-versus-tumor effect. Moreover, improved glycan pattern analyses could offer a more complete assessment and greatly needed dynamic biomarkers for GVHD.

General Significance: This review is written with a goal to encourage glycan research in the field of alloHSCT and GVHD as a perspective tool leading to improved engraftment, discovery of much needed biomarkers for GVHD, enabling an appropriate therapy and improved monitoring of therapeutic response. This article is part of a Special Issue entitled "Glycans in personalised medicine" Guest Editor: Professor Gordan Lauc.
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http://dx.doi.org/10.1016/j.bbagen.2016.02.015DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4907829PMC
August 2016

Venous thromboembolism in Croatia - Croatian Cooperative Group for Hematologic Diseases (CROHEM) study.

Croat Med J 2015 Dec;56(6):550-7

Dražen Pulanić, Kišpatićeva 12, 10000 Zagreb, Croatia,

Aim: To analyze the incidence and characteristics of venous thromboembolism (VTE) in Croatia.

Methods: The Croatian Cooperative Group for Hematologic Diseases conducted an observational non-interventional study in 2011. Medical records of patients with newly diagnosed VTE hospitalized in general hospitals in 4 Croatian counties (Šibenik-Knin, Koprivnica-Križevci, Brod-Posavina, and Varaždin County) were reviewed. According to 2011 Census, the population of these counties comprises 13.1% of the Croatian population.

Results: There were 663 patients with VTE; 408 (61.54%) had deep vein thrombosis, 219 (33.03%) had pulmonary embolism, and 36 (5.43%) had both conditions. Median age was 71 years, 290 (43.7%) were men and 373 (56.3%) women. Secondary VTE was found in 57.3% of participants, idiopathic VTE in 42.7%, and recurrent VTE in 11.9%. There were no differences between patients with secondary VTE and patients with idiopathic VTE in disease recurrence and sex. The most frequent causes of secondary VTE were cancer (40.8%), and trauma, surgery, and immobilization (38.2%), while 42.9% patients with secondary VTE had ≥2 causes. There were 8.9% patients ≤45 years; 3.3% with idiopathic or recurrent VTE. Seventy patients (10.6%) died, more of whom had secondary (81.4%) than idiopathic (18.6%) VTE (P<0.001), and in 50.0% VTE was the main cause of death. Estimated incidence of VTE in Croatia was 1.185 per 1000 people.

Conclusion: Characteristics of VTE in Croatia are similar to those reported in large international studies. Improved thromboprophylaxis during the presence of risk factors for secondary VTE might substantially lower the VTE burden.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4707926PMC
http://dx.doi.org/10.3325/cmj.2015.56.550DOI Listing
December 2015

Immunoglobulin heavy/light chain analysis enhances the detection of residual disease and monitoring of multiple myeloma patients.

Croat Med J 2015 Jun;56(3):263-71

Josip Batinić, University Hospital Centre Zagreb, Kišpatićeva 12, 10000 Zagreb, Croatia,

Aim: To evaluate the clinical utility of incorporating a novel heavy/light chain immunoassay (HLC) into the existing methods for the assessment of multiple myeloma (MM) patients.

Methods: Convenience sera samples from 90 previously treated IgG and IgA MM patients in different disease stages were analyzed. The study was conducted in Clinical Hospital Center Zagreb between 2011 and 2013. The collected sera were analyzed by standard laboratory techniques (serum protein electrophoresis, quantification of total immunoglobulins, serum immunofixation, serum free light chain [FLC] assay) and HLC assay.

Results: HLC ratios outside the normal range were found in 58 of 90 patients, including 28 out of 61 patients with total immunoglobulin measurements within the normal range and 5 out of 23 patients in complete response. Both elevated HLC isotype level and abnormal HLC ratio correlated with the parameters of tumor burden, including percentage of plasma cells in the bone marrow (P<0.001 and P=0.002, respectively) and an abnormal serum FLC ratio (for both P<0.001). In addition, abnormal HLC isotype level correlated with serum beta-2-microglobulin level (P=0.038). In terms of prognosis, abnormal HLC isotype level and abnormal HLC ratio were significantly associated with shorter overall survival (P<0.001 and P=0.002, respectively). Interestingly, suppression of the uninvolved (polyclonal) isotype pair, but not other non-myeloma immunoglobulin isotypes, was also associated with a shorter overall survival (P=0.021). In a multivariate analysis, an abnormal HLC ratio and β2-microglobulin level >3.5mg/L were independent risk factors for survival.

Conclusion: The new HLC assay has greater sensitivity in detecting monoclonal protein, correlates with tumor burden markers, and affects patients' outcome.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4500978PMC
http://dx.doi.org/10.3325/cmj.2015.56.263DOI Listing
June 2015

[Gaucher disease - guidelines for diagnosis and management of adult patients].

Lijec Vjesn 2014 Sep-Oct;136(9-10):300-2

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December 2015

Prognostic significance of constitutive phosphatidylinositol 3-kinase/Akt and mitogen-activated protein kinase phosphorylation in acute myeloid leukemia.

Leuk Lymphoma 2015 29;56(8):2281-8. Epub 2014 Dec 29.

a Clinical Unit of Cellular Immunodiagnostics and In Vitro Procedures, Clinical Department of Laboratory Diagnostics , University Hospital Center Zagreb , Zagreb , Croatia.

Acute myeloid leukemia (AML) is a malignant hematopoietic disease with poor clinical course and outcome. There is a constant need for new prognostic factors that could facilitate patient risk stratification. The aim of our research was to determine the phosphorylation levels of phosphatidylinositol 3-kinase (PI3K)/Akt and mitogen-activated protein kinase (MAPK) pathways in leukemic cells, their relation to P-glycoprotein (P-gp) expression/activity and their prognostic significance in adult de novo AML. A total of 118 patients with AML were enrolled in the study. In a multivariate Cox regression analysis we found that P-gp activity and Akt phosphorylation were independent poor prognostic factors of overall survival (OS). In contrast, phosphorylated extracellular signal-regulated kinase 1/2 (ERK1/2) represented a favorable prognostic factor of OS and relapse-free survival (RFS). A negative correlation between P-gp activity and p38 phosphorylation level was found, implying a possible role of this MAPK pathway in P-gp regulation. In addition, we found correlation between Akt and p38 phosphorylation levels, indicative of co-activation of two signaling cascades in AML.
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http://dx.doi.org/10.3109/10428194.2014.990012DOI Listing
April 2016

Plasma levels of osteopontin and vascular endothelial growth factor in association with clinical features and parameters of tumor burden in patients with multiple myeloma.

Biomed Res Int 2014 4;2014:513170. Epub 2014 Jun 4.

Department of Pathology, School of Medicine, University of Rijeka, Braće Branchetta 20, 51000 Rijeka, Croatia.

The aim of this pilot study was to determine the plasma levels of osteopontin (OPN) and vascular endothelial growth factor (VEGF) and find possible association between them and main clinical features and parameters of tumor burden in patient with multiple myeloma (MM). Plasma levels of OPN and VEGF were determined in 44 newly diagnosed MM patients and 24 healthy persons by ELISA method. These values were compared with the presence of anemia, renal dysfunction, and bone lesions as myeloma related clinical manifestations and with serum beta-2 microglobulin and Durie-Salmon clinical stage as prognosticators related to tumor mass. The value of OPN was significantly higher in MM patients with evident bone lesions (P = 0.03) and there was also a positive correlation with serum beta-2 microglobulin (r = 0.366; P = 0.04). Furthermore, patients with lower Durie-Salmon stage had significantly lower OPN and VEGF levels (P = 0.05; P = 0.04, resp.). Our preliminary results found positive association between plasma level of OPN, tumor burden, and bone destruction. Further analysis should provide information about the possible use of OPN as useful clinical biomarker for monitoring bone disease and tumor mass, as well as a prognostic factor, or a possible target for pharmacological intervention.
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http://dx.doi.org/10.1155/2014/513170DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4065766PMC
February 2015

HLA allele and haplotype polymorphisms among Croatian patients in an unrelated hematopoietic stem cell donor search program.

Transpl Immunol 2014 Sep 27;31(3):119-24. Epub 2014 Jun 27.

Tissue Typing Center, Clinical Department for Transfusion Medicine and Transplantation Biology, University Hospital Centre Zagreb, Croatia.

The aim of the present study was to investigate HLA alleles and haplotypes among Croatian patients in an unrelated HSCT program, and to analyze HLA matching in patient/donor pairs. Analysis was performed on a group of 105 patients and their donors, and 4000 unrelated donors from our registry (CBMDR) served as controls. PCR-SSO and PCR-SSP high-resolution methods for HLA-A, -B, -C, -DRB1, and -DQB1 loci were used for typing patient/donor pairs. Donors from CBMDR were tested for HLA-A, -B, and -DRB1 by PCR-SSO. No difference in frequency at HLA tested loci among patients and donors from CBMDR was observed. A fully matched donor (10/10) was found for 68 (64.8%) patients, and the highest number of mismatches was found for HLA-DRB1 and HLA-C alleles. The presence of HLA-B alleles (B*15:01, B*18:01, and B*51:01) associated with two or more HLA-C alleles as well as the presence of unusual HLA-B/HLA-C (B*35:01-C*07:01 and B*35:01-C*14:02) combinations resulted in mismatches at the HLA-C locus. Additionally, mismatches at the DRB1 locus were in most cases found for DRB1*11 alleles. The results suggest that the DRB1*11:04 allele might be considered as a limiting factor in finding a 10/10 matched donor. These data may help in the improvement of the searching protocol for unrelated donors for Croatian patients.
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http://dx.doi.org/10.1016/j.trim.2014.06.007DOI Listing
September 2014

Two different dosing regimens of human recombinant erythropoietin beta during preoperative autologous blood donation in patients having hip arthroplasty.

Int Orthop 2012 Apr 1;36(4):703-9. Epub 2011 Oct 1.

Department of Orthopaedic Surgery, Clinical Hospital Centre Zagreb, School of Medicine, University of Zagreb, Zagreb, Croatia.

Purpose: Our aim was to evaluate the effectiveness of two different dosing regimens of human recombinant erythropoietin (rHu-EPO) for preoperative autologous blood collection in patients undergoing total hip arthroplasty (THA).

Methods: Prospective randomised trials in which erythropoietin 15,000 IU was administered intravenously twice a week or 30,000 IU once a week (total 90,000 IU) combined with ferrous II sulphate (Ferro-Gradumet 2) orally and compared with Ferro-Gradumet 2 alone.

Results: Although different dosing regimens of rHu-EPO administration during preoperative autologous blood donation have similar effects on the collection of two units of autologous blood, preoperative haemoglobin level and perioperative allogenic blood transfusion, a once weekly dose regimen of rHu-EPO was more convenient (although not statistically significantly) for patients.

Conclusion: We recommend the more practical and comfortable but yet highly effective therapeutic regimen with a single weekly intravenous administration of rHu-EPO for patients scheduled for THA.
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http://dx.doi.org/10.1007/s00264-011-1367-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3311821PMC
April 2012

Efficacy and safety of colistin in the treatment of infections caused by multidrug-resistant Pseudomonas aeruginosa in patients with hematologic malignancy: a matched pair analysis.

Intern Med 2011 1;50(9):1009-13. Epub 2011 May 1.

Department of Internal Medicine, Division of Hematology, Clinical Hospital Center Zagreb, Croatia.

Objective: A rise in infections with multidrug-resistant Pseudomonas aeruginosa (MDR-PA) is a significant contributor to increased morbidity and mortality of patients with hematologic malignancies. The aim of this study was to determine the efficacy and safety of colistin (colistimethate sodium) in the treatment of serious infections caused by MDR-PA in these patients.

Patients And Methods: A matched pair analysis of renal function, toxicities, and outcome of 26 patients receiving colistin and control subjects was done. All patients had clinical signs of sepsis; P. aeruginosa was isolated from blood in 69% of patients in colistin group and 84% in control group. Patients treated with colistin received 3 million units every 8 hours for a median duration of 13 days. Additionally, patients received at least two additional antimicrobial or antifungal drugs.

Results: Resolution of infection was achieved in twenty patients (76.9%) receiving colistin and in 17 (65.4%) control subjects. Mortality rate was 11% in both groups. There was no statistically significant difference in the level of serum creatinine, creatinine clearance, or potassium levels before and after treatment between groups. Only one patient receiving colistin developed de novo renal failure and one displayed transient neurologic toxicity.

Conclusion: Our results suggest that in patients with hematologic malignancies, colistin is effective in treating severe infections caused by MDR-PA while maintaining an acceptable toxicity profile. Prospective randomized studies comparing efficacy and safety of colistin with those of other antipseudomonal drugs are needed.
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http://dx.doi.org/10.2169/internalmedicine.50.4270DOI Listing
August 2011