Evaluation of the quality of life of adult patients admitted to the bone marrow transplantation unit.

INTRODUCTION: The complexity of treatment and extended therapy duration associated with bone marrow transplantation directly affect the psychological well-being of the patients, create anxiety, and reduce their quality of life. The aim of our study was to evaluate the quality of life of patients admitted to the bone marrow transplantation unit. METHODS: This prospective and descriptive study was conducted between January and June 2021 in an adult BMT unit in Turkey. The sociodemographic characteristics of the patients were recorded. The patient's quality of life was measured twice using the Functional Assessment of Cancer Therapy-Bone Marrow Transplantation (FACT-BMT) scale at the beginning of the study and 30 days later. SPSS 15 was used for the analysis. RESULTS: A total of 40 patients were included in the study. The mean age was 46 years. Most of the patients were diagnosed with multiple myeloma and 58% had at least one comorbid disease. Most of the patients (78%) were receiving myeloablative therapy. High dose melphalan regimen was the most commonly applied regimen (25%). Thrombocytopenia was the most common side effect (14%). Although there was no change in the quality of life, it was found that the social/family well-being scores increased (p < 0.05). CONCLUSIONS: In our study, it was observed that the number of comorbid diseases was higher in patients with bone marrow transplantation. The incidence of side effects may be high in these patients. We believe that clinical pharmacists have an important role in monitoring adverse effects and improving the quality of life in bone marrow transplantation units.

Germline genetic variants in Turkish familial multiple myeloma/monoclonal gammopathy of undetermined significance cases.

Multiple myeloma (MM) is a haematological malignancy primarily affecting the elderly, with a striking male predilection and ethnic disparities in incidence. Familial predisposition to MM has long been recognized, but the genetic underpinnings remain elusive. This study aimed to investigate germline variants in Turkish families with recurrent MM cases. A total of 37 MM-affected families, comprising 77 individuals, were included. Targeted next-generation sequencing analysis yielded no previously reported rare variants. Whole exome sequencing analysis in 11 families identified rare disease-causing variants in various genes, some previously linked to familial MM and others not previously associated. Notably, genes involved in ubiquitination, V(D)J recombination and the PI3K/AKT/mTOR pathway were among those identified. Furthermore, a specific variant in BNIP1 (rs28199) was found in 13 patients across nine families, indicating its potential significance in MM pathogenesis. While this study sheds light on genetic variations in familial MM in Turkey, its limitations include sample size and the absence of in vivo investigations. In conclusion, familial MM likely involves a polygenic inheritance pattern with rare, disease-causing variants in various genes, emphasizing the need for international collaborative efforts to unravel the intricate genetic basis of MM and develop targeted therapies.

Preliminary Report of the Academic CAR-T (ISIKOK-19) Cell Clinical Trial in Turkey: Characterization of Product and Outcomes of Clinical Application

Objective: Chimeric antigen receptor T (CAR-T) cell therapies have already made an impact on the treatment of B-cell malignancies. Although CAR-T cell therapies are promising, there are concerns about commercial products regarding their affordability and sustainability. In this preliminary study, the results of the first production and clinical data of an academic CAR-T cell (ISIKOK-19) trial in Turkey are presented. Materials and Methods: A pilot clinical trial (NCT04206943) designed to assess the safety and feasibility of ISIKOK-19 T-cell therapy for patients with relapsed and refractory CD19+ tumors was conducted and participating patients received ISIKOK-19 infusions between October 2019 and July 2021. The production data of the first 8 patients and the clinical outcome of 7 patients who received ISIKOK-19 cell infusions are presented in this study. Results: Nine patients were enrolled in the trial [5 with acute lymphoblastic leukemia (ALL) and 4 with non-Hodgkin lymphoma (NHL)], but only 7 patients could receive treatment. Two of the 3 participating ALL patients and 3 of the 4 NHL patients had complete/partial response (overall response rate: 72%). Four patients (57%) had CAR-T-related toxicities (cytokine release syndrome, CAR-T-related encephalopathy syndrome, and pancytopenia). Two patients were unresponsive and had progressive disease following CAR-T therapy. Two patients with partial response had progressive disease during follow-up. Conclusion: Production efficacy and fulfillment of the criteria of quality control were satisfactory for academic production. Response rates and toxicity profiles were also acceptable for this heavily pretreated/refractory patient group. ISIKOK-19 cells appear to be a safe, economical, and efficient treatment option for CD19+ tumors. However, the findings of this study need to be supported by the currently ongoing ISIKOK-19 clinical trial.

Gamma-irradiated SARS-CoV-2 vaccine candidate, OZG-38.61.3, confers protection from SARS-CoV-2 challenge in human ACEII-transgenic mice.

The SARS-CoV-2 virus caused the most severe pandemic around the world, and vaccine development for urgent use became a crucial issue. Inactivated virus formulated vaccines such as Hepatitis A and smallpox proved to be reliable approaches for immunization for prolonged periods. In this study, a gamma-irradiated inactivated virus vaccine does not require an extra purification process, unlike the chemically inactivated vaccines. Hence, the novelty of our vaccine candidate (OZG-38.61.3) is that it is a non-adjuvant added, gamma-irradiated, and intradermally applied inactive viral vaccine. Efficiency and safety dose (either 1013 or 1014 viral RNA copy per dose) of OZG-38.61.3 was initially determined in BALB/c mice. This was followed by testing the immunogenicity and protective efficacy of the vaccine. Human ACE2-encoding transgenic mice were immunized and then infected with the SARS-CoV-2 virus for the challenge test. This study shows that vaccinated mice have lowered SARS-CoV-2 viral RNA copy numbers both in oropharyngeal specimens and in the histological analysis of the lung tissues along with humoral and cellular immune responses, including the neutralizing antibodies similar to those shown in BALB/c mice without substantial toxicity. Subsequently, plans are being made for the commencement of Phase 1 clinical trial of the OZG-38.61.3 vaccine for the COVID-19 pandemic.

Preclinical efficacy and safety analysis of gamma-irradiated inactivated SARS-CoV-2 vaccine candidates.

COVID-19 outbreak caused by SARS-CoV-2 created an unprecedented health crisis since there is no vaccine for this novel virus. Therefore, SARS-CoV-2 vaccines have become crucial for reducing morbidity and mortality. In this study, in vitro and in vivo safety and efficacy analyzes of lyophilized vaccine candidates inactivated by gamma-irradiation were performed. The candidate vaccines in this study were OZG-3861 version 1 (V1), an inactivated SARS-CoV-2 virus vaccine, and SK-01 version 1 (V1), a GM-CSF adjuvant added vaccine. The candidate vaccines were applied intradermally to BALB/c mice to assess toxicity and immunogenicity. Preliminary results in vaccinated mice are reported in this study. Especially, the vaccine models containing GM-CSF caused significant antibody production with neutralization capacity in absence of the antibody-dependent enhancement feature, when considered in terms of T and B cell responses. Another important finding was that the presence of adjuvant was more important in T cell in comparison with B cell response. Vaccinated mice showed T cell response upon restimulation with whole inactivated SARS-CoV-2 or peptide pool. This study shows that the vaccines are effective and leads us to start the challenge test to investigate the gamma-irradiated inactivated vaccine candidates for infective SARS-CoV-2 virus in humanized ACE2 + mice.

Preclinical Assessment of Efficacy and Safety Analysis of CAR-T Cells (ISIKOK-19) Targeting CD19-Expressing B-Cells for the First Turkish Academic Clinical Trial with Relapsed/Refractory ALL and NHL Patients

Objective: Relapsed and refractory CD19-positive B-cell acute lymphoblastic leukemia (ALL) and non-Hodgkin lymphoma (NHL) are the focus of studies on hematological cancers. Treatment of these malignancies has undergone recent transformation with the development of new gene therapy and molecular biology techniques, which are safer and well-tolerated therapeutic approaches. The CD19 antigen is the most studied therapeutic target in these hematological cancers. This study reports the results of clinical-grade production, quality control, and in vivo efficacy processes of ISIKOK-19 cells as the first academic clinical trial of CAR-T cells targeting CD19-expressing B cells in relapsed/refractory ALL and NHL patients in Turkey. Materials and Methods: We used a lentiviral vector encoding the CD19 antigen-specific antibody head (FMC63) conjugated with the CD8-CD28-CD3ζ sequence as a chimeric antigen receptor (CAR) along with a truncated form of EGFR (EGFRt) on human T-lymphocytes (CAR-T). We preclinically assessed the efficacy and safety of the manufactured CAR-T cells, namely ISIKOK-19, from both healthy donors' and ALL/NHL patients' peripheral blood mononuclear cells. Results: We showed significant enhancement of CAR lentivirus transduction efficacy in T-cells using BX-795, an inhibitor of the signaling molecule TBK1/IKKƐ, in order to cut the cost of CAR-T cell production. In addition, ISIKOK-19 cells demonstrated a significantly high level of cytotoxicity specifically against a CD19+ B-lymphocyte cancer model, RAJI cells, in NOD/SCID mice. Conclusion: This is the first report of preclinical assessment of efficacy and safety analysis of CAR-T cells (ISIKOK-19) targeting CD19-expressing B cells in relapsed/refractory ALL and NHL patients in Turkey.

Induction of apoptosis and inhibition of growth of human hepatoma HepG2 cells by heparin.

BACKGROUND/AIMS: Apoptotic and anti-proliferative effects of heparin on a number of cancers have been described. There have been no studies analyzing the effect of heparin on human hepatoma cells. The aim of this study was to investigate the effect of heparin on human hepatoma cell line, HepG2. METHODOLOGY: HepG2 cell line was cultured with different concentrations of heparin. Colony count, viability assay, percentage of the apoptosis and proliferative index were assessed at the end of the 7th day. Trypan blue was used to assess viability. Apoptosis and proliferative indexes were assessed by flow-cytometry. RESULTS: Hepatoma cells were arrested at the G0/G1 phase with heparin incubation and proliferative indexes decreased significantly in 20, 40 and 80 U/mL of heparin concentrations in comparison with the control (36 +/- 1%, 30 +/- 5% and 29 +/- 8% vs. 44 +/- 1%, p < 0.01). Flow cytometry revealed a statistically significant increase in apoptosis in groups incubated with 40 and 80 U/mL of heparin in comparison with the control (39 +/- 26% and 58 +/- 18% vs. 0.83 +/- 1.3%, p < 0.01). Colony counts per well and viable cells per microL decreased significantly in 80 U/mL of heparin. CONCLUSIONS: Heparin leads to a significant anti-proliferative and an apoptotic effect on human hepatoma cells in vitro.

Large volume donor plasmapheresis in inherited thrombophilia implicated in arterial thrombosis.

BACKGROUND: Life-threatening complications following apheresis are rare, and include venous thrombosis. Arterial thrombosis following apheresis has not been reported. CASE REPORT: A 48 year old donor had cerebral infarction following large volume plasma donation. The outcome was fatal. He was found to be heterozygous for both methylene tetrahydrofolate reductase (MTHFR) 677C-T mutation and Prothrombin 20210G-A allele. CONCLUSION: This case suggests that large volume plasma donation may trigger arterial thrombotic events in inherited thrombophilia. Therefore, the effects of plasmapheresis on coagulation system should be studied thoroughly.

Causes and risk factors for liver injury following bone marrow transplantation.

GOALS: A retrospective study of pretransplantation risk factors predisposing to liver injury following bone marrow transplantation (BMT). BACKGROUND: Liver complications are a major cause of morbidity and mortality following BMT. Determination of the pretransplantation factors that are likely to lead to liver injury may allow earlier diagnosis after BMT and may possibly improve prognosis. STUDY: Medical records of BMT patients were reviewed, and results of serial liver function tests and HBV/HCV serology during the pre- and posttransplantation 1-year period were noted. Presence of liver injury was defined as alanine aminotransferase levels twice the upper limit of normal. Forty-four allogeneic and 17 autologous BMTs, performed between 1990 and 2000, were analyzed in the study. RESULTS AND CONCLUSION: One-year survival was 77% (34 of 44 patients) for allogeneic BMT and 52% (9 of 17 patients) for autologous BMT. Seventy-two percent (32 of 44) of allogeneic transplant recipients and 47% (8 of 17) of autologous transplant recipients had liver injury during the first year of BMT. The most frequent causes of liver injury were graft-versus-host disease and drug hepatotoxicity for allogeneic BMT and drug hepatotoxicity for autologous BMT. Fulminant hepatic failure occurred in one allogeneic transplant recipient who was a pretransplantation HBV carrier and led to death. Multivariate regression analysis showed that pretransplantation HBV/HCV positivity and pretransplantation elevated liver enzyme levels of any cause were predictive risk factors for post-BMT liver injury, and close follow-up, early diagnosis, and treatment are highly recommended for BMT patients with these risk factors.

Psychosocial burden of beta-thalassaemia major in Antalya, south Turkey.

beta-thalassaemia is a recessively inherited blood disorder characterised by chronic anaemia. It requires monthly blood transfusions and regular iron chelation. Thousands of affected children are born annually and the magnitude of the problem is most severe in developing countries. Ninety-nine children and 32 adults with thalassaemia major, and 112 parents of patients were interviewed in Antalya, south Turkey, using specifically designed questionnaires to evaluate psychosocial burden. The education of most of the thalassaemic children of school age (60%) was affected, mainly due to having to attend hospital for investigation and transfusions. A high level of parental anxiety (82%) was reported. Nearly half of the families (47%) had employment and financial problems as a result of thalassaemia, yet there was a low level of marital breakdown (1.8%). A substantial majority (93%) of the parental couples would have chosen to terminate an affected pregnancy if they had known that the foetus had thalassaemia major. The results reflect the need for a national policy for public education and screening of thalassaemia in Turkey in order to offer prenatal diagnosis for all families at risk of homozygous thalassaemia.

Hairy cell leukemia in father and son.

Hairy cell leukemia (HCL) is an uncommon B cell disorder, and familial HCL is rarely encountered among the first degree relatives of HCL patients. A father and son, both of whom developed hairy cell leukemia, is presented in this report. The HLA haplotype shared by the father and son was A2, B18, BW6, CW7, DR3, DR10, and DQ8. Among these haplotypes, HLA A2 and Bw6 have previously been reported.

Therapeutic Trial of Cobalamin in Patients with Normal Serum Cobalamin Levels and Predicted Cobalamin Deficiency.

Diagnosis of cobalamin deficiency can be difficult due to the variation in clinical presentation and lack of specificity of the laboratory findings. Although hypersegmentation and macrocytosis are important findings observed in cobalamin deficiency they are not sensitive and spesific. Additionally, cobalamin assays in commercial laboratories, being not reliable, makes the diagnosis more difficult. The metabolite assays, such as the total homocysteine and methylmalonic acid are costly, which restricts their widespread routine use. Our aim was to find out problems in diagnosis of cobalamin deficiency in general practice, and establish a better and cost-effective decision strategy for the diagnosis of this common clinical entity. Fifty patients with the diagnosis of cobalamin deficiency were retrospectively evaluated with respect to diagnosis. Normal cobalamin levels were observed at presentation in eight (16%) patients. Reticulocyte crisis was observed in all patients on the seventh day of cobalamin replacement therapy and all hematological parameters returned to normal at the end of three months of treatment. In anemic patients with clinical and biochemical findings suggestive of megaloblastic anemia, even though serum cobalamin level is normal, a therapeutic trial of cobalamin is cost effective and prevents delay in diagnosis.

Role of endothelin-1 in a cirrhotic rat model with endotoxin induced acute renal failure.

BACKGROUND/AIMS: Bacterial infections are known to trigger renal failure in patients with cirrhosis. However, the mechanisms for this process are unclear. The aim of this study was to investigate the role of endothelin-1 (ET-1) in a cirrhotic rat model with endotoxin induced renal failure by mixed ET-1 receptor antagonist, bosentan. METHODS: Cirrrhosis was induced by twice weekly intraperitoneal injections of CCl(4) together with phenobarbital in drinking water. Cirrhotic and non-cirrhotic rats were either pretreated with physiological saline or bosentan prior to administration of low dose endotoxin. Urine and blood samples were then collected within a period of 3 h for the estimation of ET-1, NO(3)(-)/NO(2)(-) levels ( nitric oxide metabolites: NO(x)) and renal function tests. RESULTS: Cirrhotic rats had higher ET-1 and NO(x) levels in comparison with non-cirrhotic rats. Endotoxin administration to cirrhotic rats led to the deterioration of the renal function, and elevation of plasma ET-1 and NO(x) levels. Bosentan pretreatment prior to endotoxin administration caused an increase in the urine volume and creatinine clearance of cirrhotic rats, but had no effect on Na(+) excretion. CONCLUSION: ET-1 has a significant role in endotoxin induced renal impairment in cirrhotic rats, and ET-1 receptor antagonism provides partial protection of the renal function.