Deniz Sargin

A male-specific increase in the HLA-DRB4 (DR53) frequency in high-risk and relapsed childhood ALL

Previous studies reported significant HLA-DR associations with various leukemias one of which is with HLA-DRB4 (DR53) family in male patients with childhood ALL. We have HLA-DR-typed 212 high-risk or relapsed patients with childhood (n=114) and adult (n=98) ALL and a total of 250 healthy controls (118 children, 132 adult) by PCR-SSP analysis. The members of the HLA-DRB3 (DR52) family were underrepresented in patients most significantly for HLA-DRB1*12 (P=0.0007) and HLA-DRB1*13 (P=0.0001). In childhood ALL, the protective effect of DRB3 was evident in homozygous form (P=0.001). The DRB4 marker frequency was increased in males with childhood ALL (67.4%) compared to age- and sex-matched controls (42.1%, P=0.003) and female patients (35.7%, P=0.004). Besides being a general marker for increased susceptibility to childhood ALL in males, HLA-DRB4 is over-represented in high-risk patients. These results further suggest that the HLA system is one of the components of genetic susceptibility to leukemia but mainly in childhood and in boys only.

Cyclosporine-associated hyperkalemia: report of four allogeneic blood stem-cell transplant cases.

Background. Nephrotoxicity is a well-known effect of cyclosporine (CsA) that causes a reduction in glomerular filtration rate through vasoconstriction of the afferent glomerular arterioles and may result in acute renal failure. Isolated CsA-induced hyperkalemia occurring through different mechanisms is also common. However, there are only a few “case reports” addressing this phenomenon in allogeneic bone marrow transplantation patients. In this report, we propose mechanisms and methods of managing CsA-associated hyperkalemia in allogeneic transplantation. Methods. We report on four allogeneic blood stem- cell transplant cases and a review of the literature. Results. Four adult leukemia patients underwent allogeneic peripheral blood stem cell transplantation and received CsA as a part of their graft-versus-host disease prophylaxis. The patients developed hyperkalemia, despite adequate kidney function. CsA seemed to be the only pharmaceutical agent to which this electrolyte abnormality could be attributed. Renal tubule dysfunction and secondary hypoaldosteronism seemed to be the reasons for CsA-associated hyperkalemia. Conclusion. This report of four cases demonstrates that CsA should be considered among the possible causes of hyperkalemia in bone marrow transplantation. There may be a need for urgent intervention depending on the severity of hyperkalemia. Monitoring of blood CsA level and dose adjustment are important for the prevention of this complication.

Prognostic significance of ASXL1, JAK2V617F mutations and JAK2V617F allele burden in Philadelphia-negative myeloproliferative neoplasms

Background Despite insights into the genetic basis of Philadelphia-negative myeloproliferative neoplasms (Ph-negative MPNs), a significant proportion of essential thrombocythemia (ET) and primary myelofibrosis (PMF) patients present with no known MPN disease alleles. There were no previous studies investigating the impact of ASXL1 mutations in Ph-negative MPNs in Turkey. In the current study, we investigated the prognostic significance of ASXL1 mutations in Turkish MPN patients. We also aimed to determine the prognostic significance of JAK2V617F allele burden and the relationship of JAK2V617F mutation with ASXL1 mutations in Ph-negative MPNs. Methods About 184 patients from a single center diagnosed with Ph-negative MPNs were screened for ASXL1, JAK2V617F mutations, and JAK2V617F allele burden: 107 ET and 77 PMF. Results A total of 29 ASXL1 mutations were detected in 24.7% of PMF and 8.4% of ET patients. ASXL1-mutated ET patients showed a trend toward an increase in the incidence of cerebrovascular events and higher total leukocyte counts. ASXL1-mutation in PMF was associated with older age and a higher prevalence of bleeding complications. In univariate analysis, overall survival (OS) was significantly reduced in ASXL1-mutated PMF patients. In multivariate analysis, Dynamic International Prognostic Scoring System-plus high-risk category and ASXL1 mutation status were independently associated with shorter survival in PMF. In PMF, mutational status and allele burden of JAK2V617F showed no difference in terms of OS and leukemia-free survival. Conclusion We conclude that ASXL1 mutations are molecular predictors of short OS in PMF.

Relationship Between HLA Tissue Type, CMV Infection, and Acute Graft-vs-Host Disease After Allogeneic Hematopoietic Stem Cell Transplantation: Single-Center Experience

After allogeneic hematopoietic stem cell transplantation, risk factors for cytomegalovirus (CMV) reactivation include pretransplantation donor and recipient CMV serologic status and posttransplantation development of acute graft-vs-host disease (aGvHD). Human leukocyte antigen (HLA) allele type is an additional factor in CMV infection. The present study included 108 patients who received an allogeneic stem cell graft from an HLA-identical sibling between 1993 and 2004. All recipients and donors were typed for HLA-A, HLA-B, and HLA-DR alleles using serologic or molecular methods. All recipients received grafts because of a hematologic disease from HLA full-matched donors. In pretransplantation seropositive patients with aGvHD, no significant difference was observed in patients who developed CMV infection compared with those without CMV infection. Seropositive patients without aGvHD but with posttransplantation CMV infection demonstrated a higher incidence of HLA-A30, HLA-B40, and HLA-DRB1*15 compared with those without CMV infection. In conclusion, it seems that certain HLA alleles may have either a protective or predisposing role in CMV reactivation, which might be helpful in estimating the risk of aGvHD and designing individualized therapy.

Incidence of aplastic anemia in Turkey: A hospital-based prospective multicentre study

The incidence of aplastic anemia among hospitalized adult patients was prospectively determined in this first study in Turkey. New cases of aplastic anemia among patients 14 years and older who were admitted to the study centers were included in a 3 year survey. Seventy-three patients fulfilled the diagnostic criteria, yielding a mean annual incidence rate of 1.14 cases in 10(3) admissions. The male-to-female ratio of the cases (1.6:1) differed from the almost equal ratio of the larger population of Turkey. The median age was 30 years and females were younger at diagnosis. The age distribution of the cases was different from that of the population; showing two incidence peaks in both sexes. The majority of the patients (89%) had severe disease.

The Burden of JAK2V617F Mutated Allele in Turkish Patients With Myeloproliferative Neoplasms

Background Studies regarding the impact of JAK2V617F allele burden on phenotypic properties and clinical course in Philadelphia-negative myeloproliferative neoplasms (Ph-negative MPNs) have reported variable results. We aimed to analyze the association of mutated JAK2V617F allele burden with laboratory characteristics and clinical phenotype in Turkish patients (107 essential thrombocythemia (ET) and 77 primary myelofibrosis (PMF)). Methods Peripheral blood samples of 184 patients with Ph-negative MPNs were analyzed for JAK2V617F allele status and burden. JAK2 MutaScreen assay (Ipsogen, Luminy Biotech, Marseille, France) was used to detect the JAK2V617F status and quantitative JAK2V617F allele burdens in genomic DNA using TaqMan allelic discrimination. Results Frequency of JAK2V617F-positive patients with high mutation load (allele burden > 50%) was higher in PMF compared to ET (23.4% and 4.7%, respectively; P = 0.001). We found significant association between ET patients with high JAK2V617F allele burden and lower hemoglobin (Hgb) and hematocrit (Hct), higher LDH levels and more prevalent massive splenomegaly (P = 0.001, P = 0.001, P = 0.012 and P = 0.015, respectively). ET patients with high mutation load displayed higher prevalence of bleeding compared to low mutation load and wild-type mutational status (P = 0.003). Rate of DVT was significantly higher in ET patients with mutant allele burden in upper half compared to lower half and wild-type (P = 0.029). We observed significant association between PMF patients with high JAK2V617F allele burden and higher Hgb, Hct levels and leukocyte counts (P = 0.003, P = 0.021 and P = 0.001, respectively). Conclusions Our study demonstrated JAK2V617F allele burden correlates with clinical features in ET and PMF. We conclude quantification of JAK2V617F mutation contributes to the workup of Ph-negative MPNs.

Intracoronary autologous bone marrow-derived mononuclear cell transplantation improves coronary collateral vessel formation and recruitment capacity in patients with ischemic cardiomyopathy: a combined hemodynamic and scintigraphic approach.

This study investigated the effects of intracoronary autologous bone marrow−derived mononuclear cell (BMC) transplantation on coronary microcirculation. Fifteen patients with ischemic cardiomyopathy were treated by intracoronary infusion of BMCs via the patent infarct-related artery. The thermodilution-derived coronary flow reserve, index of microvascular resistance, pressure-derived collateral flow index, and coronary wedge pressure were measured at baseline and at 6 months. Successive balloon inflations during BMC transplantation were performed to observe the recruitment in pressure-derived collateral flow index and coronary wedge pressure, and the percentage changes between baseline and 6 months were calculated. The mean (SD) coronary flow reserve increased from 1.3 (0.4) to 2.1 (0.5), and the mean (SD) index of microvascular resistance decreased from 44.9 (24.4) to 21.2 (14.1) (P = .001 for both). The mean (SD) improvement in pressure-derived collateral flow index (from 0.14 [0.05] to 0.22 [0.08]) was also statistically significant (P = .001). Similarly, the percentage improvements in pressure-derived collateral flow index and coronary wedge pressure were statistically significant (P = .01 for both). The percentage improvement in perfusion assessed by single-photon emission computed tomography strongly correlated with the percentage changes in pressure-derived collateral flow index (r = 0.88, P = .001) and coronary wedge pressure (r = 0.69, P = .01). These results demonstrate for the first time (to our knowledge) that intracoronary autologous BMC transplantation improves coronary collateral vessel formation and recruitment capacity in human subjects.

The Clinical Significance of IDH Mutations in Essential Thrombocythemia and Primary Myelofibrosis

Background Limited data exist regarding impact of IDH mutations in Philadelphia-negative myeloproliferative neoplasms (Ph-negative MPNs). Prognostic significance of IDH mutations was asessed in 184 Ph-negative MPN patients - 107 essential thrombocythemia (ET) and 77 primary myelofibrosis (PMF). Methods High-resolution melting (HRM) analysis was used to detect IDH1 and IDH2 mutations. Results PMF and ET patients showed no significant difference for prevalence of IDH mutations. Mutant IDH (IDH1 or IDH2) was documented in five of PMF (6.5%) and two of ET patients (1.9%). IDH mutations in ET patients included one IDH1 R132C and one IDH2 R140Q. Of the five IDH-mutated PMF patients, four (80%) displayed IDH1 (three IDH1 R132C and one IDH1 R132S) and one (20%) carried IDH2 (IDH2 R140Q) mutation. Sixty percent (three in five) of IDH-mutated PMF patients carried JAK2V617F with following allele burdens: 31-50%, 5-12.5% and 31-50%, respectively. Three of 77 PMF patients (3.9%) simultaneously harbored IDH and JAK2V617F mutations. IDH mutations in PMF showed a trend towards higher rate in females (100% and 52.8%, respectively). Bleeding complications were significantly higher in IDH-mutated PMF patients compared to IDH wild-type counterparts. Trend towards a lower prevalance of acetylsalicylic acid (ASA) use was present in IDH mutant PMF patients compared to wild-type counterparts (20% and 63.9%, respectively). Death rate was higher in IDH-mutated PMF patients compared to IDH wild-type PMF patients (60% and 15.3%). In univariate analysis, a significantly shorter leukemia-free survival (LFS) was observed in IDH-mutated PMF patients. Conclusions We conclude that IDH mutations indicate a risk for leukemic transformation in PMF.

Isolated extramedullary cutaneous relapse despite concomitant severe graft-vs.-host disease and tissue chimerism analysis in a patient with acute lymphoblastic leukemia after allogeneic hematopoietic stem cell transplantation: A case report

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is a potentially curative treatment option for patients with acute lymphoblastic leukemia (ALL). The curative potential of allo-HSCT for ALL is, in part, due to the graft-vs.-leukemia (GVL) effect, in addition to the intensive conditioning chemo-radiotherapy. However, relapse remains the major cause of treatment failure following allo-HSCT for ALL. In the allo-HSCT setting, testing for genetic markers of hematopoietic chimerism has become a part of the routine diagnostic program. Routine chimerism analysis is usually performed in peripheral blood or bone marrow; in fact, little is known about the value of tissue chimerism in patients with extramedullary relapse (EMR) after the allo-HSCT setting. The present study reports on, a case of a patient with ALL who experienced isolated cutaneous EMR despite ongoing graft-vs.-host disease (GVHD), and the results of peripheral blood and skin tissue chimerism studies using multiplex polymerase chain reaction (PCR) of short tandem repeats (STR-PCR). The present case demonstrates that, although complete remission and/or chimerism may be achieved in the bone marrow, chimerism achieved at the tissue level, and the subsequent GVL effect, may be limited, despite concomitant severe GVHD following allo-HSCT. Our tissue chimerism analysis results provide a good example of how skin tissue may be a ‘sanctuary’ site for effector cells of GVL, despite active GVHD and complete hematopoetic chimerism.

Plasmacytoma of the Nasolacrimal Duct Simulating Dacryocystitis: An Uncommon Presentation for Extramedullary Relapse of Multiple Myeloma

The most common site for localized forms of plasma cell neoplasms (extramedullary plasmacytoma; EMP) is the upper respiratory tract, including the oropharynx, nasal cavities, sinuses and larynx. A 50-year-old woman with a history of myeloma in complete remission after autologous stem cell transplantation complained of two weeks of epiphora of the left eye with subsequent diplopia, bloody nasal discharge and progressive swelling around the nasolacrimal sac. A solitary mass in the left sinonasal area, extending to the nasolacrimal duct (NLD) was detected on MRI, whose histopathological examination was consistent with plasmacytoma. Further clinical investigation ruled out multiple myeloma (MM). The patient underwent debulking surgery and adjuvant chemotherapy followed by local radiotherapy in an attempt to achieve complete response. Despite being a rare entity, EMP of the NLD should be considered in the differential diagnosis of epiphora and dacryocystitis. To our knowledge, this is the first case of a plasmacytoma of the NLD presenting as isolated extramedullary relapse of MM. The follow-up in EMPs should include appropriate imaging studies, a systemic workup to rule out MM.