Safety of obinutuzumab alone or combined with chemotherapy for previously untreated or relapsed/refractory chronic lymphocytic leukemia in the phase IIIb GREEN study.

The safety of obinutuzumab, alone or with chemotherapy, was studied in a non-randomized, open-label, non-comparative, phase IIIb study (GREEN) in previously untreated or relapsed/refractory chronic lymphocytic leukemia. Patients received obinutuzumab 1000 mg alone or with chemotherapy (investigator's choice of fludarabine-cyclophosphamide for fit patients, chlorambucil for unfit patients, or bendamustine for any patient) on days 1, 8 and 15 of cycle 1, and day 1 of cycles 2-6 (28-day cycles), with the cycle 1/day 1 dose administered over two days. The primary end point was safety/tolerability. Between October 2013 and March 2016, 972 patients were enrolled and 971 treated (126 with obinutuzumab monotherapy, 193 with obinutuzumab-fludarabine-cyclophosphamide, 114 with obinutuzumab-chlorambucil, and 538 with obinutuzumab-bendamustine). Grade ≥3 adverse events occurred in 80.3% of patients, and included neutropenia (49.9%), thrombocytopenia (16.4%), anemia (9.6%), and pneumonia (9.0%); rates were similar in first-line and relapsed/refractory patients, and in first-line fit and unfit patients. Using expanded definitions, infusion-related reactions were observed in 65.4% of patients (grade ≥3, 19.9%; mainly seen during the first obinutuzumab infusion), tumor lysis syndrome in 6.4% [clinical and laboratory; highest incidence with obinutuzumab-bendamustine (9.3%)], and infections in 53.7% (grade ≥3, 20.1%). Serious and fatal adverse events were seen in 53.1% and 7.3% of patients, respectively. In first-line patients, overall response rates at three months post treatment exceeded 80% for all obinutuzumab-chemotherapy combinations. In the largest trial of obinutuzumab to date, toxicities were generally manageable in this broad patient population. Safety data were consistent with previous reports, and response rates were high. (clinicaltrials.gov identifier: 01905943).

Rituximab plus bendamustine or chlorambucil for chronic lymphocytic leukemia: primary analysis of the randomized, open-label MABLE study.

MABLE investigated the efficacy and safety of rituximab plus bendamustine or rituximab plus chlorambucil in fludarabine-ineligible patients with chronic lymphocytic leukemia. Patients received rituximab plus bendamustine or rituximab plus chlorambucil every four weeks for six cycles. Rituximab plus chlorambucil-treated patients without a complete response after Cycle 6 received chlorambucil monotherapy for at least six additional cycles or until complete response. The primary endpoint was complete response rate (confirmed by bone marrow biopsy) after Cycle 6 in first-line patients. Secondary endpoints included progression-free survival, overall survival, minimal residual disease, and safety. Overall, 357 patients were randomized (rituximab plus bendamustine, n=178; rituximab plus chlorambucil, n=179; intent-to-treat population), including 241 first-line patients (n=121 and n=120, respectively); 355 patients received treatment (n=177 and n=178, respectively; safety population). In first-line patients, complete response rate after Cycle 6 (rituximab plus bendamustine, 24%; rituximab plus chlorambucil, 9%; P=0.002) and median progression-free survival (rituximab plus bendamustine, 40 months; rituximab plus chlorambucil, 30 months; P=0.003) were higher with rituximab plus bendamustine than rituximab plus chlorambucil. Overall response rate and overall survival were not different. In first-line patients with a complete response, minimal residual disease-negativity was higher with rituximab plus bendamustine than rituximab plus chlorambucil (66% vs 36%). Overall adverse event incidence was similar (rituximab plus bendamustine, 98%; rituximab plus chlorambucil, 97%). Rituximab plus bendamustine may be a valuable first-line option for fludarabine-ineligible patients with chronic lymphocytic leukemia.

Investigation of AID, Dicer, and Drosha Expressions in Patients with Chronic Lymphocytic Leukemia.

Chronic lymphocytic leukemia (CLL) is the most common leukemia in Western countries. Cytogenetic lesions such as del13q14, del11q22.3, and del17p13 are identified in 50-60% of patients. Activation-induced cytidine deaminase (AID) plays a central role in somatic hyper mutation (SHM) and class switch recombination (CSR) and functions on Ig genes, but also target non-Ig genes, and over-expression of AID can lead to point mutations or translocations in non-Ig genes such as IgH/Myc translocation. Dicer and Drosha, which have a role in activation process of miRNA, also act in a double-strand DNA break (DSB) repair mechanism. In this study, whether the changes of AID, Dicer and Drosha expressions may be associated with both deletions and clinical outcomes in patients with CLL were investigated. AID expressions were increased in patients with CLL. However, cell lysate AID protein levels were only increased in patients with del17p or del11q who have poor prognosis. Decreased Dicer expressions were found in patients with deletion, whereas increased Drosha expressions were found in patients without deletion and with del13q. According to Rai and Binet staging systems, advanced-stage patients showed increased AID protein levels, decreased Dicer and Drosha expressions. Our findings may suggest that high AID expression and lower Dicer expression were observed in patients with CLL especially del17p and del11q and might associated with deletions such as del17p and del11q. AID, Dicer, and Drosha expressions might be used as an indicator of prognosis for CLL.

[Psychogenic purpura with hematuria and sexual pain disorder: a case report]. / Hematüri ve Cinsel Agri Bozuklugunun Eslik Ettigi Psikojenik Purpura; Bir Olgu Sunumu.

Psychogenic purpura (Gardner-Diamond syndrome) is the occurrence and spontaneous recurrence of painful ecchymosis following emotional stress and minor trauma. Although the exact mechanism of this syndrome remains unknown, apart from skin lesions, different types of hemorrhaging have been reported, such as epistaxis, gastrointestinal bleeding, and bleeding from the ear canals and eyes. We report a psychogenic purpura case that presented with hematuria in addition to skin lesions. Based on the psychiatric evaluation she was diagnosed with major depressive disorder, generalized anxiety disorder, and obsessive-compulsive disorder. Additionally, sexual pain disorder accompanied these disorders. With the help of antidepressant and supportive psychotherapy, the patient's ecchymosis and bleeding disappeared. During 8 months of follow-up the symptoms did not return. Vaginismus has not been reported in patients with psychogenic purpura. The presence of vaginismus, which is seen more frequently in eastern cultures and is thought to be related to sociocultural determinants, suggests that some cultural factors may be common to both psychogenic purpura and vaginismus. The aim of this case report was to call attention to a syndrome that is rarely seen and diagnosed, and to discuss its relationship to psychosocial factors. This syndrome should be considered in the differential diagnosis of not only ecchymotic lesions, but also various types of bleeding, including hematuria. Despite the fact that its etiology and treatment are not clearly understood, it should be noted that psychological factors play a role in this disease and therefore, psychopharmacological and psychotherapeutic approaches can be effective.

Mental status and physical activity in patients with homozygous familial hypercholesterolemia: A subgroup analysis of a nationwide survey (A-HIT1 registry).

BACKGROUND: Homozygous familial hypercholesterolemia (HoFH) is a rare, life-threatening disease due to high serum low-density lipoprotein (LDL) cholesterol levels. LDL cholesterol-lowering interventions are fundamental for patients with HoFH. OBJECTIVE: It was aimed to investigate the association between the mental status of patients with HoFH and healthy lifestyle behaviors. METHODS: This subgroup analysis of the A-HIT1 population included the data of patients aged ≥18 years with a clinical diagnosis of HoFH undergoing therapeutic LDL apheresis. Besides the demographic and clinical characteristics of patients, healthy lifestyle behaviors were assessed, and psychiatric symptoms were screened by Symptom Check List (SCL-90-R). RESULTS: The highest percentage for pathology was observed in dimensions of obsessive-compulsive, somatization, interpersonal sensitivity, and depression in SCL-90-R. Patients with any cardiovascular condition have more psychiatric symptoms in different fields of SCL-90-R. The outcomes of the correlative analysis indicated that lower the age of the first coronary event better the psychiatric status, probably denoting a better adaptation to disease and its treatment. Among 68 patients, 36 patients were not exercising regularly. Patients with regular physical activity had significantly lower scores in most dimensions of SCL-90-R and there was no association between regular physical activity and other investigated variables. The strongest predictor of regular exercising was global severity index of SCL-90-R. CONCLUSION: In the HoFH population, there was a high prevalence of mental disturbances. Better psychiatric status was associated with regular exercising. Therefore, assessing the mental status of patients with HoFH and referring patients in need, to a psychiatrist, may improve the outcome of patients.

Identification of red blood cell membrane defects in a patient with hereditary spherocytosis using next­generation sequencing technology and matrix­assisted laser desorption/ionization time­of­flight mass spectrometry.

Hereditary spherocytosis (HS) is characterized by the morphological transformation of erythrocytes into a spherical shape due to a hereditary defect in cell membrane proteins (ghosts) associated with disruption of erythrocyte skeletal structures. Contrary to the literature, pores were detected in the erythrocytes of a patient with HS. The aim of the present study was to determine the affected proteins and genes that were responsible for the pores. Ghost isolation was performed to determine the proteins responsible for the pores observed on the erythrocytes of the patient. Erythrocyte membrane proteins were visualized using SDS­PAGE. Exome and matrix­assisted laser desorption/ionization time­of­flight mass spectrometry (MALDI TOF MS) analyses were used to identify the genes and proteins responsible for the observed defect. Quantitative protein assessments were performed using MALDI TOF MS. A difference was detected in the components of the erythrocyte membrane proteins. Band 3 and protein 4.2, which serve a particular role in membrane structure, decreased 4.573 and 4.106 fold, respectively. Through proteomic analyses, a non­synonymous exonic mutation region was identified in the Golgi membrane protein 1 (GOLM1) gene (Chr9 rs142242230). Sorting Intolerant From Tolerant and Polymorphism Phenotyping Scores, Likelihood Ratio Tests and MutationTaster revealed that the mutation was deleterious. The pores observed in the morphology of the erythrocytes may have developed due to the decrease in these proteins, which reside in the erythrocyte membrane structure. Furthermore, genetic profiling of the patient with HS and her family was conducted in the present study. Next­generation sequencing was used, and the genetic source of HS was identified as a GOLM1 gene mutation. The assessment of specific molecular defects is often not performed as the majority of mutations are unique to a family. However, molecular analyses should be performed in severe cases where prenatal diagnosis is required, or for unique HS phenotypes to aid scientific investigation.

Clinical management, psychosocial characteristics, and quality of life in patients with homozygous familial hypercholesterolemia undergoing LDL-apheresis in Turkey: Results of a nationwide survey (A-HIT1 registry).

BACKGROUND: Homozygous familial hypercholesterolemia (HoFH) is a rare, life-threatening inherited disease leading to early-onset atherosclerosis and associated morbidity. Because of its rarity, longitudinal data on the management of HoFH in the real world are lacking, particularly on the impact the condition has on quality of life (QoL), including the impact of the extracorporeal lipid removal procedure apheresis (LA). METHODS: The A-HIT1 study included 88 patients with HoFH aged ≥12 years receiving regular LA in 19 centers in Turkey. Demographic and disease characteristics data were obtained. For patients aged ≥18 years, additional data on psychosocial status were obtained via the SF-36 score, the Hospital Anxiety and Depression Scale, and a HoFH-specific questionnaire. RESULTS: There was no standardized approach to therapy between centers. Mean (±SD) frequency of LA sessions was every 19.9 (±14) days, with only 11.6% receiving LA weekly, and 85% of patients were not willing to increase LA frequency. The most common concerns of patients were disease prognosis (31%), and physical, aesthetic, and psychological problems (27.5%, 15.9%, and 11.6%, respectively). Lower age at diagnosis was associated with better QoL, lower anxiety, improved functioning, and greater emotional well-being compared to later diagnosis. CONCLUSIONS: These findings demonstrate that adult patients with HoFH undergoing LA, experience significant impairment of QoL with an increased risk of depression. From patients' point of view, LA is time-consuming, uncomfortable, and difficult to cope with. The speed of diagnosis and referral has a considerable impact on patient well-being.

A nation-wide survey of patients with homozygous familial hypercholesterolemia phenotype undergoing LDL-apheresis in Turkey (A-HIT 1 registry).

BACKGROUND AND AIMS: Homozygous familial hypercholesterolemia (HoFH) is a genetic condition characterized by lethally high levels of low-density lipoprotein cholesterol (LDL-C) from birth, and requires rapid and aggressive intervention to prevent death due to coronary heart disease and/or atherosclerosis. Where available, lipoprotein apheresis (LA) is the mainstay of treatment to promote survival. METHODS: A-HIT1 registry was conducted with the aim of providing insight to the real-life management of HoFH patients undergoing LA in Turkey, where LA procedures are fully reimbursed and widely available. Participating centers provided patient information, including family history, treatment patterns and relevant laboratory values, via a standard questionnaire. RESULTS: The study evaluated 88 patients (mean age: 27 ±â€¯11 years, 41 women) in 19 centers. All patients were receiving regular LA with a clinical diagnosis of HoFH. Mean age at first symptom disease was 10 ±â€¯10 years, and at diagnosis it was 12 ±â€¯11 years; 74.7% were diagnosed before age 15 years; and only 31% before the age of 7. First referral of most patients was to pediatricians. Early onset coronary artery disease was present in 57.8% of patients. Mean age at first LA was 21 ±â€¯12 years. Only 11 (12.5%) patients were undergoing LA weekly. Mean frequency of apheresis sessions was 19 ±â€¯13 days. For the last four LA sessions, LDL-C levels reached the target in only in 5.7% of patients. CONCLUSIONS: Diagnosis of HoFH is delayed, and LDL targets are not reached. LA frequencies are not optimal. Urgent attention is needed to support the survival of patients with HoFH.

What have we learned from Turkish familial hypercholesterolemia registries (A-HIT1 and A-HIT2)?

BACKGROUND AND AIMS: Familial hypercholesterolemia (FH) is a common genetic disease of high-level cholesterol leading to premature atherosclerosis. One of the key aspects to overcome FH burden is the generation of large-scale reliable data in terms of registries. This manuscript underlines the important results of nation-wide Turkish FH registries (A-HIT1 and A-HIT2). METHODS: A-HIT1 is a survey of homozygous FH patients undergoing low density lipoprotein (LDL) apheresis (LA). A-HIT2 is a registry of adult FH patients (homozygous and heterozygous) admitted to outpatient clinics. Both registries used clinical diagnosis of FH. RESULTS: A-HIT1 evaluated 88 patients (27 ±â€¯11 years, 41 women) in 19 centers. All patients were receiving regular LA. There was a 7.37 ±â€¯7.1-year delay between diagnosis and initiation of LA. LDL-cholesterol levels reached the target only in 5 cases. Mean frequency of apheresis sessions was 19 ±â€¯13 days. None of the centers had a standardized approach for LA. Mean frequency of apheresis sessions was every 19 ±â€¯13 (7-90) days. Only 2 centers were aware of the target LDL levels. A-HIT2 enrolled 1071 FH patients (53 ±â€¯8 years, 606 women) from 31 outpatients clinics specialized in cardiology (27), internal medicine (1), and endocrinology (3); 96.4% were heterozygous. 459 patients were on statin treatment. LDL targets were attained in 23 patients (2.1% of the whole population, 5% receiving statin) on treatment. However, 66% of statin-receiving patients were on intense doses of statins. Awareness of FH was 9.5% in the whole patient population. CONCLUSIONS: The first nationwide FH registries revealed that FH is still undertreated even in specialized centers in Turkey. Additional effective treatment regiments are urgently needed.

A different approach to telomere analysis with ddPRINS in chronic lymphocytic leukemia.

Telomeric sequences, located at the very end of the chromosomes, compensate for the chromosomal shortening as it happens after each round of cell division. Telomeric sequences influence the progress of cellular senescence and cancer progression. It has been reported that telomeres are shortened in acute leukemias where the cell turnover is high. B-cell chronic lymphocytic leukemia (CLL) is a particularly interesting haematological malignancy in regard to telomere dynamics because most of the malignant cells in CLL are mitotically inactive. In this study, we analysed the telomere length in patients with B-cell CLL in a comparison with the control group by using ddPRINS technique. Twenty patients with CLL and four healthy donors as a control group were included. We found short telomeres and no detectable telomeric repeats at the sites of chromosome fusion. We hypothesise that the telomeric erosion in CLL may reflect the dominance of malignant cells with an abnormally long life span. These cells may have encountered many antigenic stimulants in the past and hence underwent multiple clonal expansions. Our findings imply that shortened telomeres in CLL may be reflecting the "history" of the disease and serve as an independent prognostic factor.

Cytokine Contents in Chronic Lymphocytic Leukemia: Association with ZAP70 Expression.

OBJECTIVE: Chronic lymphocytic leukemia (CLL) is a disease that shows varying clinical progression, and expression of the protein tyrosine kinase ZAP70 has been described as a very valuable prognostic factor. Patients with ZAP70 positivity are characterized by worse clinical course and significantly shorter progression-free and overall survival. In this study, intracytoplasmic interferon gamma (IFN-γ) and interleukin-4 (IL-4) content of T, B, and CLL cells in CLL patients and their correlations with Rai staging and ZAP70 positivity were investigated. MATERIALS AND METHODS: CLL patients newly diagnosed or in follow-up at the Istanbul University Istanbul Medical Faculty Hematology Department were included in this study. These patients were classified according to Rai staging and ZAP70 expression. IL-4, IFN-γ, and ZAP70 expressions in peripheral blood T, B, and CLL cells were measured by four-color flow cytometry. RESULTS: There was a statistically significant correlation between advanced disease and ZAP70 positivity. IL-4-secreting T cells were significantly increased; however, IFN-γ secretion was significantly decreased in CLL patients compared to healthy individuals, whereas IL-4-secreting B cells were significantly diminished in contrast to T cells. CONCLUSION: These findings suggest damage in the cellular immunity and that IL-4 might lead to many complications and may be important in disease progression.

Evaluation of Insulin-like Growth Factor-1 and Insulin-like Growth Factor Binding Protein-3 Expression Levels in Patients with Chronic Lymphocytic Leukemia.

OBJECTIVE: Chronic lymphocytic leukemia (CLL) is a disease of nonproliferating and mature-appearing B lymphocytes. Insulin-like growth factor-1 (IGF-1) is a small peptide hormone and has mitogenic and antiapoptotic effects, and insulin-like growth factor binding protein-3 (IGFBP-3) has antiproliferative effects on cells. In this study, we investigated plasma levels of both IGF-1 and IGFBP-3 in patients with CLL compared with controls, and we compared these plasma levels according to prognostic factors. MATERIALS AND METHODS: Patients with newly diagnosed CLL who were being followed at the Haseki Training and Research Hospital, Istanbul, Turkey, and volunteers were included in this study. Patients were stratified according to the Rai staging system. Statistical analysis was conducted using SPSS 17.0 for Windows. RESULTS: Forty-three patients [16 women (37%) and 27 men (63%)] were enrolled in this study. Twenty-one volunteers (11 women, 10 men) were included in the control group. The median age of the patients was 65±9 years (range: 18-63 years), and subjects in the control group were 68±8 years old (range: 18-63 years). Even though the plasma levels of IGF-1 were higher and those of IGFBP-3 were lower and the ratio of IGF-I/IGFBP-3 was higher in comparison with the control group, these differences were not statistically significant (p>0.05). In the study group, IGF-1 levels appeared to be increased in parallel to more advanced Rai stages. There were no significant differences between the other groups (p=0.105). CONCLUSION: Plasma IGF-I levels were found higher in patients than in the control group and plasma IGFBP-3 levels were lower; however, neither result was statistically significant. Plasma IGF level increment was observed in concordance with Rai staging. These results prompted us to think that plasma IGF-1 levels in CLL patients are correlated with tumor burden and Rai staging and therefore could be a valuable prognostic factor. Further comprehensive studies are required to support our results.

Genotoxicity and sister chromatid exchange in patients with myelodysplastic disorders.

In this study, we aimed to evaluate genotoxicity by sister chromatid exchange frequency in the peripheral lymphocytes of patients with myelodysplastic syndrome (MDS). The study population consisted of 16 patients (females/males:6/10; mean age: 61.68 +/- 13.08 years) diagnosed with "refractory anemia" according to FAB classification. The results were compared with an age- and sex-matched control group. The sister chromatid exchange frequency in the study group was found to be significantly higher than the control group (8.3 +/- 11 vs. 6.83 +/- 1.07, P=0.0046). We suggest that increased DNA damage, which is revealed by the increased sister chromatid exchange in the present study may play a role in the etiopathogenesis of MDS.

Real-Time PCR analysis of af4 and dek genes expression in acute promyelocytic leukemia t (15;17) patients.

Among several newly identified oncogenes, dek and af4 are attractive targets for researchers interested with leukemia. In this study quantitative Real-Time RT-PCR technique was used to define alterations in expression of dek and af4 genes associated with acute promyelocytic leukaemia (APL) t (15; 17). RNA samples obtained from bone marrow aspirates of fourteen APL patients, cDNA portions were labelled with Syber Green 1 dye and LightCycler analysis have been performed. Expression changes in patients were found not significant in comparison to healthy donors for af4 (P = 0.192) and dek (P = 0.0895). We suggest that af4 gene may have a role in leukomogenesis restricted to lymphoblastic lineage; also further studies must carry on with a larger series of patients in order to understand the relationship between the dek gene and APL. Our study was the first attempt for analysing dek and af4 genes in APL t (15; 17) patients by quantitative Real-Time RT-PCR. This rapid and sensitive method could be used to screen these genes in different types of leukaemia.

Real-time PCR analysis of the apoptosis related genes in ATRA treated APL t(15;17) patients.

All-trans retinoic acid (ATRA) treatment of the acute promyelocytic leukemia (APL) have subsequently resulted in cell apoptosis, but the molecular mechanism of this effect remains elusive. In order to understand a possible involvement of genes regulating apoptotic signal pathways, expression levels of bcl2, bax, dapk1, myc, bad, wt1, and mcl genes were analyzed during ATRA treatment in five APL patients with t (15;17) using Real- time PCR (LightCycler). Two samples from each patient were compared to each other: primary diagnostic sample and a sample taken at remission. Effect of the ATRA treatment was demonstrated by the concomitant induction of cd14 and il1beta genes in four patients. Also other apoptosis related genes were found down-regulated in general but especially the down regulated levels of wt1 and bax attract attention. Result suggested that ATRA dependent apoptosis of APL was under the control of both internal and external pathways without relationships to the amount of the blast populations. Ratio of bcl2 to bax may be more important for this regulation than the ratio of bcl2 to bad. Either bcl2 family or less known apoptosis related genes as wt1 will still be required to further studies in this setting.

Chronic lymphocytic leukemia and multiple myeloma in the same patient: case report.

We hereby report the occurrence of a non-secreting multiple myeloma (MM) during the course of chronic lymphocytic leukemia (CLL). A 73-year-old patient developed a non-secreting MM 7 years after the diagnosis of CD5 (+) B cell CLL. He received intermittent chlorambucil and prednisolone therapy. The occurrence of tumors in the frontal bone led to resection of the tissue and histopathologic examination revealed neoplastic plasma cell islands within the CLL infiltration. There was no immunoglobulin or light chain accumulation in the serum. Clonal relationship between these diseases has been shown by comparing the isotypes and idiotype of both the heavy and light chains. In our case, the MM was of non-secreting type and thus we could not establish any relation between the 2 disorders. Such a case has not been reported until now in the literature. CLL and MM in the same patient is a rare occurence and investigation of the transformation event at the molecular level will contribute to our understanding of B-cell ontogenesis.

Coexistence of chronic neutrophilic leukemia with multiple myeloma.

A case report of simultaneous presentation of chronic neutrophilic leukemia and multiple myeloma (IgG kappa) in a 71-year-old male is described. The patient showed mature neutrophilic leukocytosis, hepatosplenomegaly, high neutrophil alkaline phosphatase score, hyperuricemia, neutrophils with toxic granulation and Döhle bodies, absence of Philadelphia chromosome and of the bcr-abl fusion gene. Moreover, a monoclonal IgG kappa paraproteinemia (36.93 g l(-1)) was detected. Bence-Jones proteinuria was 3.84 g l(-1). The bone marrow was grossly hypercellular with marked myeloid hyperplasia and aggregates of plasma cells. The patient died of severe bronchopneumonia after the transformation of chronic neutrophilic leukemia to acute myelomonocytic leukemia, 1.5 years following diagnosis.

Quantification of All-Trans-Retinoic Acid (ATRA) Dependent Expression of CXCR4 Gene in Acute Promyelocytic Leukaemia.

CXCR4 is the receptor of CXC chemokine SDF-1 and may play a role in the homing of hematopoietic stem cells. We have investigated the CXCR4 gene expression during ATRA treatment in acute promyelocytic leukaemia (APL) patients. APL is a characteristic disorder with a specific translocation between PML and RAR alpha genes on chromosome 15 and 17. ATRA-induced differentiation of APL cells is strictly dependent on the presence of PML-RAR alpha. In our study, five APL patiens were involved. Two samples from each patient were compared to each other: Primary diagnostic sample and a sample taken at remission. Quantitative real-time PCR (LightCycler) has been used for quantification, which is a recently developed method for rapid and sensitive detection of gene expression. CXCR4 gene ratios were found under-expressed in cases 1 and 6 with blast counts at diagnosis 18%, and 20% but only moderately under-expressed in cases two and four where the blast count was at diagnosis 50%, and 80%. It was over-expressed only in case three where the blast count was 95%. These findings indicate that ATRA treatment might be effective in CXCR4 gene expression related to amount of the blast population in APL. Further gene expression studies would be helpful to understand how ATRA works on CXCR4 related molecular pathways in APL pathogenesis.

Clozapine treatment of refractory schizophrenia during essential chemotherapy: a case study and mini review of a clinical dilemma.

BACKGROUND: Clozapine remains the antipsychotic of choice for refractory schizophrenia. Given the particular side effects of clozapine including neutropenia and myelosuppression, safety and efficacy of add-on chemotherapy for patients who are already under clozapine treatment remain unknown. OBJECTIVE: We present evidence from a patient with a diagnosis of refractory schizophrenia on clozapine medication, who required essential chemotherapy for chronic lymphocytic leukemia (CLL). We have also reviewed literature regarding this challenging clinical dilemma. METHOD: We report details about a patient with treatment-resistant schizophrenia who was given chemotherapy (fludarabine, cyclophosphamide and rituximab) for CLL in the course of concomitant treatment with clozapine and granulocyte-colony stimulating factor (G-CSFs). In addition, we have reviewed literature using the PUBMED data base. RESULTS: Current evidence remains insufficient to provide authoritative guide to clinicians regarding the efficacy and safety of the combined use of clozapine and chemotherapy. However, general conclusion from our case and of the published evidence is that a combination of clozapine use and chemotherapeutic agents do not cause additional hematological worsening with no decreasing efficacy concerns raised. CONCLUSION: Continuing with clozapine in the course of chemotherapy may be relatively safer for patients who responded well to clozapine concomitant with G-CSF treatment.

Investigation of circulating lncRNAs in B-cell neoplasms.

Long non-coding RNAs (lncRNA) which are longer than 200 base pairs in length, play an important role in cellular machinery. Chronic lymphocytic leukemia (CLL) and multiple myeloma (MM) are neoplasms of B-cells. In our study we aimed to investigate circulating lncRNA levels of CLL and MM patients. For this purpose we selected 5 candidate lncRNAs (TUG1, LincRNA-p21, MALAT1, HOTAIR, and GAS5) where the first two are regulated by p53. Analyses were performed by real-time PCR using cDNA synthesized from plasma RNAs. In both disease groups differential levels of plasma lncRNAs were observed. LincRNA-p21 was the only molecule displaying significant changes in the CLL group while all remaining lncRNAs showed significant differences in the MM group. In the MM group only TUG1 showed higher levels than the healthy volunteers. In conclusion, the expression levels of the candidate lncRNA molecules display a general trend for tissue- and disease-specific expression which can provide important potential biomarkers specific to the particular disease type. However, further studies are necessary to elucidate their involvement in disease development and progression.