Increase In Mean Corpuscular Volume Research Articles

Increased mean corpuscular volume of erythrocytes during capecitabine treatment: a simple surrogate marker for clinical response.

Capecitabine, as all fluoropyrimidines, interferes with vitamin metabolism and may thus have an impact on hematopoiesis. It is metabolized to its active form 5-fluoruracil by the enzyme thymidine phosphorylase, which exists in higher concentrations in tumor tissue and liver than in normal tissues. In the study, we investigated the changes in mean corpuscular volume (MCV) of red blood cells and the possible correlation of these changes with the clinical outcome of capecitabine treatment in women with metastatic breast cancer. Data from 75 metastatic breast cancer patients were analyzed retrospectively. Capecitabine was used at a dose of 2500 mg/m² daily for 14 days of every 3-week period. Mean corpuscular volume of red blood cells and other parameters of complete blood count were recorded at the beginning of the treatment, in the ninth week, and periodically thereafter. Mean age was 51.5 ± 10.8 and 61.3% of the patients were premenopausal. Capecitabine was administered as the median 3rd line (min-max: 1-9) treatment and a median of 6 cycles (min-max: 1-24) for metastatic breast cancer. Median ΔMCV level (post-treatment values at ninth week - baseline) was 8. ΔMCV was ≥8 in 37 patients and <8 in 38 patients. The 35 of the 37 patients with ΔMCV level ≥8 and 25 of the 38 patients with ΔMCV level <8 had clinical benefit (complete response + partial response + stable disease) from capecitabine treatment (P = 0.02). However, the difference between progression-free survival of the patients with ΔMCV levels higher than 8 and those with ΔMCV levels lower than 8 according to Kaplan-Meier survival analysis was not statistically significant (6.7 and 4.3 months, respectively, P = 0.26). Additionally, median ΔMCV level was 9.1 (min-max: -2.4 to 24.9) among patients who had clinical benefit and 5.90 (min-max: -0.8 to 12.3) among nonresponders (P = 0.016). Capecitabine increases the mean corpuscular volume levels of red blood cells by a yet unidentified mechanism. Early increment of mean corpuscular volume levels is higher than 8, i.e. by the 9th week, might predict clinical benefit from the treatment.

The Potential Ameliorative Effect of Nano-Zinc and Zinc Against Copper Hepatorenal Toxicosis in Rats

This study was designed to evaluate the effect of Nano-Zinc (N-Zn) and Zinc (Zn) against copper (Cu) toxicosis in rats. Sixty male albino rats were randomly divided into 6 groups (n=10); control group, Cu-treated group: orally received CuSo4 (100 mg/kg bwt/day ), N-Zn-treated group: intraperitoneally (IP) injected with N-ZnO (5 mg/kg bwt/day), Zn-treated group: IP injected with ZnO (5 mg/kg bwt/day), Cu+N-Zn - and Cu+Zn -treated groups received the same previous doses and routes. All the experimental treatments were given 3 times / week and continued for eight weeks. Results showed that Cu- treated group caused a significant decrease in body weight and a significant increase in relative liver and kidney weights. Also, Cu caused a significant decrease in red blood cells (RBCs) count, hemoglobin (Hb) concentration, mean corpuscular hemoglobin concentration (MCHC) and platelets count with a significant increase in mean corpuscular volume (MCV) without any changes in leukocytic count. Biochemical analysis showed a significant elevation in serum liver enzymes, total and indirect bilirubin with a significant decrease in serum levels of total proteins and albumin. Also, there was a significant elevation in serum urea and creatinine levels. Cu induced a significant increase in renal and hepatic malondialdhyde (MDA) and a significant decrease in reduced glutathione (GSH). Histopathologically, Cu revealed severe degenerative and necrotic lesions in the livers and kidneys. N-Zn and Zn- treatments attenuated Cu-induced oxidative damage, alterations in the liver and kidney function tests and histopathology. Moreover, Zn treatment showed better protection against Cu-induced toxicity as compared to N-Zn.

Is macrocytosis a potential biomarker of the efficacy of dose-dense paclitaxel-carboplatin combination therapy in patients with epithelial ovarian cancer?

The aims of this study were to investigate a clinical observation that patients with epithelial ovarian cancer treated with first-line platinum-paclitaxel chemotherapy combination (TP) develop macrocytosis and to explore the possible predictive role of macrocytosis in response rate, progression-free survival (PFS), and overall survival. A retrospective analysis of laboratory and clinical data on 184 consecutive ovarian cancer patients treated with first-line TP chemotherapy in a single oncology center from 2004 to 2015 was carried out. Macrocytosis was defined as an increase in mean corpuscular volume of peripheral red blood cells above 97.2 fl during the treatment and/or 30 days after the last chemotherapy cycle. One hundred and forty-one patients were treated with a conventional 3-weekly TP schedule, whereas 43 patients were treated with a dose-dense schedule. Macrocytosis was induced in 35% of patients overall. It was induced significantly more often in patients treated with the dose-dense schedule than in those treated with the 3-weekly schedule (67 vs. 26%, P=1.29×10). Macrocytosis did not correlate with PFS and overall survival in the overall patient population, nor in patients treated with the 3-weekly schedule. It correlated with PFS (hazard ratio=0.42, 95% confidence interval=0.18-0.94, P=0.036) and objective response on therapy in patients treated with the dose-dense schedule (P=0.0285). Dose-dense TP chemotherapy induces macrocytosis significantly more often than does a 3-weekly schedule in ovarian cancer patients. In patients treated with a dose-dense schedule, macrocytosis can potentially be predictive for longer PFS and better response rate. This finding needs further confirmation, preferentially in a prospective study.

Immunotoxic effects of thymus in mice following exposure to nanoparticulate TiO2.

Titanium dioxide nanoparticles (TiO2 NPs) have been extensively used in industry, medicine, and daily life, and have shown potential toxic effects for animals or humans. We noted that the effects of TiO2 NPs on the immune system and its mechanism of action in animals or humans have not been elucidated. Thus, mice were exposed to the TiO2 NPs (0, 1.25, 2.5, or 5 mgkg-1 body weight) for 9 consecutive months. Exposure to TiO2 NPs was accumulated in the thymus, leading to a decrease in body weight and increases in the weight of the thymus or thymus indices. In the blood, exposure to TiO2 NPs significantly decreased white blood cell, red blood cell, reticulocyte, haemoglobin, and mean corpuscular haemoglobin concentration; and increased mean corpuscular volume, mean corpuscular haemoglobin, platelets, and mean platelet volume. The reductions of lymphocyte subsets, including CD3+, CD4+, CD8+, B cell, and natural killer cell, were observed in the TiO2 NP-treated mouse thymus. Appearance of starry-sky aspect of the cortex that is given by the body of macrophages, bleeding, severe hemolysis or congestion, fatty degeneration, and cell apoptosis or necrosis were observed in the thymus following TiO2 NPs exposure. Importantly, TiO2 NPs increased expression of nucleic factor-κB(NF-κB), IκB kinase1/2, interleukin-1β, interleukin -4, regulated upon activation normal T-cell expressed and secreted, cyclooxygenase 2, neutrophil gelatinase-associated lipocalin, purinergic receptors-7, interferon-inducible protein 10, hypoxia inducible factor 1-α, p-c-Jun N-terminal kinase, p-p38, and p-extracellular signal-regulated kinase 1/2 protein, respectively; whereas suppressed expression of IκB, peroxisome proliferater-activated receptor-γ, trefoil factor 1, peroxisome proliferator activated receptor gamma coactivator-1α, and prostaglandin E2 proteins in the thymus, respectively. Taken together, these results suggest that TiO2 NPs exerts toxic effects on lymphoid organs and T cell and innate immune cell homeostasis in mice and that these immunotoxic potential effects may result from the activation of NF-κB-mediated mitogen-activated protein kinases (MAPKs) pathway.

A Black Cohosh Extract Causes Hematologic and Biochemical Changes Consistent with a Functional Cobalamin Deficiency in Female B6C3F1/N Mice.

Black cohosh rhizome, available as a dietary supplement, is most commonly marketed as a remedy for dysmenorrhea and menopausal symptoms. A previous subchronic toxicity study of black cohosh dried ethanolic extract (BCE) in female mice revealed a dose-dependent ineffective erythropoiesis with a macrocytosis consistent with the condition known as megaloblastic anemia. The purpose of this study was to investigate potential mechanisms by which BCE induces these particular hematological changes. B6C3F1/N female mice (32/group) were exposed by gavage to vehicle or 1,000 mg/kg BCE for 92 days. Blood samples were analyzed for hematology, renal and hepatic clinical chemistry, serum folate and cobalamin, red blood cell (RBC) folate, and plasma homocysteine and methylmalonic acid (MMA). Folate levels were measured in liver and kidney. Hematological changes included decreased RBC count; increased mean corpuscular volume; and decreased reticulocyte, white blood cell, neutrophil, and lymphocyte counts. Blood smear evaluation revealed increased Howell-Jolly bodies and occasional basophilic stippling in treated animals. Plasma homocysteine and MMA concentrations were increased in treated animals. Under the conditions of our study, BCE administration caused hematological and clinical chemistry changes consistent with a functional cobalamin, and possibly folate, deficiency. Further studies are needed to elucidate the mechanism by which BCE causes increases in homocysteine and MMA.

Various Characteristics of Hybrid between River Puffer, Takifugu obscurus and Tiger Puffer, T. rubripes, and Their Hybrid Triploid.

ABSTRACTA comparison of the growth, hematological values, fatty acids, and gonadal and growth hormonal changes of river puffer, Takifugu obscurus, tiger puffer, T. rubripes, their hybrids (river puffer × tiger puffer) and hybrid triploids was performed during 3 months of their early growth period. Several features were observed during these 3 months: hybrids showed the highest levels of specific growth rate, 1.48%; hybrid triploids showed the smallest change in viscera fat (P<0.05), but GSI was not significantly different among groups (P>0.05). Considering hematological parameters, hybrid triploids had increased mean corpuscular volume and mean corpuscular hemoglobin (P<0.05), but other parameters were not significantly different between groups (P>0.05). With respect to fatty acids, puffer fish, hybrids and hybrid triploids contained fatty acids such as SFAs, MUFAs, n-3 PUFAs and n-6 PUFAs. There were significantly different amounts of total fatty acids between groups (P<0.05), however, rates of changes in fatty acids did not differ significantly between groups (P>0.05). Gonadal hormone (estradiol and testosterone) changes in the river puffer and tiger puffer were significantly higher than that observed in hybrids and hybrid triploids. The hybrids and tiger puffers had higher amounts of growth hormone (thyroid stimulating hormone and thyroxine) than the hybrid triploids and river puffers (P<0.05).

Association between exposure to pesticides and disorder on hematological parameters and kidney function in male agricultural workers.

Pesticides occupy a critical position among many chemicals to which man can be exposed; their diffusion into the environment causes killing and damaging of some forms of life. The lack of highly selective pesticide action represents risk both for man and other desirable forms of life present in the environment. The present study was designed to evaluate the relation between exposure to pesticides and disorder on hematological parameters and kidney function of male agricultural workers with the mean age 37.11±9.3. Another 100 unexposed men matched for age, and socioeconomic status were recruited as a control to compare the levels of hemoglobin, hematocrit, red blood cells (RBCs), mean corpuscular volume (MCV), mean corpuscular hemoglobin (MCH), mean corpuscular hemoglobin concentration (MCHC), and urea and creatinine concentration. The results indicate that there was no significant difference in hemoglobin concentration and hematocrit value among exposed group as compared to control group. However, there was a significant decrease (P<0.05) in the RBCs count and a highly significant increase (P<0.01) in MCV among exposed group. There was no significant difference in MCH and MCHC among exposed group. There was a significant increase (P<0.05) in urea (39.4±22mg/dl) among exposed group as compared to control (35.7±26.3mg/dl). Also, there was a highly significant increase (P<0.01) in creatinine among exposed group (0.953±0.3mg/dl) as compared to control (0.8±0.2mg/dl). In conclusion, exposure to pesticides produces a variety of hematological parameter disorders as well as kidney malfunction in human.

Hereditary hemochromatosis: study of laboratory alterations related to polymorphism

ABSTRACT Introduction: Hereditary hemochromatosis (HH) is an inherited condition associated with excessive iron storage. Its strong presence is underestimated because patients are asymptomatic. In the city of Caxias do Sul (RS), due to the higher frequency of the disease, it is necessary to perform a study that relates the HH genotypes to laboratory analyses. Objective: The objective of this study was to evaluate the association of the C282Y, H63D and S65C polymorphisms and laboratory markers in the study cases. Methods: The study was carried out based on the analysis of medical records from 283 patients assisted from January 2010 to January 2013, older than 18 years of age, who performed the genotyping protocol for HH and laboratory exams. The analysis of markers between genotype and laboratory exams was performed by the SPSS20.0 software. Results: The most frequent genetic alterations were in H63D/WT 84 (31%) and C282Y/WT 17 (6.2%). The most compatible genotype for HH was C282Y/C282Y, even though it did not show significant results. The elevated serum ferritin level was slightly higher (p < 0.05) in the study groups, and all of them were above the reference value. We observed in C282Y/C282Y and H63D/C282Y genotypes an insignificant increase in mean corpuscular volume (MCV) and in mean corpuscular hemoglobin (MCH). Conclusion: According to the study, it was possible to observe a significant elevated serum ferritin level in all HH genotypes.

Markers of poor adherence among adults with HIV attending Themba Lethu HIV Clinic, Helen Joseph Hospital, Johannesburg, South Africa.

BackgroundTo date, there is no consensus on ideal ways to measure antiretroviral treatment (ART) adherence in resource limited settings. This study aimed to identify markers of poor adherence to ART.MethodsRetrospective data of HIV-positive ART-naïve adults initiating standard first-line ART at Themba Lethu Clinic, Helen Joseph Hospital, Johannesburg, South Africa from April 2004 to December 2011 were analysed. Poisson regression models with robust error variance were used to assessed the following potential markers of poor adherence ‘last self-reported adherence, missed clinic visits, mean corpuscular volume (MCV), CD4 count against definition of adherence, suppressed HIV viral load using traditional test metrics’.ResultsA total of 11 724 patients were eligible; 1712 (14.6%) had unsuppressed viral load within 6 months after initiating ART. The main marker of poor adherence was a combination of change in CD4 count and MCV; change in CD4 ≥expected and change in MCV <14.5 fL (RR 2.82, 95% CI 2.16–3.67), change in CD4 <expected and change in MCV <14.5 fL (RR 5.49, 95% CI 4.13–7.30) compared to change in CD4 ≥expected and change in MCV ≥14.5 fL.ConclusionsA combination of less than expected increase in CD4 and MCV at 6 months after treatment initation was found to be a marker of poor adherence. This could help identify and monitor poor treatment adherence in the absence of viral load testing.

Early Detection of Myelodysplastic Syndromes: Maximizing the Utility of Automated Hematology

Introduction:Myelodysplastic syndromes (MDS) are a heterogeneous group of clonal myeloid disorders, affecting primarily older individuals and characterized by abnormal hematopoiesis, varying degrees of bone marrow failure, and an increased risk for transformation to acute myeloid leukemia (AML). Despite recent technical advances in diagnostic hematology, accurate diagnosis and staging of MDS still relies heavily on morphologic assessment of peripheral blood and bone marrow cells, usually by an experienced hematopathologist. Peripheral cytopenias and the presence of dysplastic changes are required in all cases, to consider a diagnosis of MDS. However, the initial assessment of dysplasia in peripheral blood cells by manual differential can often be subjective. Furthermore, important components of the CBC generated by modern analyzers and relevant to the morphologic properties of blood cells, are often overlooked. These factors may contribute to why the true incidence of MDS is under-estimated. We undertook a retrospective case-control study to evaluate MDS relevant parameters generated by automated cell counters at our institution, to fully exploit the potential for modern analyzers to assist in the diagnosis of MDS, and to assist in the diagnostic yield for these important and usually fatal diseases.Methods:We identified patients with MDS who had peripheral blood counts reported by theSysmexXN-3000 automated analyzer over a one year period (from 6/2015 to 6/2016). The modern Sysmex cell counter generates several parameters directly relevant to the morphologic properties of blood cells including standard deviation of red cell distribution width (RDW-SD), mean platelet volume (MPV), immature platelet fraction (IPF), reticulocyte hemoglobin (RET-HE), immature granulocytes (IG) and immature reticulocyte fraction (IRF). A control group was selected consisting of patients with normal blood counts reported by the same analyzer and generated during the study period. The study and control groups were matched in age, gender and ethnicity to reduce bias. All parameters generated by automated hematology testing were statistically compared between the two groups and significant differences were used to develop a predictive model. Statistical analysis was largely descriptive for patient demographics (age, gender, and race/ethnicity) and complete blood count (CBC) parameters. Counts and percentages were used to summarize the distribution of categorical variables and median, range, mean, and standard deviation were used for continuous variables. CBC parameters were compared by treatment group (MDS vs. Control) using two sample tests (t-test or binomial exact test).Results:Of a sample size of over 200 patients during the study period, there were 80 evaluable patients for this interim analysis and results are presented in tabulated form (see table below). In our sample, we confirmed what has been previously reported in the literature, as statistically significant parameters in correctly predicting an MDS diagnosis (iereduced hemoglobin [Hgb, p<0.0001], hematocrit [Hct, p<0.0001] , white cell [WBC, p<0.0001] and platelet counts [Plts, p<0.0001]; increased mean corpuscular volume [MCV, p<0.001], mean corpuscular hemoglobin [MCH, p<0.0001] and red cell distribution width [RDW p<0.0001]. In addition to these parameters, we also found that decreased red blood cell counts (RBC, p<0.0001), neutrophils (ANC, p<0.0001) and lymphocytes (ANL, p<0.0001) were important predictive abnormalities. The performance of a predictive model incorporating the parameters listed in addition to RDW-SD, MPV, IPF, RET-HE, IG and IRF will be presented.Conclusion:Maximizing the utility of new and improved automated hematology analyzer technologies for early detection of MDS will greatly benefit both clinicians and patients by facilitating earlier diagnosis of MDS, eliminating subjectivity in the initial assessment of dysplasia and promoting better use of results from minimally invasive peripheral blood collection. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

ROLE OF HEAVY METALS BIOACCUMULATION ON SOME PHYSIOLOGICAL AND HISTOPATHOLOGICAL CHANGES IN THE CULTURED OREOCHROMIS NILOTICUS AND MUGIL CEPHALUS AT EL-FAYOUM GOVERNORATE, EGYPT

As the world population increase, the demand for high protein foods would gradually rise. Heavy metals are natural trace components of the aquatic environment, but their levels have been increased due to industrial wastes, geochemical structure, agricultural and mining activities. The absorption and accumulation of different pollutants vary among different biological systems. Therefore, the present study aims to high lighten the impact of the bioaccumulation of heavy metals in different organs of fish and the factors affecting their dissemination. It is also concerned with the study of some physiological and biochemical parameters of the two studied fish species and their ability to resist stressors. This is confirmed by histopathological investigation on the diagnosis of fish diseases caused by the heavy metals. Bioaccumulation of heavy metals in fish tissues led to histopathological alterations in liver and kidneys of both fish species collected from the studied fish farms that irrigated with agricultural drainage water (El-Berka and El-Wadi).These alterations didn’t occur in case of Demo fish farm that irrigated with fresh water of Bahr Yousef (branch of the river Nile). Data representing the hematological parameters of both fish species collected from Demo fish farm showed blood picture values within normal ranges. However, there was a highly significant decrease in values of erythrocytes count, hemoglobin content and hematocrit value for both studied fish species collected from the other studied fish farms (El-Berka and El-Wadi). This decrease was accompanied by an increase in mean corpuscular volume as a case of macrocytic anemia in case of Oreochromis niloticus and microcytic anemia in case of Mugil cephalus. The present results revealed that there were highly significant differences in the other blood indices and blood leucocytes of each species individually collected from the different studied fish farms. The results declared highly significant differences in serum glucose, total protein, creatinine, and uric acid concentrations, in addition to ASAT and ALAT activities for each species in the studied fish farms that resemble different aquatic habitats.

D43 - Capecitabine and Regorafenib-related increased mean corpuscular volume of red blood cell may be a predictive marker of treatment response and survival in patients with metastatic colorectal cancer

Background: Erythrocyte mean corpuscular volume (MCV) increase has been described in patients treated with capecitabine. Moreover, tyrosine kinase inhibitors have been shown to induce macrocytosis in patients with renal cancer cell and gastrointestinal stromal tumors, presumably via the inhibition of erythroid progenitor cells of the bone marrow. Therefore, the aim of our study was to evaluate the potential association of the erythrocyte MCV increase with tumor response and survival in patients with metastatic colorectal cancer (mCRC) treated with capecitabine and regorafenib. Patients and methods: A retrospective review of 30 patients with mCRC who were treated with capecitabine or regorafenib for at least 3 months at the Department of Experimental, Diagnostic and Specialty Medicine, University of Bologna, Sant'Orsola-Malpighi Hospital, Bologna, Italy. Complete blood count (CBC) including red blood cell indices were recorded at baseline and after 4, 8 and 12 weeks from capecitabine or regorafenib treatment. Results: Baseline MCV levels and MCV levels after 4, 8 and 12 weeks were registered for each patient treated with capecitabine or regorafenib. Median ΔMCV [(post-treatment MCV values after 12 weeks) - (baseline MCV values)] was calculated. Patients were grouped according to ΔMCV into two groups in order to carry out survival analysis and correlation with tumor response. Moreover, univariate and multivariate analysis was performed to investigate if MCV increase was independently associated with favorable survival outcomes. Conclusions: Erythrocyte MCV increase may be used as a predictive marker for treatment response, PFS and OS in patients with mCRC treated with capecitabine or regorafenib. In the future, response to TAS-102 (trifluridine-tipiracil) and MCV increase will be also evaluated.

Hematological manifestations of autoimmune gastritis

Aim of investigation. To estimate hematological disorders in patients with high titer of anti-parietal cell antibodies (APCA). Material and methods. Overall 71 patient with high serum APCA titer were included in original study. At all patients scores of clinical and biochemical blood tests were investigated. The special attention was given to RBC color index (CI), mean corpuscular volume (MCV), mean hemoglobin content per cell and serum iron and vitamin В12 concentration. Results. The mean indices of clinical and biochemical blood tests in APCA-positive patients were within normal range. Hematological changes were revealed in 25,4% of patients. In 11,3% of the cases either macrocytic or microcytic anemia was diagnosed. Increase in mean corpuscular volume and serum cobalamin level were found out in 16,9% of the cases, while low hemoglobin level - only at 25% of them. No Helicobacter pylori infection has been revealed in the patients with macrocytic anemia, however no significant difference on its prevalence in patients with different serum cobalamin level was found out. Conclusion. The majority of cases with high APCA titer has no hematological signs of autoimmune gastritis. In 25,4% of patients with APCA changes in common blood count were revealed, most often - of MCV and the CI. Anemia was diagnosed in 11,3% of patients. In investigated group cobalamin deficiency was found in 16,9% of patients, iron deficiency - in 9,9% of the cases. In 75% of patients increase in MCV was the only sign of cobalamin deficiency. Iron deficiency was more common in women.

Sub-acute and chronic toxicity profiles of Markhamia tomentosa ethanolic leaf extract in rats

Ethnopharmacological relevanceMarkhamia tomentosa (Benth.) K. Schum Ex Engl. (Bignoniaceae) is used in traditional African medicine for the treatment of diarrhoea, oedema, pain and malaria. The leaf extract was reported to show no visible sign of toxicity on acute exposure. This present study investigates the sub-acute and chronic toxicity effects of Markhamia tomentosa in rats. Materials and methodsThe animals (n=6/group) were treated daily with the extract at doses of 40, 200 and 1000mg/kg orally for 28 and 90 days. Control rats received distilled water and all animals were weighed at 7 days interval. The haematological, biochemical and histological parameters were determined. ResultsThe extract showed non-significant changes in body weight gain of treated compared to control rats in both studies. Extract significantly decreased red blood cell (RBC), mean cell haemoglobin concentration and increased mean corpuscular volume (MCV) parameters after the 28 day study. In the 90 day study, a significant increase in white blood cell, RBC, platelets and decrease in MCV and mean cell haemoglobin (MCH) parameters were observed. Biochemical parameters were significantly changed in both studies; triglycerides, total protein, alanine transaminase, aspartate transaminase and albumin showed significant increase while creatinine, blood urea nitrogen and uric acid levels showed significant decrease. Significant increase in liver weight with no treatment-related histological changes was observed in all harvested vital organs. ConclusionMarkhamia tomentosa extract elicited non-toxic effect in the liver and kidney function parameters in rats. Thus, the extract is safe when administered orally.

Does lymphopenia or macrocytosis reflect 6‐thioguanine levels in patients with inflammatory bowel disease treated with azathioprine or 6‐mercaptopurine?

The thiopurine drugs, 6-mercaptopurine and azathioprine, remain the mainstay of immunomodulator therapy for inflammatory bowel disease (IBD). Optimal management depends on achieving therapeutic levels of 6-thioguanine (6-TGN), but measuring thiopurine metabolites is associated with significant cost. Thiopurines cause lymphopenia and an increase in mean corpuscular volume (MCV). It is unclear whether any clinically useful correlation exists between 6-TGN levels and lymphocyte count or MCV. The aim of this study is to investigate the correlation between 6-TGN levels and lymphocyte count and MCV in thiopurine-treated patients with IBD. We analysed a prospectively acquired database of 67 patients with IBD treated with thiopurine therapy. The data were analysed looking at the relationship between 6-TGN levels and both lymphocyte count and MCV by using the Spearman's rank correlation coefficient. Twenty-seven (40%) patients had therapeutic 6-TGN levels. Thirty-three (49%) patients had sub-therapeutic 6-TGN levels. A weak positive correlation between 6-TGN levels and lymphocyte count was demonstrated, but this was not statistically significant (Spearman's R = 0.14, P = 0.23). Spearman's rank correlation coefficient between 6-TGN levels and MCV was statistically significant (R = 0.42, P = 0.0005). MCV >101 fL excluded a subtherapeutic 6-TGN level with positive predictive value of 92%. There is no specific lymphopenia that can be assumed to indicate a therapeutic 6-TGN level. The relationship between 6-TGN levels and MCV is likely to be clinically relevant. If MCV is elevated, 6-TGN is unlikely to be sub-therapeutic. MCV is a potential surrogate marker which can rule out sub-therapeutic thiopurine metabolites in patients with IBD treated with azathioprine or 6-mercaptopurine.

In vitro alteration of hematological parameters and blood viscosity by the perfluorocarbon: Oxycyte

While perfluorocarbons (PFCs) may be useful in some clinical situations, previous studies have shown that interferences with chemistry analytes can occur with blood samples containing PFCs. This in vitro study focused on how the PFC Oxycyte may affect hematology measurements in blood samples. Swine blood diluted with Oxycyte or saline (Controls) were analyzed for Hemoglobin (Hb), Mean Corpuscular Volume (MCV),Hematocrit (Hct) and Fluorocrit (Fct) using a HemaVet, ABL-735 (ABL), or microhematocrit. Ancillary tests (blood viscosity, electrolytes, cell counts, and red blood cell morphology) were performed secondarily. Increasing Oxycyte resulted in increases in MCV, Hct, and visible cell shape change and morphology vs. Effects correlated with lower sodium in Oxycyte samples vs. With increasing Oxycyte, Hb became higher than Controls or became unpredictable depending on the instrument (HemaVet or ABL, respectively). Fct was smaller than predicted and likely represented the heaviest components of Oxycyte. At ≥50 % Oxycyte, RBC hemolysis rendered further measurements impractical. Viscosity first increased then decreased with increasing Oxycyte, peaking at ~40 % Oxycyte. Hct, MCV, Hb, and RBC morphology may be affected by Oxycyte. These observations correlated with lower sodium and increasing Oxycyte, causing hemolysis at high Oxycyte concentrations. These changes were due to alterations in the blood samples in vitro and this should be considered when interpreting hematology parameters from in vivo studies.

Macrocytosis as a potential parameter associated with survival after tyrosine kinase inhibitor treatment

Aim of the studyAs a rise in mean corpuscular volume (MCV) of the erythrocyte is frequently seen during treatment with imatinib and sunitinib, we investigated whether macrocytosis (MCV > 100 fl) also occurs as a class effect in other tyrosine kinase inhibitors (TKIs) and whether occurrence of macrocytosis is associated with outcome. Materials and methodsIn 533 patients, using 5 TKIs, we investigated if macrocytosis and an increase in MCV were associated with progression-free survival and overall survival (OS) in specific tumour-treatment combinations. ResultsMacrocytosis as well as an increase in MCV from baseline of >10 fl (ΔMCV +10 fl), when included as a time-dependent covariate, were associated with improved OS in patients with renal cell cancer (RCC) treated with sunitinib (macrocytosis, hazard ratio [HR] = 0.61, p = 0.031, and ΔMCV +10 fl, HR = 0.58, p = 0.016). ConclusionIn sunitinib-treated patients with RCC, the occurrence of macrocytosis, or a substantial increase in MCV levels after start of treatment, could potentially serve as a positive prognostic factor for survival, if validated prospectively.

Association of the RUNX1/AML1 Gene Mutation and Familial MDS/AML: A Case Report and Review of Literature

Myelodysplastic syndrome (MDS) and Acute Myeloid Leukemia (AML) are mostly sporadic hematopoetic malignancies, which generally thought inheritable, though specific gene abnormalities may play a role in the progression of myelodysplasia. Recently, many reports have revealed that mutations in the RUNX1/AML1 gene are involved in defective hematopoiesis. Moreover, patients with such mutations have a significant poorer prognosis than cases without RUNX1 mutations. Since familial occurrence of MDS/AML is rare, there are few reports about the relationship between RUNX1 mutations and familial MDS/AML. In the study of a familial MDS/AML, we found a61-year-old male with MDS who developed into AML later. He had a history of leukocytopenia and thrombocytopenia for decades before developing into pancytopenia. We identified a RUNX1mutationin this patient through sequencing. Furthermore, the same mutation was present in his son (II-1) who suffered from MDS as well as his granddaughter. Intriguingly, II-1 was 10years old when diagnosed with MDS, nearly 50 years earlier than his father. Myelodysplastic features in bone marrow sections of these two patients were not obvious in the early stage. They mainly showed active erythrocyte proliferation, together with an increased mean corpuscular volume, which can indicate inflection points in MDS progression. To date, patients with familial MDS had no antecedent hematological abnormalities in the early stage. In this study, we found a new inheritable mutation of the RUNX1 gene in the familial MDS which is frequently deregulated in hematological malignancies. As RUNX1 was present in the early stage of familial MDS, this genetic mutation may serve as an early diagnostic marker and contribute to the treatment of MDS/AML. DisclosuresNo relevant conflicts of interest to declare.

Adenosine Deaminase 2 Deficiency As a Cause of Pure Red Cell Aplasia Mimicking Diamond Blackfan Anemia

Diamond Blackfan anemia (DBA) is an inherited pure red cell aplasia. Most cases present in the first year of life with elevation in erythrocyte adenosine deaminase (eADA) and frequently with increased mean corpuscular volume (MCV) and hemoglobin F (hgb F). Approximately 70 percent of cases are due to a mutation in one of several ribosomal protein (RP) genes or in GATA1, whereas the remaining cases are genetically uncharacterized. Here we report a child born with severe anemia and diagnosed with DBA at 2 months of age. His bone marrow was normocellular with a paucity of erythroid progenitors and scattered lymphocytes. An eADA level was not obtained prior to the first red cell transfusion. He was red cell transfusion dependent and his anemia did not respond to a steroid trial. His 4 year old sister, who had normal hemoglobin, MCV, hgb F, and eADA measurements, served as his HLA identical donor for hematopoietic stem cell transplantation (HSCT). HSCT resulted in 100% donor chimerism, but red cell engraftment was not achieved. He subsequently underwent a mismatched unrelated HSCT with trilineage engraftment.Ten years later, at the age of 14 years, the sister presented with profound hypoproductive normocytic anemia. The bone marrow showed absence of erythroid precursors and presence of lymphoid aggregates. Findings of immunodeficiency included numerous cutaneous warts, recurrent aphthous ulcers, Epstein Barr virus (EBV) reactivation, low IgM, and low numbers and percentages of CD19+ and CD3-56+16+ lymphocytes. The anemia and reticulocytopenia persisted despite resolution of EBV reactivation. Upon her presentation, levels of iron, ferritin, transferrin saturation, and liver transaminases were elevated. A liver biopsy obtained after transfusion of a total of 60 ml/kg packed red blood cells demonstrated 4.8 mg Fe/g dry liver weight with stage 2 portal fibrosis.Targeted DNA sequencing studies performed on the affected sister were negative for single nucleotide variants in any of 12 RP genes previously implicated in DBA and a genome wide chromosome microarray was normal. Whole exome analysis of her and her parents demonstrated that she carried compound heterozygous variants in CECR1 (cat eye syndrome chromosome region, candidate 1). The variant p.R169Q had been previously reported as pathogenic, while the p.G358R variant was of uncertain significance. These variants are present at frequencies of 4.9X10-4 and 2.6X10-5 in the Exome Aggregation Consortium database, respectively. Analysis of buccal swab DNA of the proband showed the same biallelic variants. An unaffected 16-year-old sibling had a normal genotype. CECR1 encodes adenosine deaminase 2 (ADA2) and ADA2 levels in the plasma of the affected sister were markedly low, consistent with a deficiency state.CECR1 is highly expressed in cells of myeloid origin and ADA2 is a secreted protein implicated in macrophage differentiation and proliferation. Deficiency of ADA2 (DADA2) results in aberrant monocyte differentiation favoring M1 over M2 macrophages, thereby resulting in a proinflammatory state. Recent descriptions of patients with DADA2 due to CECR1 mutations reported a spectrum of phenotypes including intermittent fevers, lacunar stroke in childhood, livedoid rash, polyarteritis nodosa, and immunodeficiency with B lymphopenia and low IgM levels. Our cases are similar to the report of one of two brothers, homozygous for CECR1 p.R169Q, described by van Montfrans, et al,. (NEJM, 2014). The eldest was given a diagnosis of atypical DBA (refractory pure red cell aplasia) in infancy and underwent a HSCT from his asymptomatic, HLA identical brother. This HSCT resulted in non-engraftment, necessitating a subsequent unrelated donor HSCT. The younger sibling donor later developed hepatosplenomegaly, profound lymphopenia, and evidence of an inflammatory state.Together, these three cases support pure red cell aplasia as a presentation of DADA2 and that this may be confused with DBA, particularly when manifest in infancy. We propose DADA2 should be considered in patients with genetically uncharacterized DBA. Differentiating features to suggest DADA2 may include normal eADA, MCV, and hgb F levels and findings of associated immunodeficiency. Additionally, the macrophage activation due to DADA2 may have played a role in the iron overload observed in our second patient prior to any red cell transfusion. DisclosuresNo relevant conflicts of interest to declare.

Effects of dietary allspice, Pimenta dioica powder on physiological responses of Oreochromis mossambicus under low pH stress

This study investigated the effects of the supplementation with allspice (0, 5, 10, 15, or 20 g kg−1) on the haemato-immunological and biochemical variables in tilapia, Oreochromis mossambicus under acidic stress condition. In a 60-day feeding trial, 15 aquariums (80-L) were stocked with 18 fish (20.05 ± 0.10 g) each. Then, acidic stress was achieved by exposing the sampled fish to acidic water (pH 5.5) for 3 days. Allspice supplementation influenced the haematological indices, serum glucose, protein, globulin and innate immune parameters such as respiratory burst activity, lysozyme, and myeloperoxidase activities. In general, at acidic pH decreased circulating red blood cell numbers (RBC), increased mean corpuscular volume (MCV), mean corpuscular hemoglobin (MCH) and the innate immune parameters were observed. On the other hand, the inclusion of allspice prevented an increase in blood glucose MCV and MCH, decreases in albumin, RBC, lysozyme activity and respiratory burst avtivity. In conclusion, this study demonstrated that allspice supplementation at 10 g kg−1 for 60 days, has adequate beneficial effects on improvement of haemato-immunological and biochemical status of O. mossambicus after stressful management.