Cells In Blood Of Cancer Patients Research Articles

Immune toxicity and flow cytometry of circulating blood cells in cancer patients receiving immune therapy.

e15126 Background: The mechanisms by which immune checkpoint inhibitors (ICI) cause immune related adverse events (irAE) are not clear. No current blood tests predict which patients will suffer irAEs. Methods: 70 cancer patients had blood drawn prior to ICI and then 4-6 weeks later. 63 had lung cancer; median age was 69 yrs; 21 were female and median ICI treatment duration was 142 days. Patient blood samples were analyzed using flow cytometry for over 50 lymphoid and myeloid markers to determine levels of circulating white blood cells, as well as their changes over time. Medical records were reviewed for irAE’s grades in 8 groups: rash, colitis, hypothyroidism, hyperthyroidism, hypophysitis, hepatitis, adrenal insufficiency, and pneumonitis. To determine association between toxicity and cell counts we used logistic regression and random forest for the univariate and multivariate analysis. We included a random permutation of the baseline age (which is associated with higher toxicity rates) as the analytical control in the random forest model to help identify the threshold of association strength of a random noise and to identify only those cell subsets that were statistically significant (reported below). Results: Patients with elevated baseline levels of specific subsets of T-cells were more likely to develop irAE’s, and elderly patients were more likely to develop Grade 2 irAE’s. T-cell populations associated with any toxicity included CD3+CD8+PD1+; CD3+CD8+; CD25+CD127lowFoxP3+ and CD3+CD8+Ki-67+. Also, patients who developed any irAE’s demonstrated changes in the following cell types after 2 doses of immune therapy compared to their baseline readings. These included changes in the percentage of circulating cells that were CD3+CD8+PD1+; CD3+CD8+HLA-DR+; CD3+CD4+HLA-DR+; CD3+CD8+CCR7-; CD56+; CD3-CD19-; CD3+CD8+; CD16+CD56dim. Patients with grade ≥2 toxicities, or organ specific toxicities demonstrated statistically significant differing levels of T-cells subsets, though the number of patients in each group was limited. Patients with > median baseline expression of CD3+ CD8+ PD1+ cells had greater survival compared with those that had < median levels. Conclusions: Flow cytometry analysis of patients receiving immune therapy at baseline and 6 weeks after initiating therapy may predict which patients are at greater likelihood of any/organ specific irAEs, potentially leading to an improved understanding their mechanisms. Responding to leukocyte changes by substitution of drugs or shortening of treatment duration may reduce irAEs.

Quantitative Changes of Red Blood cells in Cancer Patients under Palliative Radiotherapy-A Retrospective Study

Quantitative Changes of Red Blood cells in Cancer Patients under Palliative Radiotherapy-A Retrospective Study

Формирование хромосомной и микросателлитной нестабильности в клетках крови онкологических больных при комбинированном воздействииin vitroионизирующей радиации и комутагенов

Формирование хромосомной и микросателлитной нестабильности в клетках крови онкологических больных при комбинированном воздействии<i>in vitro</i>ионизирующей радиации и комутагенов

Haemoglobin Increment by Red Blood Cells Transfusion in Cancer Patients With Anaemia

Severe anaemia is usually treated with red blood cell (RBC) transfusion and in some cases moderate anaemia also requires transfusion. Traditionally one unit of red blood cells is transfused to increase the hemoglobin (Hb) level by 1 gm/dl, although no consensus guideline is available in our country. This study was done to see how much hemoglobin level was increased after transfusion of one unit of red blood cells in cancer patients with anaemia in our people. During the period of July 2012 to December 2012, 160 patients were studied in the Department of Transfusion Medicine of National Institute of Cancer Research and Hospital (NICRH), Mohakhali, Dhaka. All patients were aged &gt;18 years of both sexes having a haemoglobin level of &lt;10 gm/dl, and had no transfusion of platelets, plasma or colloid within 24 hours of red cells transfusion or with active bleeding or drain loss. The average increment of haemoglobin level was 0.74 gm/dl (0.74±0.11) gm/dl for each unit of red blood cells transfusion. This rise of haemoglobin level was different from the traditional calculation which was statistically significant (p&lt;0.01). The traditional calculation for correction of anaemia by red blood cell transfusion is not suitable for the people of our country.&#x0D; JCMCTA 2014 ; 25 (2) : 21-25

Immune senescence and cancer in elderly patients: Results from an exploratory study

BackgroundThe challenge of immune senescence has never been addressed in elderly cancer patients. This study compares the thymic output and peripheral blood telomere length in ≥70year old cancer patients. Patients and methodsFifty-two elderly cancer patients and 39 age-matched controls without personal history of cancer were enrolled. All patients underwent a Comprehensive Geriatric Assessment (CGA), from which a multidimensional prognostic index (MPI) score was calculated. Peripheral blood samples were studied for naïve and recent thymic emigrant (RTE) CD4+ and CD8+ cells by flow cytometry. T-cell receptor rearrangement excision circle (TREC) levels, telomere length and telomerase activity in peripheral blood cells were quantified by real-time PCR. ResultsThe percentages of CD8+ naïve and CD8+ RTE cells and TREC levels were significantly lower in cancer patients than in controls (p=0.003, p=0.004, p=0.031, respectively). Telomere lengths in peripheral blood cells were significantly shorter in cancer patients than in controls (p=0.046) and did not correlate with age in patients, whereas it did in controls (r=−0.354, p=0.031). Short telomere (≤median)/low TREC (≤median) profile was associated with higher risk of cancer (OR=3.68 [95% CI 1.22–11.11]; p=0.021). Neither unfitness on CGA nor MPI score were significantly related to thymic output or telomere length in either group. ConclusionsImmune senescence is significantly worse in elderly cancer patients than in age-matched controls. The low thymic output and the shorter telomeres in peripheral blood cells of cancer patients may reflect a pre-existing condition which facilitates the onset of malignancies in elderly people.

A Canonical Transforming Growth Factor Beta-Dependent Signaling Pathway is Present in Peripheral Blood Cells of Cancer Patients with Skeletal Metastasis

Background: Patients with advanced metastatic cancer often have elevated levels of circulating transforming growth factor beta (TGF-β) that is thought to stimulate receptor mediated signaling through phosphorylated SMAD transcription factors in peripheral blood mononuclear cells. Methods: To identify this TGF-β-dependent gene expression profile in cancer patients, we first evaluated a multi-gene expression profile from ex-vivo treated PBMCs with TGF-β1 stimulation. Change in expression, when challenged with a specific TGF-β receptor type kinase inhibitor was then derived to be ligand and inhibitor specific. Once this profile was established, we examined its role in identifying the activation of a canonical TGF-β1 signaling pathway in patient samples. Results: We discovered a 37 gene sub-set where the expression profile from ex-vivo treated PBMCs was significantly associated with SMAD phosphorylation in cancer patients. We found significant correlation between the ex-vivo derived expression signature and circulating levels of TGF-β1 in patient samples. Additionally, we report association between the expression profile and the presence of several plasma proteins in disease samples that are known to be concomitantly present with TGF-β- dependent pathway activation. Conclusion: An expression profile for TGF-β1 cytokine mediated-signaling in cancer patients is identified, which may serve as a biomarker to measure the pharmacodynamic effect of TGF-β inhibitors during clinical drug development and as marker of disease diagnosis.

MiRNA: Small Molecules as Potential Novel Biomarkers in Cancer

Four different types of small RNAs functionally associated with gene silencing have been discovered in animals including small interfering RNAs (siRNAs), microRNAs (miRNAs), and Piwi-interacting RNAs (piRNAs). Experimental evidence suggests that miRNAs regulate the expression of more than 30% of protein-coding genes. These molecules can also act as oncogenes or tumor suppressors. Expression profiling has revealed characteristic miRNA signatures not only in human cancers but also in serum and blood cells of cancer patients. Numerous human miRNA genes map to chromosomal regions which are susceptible to amplification, deletion or translocation in the process of tumor development. Despite the pivotal role of miRNA in cancer precise mechanisms of action are yet to be elucidated. This review is focused on recent findings related to the emerging field of miRNA serving as novel potential biomarkers in cancer diagnosis, prognosis and possibly, therapies.

MiRNAs in lung cancer - Studying complex fingerprints in patient's blood cells by microarray experiments

BackgroundDeregulated miRNAs are found in cancer cells and recently in blood cells of cancer patients. Due to their inherent stability miRNAs may offer themselves for blood based tumor diagnosis. Here we addressed the question whether there is a sufficient number of miRNAs deregulated in blood cells of cancer patients to be able to distinguish between cancer patients and controls.MethodsWe synthesized 866 human miRNAs and miRNA star sequences as annotated in the Sanger miRBase onto a microarray designed by febit biomed gmbh. Using the fully automated Geniom Real Time Analyzer platform, we analyzed the miRNA expression in 17 blood cell samples of patients with non-small cell lung carcinomas (NSCLC) and in 19 blood samples of healthy controls.ResultsUsing t-test, we detected 27 miRNAs significantly deregulated in blood cells of lung cancer patients as compared to the controls. Some of these miRNAs were validated using qRT-PCR. To estimate the value of each deregulated miRNA, we grouped all miRNAs according to their diagnostic information that was measured by Mutual Information. Using a subset of 24 miRNAs, a radial basis function Support Vector Machine allowed for discriminating between blood cellsamples of tumor patients and controls with an accuracy of 95.4% [94.9%-95.9%], a specificity of 98.1% [97.3%-98.8%], and a sensitivity of 92.5% [91.8%-92.5%].ConclusionOur findings support the idea that neoplasia may lead to a deregulation of miRNA expression in blood cells of cancer patients compared to blood cells of healthy individuals. Furthermore, we provide evidence that miRNA patterns can be used to detect human cancers from blood cells.

Aberrant allele-specific replication, independent of parental origin, in blood cells of cancer patients

BackgroundAllelic counterparts of biallelically expressed genes display an epigenetic symmetry normally manifested by synchronous replication, different from genes subjected to monoallelic expression, which normally are characterized by an asynchronous mode of replication (well exemplified by the SNRPN imprinted locus). Malignancy was documented to be associated with gross modifications in the inherent replication-timing coordination between allelic counterparts of imprinted genes as well as of biallelically expressed loci. The cancer-related allelic replication timing aberrations are non-disease specific and appear in peripheral blood cells of cancer patients, including those with solid tumors. As such they offer potential blood markers for non-invasive cancer test. The present study was aimed to gain some insight into the mechanism leading to the replication timing alterations of genes in blood lymphocytes of cancer patients.MethodsPeripheral blood samples derived from patients with prostate cancer were chosen to represent the cancerous status, and samples taken from patients with no cancer but with benign prostate hyperplasia were used to portray the normal status. Fluorescence In Situ Hybridization (FISH) replication assay, applied to phytohemagglutinin (PHA)-stimulated blood lymphocytes, was used to evaluate the temporal order (either synchronous or asynchronous) of genes in the patients' cells.ResultsWe demonstrated that: (i) the aberrant epigenetic profile, as delineated by the cancer status, is a reversible modification, evidenced by our ability to restore the normal patterns of replication in three unrelated loci (CEN15, SNRPN and RB1) by introducing an archetypical demethylating agent, 5-azacytidine; (ii) following the rehabilitating effect of demethylation, an imprinted gene (SNRPN) retains its original parental imprint; and (iii) the choice of an allele between early or late replication in the aberrant asynchronous replication, delineated by the cancer status, is not random but is independent of the parental origin.ConclusionThe non-disease specific aberrant epigenetic profile displayed in peripheral blood cells of patients with a solid tumour (unlike genetic aberrations) can be reversed, by an epigenetic drug applied in vitro, to the normal. It appears that the cancerous status differentiates between two allelic counterparts in a non-random manner, but independent of the parental origin

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Peripheral blood cells from weight-losing cancer patients control the hepatic acute phase response by a primarily interleukin-6 dependent mechanism.

Cancer cachexia is associated with an elevated hepatic acute phase protein response, poor outcome and elevated cytokine production from peripheral blood mononuclear cells (PBMC). This study investigates the mechanism by which PBMC can induce a hepatic acute phase response. Supernatants from the peripheral blood cells of cancer patients induced significantly higher C-reactive protein (CRP) from hepatocytes (198+/-21 ng ml-1) than did supernatants from healthy controls (64+/-20, p<0.005). CRP production in vitro correlated with IL-6 production by PBMC from patients with pancreatic cancer (r=0.76, p<0.0001). This C-reactive protein production was reduced by 84% using neutralising antibody to IL-6 (p<0.001). There was a significant negative correlation between PBMC-induced hepatocyte C-reactive protein production and survival (r=-0.45, p<0.01). PBMC from cancer patients induce the hepatic acute phase response via a primarily IL-6-dependent mechanism.

Ultrastructural changes of neutrophils following IL-2 treatment in vivo.

An ultrastructural analysis of peripheral blood cells of cancer patients following recombinant interleukin-2 (rIL-2) treatment at high doses (rIL-2, 18 x 10(6) I.U./m2/day) has been performed. Characteristic patterns of intense phagocytosis (neutrophils with large vaculoes containing electron-dense bodies) were observed in granulocytes of the treated patients with respect to the basal situation. These characteristics were particularly evident in the advanced stages of the therapy (24 and 48 h). The state of neutrophil activation was sometimes accompanied by the appearance of a close net of cell membranes, probably derived from lamellopodia.

DNA base adducts in urine andwhite blood cells of cancer patients receiving combination chemotherapies which includeN-methyl-N-nitrosourea

Abstract Urinary 3-methyladenine (3-MeAde) excretion andlymphocyte DNA adduct formation was studied in 15 patients receiving methylnitrosourea (MNU) at several dose levels (250 mg, 300 mg and600 mg total dose, 143-385 mg m(-2)) as part of various combination chemotherapies for advanced tumours (malignant melanoma, lymphoblastic lymphosarcorna andHodgkin's disease). Urinary 3-MeAde levels were significantly increased over background in patients at all dose levels (p < 0.001) andthe increases were dose-dependent (r = 0.77, p < 0.01). There were large interindividual variations in the excretion of 3-MeAde at each dose of MNU. In a subset of patients, N7-methyl-2-deoxyguanosine (7-MedG) andO(6)-methyl-2'-deoxyguanosine (O(6)-WedG) levels in DNA from blood leucocytes showed dose-dependent increases, however there were no simple relationships between urinary methylated DNA bases andleucocyte DNA adducts. Levels of adducts in leucocyte DNA (7-MedG, < 17-217 μmol mol(-1) dG; O(6)-WedG, < 1.6-35 μmol mol(-1) dG) were comparable with those reported for other methylating chemotherapeutic drugs. Leucocyte DNA andurinary methyl adducts may be useful markers of individual responses to treatment with methylating drugs.

The use of carcinogen-DNA adduct antisera for quantitation and localization of genomic damage in animal models and the human population.

The use of antibodies to detect chemical carcinogen-induced DNA damage involves quantitative determination and morphological localization utilizing antisera specific for carcinogen-DNA adducts. In recent years a large number of polyclonal and monoclonal antisera have been produced against individual adducts and modified DNAs with addition products varying in structure from ethyl and methyl groups to aromatic amines, polycyclic aromatic hydrocarbons, aflatoxins, and platinum-ammine complexes. The quantitative assays developed through the use of these antisera are able to detect attomole (10(-18) M) adduct concentrations, corresponding to one adduct in 10(8) nucleotides or a few hundreds of modifications per mammalian cell genome. This review focuses on data generated during the past 3 yr utilizing this immunotechnology as a tool to probe mechanisms of carcinogen-DNA interactions in various model systems and in the human population. Areas discussed in depth include quantitative and morphological studies involving detection of 2-acetylaminofluorene-DNA adducts in rat liver, O6-ethyl and O6-methyl deoxyguanosine adducts in rat brain, benzo[a]pyrene-DNA adducts in mouse skin and cis-diamminedichloroplatinum (II)-DNA adducts in peripheral nucleated blood cells of cancer patients.

Adriamycin distribution in plasma and blood cells of cancer patients with altered hematocrit

Adriamycin (AM) distribution in the cellular and plasma components of blood has been investigated in cancer patients with hematocrit values ranging from 23 to 49 after i.v. drug doses ( 40–70 mg/m 2 ). AM was measured by a fluorimetric technique in total blood, plasma and blood cells. Blood levels were found to be related to the dose, and when the number of blood cells per milliliter was low, a smaller amount of AM was found in the cell fraction and a larger amount was found in the plasma fraction. A further result of these studies was that, as already shown in Walker-bearing rats, AM accumulated to a marked extent in blood cells, particularly platelets, as expressed by the drug concentration per unit volume, and persisted longer in white blood cells and platelets than red cells, suggesting that the various cells have different roles in transport, storage or metabolism of the compound.

Adenosine deaminase and AMP deaminase activities in blood of cancer patients.

Adenosine deaminase and AMP deaminase activities were measured in plasma and blood cells of cancer patients and compared with those of normal subjects.