Myelotoxic Effects Research Articles

Single agent vemurafenib or rituximab-vemurafenib combination for the treatment of relapsed/refractory hairy cell leukemia, a multicenter experience

BackgroundHairy cell leukemia (HCL) is a rare mature B-cell malignancy that is primarily treated with purine analogues. However, relapse remains a significant challenge, prompting the search for alternative therapies. The BRAF V600E mutation prevalent in HCL patients provides a target for treatment with vemurafenib. Patients and methodsThis multicenter retrospective study included nine patients with relapsed/refractory (R/R) HCL from six different centers. Patient data included demographics, prior treatments, clinical outcomes, and adverse events. ResultsPatients received different treatment regimens between centers, including vemurafenib alone or in combination with rituximab. Despite the differences in protocols, all patients achieved at least a partial response, with seven patients achieving a complete response. Adverse events were generally mild with manageable side effects. The absence of myelotoxic effects and manageable side effects make BRAF inhibitors attractive, especially for patients ineligible for purine analogues or those with severe neutropenia. ConclusionSingle agent vemurafenib or in combination with rituximab appears to be a promising therapeutic option for R/R HCL. Further research is needed to establish standardized treatment protocols and to investigate long-term outcomes.

Metabolomic Study of Urine from Workers Exposed to Low Concentrations of Benzene by UHPLC-ESI-QToF-MS Reveals Potential Biomarkers Associated with Oxidative Stress and Genotoxicity.

Benzene is a human carcinogen whose exposure to concentrations below 1 ppm (3.19 mg·m−3) is associated with myelotoxic effects. The determination of biomarkers such as trans-trans muconic acid (AttM) and S-phenylmercapturic acid (SPMA) show exposure without reflecting the toxic effects of benzene. For this reason, in this study, the urinary metabolome of individuals exposed to low concentrations of benzene was investigated, with the aim of understanding the biological response to exposure to this xenobiotic and identifying metabolites correlated with the toxic effects induced by it. Ultra-efficient liquid chromatography coupled to a quadrupole-time-of-flight mass spectrometer (UHPLC-ESI-Q-ToF-MS) was used to identify metabolites in the urine of environmentally (n = 28) and occupationally exposed (n = 32) to benzene (mean of 22.1 μg·m−3 and 31.8 μg·m−3, respectively). Non-targeted metabolomics analysis by PLS-DA revealed nine urinary metabolites discriminating between groups and statistically correlated with oxidative damage (MDA, thiol) and genetic material (chromosomal aberrations) induced by the hydrocarbon. The analysis of metabolic pathways revealed important alterations in lipid metabolism. These results point to the involvement of alterations in lipid metabolism in the mechanisms of cytotoxic and genotoxic action of benzene. Furthermore, this study proves the potential of metabolomics to provide relevant information to understand the biological response to exposure to xenobiotics and identify early effect biomarkers.

Relationship of irradiated bone marrow volume and neutropenia in patients undergoing concurrent chemoradiation therapy for cervical cancer.

Concurrent chemoradiation therapy (CCRT) is the standard of care in the management of cervical cancer (International Federation of Gynecology and Obstetrics [FIGO] 2008 Stages IB2-IVA). Apart from the myelotoxic effects of chemotherapy, irradiation of pelvic bone marrow (BM) in the radiation field, can also contribute to hematological toxicity. We examined the relationship of irradiated BM volume and neutropenia in cervical cancer patients undergoing CCRT. This prospective study was conducted in a tertiary cancer center with a longitudinal study design. A total of 43 patients undergoing CCRT for cervical cancer were included. Using auto bone segmentation, the external contour of pelvic bones from L4 vertebral body to ischial tuberosities were delineated as BM. The volume of BM receiving 10, 20, 40, 50 Gy was calculated. Complete blood counts were done weekly to evaluate the neutropenia and were graded according to Common Terminology Criteria for Adverse Events, version 3.0. The risk of developing neutropenia was analyzed using logistic regression. Twenty-seven patients (62.8%) received 5 cycles of chemotherapy, 14 patients (32.6%) received 4 cycles of chemotherapy and 2 patients (4.7%) received 3 cycles of chemotherapy. Overall, 22 patients (51.2%) experienced acute neutropenia. On multivariate analysis increased BM V50Gy had a statistically significantly odds of developing any grade of neutropenia (odds ratio [OR] =1.43; 95% confidence interval [CI], 1.03-1.97; P = 0.028). When comparing patients receiving BM V40Gy ≥40% with BM V40Gy <40% odds of any grade of neutropenia was increased (OR = 2.03; 95% CI, 0.55-7.42; P = 0.28). Moreover, when comparing patients receiving BM V50Gy ≥15% with BM V50Gy <15% odds of any grade of neutropenia was increased (OR = 2.13; 95% CI, 0.57-7.97; P = 0.26). High-dose irradiation to the larger volume of BM prevents compensatory hyperplasia which leads to neutropenia in patients undergoing CCRT for cervical cancer.

CORRECTION OF THROMBOCYTOPOIESIS IN RATS WITH WALKER-256 CARCINOMA USING AN ANTIOXIDANT SUPPLEMENT IN THE SETTING OF CYTOSTATICS

— In this study, we’ve evaluated the myelotoxic effect of treating Walker-256 carcinoma with cytostatics, followed by correction of thrombocytopenia with liposomal and liposome-free mexidol. The study included 60 rats, which, depending on the type of treatment, were divided into 5 groups. We recorded the greatest increase in the number of platelets on the background of liposomal mexidol both on the 3rd and 7th day after the start of chemotherapy. At the end of the monitoring, the myeloprotective effect was 30% higher in the liposomal mexidol compared to its non-liposomal form. Conclusion: Activation of thrombocytopoiesis on the background of cytostatic therapy helps to reduce the complications related to the use of chemotherapy.

Anemia-Induced Bleeding in Patients with Platelet Disorders.

Anemia is not only a consequence of bleeding, but also a modifiable risk factor for bleeding in patients with thrombocytopenia or platelet function defects. In this review we outline the mechanism of anemia-induced bleeding in patients with platelet disorders, which involves a disturbance in normal red blood cell (RBC) rheology and reduced platelet margination to the endothelial surface due to a decrease in RBC mass, leading to impaired primary hemostasis and bleeding. Biologically, anemia reduces the mass of RBCs in the central column of flowing blood through a vessel resulting in fewer platelets coming into contact with the endothelial surface at the periphery of the flowing blood column. Thus, anemia results in impaired primary hemostasis. Von Willebrand factor (vWF) is another component of primary hemostasis and vWF deficiency, especially a deficiency of the highest vWF multimers, can also manifest with bleeding when concomitant anemia occurs. Clinically, patients at greatest risk for anemia-induced bleeding include patients with hematological malignancies in whom anemia and thrombocytopenia occur as a result of the underlying disease or the myelotoxic effects of treatment; patients with renal insufficiency with uremic thrombocytopathy and hypoproliferative anemia; and patients with inherited or acquired bleeding disorders affecting primary hemostasis (eg, Bernard-Soulier syndrome, von Willebrand disease) with chronic blood loss and iron deficiency anemia. Underlying abnormalities of any components of primary hemostasis plus concomitant anemia may result in major bleeding disorders; therefore, correction of remediable abnormalities-most notably, correction of the anemia- would be expected to have important clinical benefit. In this review we discuss how the correction of the anemia may lead to improvement of bleeding outcomes in patients with a primary hemostatic defect, supported by evidence from animal models, clinical trials and clinical experience.

IBCL-341: Inhibitor of B-RAFV600E Mutation in Hairy Cell Leukemia

Context: The use of standard therapy (ST) in hairy cell leukemia (HCL) is often impossible at the time of deep neutropenia (DN) or the development of infectious complications (IC). HCL patients who do not respond to ST present a special therapeutic problem. Objective: Vemurafenib has been used to treat resistant HCL since 2012. Vemurafenib does not have a myelotoxic effect and so can be used in therapy of HCL with DN, as well as in early relapse after ST or as a primary refractory course of HCL (RR). Design: The applicability of vemurafenib in patients with HCL with DN, including patients with IC and RR. Setting: Study setting can be used in hematological inpatient (including intensive care department) and outpatient departments. Patients: Vemurafenib was used in 27 patients with HCL (m: f = 2.4; median age 57 years (24–78 years): six RR patients and 21 patients with DN, including 7 patients with severe infectious manifestations in the intensive care department, including 1 patient on extracorporeal membrane oxygenation. Intervention: Vemurafenib was used in a dose of 240 mg 1–2 times a day. In 26 patients, vemurafenib was used for 3 months or more. Main Outcomes Measures: The response to therapy was evaluated by control of neutrophil count, size of the spleen, and resolution of the IC. Results: In patients with DN, the response was achieved in 95%, followed by 1 course of ST with cladribine. In 1 patient, within 1 month of vemurafenib therapy, the effect was not obtained. Among RR patients, 67% achieved remission of the disease after a course of therapy with vemurafenib for 3 months, followed by a ST of cladribine and maintenance therapy with rituximab or obinutuzumab. There were no complications with the use of vemurafenib. Short agranulocytosis within three days after the course of cladribine was observed in only two patients. Conclusion: Therapy of HCL patients with DN, IC, and RR is a complex therapeutic problem. In cases with proven BRAFV600E mutation, vemurafenib can be effectively used not only in RR patients but as an effective preliminary therapy in patients with DN and IN before a ST with purine analogues.

Diurnal expression of MRP4 in bone marrow cells underlies the dosing-time dependent changes in the oxaliplatin-induced myelotoxicity

The expression and function of some xenobiotic transporters varies according to the time of day, causing the dosing time-dependent changes in drug disposition and toxicity. Multidrug resistance-associated protein-4 (MRP4), an ATP­binding cassette (ABC) efflux transporter encoded by the Abcc4 gene, is highly expressed in bone marrow cells (BMCs) and protects them against xenobiotics, including chemotherapeutic drugs. In this study, we demonstrated that MRP4 was responsible for the extrusion of oxaliplatin (L-OHP), a platinum (Pt)-based chemotherapeutic drug, from BMCs of mice, and that the efflux transporter expression exhibited significant diurnal variation. Therefore, we investigated the relevance of the diurnal expression of MRP4 in BMCs for L-OHP-induced myelotoxicity in mice maintained under standardized light/dark cycle conditions. After intravenous injection of L-OHP, the Pt content in BMCs varied according to the injection time. Lower Pt accumulation in BMCs was detected in mice after injection of L-OHP at the mid-dark phase, during which the expression levels of MRP4 increased. Consistent with these observations, the myelotoxic effects of L-OHP were attenuated when mice were injected with L-OHP during the dark phase. This dosing schedule also alleviated the L-OHP-induced reduction of the peripheral white blood cell count. The present results suggest that the myelotoxicity of L-OHP is attenuated by optimizing the dosing schedule. Diurnal expression of MRP4 in BMCs is associated with the dosing time-dependent changes in L-OHP-induced myelotoxicity.

Daily Intravenous Infusion of Busulfan Impurity 5 for 4 Days Is Not Associated With Toxic Effects in the Rat.

The alkylating agent busulfan is used in conditioning treatment of chronic myelogenous or granulocytic leukemia prior to stem cell transplantations. Its cytotoxic activity results in primary damage or destruction of hematopoietic cells. While the toxicity of busulfan is well investigated, little is known about the toxic effects of its impurities. In this study, the effect of 4-day intravenous infusion (3 h/d) of 4.8 mg/kg/d busulfan and 0.49, 4.9, and 49 mg/kg/d busulfan impurity 5 (4-((methylsulfonyl)oxy)butyl acetate) was investigated in rats. Whereas busulfan elicited myelotoxic and hepatotoxic effects, no toxic effects were observed in animals receiving the impurity at dosages up to 10 times higher than busulfan. The highest impurity dose of 49 mg/kg/d is therefore considered the no-observed-adverse-effect level of busulfan impurity 5.

Comparative Study on Myelotoxic and Antineoplastic Action of Synadenium umbellatum, Vitis vinifera and Resveratrol

Cancer is one of the pathologies that most challenge medicine, not only because of the complexity of its development, but also because of the difficulty of treatment that is not always effective. Due to the significant toxicity and adverse effects profile presented by the main chemotherapeutic agents used to treat neoplasm, there is a constant interest in the search for new drugs that may be a more effective alternative. Therefore, the search for new compounds of plant origin becomes an interesting tool for the discovery of drugs with antitumor activity. Synadenium umbellatum is a plant native to tropical Africa known as cola-nota, hazel, cancerous, miraculous, among others. The plant is used by the Brazilian population as having anti-inflammatory, analgesic, antineoplastic properties, among others. However, the literature is lacking on reports of the toxicity of Synadenium umbellatum macerate. Resveratrol is a polyphenolic compound found in different plant species, mainly in grape species (Vitis) and their seeds. Vitis vinifera is a species of grape easily found in several regions, also containing a high concentrations of phenolic compounds, including resveratrol in its fruits, leaves and seeds. Therefore, this study was aimed to evaluate the myelotoxicity of macerate, extract and resveratrol and their antitumor activity in Balb/c mice with Ehrlich tumor. The hematological evaluation was obtained by flow cytometry and the tumors were measured using a pachymeter and the tumor masses by means of weighing. No statistically significant difference was observed between results from the control group and the treatment groups. It was concluded that macerate, crude extract and resveratrol did not demonstrate a myelotoxic effect and did not cause a decrease in tumor mass.

Sacituzumab Govitecan-hziy in Refractory Metastatic Triple-Negative Breast Cancer

BackgroundStandard chemotherapy is associated with low response rates and short progression-free survival among patients with pretreated metastatic triple-negative breast cancer. Sacituzumab govitecan-hziy is an antibody–drug conjugate that combines a humanized monoclonal antibody, which targets the human trophoblast cell-surface antigen 2 (Trop-2), with SN-38, which is conjugated to the antibody by a cleavable linker. Sacituzumab govitecan-hziy enables delivery of high concentrations of SN-38 to tumors.MethodsWe conducted a phase 1/2 single-group, multicenter trial involving patients with advanced epithelial cancers who received sacituzumab govitecan-hziy intravenously on days 1 and 8 of each 21-day cycle until disease progression or unacceptable toxic effects. A total of 108 patients received sacituzumab govitecan-hziy at a dose of 10 mg per kilogram of body weight after receiving at least two previous anticancer therapies for metastatic triple-negative breast cancer. The end points included safety; the objective response rate (according to Response Evaluation Criteria in Solid Tumors, version 1.1), which was assessed locally; the duration of response; the clinical benefit rate (defined as a complete or partial response or stable disease for at least 6 months); progression-free survival; and overall survival. Post hoc analyses determined the response rate and duration, which were assessed by blinded independent central review.ResultsThe 108 patients with triple-negative breast cancer had received a median of 3 previous therapies (range, 2 to 10). Four deaths occurred during treatment; 3 patients (2.8%) discontinued treatment because of adverse events. Grade 3 or 4 adverse events (in ≥10% of the patients) included anemia and neutropenia; 10 patients (9.3%) had febrile neutropenia. The response rate (3 complete and 33 partial responses) was 33.3% (95% confidence interval [CI], 24.6 to 43.1), and the median duration of response was 7.7 months (95% CI, 4.9 to 10.8); as assessed by independent central review, these values were 34.3% and 9.1 months, respectively. The clinical benefit rate was 45.4%. Median progression-free survival was 5.5 months (95% CI, 4.1 to 6.3), and overall survival was 13.0 months (95% CI, 11.2 to 13.7).ConclusionsSacituzumab govitecan-hziy was associated with durable objective responses in patients with heavily pretreated metastatic triple-negative breast cancer. Myelotoxic effects were the main adverse reactions. (Funded by Immunomedics; IMMU-132-01 ClinicalTrials.gov number, NCT01631552.)

Mutagenicity and genotoxicity effects of Verbena officinalis leaves extract in Sprague-Dawley Rats

Ethnopharmacological relevanceTraditionally, Verbena officinalis L. has been used for reproductive and gynaecological purposes. However, the mutagenicity and genotoxicity of V. officinalis have not been extensively investigated. Aim of the studyTo assess the in vitro mutagenicity and in vivo genotoxicity of aqueous extract of V. officinalis leaves using a modified Ames test and rat bone marrow micronucleus assay according to OECD guidelines. Materials and methodsIn vitro Ames test was carried out using different strains of Salmonella (TA97a, TA98, TA100, and TA1535) and Escherichia coli WP2 uvrA (pKM101) in the presence or absence of metabolic activation (S9 mixture). For micronucleus experiment, male and female Sprague-Dawley rats (n = 6/group) were received a single oral daily dose of 500, 1000, and 2000 mg/kg of V. officinalis extract for three days. Negative and positive control rats were received distilled water or a single intraperitoneal injection of 50 mg/kg of cyclophosphamide, respectively. Following dissection, femurs were collected and bone marrow cells were stained with May-Grünwald-Giemsa solution for micronucleus assessment. ResultsAmes test results demonstrated that 5, 2.5, 1.25 and 0.625 mg/ml of V. officinalis extract induced a significant mutagenic effect against TA100 and TA98 strains (with and without metabolic activation). Findings of the animal study showed there were no significant increase in the micronucleated polychromatic erythrocytes (MNPE) and no significant alterations in the polychromatic erythrocytes (PCE) to normochromatic erythrocytes (NCE) ratio of treated rats as compared with their negative control. Meanwhile, significantly increased in the MNPEs was seen in the cyclophosphamide-treated group only. ConclusionAqueous extract of V. officinalis has mutagenic effect against TA98 and TA100 strains as demonstrated by Ames test, however, there is no in vivo clastogenic and myelotoxic effect on bone marrow micronucleus of rats indicating that the benefits of using V. officinalis in traditional practice should outweigh risks.

Modification of the Myelotoxic and Antitumor Effects of Polychemotherapy by Polysaccharides from Tussilago farfara L.

The experiments on C57Bl/6 mice with Lewis lung carcinoma showed that addition of Tussilago farfara L. polysaccharides to conventional cisplatin/paclitaxel polychemotherapy moderated neutropenia caused by antitumor therapy and increased its efficiency. The stimulating effect of polysaccharides on the granulopoietic lineage cells is comparable with that of recombinant CSF Neupogen.

Subchronic Systemic Toxicity of New Endodontic Material Based on Calcium Hydroxyapatite and Calcium Silicates

As an alternative to MTA, a new endodontic material based on hydroxyapatite and calcium silicates (ALBO‐MPSA) has been synthesized, and its biocompatibility has been studied in many in vitro and in vivo studies. The current study aims to evaluate a subchronic systemic toxicity of ALBO‐MPSA on the rat animal model, as a continuation of the previous studies. Biochemical parameters of blood and histological parameters of the liver, kidneys, and spleen of the rats were analyzed after 120 days of consumption of the aqueous extract of ALBO‐MPSA. The results showed no myelotoxic effect or autoimmune effect on peripheral blood cells and no pathological effect on the liver, kidney, and spleen tissues. Besides, no changes in the skin and hair of the rats, neither the change in the consumption of food and water, nor the change in their usual behavior were noticed during the experiment.

Changes in blood parameters of patients with laryngeal squamous cell carcinoma during polychemotherapy with cetuximab.

e17579 Background: Our purpose was to evaluate changes in blood parameters in patients with laryngeal squamous cell carcinoma (LSCC) during polychemotherapy (PCT) with cetuximab. Methods: Levels of white blood cells (WBC), immature granulocytes (IG) and neutrophils (Ne), as well as levels of C-reactive protein (CRP), lactate dehydrogenase (LDH) and creatinine were studied in the blood of 20 patients with stage I-III LSCC before therapy with cetuximab/cisplatin+5-fluorouracil and on days 2, 9 and 16 of the therapy. The control group (21 patients) received similar PCT without cetuximab. Treatment was assessed using the RECIST criteria. Results: Partial response was observed in 16 (80%) patients of the main group and in 5 (23.8%) controls, stabilization - 4 (20%) and 12 (57.4%), respectively, progression – in 4 (19%) patients of the control group. Patients of the main group with treatment effect showed WBC increase by 2 times after every cetuximab injection (days 2, 9, 16) compared with the initial levels due to Ne and IG increase by 2.7 and 4 times, respectively. WBC and IG levels measured on days 2, 9 and 16 were 13.40±2.86×109/L, 13.52±1.88×109/L, 12.25±2.08×109/L and 0.044±0.021×109/L, 0.056±0.015×109/L, 0.060±0.008×109/L, respectively (p &lt; 0.001). A transient increase in the indexes was replaced by their decrease to the initial values, with the values similar to the reference ones by the end of the treatment. At the same time, we observed decrease in CRP and creatinine levels up to the reference levels (7.69±3.28 mg/L and 74.75±6.54 umol/L, respectively); LDH did not increase. Stabilization was characterized by unchanged WBC levels, positive dynamics of IG and slow decline of CRP level exceeding the reference one (10.0 mg/L) by the treatment end. Reduction of WBC and increase in IG and CRP levels were noted in the controls regardless of the PCT results which could be explained by severity of intoxication syndrome, partially due to the disease and partially due to PCT toxicity. Conclusions: A dual transient increase in WBC and IG levels, reduction of CRP and creatinine during the treatment and unchanged LDH indicate minimization of myelotoxic and general toxic effects of PCT in combination with cetuximab.

Palbociclib and Letrozole in Advanced Breast Cancer

BackgroundA phase 2 study showed that progression-free survival was longer with palbociclib plus letrozole than with letrozole alone in the initial treatment of postmenopausal women with estrogen-receptor (ER)–positive, human epidermal growth factor receptor 2 (HER2)–negative advanced breast cancer. We performed a phase 3 study that was designed to confirm and expand the efficacy and safety data for palbociclib plus letrozole for this indication.MethodsIn this double-blind study, we randomly assigned, in a 2:1 ratio, 666 postmenopausal women with ER-positive, HER2-negative breast cancer, who had not had prior treatment for advanced disease, to receive palbociclib plus letrozole or placebo plus letrozole. The primary end point was progression-free survival, as assessed by the investigators; secondary end points were overall survival, objective response, clinical benefit response, patient-reported outcomes, pharmacokinetic effects, and safety.ResultsThe median progression-free survival was 24.8 months (95% confidence interval [CI], 22.1 to not estimable) in the palbociclib–letrozole group, as compared with 14.5 months (95% CI, 12.9 to 17.1) in the placebo–letrozole group (hazard ratio for disease progression or death, 0.58; 95% CI, 0.46 to 0.72; P<0.001). The most common grade 3 or 4 adverse events were neutropenia (occurring in 66.4% of the patients in the palbociclib–letrozole group vs. 1.4% in the placebo–letrozole group), leukopenia (24.8% vs. 0%), anemia (5.4% vs. 1.8%), and fatigue (1.8% vs. 0.5%). Febrile neutropenia was reported in 1.8% of patients in the palbociclib–letrozole group and in none of the patients in the placebo–letrozole group. Permanent discontinuation of any study treatment as a result of adverse events occurred in 43 patients (9.7%) in the palbociclib–letrozole group and in 13 patients (5.9%) in the placebo–letrozole group.ConclusionsAmong patients with previously untreated ER-positive, HER2-negative advanced breast cancer, palbociclib combined with letrozole resulted in significantly longer progression-free survival than that with letrozole alone, although the rates of myelotoxic effects were higher with palbociclib–letrozole. (Funded by Pfizer; PALOMA-2 ClinicalTrials.gov number, NCT01740427.)

P08.05 Combined presence of three MGMT gene-polymorphisms in a glioblastoma patient, who developed severe myelosuppression following temozolomide chemotherapy

AbstractIntroduction:Temozolomide chemotherapy can cause thrombocytopenia or neutropenia in 3 and 4 percent of patients, respectively; however pancytopenia cases were very rarely reported. MGMT (O6-methylguanine-DNA-methyltransferase) enzyme repairs temozolomide-induced guanine base mutations in the DNA and it is important both for the tumor response and myelotoxic side effects in glioblastoma patients. DNA repair mechanisms exert diverging effects on DNA injuries caused by different mutagens; and hence, the same variants of the same DNA repair genes may differentially influence cytotoxic or tumorigenic DNA damage. Until recently, only one case-series study exists which showed that rs2308321 and rs2308327 variants of the MGMT-gene is related with general myelotoxicity of temozolomide. Another study have reported rs12917 variant of the MGMT-gene in two patients with temozolomide-induced severe myelosuppression.Materials and Methods:We performed full-sequencing of the MGMT gene (via Applied Biosystems Biosequencing®) in a female glioblastoma patient, who developed pancytopenia and sepsis following temozolomide treatment.Results:We have encountered that this patient carried all the rs2308321, rs2308327 and rs12917 variants of the MGMT-gene associated with temozolomide myelotoxicity. Interestingly, rs12917 variant was previously reported to associate with lesser risks of gallbladder cancer and glial tumors and with higher risk of non-Hodgkin lymphomas following exposure to organic chlorinated solvents or hair-dyes.Conclusions:The sum effect of multiple rare variants and/or coexposure to multiple environmental mutagens may have triggered glioblastoma formation and myelotoxicity in this patient. In future, routine full-sequencing of MGMT gene may help to predict patients with high risk of temozolomide-toxicity.

Chemotherapy-induced neutropenia among pediatric cancer patients in Egypt: Risks and consequences.

Chemotherapy-induced neutropenia (CIN) is the major dose-limiting toxicity of systemic chemotherapy and it is associated with significant morbidity, mortality and treatment cost. The aim of the present study was to identify the risk factors that may predispose pediatric cancer patients who receive myelosuppressive chemotherapy to CIN and associated sequelae. A total of 113 neutropenia episodes were analyzed and the risk factors for CIN were classified as patient-specific, disease-specific and regimen-specific, while the consequences of CIN were divided into infectious and dose-modifying sequelae. The risks and consequences were analyzed to target high-risk patients with appropriate preventive strategies. Among our patients, 28% presented with a single neutropenia attack, while 72% experienced recurrent attacks during their treatment cycles. The mean absolute neutrophil count was 225.5±128.5 ×109/l (range, 10-497 ×109/l), starting 14.2±16.3 days (range, 2-100 days) after the onset of chemotherapy and resolving within 11.2±7.3 days, either with (45.1%) or without (54.9%) granulocyte colony-stimulating factor (G-CSF). No significant association was observed between any patient characteristics or disease stage and the risk for CIN. However, certain malignancies, such as acute lymphocytic leukemia (ALL), neuroblastoma and Burkitt's lymphoma, and certain regimens, such as induction block for ALL and acute myelocytic leukemia, exerted the most potent myelotoxic effect, with severe and prolonged episodes of neutropenia. G-CSF significantly shortened the duration of the episodes and enhanced bone marrow recovery. Febrile neutropenia was the leading complication among our cases (73.5%) and was associated with several documented infections, particularly mucositis (54.9%), respiratory (45.1%), gastrointestinal tract (38.9%) and skin (23.9%) infections. A total of 6% of our patients succumbed to infection-related complications. Neutropenia was responsible for treatment discontinuation (13.3%), dose delay (13.3%) and dose reduction (5.3%) in our patients. The mean cost for each episode in our institution was 9,386.5±6,688.9 Egyptian pounds, which represented a significant burden on health care providers.

Tacrolimus Metabolite M-III May Have Nephrotoxic and Myelotoxic Effects and Increase the Incidence of Infections in Kidney Transplant Recipients

BackgroundTacrolimus (Tac) is one of the most commonly used immunosuppressive drugs after solid organ transplantation. Eight Tac metabolites have been described, but their clinical importance remains unclear. The aim of this study was quantification of the 2 major Tac metabolites, 13-O-demethyl (M-I) and 15-O-demethyl (M-III), in kidney transplant recipients and to link them with parameters of kidney and liver function, peripheral blood cell counts, and infection incidence. MethodsIn 81 kidney transplant recipients, concentrations of Tac, M-I, and M-III were measured with the use of liquid chromatography combined with tandem mass spectrometry (LC-MS-MS). ResultsThere was a negative correlation between M-III levels and estimated glomerular filtration rate (eGFR; r = −0.244; P < .05). Also, a negative correlation between M-III concentrations and red blood cell count (RBC) was found (r = −0.349; P < .05). Neither concentrations of Tac nor of M-I correlated with eGFR or RBC. M-I, M-III, and Tac were not related to alanine aminotransferase activity. Significantly higher Tac and M-III concentrations in the group with all types of infections in comparison with the group without infections were observed (6.95 ± 2.09 ng/mL vs 5.73 ± 2.43 ng/mL [P = .03] and 0.27 ± 0.17 ng/mL vs 0.20 ± 0.11 ng/mL [P = .04], respectively). ConclusionsThe results suggest that higher concentrations of M-III may have a nephrotoxic or myelotoxic effect and result in higher incidence of infections. Further studies are needed to confirm if monitoring of M-III could minimalize adverse effects such as nephrotoxicity or infections.

Acute toxicity, cytotoxicity, genotoxicity and antigenotoxic effects of a cellulosic exopolysaccharide obtained from sugarcane molasses

The acute toxicity, cytotoxicity, genotoxicity and antigenotoxic effects of BC were studied. Cytotoxicity of BC was evaluated in cultured C3A hepatoma cells (HepG2/C3A) using a lactate dehydrogenase (LDH) activity assay. Acute toxicity was tested in adults Wistar rats treated with a single dose of BC. The genotoxicity of BC was evaluated in vivo by the micronucleus assay. BC (0.33–170μg/mL) added to C3A cell culture medium caused no elevation in LDH release over the background level recorded in untreated cell wells. The treatment with the BC in a single oral dose (2000mg/kg body weight) caused no deaths or signs of toxicity. BC attenuated CP-induced and inhibition the incidence of MNPCE (female: 46.94%; male: 22.7%) and increased the ratio of PCE/NCE (female: 46.10%; male: 35.25%). There was no alteration in the LDH release in the wells where C3A cells were treated with increasing concentrations of BC compared to the wells where the cells received the cell culture medium only (background of approximately 20% cell death), indicated that in the dose range tested BC was not cytotoxic. BC was not cytotoxic, genotoxic or acutely toxic. BC attenuated CP-induced genotoxic and myelotoxic effects.

Special issue: Micro and Nano Flows (MNF2014)

microand nanoflows and provided a platform for identifying synergies and exploring cross-over opportunities in biomedicine/biotechnology and thermofluids engineering. Such cross-over was nicely illustrated in the plenary lecture given by Professor Dimitris Drikakis entitled “Advances and Challenges in Computational Research of Micro Nano Flows” whose lecture presented application examples across a range of technology sectors. The lead paper of this issue, which presents recent advances in multiscale modelling with a focus on a variety of mesoscale and hybrid molecular-continuum methods, is based on his plenary lecture. The remaining articles in this issue were selectively invited and successfully passed the journal’s high-standard peer-review process. In the last 20 years, a key goal in the drug discovery field has been the development of reliable in vitro models. The paper by Rasponi et al. presents the development of lab on a chip (LoC) technology that allows for testing myelotoxic effects of drugs and chemicals. The LoC platform consists of 180 bioreactor chambers, designed to host a controlled and limited number of cells in suspension. The probability of each chamber to contain a colony-forming unit was evaluated based on the clonogenicity of the cell population and on a specifically developed statistical model. Kefala et al. presented a labyrinth split and merge (SAM) micromixer for bioanalytical applications. By means of a computational study, they demonstrated the mixing advantages of SAM compared to passive micromixers. Experimental validation based on fluorescence microscopy was conducted for enzymatic digestion of DNA. Ritos et al. introduced flow simulations of water through carbon nanotube membranes of realistic thickness, based on a new hybrid molecular-continuum model. The results of their model for a membrane thickness of 150 nm compared well with computationally more expensive molecular dynamics (MD) simulations. There is an increasing interest in understanding heat and fluid flow on small scales. This interest stems from the need to address design issues associated with small devices such as microand nanofluidics as well as from the need to understand phenomena and interactions occurring on micro-/nanometre scales. Microfluidics and nanofluidics technologies are relevant to many applications in engineering, physics, chemistry, biochemistry, nanotechnology, and biotechnology. Advances have been made in terms of practical application ranging from the design of systems allowing smaller volumes of fluids to be processed, aiming at achieving multiplexing, automation, and high-throughput screening, to on-chip characterisation. This Special Issue was seeded as a result of a Special Session at the 2014 Conference on Micro and Nano Flows (MNF2014), held at University College London, 7–10 September, which was the fourth, successful conference of the series. The Special Session was entitled Biomedical Microfluidics of Lab-on-a-Chip Technology and was organised by the two lead editors. A unique feature of the conference series is that it provides a forum for scientists and engineers working on small scale flows in the areas of both biofluid mechanics and thermofluids engineering to present their recent research findings. This allowed for interdisciplinary exchange of ideas that advanced understanding of