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ABSTRACT: Background:Testicular cancer patients have an increased risk for cardiovascular disease (CVD), which might be related to the increased prevalence of the metabolic syndrome (MetS) in this group of patients.Methods:We assessed the prevalence of MetS and calculated the 10-year CVD risk in a cohort of 255 testicular germ cell tumour survivors (median age, 38.7 years; interquartile range, 31-48) at a mean of 7.8 years after anti-cancer treatment, and compared these with data obtained from 360 healthy men.Results:Survivors had an age-adjusted increased risk for MetS of 1.9 compared with that of healthy controls. The risk for MetS was highest in survivors treated with combination chemotherapy (CT) 2.4 (Adult Treatment Panel of the National Cholesterol Education Program classification) and 2.2 (International Diabetes Federation classification). The risk of MetS was especially increased in survivors with testosterone levels in the lowest quartile (OR, 2.5). Ten-year cardiovascular risk as assessed by the Framingham Risk Score (3.0%) and Systemic Coronary Risk Evaluation (1.7%) algorithms was low, independent of treatment, and was comparable to controls.Conclusion:Testicular germ cell tumour survivors have an increased prevalence of MetS, with hypogonadism and CT treatment being clear risk factors for the development of the syndrome. The increased prevalence of MetS was not associated with an increased 10-year cardiovascular risk.British Journal of Cancer advance online publication, 9 May 2013; doi:10.1038/bjc.2013.226 www.bjcancer.com.
British Journal of Cancer 05/2013; · 5.04 Impact Factor
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Journal of Thrombosis and Haemostasis 04/2012; 10(6):1185-8. · 5.73 Impact Factor
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ABSTRACT: Microparticles, also known as microvesicles, found in blood plasma, urine, and most other body fluids, may serve as valuable biomarkers of diseases such as cardiovascular diseases, systemic inflammatory disease, thrombosis, and cancer. Unfortunately, the detection and quantification of microparticles are hampered by the microscopic size of these particles and their relatively low abundance in blood plasma. The use of a combination of microfluidics and atomic force microscopy to detect microparticles in blood plasma circumvents both problems. In this study, capture of a specific subset of microparticles directly from blood plasma on antibody-coated mica surface is demonstrated. The described method excludes isolation and washing steps to prepare microparticles, improves the detection sensitivity, and yields the size distribution of the captured particles. The majority of the captured particles have a size ranging from 30 to 90 nm, which is in good agreement with prior results obtained with microparticles immediately isolated from fresh plasma. Furthermore, the qualitative shape of the size distribution of microparticles is shown not to be affected by high-speed centrifugation or the use of the microfluidic circuit, demonstrating the relative stable nature of microparticles ex vivo.
Biomedical Microdevices 03/2012; 14(4):641-9. · 3.03 Impact Factor
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ABSTRACT: Results of plasma microparticles (MPs) measurements reported in the literature vary widely. This is clearly not only related to the lack of well-standardised MP assays, but also to variations in pre-analytical conditions. In this review we will discuss the pre-analytical variables related to plasma and MP preparation which may affect MP analysis. Additionally we will address several analytical issues in commonly used MP assays and briefly discuss some novel approaches for the detection and characterisation of MPs. Ideally MP measurements should be performed in plasma, freshly prepared directly after blood withdrawal. As platelet contamination seems to be one of the major pre-analytical problems in processing plasma for MP measurement, the use of platelet-free plasma may be preferred. When frozen-thawed plasma is used, especially PMP and annexinV-positive MP counts should be interpreted with caution. When flow cytometry is chosen as a method for quantification of MPs, some analytical conditions should be standardised, e.g. settings of the flow cytometer, quality of the antibodies, and use of counting beads. Fluorescence-nanoparticle tracking analysis and atomic force microscopy can accurately count nanosized MPs, but unfortunately the operational procedures of both methods are still time consuming and they give no information on the functional properties of MPs. The MP-TF activity assay provides information on MPs carrying active TF, regardless of their parental origin. Ultimately, standardisation of pre-analytical procedures and the introduction of reliable and rapid methods for the measurement of MPs are urgently needed to facilitate their use as biomarker in the pathophysiology of diseases.
Thrombosis and Haemostasis 12/2010; 105(3):396-408. · 5.04 Impact Factor
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ABSTRACT: The prognosis of testicular germ cell tumors (GCT) is excellent, and survival of GCT patients has significantly increased. However, skeletal morbidity may potentially be increased in these patients due to chemotherapy-associated hypogonadism.
Our objective was assessment of skeletal fragility in testicular GCT patients.
We conducted a cross-sectional study in long-term survivors and newly diagnosed patients at a single center with recruitment over a 2-yr period.
We studied 199 cured long-term survivors of GCT, a mean of 7.4 yr after unilateral orchidectomy, and 45 newly diagnosed patients within 3 months of unilateral orchidectomy but before anticancer treatment. Bone mineral density (BMD) measurements were performed, and the presence of vertebral fractures (VF) was assessed in lateral thoracolumbar x-rays of the spine using the Genant's semiquantitative method.
Sixty-three patients (25.8%) had Z-scores between -1 and -2 sd, and 12 patients (5.7%) had Z-scores below -2 sd. Moderate and severe VF (grade 2 or higher) were observed in 13.6% of cured long-term survivors and in 15.6% of newly diagnosed patients. Including mild (grade 1) VF, the prevalence was 40.2 and 31.1%, respectively. There was no relationship between severity or number of VF and age, tumor type, staging, previous chemotherapy, gonadal status, vitamin D levels, or BMD values.
We identify a relatively high prevalence of mild to moderate VF independently of BMD or previous chemotherapy in long-term survivors and in newly diagnosed patients with GCT. Although the pathogenesis of these fractures remains unclear, their presence represents a potential cause of skeletal morbidity in otherwise healthy survivors of testicular GCT.
The Journal of clinical endocrinology and metabolism 11/2010; 95(11):4933-42. · 6.50 Impact Factor
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ABSTRACT: Multiple myeloma (MM) is associated with an increased risk of venous thromboembolic (VTE) complications. Aim of this study was to measure microparticle-associated tissue factor (MP-TF) activity in patients with newly diagnosed MM before and after chemotherapy and to investigate whether MP-TF activity is associated with VTE. MP-TF activity was assessed in 122 newly diagnosed MM patients who were eligible for combination chemotherapy. MP-TF activity levels (17.6 fM Xa/min [8.6-33.2] (median [IQR]) were higher in untreated MM patients compared to normal healthy volunteers (4.1 fM Xa/min [2.3-6.6], p <0.001). MP-TF activity prior to the start of treatment was not different between patients who developed a VTE during follow-up (n=15) and those who did not (n=107). In 75 patients in whom plasma was obtained before and after chemotherapy, MP-TF activity decreased significantly (from 17.4 [10.2-32.8] to 12.0 [7.0-18.5] fM Xa/min, P=0.006). MP-TF activity remained, however, elevated in patients who developed VTE (15.1 [10.3-25.2]), in contrast to patients not developing VTE (11.4 [7.0-25.2], P<0.001). In conclusion, MP-TF activity is increased in patients with MM. Whether MP-TF activity has a pathogenetic role in VTE in MM patients remains to be established in future studies.
Thrombosis and Haemostasis 11/2010; 105(1):14-20. · 5.04 Impact Factor
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ABSTRACT: Microparticles (MPs) carrying active tissue factor (TF) have been detected in the plasma of cancer patients in particular in those presenting with acute deep vein thrombosis (DVT) or pulmonary embolism (PE). Experimental studies in mice have revealed that circulating MPs carrying TF contribute to thrombus formation.
To study whether unselected patients with an acute confirmed PE have elevated TF activity in the MP fraction (MP-TF activity).
Plasma MP-TF activity was measured in 159 non-selected patients with clinically suspected PE and in 48 healthy controls as previously described. Blood was collected at time of inclusion. The diagnosis of acute PE was confirmed in 54 patients and excluded in 105 patients.
Median MP-TF activity in 159 patients with clinically suspected PE was 72 fM Xa/min [range 32-6657] fM Xa/min and higher than in healthy controls (66 [range 28-183] fM Xa/min; P<0.05). There was no significant difference (P=0.169) in MP-TF activity between patients with confirmed PE (median 84.5 fM Xa/min [range 36-2149]) and patients without PE (72 fM Xa/min [range 32-6657]) fM Xa/min). In the 159 patients with clinically suspected PE we observed in an exploratory analysis higher MP-TF activity levels in patients with active cancer (median 137 fM Xa/min [range 36-6657]) and cardiovascular disease (median 131.5 fM Xa/min [range 45-2149]) than in patients without these disorders (P=0.0004 and P=0.014, respectively).
In patients presenting with clinically suspected PE plasma MP-TF activity was not associated with confirmed PE.
Thrombosis Research 10/2010; 126(4):345-9. · 2.44 Impact Factor
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ABSTRACT: G-protein-coupled receptors (GPCRs) have been implicated in the tumorigenesis and metastasis of human cancers and are considered amongst the most desirable targets for drug development. Utilizing a robust quantitative PCR array, we quantified expression of 94 human GPCRs, including 75 orphan GPCRs and 19 chemokine receptors, and 36 chemokine ligands, in 40 melanoma metastases from different individuals and benign nevi. Inter-metastatic site comparison revealed that orphan GPR174 and CCL28 are statistically significantly overexpressed in subcutaneous metastases, while P2RY5 is overexpressed in brain metastases. Comparison between metastases (all three metastatic sites) and benign nevi revealed that 16 genes, including six orphan receptors (GPR18, GPR34, GPR119, GPR160, GPR183 and P2RY10) and chemokine receptors CCR5, CXCR4, and CXCR6, were statistically significantly differentially expressed. Subsequent functional experiments in yeast and melanoma cells indicate that GPR18, the most abundantly overexpressed orphan GPCR in all melanoma metastases, is constitutively active and inhibits apoptosis, indicating an important role for GPR18 in tumor cell survival. GPR18 and five other orphan GPCRs with yet unknown biological function may be considered potential novel anticancer targets in metastatic melanoma.
Pigment Cell & Melanoma Research 09/2010; 24(1):207-18. · 5.06 Impact Factor
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ABSTRACT: Microparticles (MPs) are small vesicles released from cells of different origin, bearing surface antigens from parental cells. Elevated numbers of blood MPs have been reported in (cardio)vascular disorders and cancer. Most of these MPs are derived from platelets.
To investigate whether atomic force microscopy (AFM) can be used to detect platelet-derived MPs and to define their size distribution.
Blood MPs isolated from seven blood donors and three cancer patients were immobilized on a modified mica surface coated with an antibody against CD41 prior to AFM imaging. AFM was performed in liquid-tapping mode to detect CD41-positive MPs. In parallel, numbers of CD41-positive MPs were measured using flow cytometry. Mouse IgG1 isotype control was used as a negative control.
AFM topography measurements of the number of CD41-positive MPs were reproducible (coefficient of variation=16%). Assuming a spherical shape of unbound MPs, the calculated diameter of CD41-positive MPs (dsph) ranged from 10 to 475 nm (mean: 67.5+/-26.5 nm) and from 5 to 204 nm (mean: 51.4+/-14.9 nm) in blood donors and cancer patients, respectively. Numbers of CD41-positive MPs were 1000-fold higher than those measured by flow cytometry (3-702x10(9) L(-1) plasma vs. 11-626x10(6) L(-1) plasma). After filtration of isolated MPs through a 0.22-microm filter, CD41-positive MPs were still detectable in the filtrate by AFM (mean dsph: 37.2+/-11.6 nm), but not by flow cytometry.
AFM provides a novel method for the sensitive detection of defined subsets of MPs in the nanosize range, far below the lower limit of what can be measured by conventional flow cytometry.
Journal of Thrombosis and Haemostasis 10/2009; 8(2):315-23. · 5.73 Impact Factor
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Journal of Thrombosis and Haemostasis 07/2009; 7(8):1421-3. · 5.73 Impact Factor
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ABSTRACT: Release of non-protein bound iron plays an important role in the toxicity inflicted by chemotherapy in cancer patients. Since large variations have been described for different methods measuring non-transferrin bound iron (NTBI), we aimed to obtain more accurate values. After binding to the chelator nitrilotriacetic acid disodium salt (NTA) and ultrafiltration, the NTBI can be measured spectrophotometrically by the addition of thioglycolic acid (TGA) and baptophenanthroline disulfonic acid (BPT). Results demonstrated that NTBI values increased with NTA concentration. In samples incubated with 80 mM NTA, >5-fold higher NTBI values were found compared to using 10 mM NTA. Optimal concentration of NTA was established by additions of iron to serum with known latent iron-binding capacity (LIBC). Iron addition curves showed that NTBI could be measured starting from the LIBC of the serum with optimal yield after incubation with 4 mM NTA in 5 mM Tris-HCl pH 6.5, with 3mM TGA and 6.2 mM BPT for the colour reaction. The results showed excellent correlation with 195 samples measured also by HPLC. For the spectrophotometric method, significantly higher NTBI values were measured in patient samples with maximal iron saturation compared to patients with lower iron saturation.
Analytical Biochemistry 12/2008; 385(1):13-9. · 3.00 Impact Factor
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ABSTRACT: Cancer, in particular mucinous adenocarcinoma, is associated with venous thromboembolism (VTE). Tissue factor (TF), initiator of coagulation, plays a central role in the paradigm that clotting and tumor growth form a vicious circle, in which hypercoagulability facilitates the aggressive biology of cancer and vice versa. Expression of TF in tumors is associated with poor differentiation and poor prognosis.
We investigated the association between clinically manifest VTE and procoagulant properties of circulating microparticles (MP) isolated from blood of unselected pancreatic and breast adenocarcinoma patients' consecutive subjects, who presented with ultrasound or CT-scan confirmed VTE, and healthy subjects.
Patients with disseminated breast and pancreatic cancer had significantly increased levels of MP-associated TF activity compared with healthy controls, subjects with idiopathic acute VTE and non-metastatic cancer patients. Patients with both high MP-associated TF-activity and MP-associated epithelial mucin (MUC1) had a lower survival rate at 3-9 months follow-up than those with low TF-activity and no MUC1 expression: the likelihood of survival was 0.42 (95% CI: 0.19- 0.94) for an individual with these two predictor variables present, after adjustment for other factors (age cohort, type of cancer, VTE) in the Cox proportional hazards model.
Our results suggest an important role for MP-associated TF and MUC1 in the pathogenesis of thrombosis in disseminated mucinous adenocarcinoma patients. Future studies should reveal the mechanism underlying the observed associations.
Journal of Thrombosis and Haemostasis 04/2007; 5(3):520-7. · 5.73 Impact Factor
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ABSTRACT: The incidence of venous thrombosis (VT) for cancer patients is increased compared with patients without cancer, but estimations of the incidence for different types of cancer have rarely been made because of the low incidence of various types of cancer. Large registries offer an opportunity to study the risk of VT in large cohorts of cancer patients, which is essential in decisions on prophylactic anti-coagulant treatment.
This cohort study estimates the incidence of VT in cancer patients by using record linkage of a Cancer Registry and an Anticoagulation Clinic database in the Netherlands. Cumulative incidences in patients with different types of malignancies were estimated. We calculated relative risks (RRs) in relation to the presence of distant metastases and treatment.
Tumors of the bone, ovary, brain, and pancreas are associated with the highest incidence of VT (37.7, 32.6, 32.1, and 22.7/1000/0.5 year). Patients with distant metastases had a 1.9-fold increased risk [RRadj: 1.9; 95% confidence interval (CI): 1.6-2.3]. Chemotherapy leads to a 2.2-fold increased risk (RR(adj): 2.2; 95% CI: 1.8-2.7) and hormonal therapy leads to a 1.6-fold increased risk (RRadj: 1.6; 95% CI: 1.3-2.1) compared with patients not using these treatment modalities. Patients with radiotherapy or surgery did not have an increased risk.
We compared the overall incidences of VT in the first half year in our study to the risk of major bleeding as described in the literature. For patients with distant metastases, for several types of cancer, prophylactic anti-thrombotic treatment could be beneficial.
Journal of Thrombosis and Haemostasis 04/2006; 4(3):529-35. · 5.73 Impact Factor
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ABSTRACT: To estimate the risk of venous thrombosis associated with pancreatic malignancies we followed a cohort of patients with pancreatic cancer (n = 202). We calculated incidence rates of venous thrombosis and compared this with population rates using a Standardised Morbidity Ratio (SMR). The effects of location, histology and treatment were assessed by Cox-modelling. The incidence of venous thrombosis was 108.3/1000 patient-years (95% confidence interval (CI) 64.4-163.8), 58.6-fold increased (SMR 58.6, 95% CI 36.9-92.9). Patients with a tumour of the corpus/cauda had a 2-fold increased risk compared with those with a tumour of the caput. Patients treated with chemotherapy had a 4.8-fold increased risk (HR(adj) 4.8, 95% CI 1.1-20.8), whereas radiotherapy did not increase the risk. In a postoperative period of 30 d, patients had a 4.5-fold increased risk of venous thrombosis (HR(adj) 4.5, 95% CI 0.5-40.9). The risk was 1.9-fold increased in the presence of distant metastases (HR(adj) 1.9, 95% CI 0.7-5.1). Anti-thrombotic prophylaxis seems warranted in the first month after surgery, during and after treatment with chemotherapy, and when distant metastases have been diagnosed.
European Journal of Cancer 03/2006; 42(3):410-4. · 5.54 Impact Factor
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Journal of Thrombosis and Haemostasis 12/2005; 3(11):2409-19. · 5.73 Impact Factor
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ABSTRACT: Well known risk factors for upper extremity deep venous thrombosis are the presence of a central venous catheter (CVC) and malignancy, but other potential risk factors, such as surgery, injury and hormone replacement therapy (HRT), have not yet been explored.
We performed a population-based case-control study including 179 consecutive patients, aged 18-70 years with upper extremity deep venous thrombosis and 2399 control subjects. Participants reported on acquired risk factors in a questionnaire and factor V Leiden and prothrombin 20210A mutation were ascertained. Information on CVC was obtained from discharge letters.
Forty-two patients (23%) and one control subject (0.04%) had a CVC (ORadj: 1136, 95% CI: 153-8448, adjusted for age and sex). Cancer patients without a CVC had an eightfold increased risk of venous thrombosis of the arm (ORcrude: 7.7, 95% CI: 4.6-13.0). Other evident risk factors were prothrombotic mutations, surgery, immobilization of the arm (plaster cast), oral contraceptive use and family history, with odds ratios varying from 2.0 up to 13.1. The risk in the presence of injury and during puerperium was twofold or more increased, although not significantly. In contrast HRT, unusual exercise, travel and obesity did not increase the risk. Hormone users had an increased risk in the presence of prothrombotic mutations or surgery. Obese persons (BMI > 30 kg m(-2)) undergoing surgery had a 23-fold increased risk of arm thrombosis compared with non-obese persons not undergoing surgery.
A CVC is a very strong risk factor for arm thrombosis. Most risk factors for thrombosis in the leg are also risk factors for arm thrombosis.
Journal of Thrombosis and Haemostasis 11/2005; 3(11):2471-8. · 5.73 Impact Factor
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ABSTRACT: We investigated the risk factors for venous thrombosis in cancer patients with implantable ports undergoing chemotherapy. One hundred and seventy one ports were placed in a central ("chest ports") and 84 in a peripheral vein ("arm ports"), 181 received prophylactic nadroparin and 10 coumarin. Clinically overt thrombosis was confirmed by ultrasound or angiography. Catheter-related thrombosis incidence without anticoagulants was 28% in arm and 33% in chest ports, but with anticoagulants this was 32% in arm and only 1% in chest ports (odds ratio (OR) 34.8 95% confidence interval (CI) 7.3-165). Left-sided placement compared with right-sided and catheter tip position in the superior vena cava compared with right atrium were associated with a 3.5 respectively 2.6-fold increased risk. Thrombosis was associated with elevated homocysteine levels (OR=3.8, 95% CI 1.3-11.3), but not with factor V Leiden or prothrombin 20210A gene mutations, or high concentration of factor VIII, IX or XI. Prophylaxis with anticoagulants is recommended for chest, but not for arm ports. Determination of plasma homocysteine levels may identify patients at an increased risk for thrombosis.
European Journal of Cancer 11/2004; 40(15):2253-9. · 5.54 Impact Factor
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ABSTRACT: Only limited data on the incidence of venous thrombosis in different types of malignancy are available. Patients with adenocarcinoma are believed to have the highest risk of developing venous thrombosis.
To study the incidence of thrombosis in patients with lung cancer, with an emphasis on the comparison between adenocarcinoma and squamous cell carcinoma, we have performed a cohort study of patients with non-small-cell lung cancer. In addition the risk associated with treatment and extent of disease was assessed.
A total of 537 patients with a first diagnosis of lung carcinoma were included. Patient and tumor characteristics as well as venous thrombotic events were recorded from the medical records and from the Anticoagulation Clinic.
Thrombotic risk in lung cancer patients was 20-fold higher than in the general population (standardized morbidity ratio (SMR): 20.0 (14.6-27.4). In the group of patients with squamous cell cancer we found 10 (10/258) cases (incidence: 21.2 per 1000 years) of venous thrombosis whereas in the group of patients with adenocarcinoma 14 (14/133) cases (incidence: 66.7 per 1000 years) occurred. The crude adjusted hazard ratio was 3.1 (95% CI: 1.4-6.9). The risk increased during chemotherapy and radiotherapy and in the presence of metastases.
The risk of venous thrombosis in lung cancer patients is increased 20-fold compared to the general population. Patients with adenocarcinoma have a higher risk than patients squamous cell carcinoma. During chemotherapy or radiotherapy and in the presence of metastases the risk is even higher.
Journal of Thrombosis and Haemostasis 11/2004; 2(10):1760-5. · 5.73 Impact Factor
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ABSTRACT: Cisplatin-induced toxicities are mainly caused by the formation of free radicals, leading to oxidative organ damage. Plasma concentrations of antioxidants decrease significantly during cisplatin chemotherapy for cancer. Forty-eight cancer patients treated with cisplatin-based chemotherapy were randomised in a double-blind manner to receive either supplementation with vitamin C, vitamin E and selenium dissolved in a beverage or to receive a placebo beverage. Primary outcome measures were the amount of nephrotoxicity and ototoxicity induced by cisplatin. No significant differences were found between the two study groups with respect to these primary outcome measures. However, patients who achieved the highest plasma concentrations of the three antioxidant micronutrients had significantly less loss of high-tone hearing. In addition, significant correlations were found between the reduced/oxidised vitamin C ratio and malondialdehyde (MDA), markers of oxidative stress, and cisplatin-induced ototoxicity and nephrotoxicity. The lack of protection against cisplatin-induced toxicities in patients in the intervention arm may be related to poor compliance and/or inadequate supplementation. Supplementation with a higher dose (intensity) and in combination with other antioxidants should be investigated further.
European Journal of Cancer 08/2004; 40(11):1713-23. · 5.54 Impact Factor
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ABSTRACT: Non-protein bound iron (NPBI) is able to catalyse oxidative reactions, causing damage to vital structures. Adverse effects induced by cisplatin seem, in part, to be mediated by free radicals. In the present study, we have measured plasma NPBI, various other iron parameters and antioxidants in 28 cancer patients undergoing cisplatin-based chemotherapy at various time points before and during chemotherapy. No NPBI was present prior to therapy, but within 1-4 days following the first administration of chemotherapy, mean NPBI rose significantly to 10.6+/-6.6 micromol/l (range, 0.6-21.3 micromol/l) in 18 (64.3%) of the 28 patients measured. The rise in NPBI was accompanied by a significant rise in total plasma iron and ferritin and a marked decrease in the latent iron-binding capacity. Concomitantly, plasma vitamins C and E decreased significantly, indicating consumption of antioxidants. Similar observations were also made during the fourth chemotherapy cycle. The increase in NPBI preceded and correlated significantly with chemotherapy toxicity, such as a decrease in leucocyte count and haemoglobin, with a transient rise in various liver enzymes and with known cisplatin-related toxicity, i.e. the loss of renal and hearing function. In conclusion, cisplatin chemotherapy induces oxidative damage which rapidly leads to release of iron from intracellular proteins and the appearance of NPBI. Bone marrow, red blood cells, liver and kidney seem to be a likely source of NPBI. The observed high levels of NPBI may be a major causative determinant in chemotherapy-induced toxicity.
Clinical Science 06/2004; 106(5):475-84. · 4.61 Impact Factor
