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1.  U-SPECT-BioFluo: an integrated radionuclide, bioluminescence, and fluorescence imaging platform 
EJNMMI Research  2014;4:56.
In vivo bioluminescence, fluorescence, and single-photon emission computed tomography (SPECT) imaging provide complementary information about biological processes. However, to date these signatures are evaluated separately on individual preclinical systems. In this paper, we introduce a fully integrated bioluminescence-fluorescence-SPECT platform. Next to an optimization in logistics and image fusion, this integration can help improve understanding of the optical imaging (OI) results.
An OI module was developed for a preclinical SPECT system (U-SPECT, MILabs, Utrecht, the Netherlands). The applicability of the module for bioluminescence and fluorescence imaging was evaluated in both a phantom and in an in vivo setting using mice implanted with a 4 T1-luc + tumor. A combination of a fluorescent dye and radioactive moiety was used to directly relate the optical images of the module to the SPECT findings. Bioluminescence imaging (BLI) was compared to the localization of the fluorescence signal in the tumors.
Both the phantom and in vivo mouse studies showed that superficial fluorescence signals could be imaged accurately. The SPECT and bioluminescence images could be used to place the fluorescence findings in perspective, e.g. by showing tracer accumulation in non-target organs such as the liver and kidneys (SPECT) and giving a semi-quantitative read-out for tumor spread (bioluminescence).
We developed a fully integrated multimodal platform that provides complementary registered imaging of bioluminescent, fluorescent, and SPECT signatures in a single scanning session with a single dose of anesthesia. In our view, integration of these modalities helps to improve data interpretation of optical findings in relation to radionuclide images.
PMCID: PMC4209452  PMID: 25386389
Bioluminescence imaging; Fluorescence imaging; Multimodal molecular imaging; SPECT; Small animal; Nuclear medicine
2.  Drought adaptation of stay-green sorghum is associated with canopy development, leaf anatomy, root growth, and water uptake 
Journal of Experimental Botany  2014;65(21):6251-6263.
The positive effects of stay-green quantitative trait loci on grain yield of sorghum under post-anthesis drought are emergent consequences of their effects on water-use patterns, resulting from changes in pre-anthesis canopy size.
Stay-green sorghum plants exhibit greener leaves and stems during the grain-filling period under water-limited conditions compared with their senescent counterparts, resulting in increased grain yield, grain mass, and lodging resistance. Stay-green has been mapped to a number of key chromosomal regions, including Stg1, Stg2, Stg3, and Stg4, but the functions of these individual quantitative trait loci (QTLs) remain unclear. The objective of this study was to show how positive effects of Stg QTLs on grain yield under drought can be explained as emergent consequences of their effects on temporal and spatial water-use patterns that result from changes in leaf-area dynamics. A set of four Stg near-isogenic lines (NILs) and their recurrent parent were grown in a range of field and semicontrolled experiments in southeast Queensland, Australia. These studies showed that the four Stg QTLs regulate canopy size by: (1) reducing tillering via increased size of lower leaves, (2) constraining the size of the upper leaves; and (3) in some cases, decreasing the number of leaves per culm. In addition, they variously affect leaf anatomy and root growth. The multiple pathways by which Stg QTLs modulate canopy development can result in considerable developmental plasticity. The reduction in canopy size associated with Stg QTLs reduced pre-flowering water demand, thereby increasing water availability during grain filling and, ultimately, grain yield. The generic physiological mechanisms underlying the stay-green trait suggest that similar Stg QTLs could enhance post-anthesis drought adaptation in other major cereals such as maize, wheat, and rice.
PMCID: PMC4223986  PMID: 25381433
Canopy development; crop water use; drought adaptation; leaf anatomy; root architecture; sorghum; stay-green.
3.  Noninvasive detection of epicardial and endocardial activity of the heart 
Netherlands Heart Journal  2011;19(11):488-491.
Determining electrical activation of the heart in a noninvasive way is one of the challenges in cardiac electrophysiology. The ECG provides some, but limited information about the electrical status of the heart. This article describes a method to determine both endocardial and epicardial activation of the heart of an individual patient from 64 electrograms recorded from the body surface. Information obtained in this way might be helpful for the treatment of arrhythmias, to assess the effect of drugs on conduction in the heart and to assess electrical stability of the heart.
PMCID: PMC3203979  PMID: 22006012
ECG; Inverse problem; Forward problem; Electrophysiology; Body surface mapping
4.  Closed-form analytical expressions for the potential fields generated by triangular monolayers with linearly distributed source strength 
The solution of the mixed boundary value problem of potential theory involves the computation of the potential field generated by monolayer and double layer source distributions on surfaces at which boundary conditions are known. Closed-form analytical expressions have been described in the literature for the potential field generated by double layers having a linearly distributed strength over triangular source elements. This contribution presents the corresponding expression for the linearly distributed monolayer strength. The solution is shown to be valid for all observation points in space, including those on the interior, edges and vertices of the source triangle.
PMCID: PMC3249024  PMID: 22033662
Boundary element method; Bioelectricity; Linear shape functions
5.  Regulation of tillering in sorghum: environmental effects 
Annals of Botany  2010;106(1):57-67.
Background and Aims
Tillering has a significant effect on canopy development and, hence, on resource capture, crop growth and grain yield in sorghum. However, the physiological basis of tillering and its regulation by environmental effects are not fully understood. The objective of this study was to understand and quantify the environmental effects on tillering in sorghum using a carbohydrate supply–demand framework.
A series of five experiments with a wide range of radiation and temperature conditions was conducted and details of the tillering responses of a single representative hybrid were monitored. The concept of internal plant competition for carbohydrate was developed for analysis of these responses.
Key Results
Tiller appearance was highly synchronized with main shoot leaf appearance, with a consistent hierarchy for tillering across environments. The main environmental effect was on the frequency of tiller appearance, in particular of the lower-rank tillers. This explained some of the observed environmental differences in the onset of tillering. A generalized index of internal plant competition, which took account of plant assimilate supply and demand (S/Dindex) during the critical period for tillering, explained most of the variation in maximum tiller number observed across the five experiments.
This result was consistent with the hypothesis that internal plant competition for assimilates regulates tillering in sorghum. Hence, the framework outlined has a predictive value that could provide the basis for dynamic simulation of tillering in crop growth models.
PMCID: PMC2889793  PMID: 20421230
Carbohydrate supply–demand ratio; internal plant competition; leaf area development; modelling; radiation; Sorghum bicolor; temperature; tiller hierarchy
6.  Regulation of tillering in sorghum: genotypic effects 
Annals of Botany  2010;106(1):69-78.
Background and Aims
Genotypic variation in tillering can be caused by differences in the carbon supply–demand balance within a plant. The aim of this study was to understand and quantify the effects of genotype on tillering as a consequence of the underlying internal competition for carbohydrates.
Five sorghum hybrids, derived from inbred lines with a common genetic background and with similar phenology and plant height but contrasting tillering, were grown in five experiments. The experiments covered a wide range in radiation and temperature conditions, so that number of tillers produced varied significantly. Data on leaf area, tiller number, and biomass accumulation and partitioning were collected at regular intervals. To quantify internal plant competition for carbohydrates, a carbohydrate supply–demand index (S/Dindex) was developed and related to variation in tillering.
Key Results
The appearance of main shoot leaves and tillers was highly co-ordinated across genotypes. High-tillering hybrids had a greater appearance frequency of early tiller ranks than low-tillering hybrids, and this was associated with narrower and hence smaller main shoot leaves. A generalized S/Dindex of internal plant competition accounted for most of the observed variation in maximum tiller number (Ntiller,max) across genotypes. However, genotypic differences in the relationship between the S/Dindex and Ntiller,max suggested that high-tillering hybrids also had a lower S/D threshold at which tillers appeared, possibly associated with hormonal effects.
The results support the hypothesis that genotypic differences in tillering were associated with differences in plant carbon S/D balance, associated with differences in leaf size and in the threshold at which tillers grow out. The results provide avenues for phenotyping of mapping populations to identify genomic regions regulating tillering. Incorporating the results in crop growth simulation models could provide insight into the complex genotype-by-management-by-environment interactions associated with drought adaptation.
PMCID: PMC2889794  PMID: 20430784
Carbohydrate supply–demand ratio; genotype-by-environment interaction; internal plant competition; leaf area development; leaf width; Sorghum bicolor; tiller number; tiller onset
7.  Imatinib Mesylate in Advanced Dermatofibrosarcoma Protuberans: Pooled Analysis of Two Phase II Clinical Trials 
Journal of Clinical Oncology  2010;28(10):1772-1779.
Dermatofibrosarcoma protuberans (DFSP) is a dermal sarcoma typically carrying a translocation between chromosomes 17 and 22 that generates functional platelet-derived growth factor B (PDGFB).
Patients and Methods
Two distinct phase II trials of imatinib (400 to 800 mg daily) in patients with locally advanced or metastatic DFSP were conducted and closed prematurely, one in Europe (European Organisation for Research and Treatment of Cancer [EORTC]) with 14-week progression-free rate as the primary end point and the other in North America (Southwest Oncology Group [SWOG]) with confirmed objective response rate as the primary end point. In the EORTC trial, confirmation of PDGFB rearrangement was required, and surgery was undertaken after 14 weeks if feasible. The SWOG study confirmed t(17;22) after enrollment.
Sixteen and eight patients were enrolled onto the EORTC and SWOG trials, respectively. Tumor size ranged from 1.2 to 49 cm. DFSP was located on head/neck, trunk, and limb in seven, 11, and six patients, respectively, and was classic, pigmented, and fibrosarcomatous DFSP in 13, one, and nine patients, respectively. Metastases were present in seven patients (lung involvement was present six patients). Eleven patients (4%) had partial response as best response, and four patients had progressive disease as best response. Median time to progression (TTP) was 1.7 years. Imatinib was stopped in 11 patients because of progression, one patient because of toxicity, and two patients after complete resection of disease. Median overall survival (OS) time has not been reached; 1-year OS rate was 87.5%.
Imatinib is active in DFSP harboring t(17;22) including fibrosarcomatous DFSP, with objective response rate approaching 50%. Response rates and TTP did not differ between patients taking 400 mg daily versus 400 mg twice a day.
PMCID: PMC3040044  PMID: 20194851
8.  Indoor Pedestrian Navigation Using Foot-Mounted IMU and Portable Ultrasound Range Sensors 
Sensors (Basel, Switzerland)  2011;11(8):7606-7624.
Many solutions have been proposed for indoor pedestrian navigation. Some rely on pre-installed sensor networks, which offer good accuracy but are limited to areas that have been prepared for that purpose, thus requiring an expensive and possibly time-consuming process. Such methods are therefore inappropriate for navigation in emergency situations since the power supply may be disturbed. Other types of solutions track the user without requiring a prepared environment. However, they may have low accuracy. Offline tracking has been proposed to increase accuracy, however this prevents users from knowing their position in real time. This paper describes a real time indoor navigation system that does not require prepared building environments and provides tracking accuracy superior to previously described tracking methods. The system uses a combination of four techniques: foot-mounted IMU (Inertial Motion Unit), ultrasonic ranging, particle filtering and model-based navigation. The very purpose of the project is to combine these four well-known techniques in a novel way to provide better indoor tracking results for pedestrians.
PMCID: PMC3231746  PMID: 22164034
indoor localization; inertial tracking; model-based navigation; ultrasound range sensors
9.  Efficacy and safety of motesanib, an oral inhibitor of VEGF, PDGF, and Kit receptors, in patients with imatinib-resistant gastrointestinal stromal tumors 
This multicenter phase 2 study assessed the tolerability and efficacy of motesanib, an oral inhibitor of Kit, platelet-derived growth factor receptor (PDGFR), and vascular endothelial growth factor receptors (VEGFR), in patients with imatinib-resistant gastrointestinal stromal tumors (GIST).
Patients with advanced GIST who failed imatinib mesylate after ≥8 weeks of treatment with ≥600 mg daily received motesanib 125 mg orally once daily continuously for 48 weeks or until unacceptable toxicity or disease progression occurred. The primary endpoint was confirmed objective tumor response per RECIST and independent review. Secondary endpoints included progression-free survival (PFS), time to progression (TTP); objective response by 18FDG-PET and by changes in tumor size and/or density (Choi criteria); pharmacokinetics and safety.
In the patients evaluable for response (N = 102), the objective response rate was 3%; 59% of patients achieved stable disease, with 14% achieving durable stable disease ≥24 weeks; 38% had disease progression. Higher objective response rates were observed per 18FDG-PET (N = 91) (30%) and Choi criteria (41%). The median PFS was 16 weeks (95% CI = 14–24 weeks); the median TTP was 17 weeks (95% CI = 15–24 weeks). The most common motesanib treatment-related grade 3 adverse events included hypertension (23%), fatigue (9%), and diarrhea (5%). Motesanib did not accumulate with daily dosing.
In this study of patients with imatinib-resistant GIST, motesanib treatment resulted in acceptable tolerability and modest tumor control as evident in the proportion of patients who achieved stable disease and durable stable disease.
PMCID: PMC3123696  PMID: 20838998
Angiogenesis; GIST; Imatinib; Kit receptor; Motesanib; VEGF receptor
10.  Non-Invasive Imaging of Cardiac Activation and Recovery 
Annals of Biomedical Engineering  2009;37(9):1739-1756.
The sequences of activation and recovery of the heart have physiological and clinical relevance. We report on progress made over the last years in the method that images these timings based on an equivalent double layer on the myocardial surface serving as the equivalent source of cardiac activity, with local transmembrane potentials (TMP) acting as their strength. The TMP wave forms were described analytically by timing parameters, found by minimizing the difference between observed body surface potentials and those based on the source description. The parameter estimation procedure involved is non-linear, and consequently requires the specification of initial estimates of its solution. Those of the timing of depolarization were based on the fastest route algorithm, taking into account properties of anisotropic propagation inside the myocardium. Those of recovery were based on electrotonic effects. Body surface potentials and individual geometry were recorded on: a healthy subject, a WPW patient and a Brugada patient during an Ajmaline provocation test. In all three cases, the inversely estimated timing agreed entirely with available physiological knowledge. The improvements to the inverse procedure made are attributed to our use of initial estimates based on the general electrophysiology of propagation. The quality of the results and the required computation time permit the application of this inverse procedure in a clinical setting.
PMCID: PMC2721141  PMID: 19562487
Fastest route algorithm; Non-invasive imaging; Activation; Recovery; Electrotonic interaction
11.  Pre-anthesis ovary development determines genotypic differences in potential kernel weight in sorghum 
Journal of Experimental Botany  2009;60(4):1399-1408.
Kernel weight is an important factor determining grain yield and nutritional quality in sorghum, yet the developmental processes underlying the genotypic differences in potential kernel weight remain unclear. The aim of this study was to determine the stage in development at which genetic effects on potential kernel weight were realized, and to investigate the developmental mechanisms by which potential kernel weight is controlled in sorghum. Kernel development was studied in two field experiments with five genotypes known to differ in kernel weight at maturity. Pre-fertilization floret and ovary development was examined and post-fertilization kernel-filling characteristics were analysed. Large kernels had a higher rate of kernel filling and contained more endosperm cells and starch granules than normal-sized kernels. Genotypic differences in kernel development appeared before stamen primordia initiation in the developing florets, with sessile spikelets of large-seeded genotypes having larger floret apical meristems than normal-seeded genotypes. At anthesis, the ovaries for large-sized kernels were larger in volume, with more cells per layer and more vascular bundles in the ovary wall. Across experiments and genotypes, there was a significant positive correlation between kernel dry weight at maturity and ovary volume at anthesis. Genotypic effects on meristem size, ovary volume, and kernel weight were all consistent with additive genetic control, suggesting that they were causally related. The pre-fertilization genetic control of kernel weight probably operated through the developing pericarp, which is derived from the ovary wall and potentially constrains kernel expansion.
PMCID: PMC2657540  PMID: 19228817
Grain size; grain filling; kernel size; meristem; ovary; pericarp; sorghum
12.  ECGSIM: an interactive tool for studying the genesis of QRST waveforms 
Heart  2004;90(2):165-168.
Background: Discussion about the selection of diagnostic features of the ECG and their possible interpretation would benefit from a model of the genesis of these signals that has a sound basis in electrophysiology as well as in physics. Recent advances in computer technology have made it possible to build a simulation package whereby the genesis of ECG signals can be studied interactively.
Design: A numerical method was developed for computing ECG signals on the thorax, as well as electrograms on both endocardium and epicardium. The source representation of the myocardial electric activity is the equivalent double layer. The transfer factors between the electric sources and the resulting potentials on the heart surface as well as on the body surface were computed using a realistic thorax model.
Results and conclusion: The resulting transfer factors were implemented in a simulation program. The program allows the user to make interactive changes in the timing of depolarisation and repolarisation on the ventricular surface, as well as changing the local source strength, and to inspect or document the effect of such changes instantaneously on electrograms and body surface potentials, visualised by waveforms as well as by potential maps and movies. The entire simulation package can be installed free of charge from
PMCID: PMC1768085  PMID: 14729788
QRST waveforms; interactive simulation; EDL source model; T wave simulation
13.  Intensive induction chemotherapy with C-BOP/BEP for intermediate- and poor-risk metastatic germ cell tumours (EORTC trial 30948) 
British Journal of Cancer  2005;93(11):1209-1214.
New chemotherapy regimens are continuously explored in patients with high-risk malignant germ cell tumours (MGCTs). This multicentre phase II trial assessed the efficacy and toxicity of C-BOP/BEP chemotherapy in intermediate and poor prognosis MGCT (IGCCCG criteria). C-BOP/BEP treatment consisted of cycles of cisplatin, vincristine, bleomycin and carboplatin, followed by one cycle of vincristine and bleomycin and three cycles of BEP (bleomycon, etoposide, cisplatin). The trial was designed to demonstrate a 1-year progression-free survival rate of 80%, that is, to exclude a 1-year rate of 70% or less, with a one-sided significance level of 5%. Secondary end points included toxicity, overall survival and the postchemotherapy complete response rate. In total, 16 European hospitals entered 66 eligible patients (intermediate prognosis group: 37; poor prognosis group: 29). A total of 45 patients (68.2%, 95% confidence interval (95% CI): 56.9–79.4%) achieved a complete response (intermediate prognosis: 30; poor prognosis: 15). After a median observation time of 40.4 months (range: 13.7–66.3), the 1-year progression-free survival rate was 81.8% 95% CI: 72.5–91.1%). The 2-year overall survival was 84.5% (95% CI: 75.6–93.3%). In all, 51 patients experienced at least one episode of WHO grade 3/4 leucopenia, and at least one event of grade 3/4 thrombocytopenia occurred in 30 patients. There was no toxic death. With an 82% 1-year progression-free survival and a lower limit of the 95% CI above 70%, the efficacy of C-BOP/BEP is comparable to that of published alternative chemotherapy schedules in high-risk MGCT patients. The treatment's toxicity is manageable in a multicentre setting. In poor prognosis patients, C-BOP/BEP should be compared to standard chemotherapy of four cycles of BEP.
PMCID: PMC2361516  PMID: 16251877
intermediate and poor prognosis metastatic germ cell tumours; bleomycin; carboplatin; vincristine; cisplatin; etoposide
14.  Ecteinascidin-743: Evidence of Activity in Advanced, Pretreated Soft Tissue and Bone Sarcoma Patients 
Sarcoma  2006;2006:56282.
Purpose. To evaluate the activity and safety of ecteinascidin (ET-743) in pretreated patients with advanced or metastatic soft tissue and bone sarcoma. Patients or subjects. Eighty-nine patients received ET-743 as a 24-hour continuous infusion at a dose of 900–1500 μg/m2 every 3 weeks. Results. We observed one complete remission, 5 partial remissions, one minimal response, and 16 patients with a disease stabilization of 6 months or more. The objective response rate was 6.7% and the clinical benefit rate at 3 and 6 months was 37.7% and 23.4%, respectively. Responses were noted in patients with lipo-, leiomyo-, osteo-, and myogenic sarcoma, with a median duration of 9.85 months. Toxicity mainly involved an asymptomatic elevation of transaminases and neutropenia. Estimated 1- and 2-year survival rates were 39.4% and 15.8%. Median overall survival was 8.25 months. Discussion. This retrospective analysis confirms that ET-743 induces objective responses and progression arrest in a clinically relevant proportion of patients.
PMCID: PMC1820623  PMID: 17496996
15.  Diffusion-Weighted Magnetic Resonance Imaging Allows Noninvasive In Vivo Monitoring of the Effects of Combretastatin A-4 Phosphate after Repeated Administration1 
Neoplasia (New York, N.Y.)  2005;7(8):779-787.
The noninvasive assessment of anticancer treatment efficacy is very important for the improvement of therapeutic window. The purpose of the present study was to evaluate the antitumoral effects of the vascular targeting agent, combretastatin A-4 phosphate (CA-4-P), at selected time points after repeated intraperitoneal drug administrations (25 mg/kg), using diffusion-weighted magnetic resonance imaging (DW-MRI). The experiments were performed during an overall follow-up period of 3 weeks on WAG/Rij rats with subcutaneously growing rhabdomyosarcomas. Each animal served as its own baseline. The DW-MRI studies were quantified by calculating the apparent diffusion coefficient (ADC) for different low and high b-values to separate the effects on tumor vasculature and cellular integrity. The changes in ADC as well as the extent of necrosis development (proportional to the tumor volume), measured on the MR images, were of comparable magnitude after each treatment. All ADC values showed a significant decrease at 6 hours, followed by a significant increase at 2 days for various CA-4-P administrations. DW-MRI allowed us to monitor both reduction in perfusion and changes in the extent of tumor necrosis after CA-4-P injection. Repeated CA-4-P administration retains efficacy in rat rhabdomyosarcomas, with similar findings after each drug administration.
PMCID: PMC1501887  PMID: 16207480
vascular targeting; anticancer therapy; DW-MRI; necrosis; CA-4-P
16.  A phase I study with MAG-camptothecin intravenously administered weekly for 3 weeks in a 4-week cycle in adult patients with solid tumours 
British Journal of Cancer  2004;90(12):2261-2267.
PMCID: PMC2409516  PMID: 15150611
camptothecin; clinical trials, phase I; drug carriers; drug delivery systems; pharmacokinetics; polymers
17.  A phase II trial with rosiglitazone in liposarcoma patients 
British Journal of Cancer  2003;89(8):1409-1412.
PMCID: PMC2394353  PMID: 14562008
liposarcoma; rosiglitazone; PPARγ
18.  Effect of antivascular endothelial growth factor treatment on the intratumoral uptake of CPT-11 
British Journal of Cancer  2003;88(12):1979-1986.
PMCID: PMC2741115  PMID: 12799646
anti-VEGF mAb; CPT-11; tumour delivery; Hoechst 33342; perfusion
19.  A Sarcoma at the Site of Previous Extravasation of Adriamycin 
Sarcoma  2002;6(4):135-139.
We report the case of a 66-year-old man presenting with a high-grade pleomorphic sarcoma at the left elbow 16 years after the extravasation of adriamycin given for a malignant ifbrous histiocytoma of the tibia.We suggest that this sarcoma originated in a multistep way over many years, out of the chronic inflammatory tissue that developed due to a non-specific cellular damage at the nuclear level, interfering with normal cell replication necessary for normal healing tissue healing. As a result, the non-healed chronic inflammatory tissue transformed over several years into a preneoplastic mesenchymal tumour and later into a high-grade pleomorphic sarcoma.
PMCID: PMC2395497  PMID: 18521350
20.  A prolonged methoxymorpholino doxorubicin (PNU-152243 or MMRDX) infusion schedule in patients with solid tumours: a phase 1 and pharmacokinetic study 
British Journal of Cancer  2000;82(4):767-771.
The aim of this phase I study was to assess feasibility, pharmacokinetics and toxicity of methoxymorpholino doxorubicin (MMRDX or PNU-152243) administered as a 3 h intravenous infusion once every 4 weeks. Fourteen patients with intrinsically anthracycline-resistant tumours received 37 cycles of MMRDX. The first cohort of patients was treated with 1 mg m−2of MMRDX. The next cohorts received 1.25 mg m−2and 1.5 mg m−2respectively. Common toxicity criteria (CTC) grade III/IV nausea and vomiting were observed in 1/18 cycles at 1.25 mg m−2and in 2/11 cycles at 1.5 mg m−2. Transient elevation in transaminases up to CTC grade III was observed in 2/16 cycles at 1.25 mg m−2and 4/11 cycles at 1.5 mg m−2. No cardiotoxicity was observed. At 1.25 mg m−2CTC grade IV neutropenia occurred in 1/17 cycles. At 1.5 mg m−2CTC grade III neutropenia was seen in 2/7 and grade IV in 3/7 evaluable cycles. Thrombocytopenia grade III was observed in 2/9 and grade IV in 1/9 evaluable cycles. One patient treated at 1.5 mg m−2died with neutropenic fever. Therefore, dose-limiting toxicity was reached and 1.25 mg m−2was considered the maximum tolerated dose for MMRDX as 3 h infusion. No tumour responses were observed. Pharmacokinetic parameters showed a rapid clearance of MMRDX from the circulation by an extensive tissue distribution. Renal excretion of the drug and its metabolite was negligible. In conclusion, prolongation of MMRDX infusion to 3 h does not improve the toxicity profile as compared with bolus administration. © 2000 Cancer Research Campaign
PMCID: PMC2374418  PMID: 10732743
methoxymorpholino doxorubicin; pharmacokinetics; phase I study
21.  Phase I study on docetaxel and ifosfamide in patients with advanced solid tumours. 
British Journal of Cancer  1998;77(1):153-158.
Docetaxel and ifosfamide have shown significant activity against a variety of solid tumours. This prompted a phase I trial on the combination of these drugs. This phase I study was performed to assess the feasibility of the combination, to determine the maximum tolerated dose (MTD) and the side effects, and to propose a safe schedule for further phase II studies. A total of 34 patients with a histologically confirmed solid tumour, who were not pretreated with taxanes or ifosfamide and who had received no more than one line of chemotherapy for advanced disease were entered into the study. Treatment consisted of docetaxel given as a 1-h infusion followed by ifosfamide as a 24-h infusion (schedule A), or ifosfamide followed by docetaxel (schedule B) every 3 weeks. Docetaxel doses ranged from 60 to 85 mg m(-2) and ifosfamide doses from 2.5 to 5.0 g m(-2). Granulocytopenia grade 3 and 4 were common (89%), short lasting and ifosfamide dose dependent. Febrile neutropenia and sepsis occurred in 17% and 2% of courses respectively. Non-haematological toxicities were mild to moderate and included alopecia, nausea, vomiting, mucositis, diarrhoea, sensory neuropathy, skin and nail toxicity and oedema. There did not appear to be any pharmacokinetic interaction between docetaxel and ifosfamide. One complete response (CR) (soft tissue sarcoma) and two partial responses (PRs) were documented. A dose of 75 mg m(-2) of docetaxel combined with 5.0 g m(-2) ifosfamide appeared to be manageable. Schedule A was advocated for further treatment.
PMCID: PMC2151260  PMID: 9459161
22.  Broad phase II and pharmacokinetic study of methoxy-morpholino doxorubicin (FCE 23762-MMRDX) in non-small-cell lung cancer, renal cancer and other solid tumour patients. 
British Journal of Cancer  1998;77(1):139-146.
The aim was to perform a broad phase II and pharmacokinetic study of methoxymorpholino-doxorubicin (MMRDX), a drug active against multidrug-resistant tumour cells in vitro when given by i.v. bolus at 1.5 mg m(-2) every 4 weeks, in metastatic or unresectable solid tumour patients with known intrinsic drug resistance. Patients received a maximum of six cycles. Plasma, urine and leucocyte MMRDX and its 13-dihydro metabolite pharmacokinetic analysis was performed in patients without liver metastases. Patients (n = 48, 21 NSCLC, 19 renal cell, three head and neck tumour, three cervical cancer and two adenocarcinoma of unknown primary) received 132 cycles of MMRDX. Common toxicity criteria (CTC) grade III/IV thrombocytopenia (12% of cycles) and neutropenia (27% of cycles) occurred with median nadir on day 22. Transient transaminases elevation > grade III/IV was observed in 7% of cycles, late and prolonged nausea > or = grade II in 34% and vomiting > or = grade II in 39%. In two patients, the left ventricular ejection fraction was reduced > or = 15%. Of 37 evaluable patients, one out of 17 NSCLC had a partial response. Mean (+/- s.d.) MMRDX AUC0-infinity calculated up to 24 h after dosing was 20.4 +/- 6.2 microg h l(-1) (n = 11) and t(1/2, gamma) was 44.2 h. Mean plasma clearance (+/- s.d.) was 37.2 +/- 7.3 l h(-1) m(-2) and volume of distribution 1982 +/- 64 l m(-2). MMRDX leucocyte levels 2 and 24 h after infusion were 450 to 600-fold higher than corresponding MMRDX plasma levels. In urine, 2% of the MMRDX dose was excreted unchanged, and 2% as metabolite. The main side-effects of 1.5 mg m(-2) every 4 weeks of MMRDX are delayed nausea and vomiting and haematological toxicity. MMRDX is characterized by extensive clearance and rapid and extensive distribution into tissues. A low response rate was observed in patients with tumours with intrinsic chemotherapy resistance.
PMCID: PMC2151269  PMID: 9459159
23.  Serum alpha-fetoprotein surge after the initiation of chemotherapy for non-seminomatous testicular cancer has an adverse prognostic significance. 
British Journal of Cancer  1998;78(10):1350-1355.
It has been recognized that the tumour markers alpha-fetoprotein (AFP) and human chorionic gonadotrophin (HCG) may show a transient elevation after the initiation of chemotherapy in non-seminomatous testicular cancer. We investigated the prognostic importance of these so-called marker surges in a cohort of patients treated with cisplatin combination chemotherapy between 1983 and 1991. A total of 669 patients were studied. Of 352 patients who had an elevated AFP at the start of treatment and for whom we had data at both day 1 and day 8, 101 (29%) had a surge. Of 317 patients for whom we had data for HCG, 80 patients (25%) had a surge. It was found that an AFP surge was a strong adverse prognostic factor for progression [hazard ratio (HR) 2.28, P=0.005]. There was no statistically significant difference in survival (HR 1.65, P=0.13). There was no prognostic significance of a HCG surge, either for progression or for survival. To investigate whether a surge was an independent prognostic factor for progression and survival, multivariate Cox regression models were fitted using the independent prognostic factors for progression and survival and the surge/decline variable. An AFP surge was retained in the final model for progression. A HCG surge was of no prognostic importance for progression or survival. We conclude that an AFP surge has an adverse prognostic significance, independent of pretreatment characteristics.
PMCID: PMC2063177  PMID: 9823978
24.  Doxorubicin vs epirubicin, report of a second-line randomized phase II/III study in advanced breast cancer. EORTC Breast Cancer Cooperative Group. 
British Journal of Cancer  1998;77(12):2257-2263.
The EORTC Breast Cancer Cooperative Group carried out a randomized trial to compare doxorubicin with epirubicin as second-line chemotherapy in patients with metastatic breast cancer. Two hundred and fifty-nine patients with at least one site of metastatic disease entered this trial, of whom 232 patients were eligible. Treatment consisted of doxorubicin 75 mg m(-2) or epirubicin 90 mg m(-2) i.v. every 3 weeks. The overall response rates for doxorubicin and epirubicin were 36% and 28% respectively (P = 0.173). The median time to progression was 23 weeks for doxorubicin and 19 weeks for epirubicin (P = 0.063) and the median duration of response was 40 weeks for doxorubicin and 32 weeks for epirubicin (P = 0.059). The median survival was 47 weeks for doxorubicin and 44 weeks for epirubicin (P = 0.196). Leucocyte count on retreatment day (P = 0.011) and platelet nadir (P = 0.031) were significantly lower in the doxorubicin-treated group. Also mucositis (P < 0.001), diarrhoea (P = 0.005) and haemorrhage (P = 0.048) were significantly worse in the doxorubicin arm. Nine patients on doxorubicin and two patients on epirubicin experienced congestive heart failure (CHF). At the dose levels used in this study, no statistical differences in response rate and survival were found between the two treatment arms. Treatment with doxorubicin tended to result in a slightly longer duration of response and time to progression but doxorubicin was more toxic than epirubicin.
PMCID: PMC2150384  PMID: 9649142
25.  Immunohistochemical study of topoisomerase II-alpha expression in primary ductal carcinoma of the breast. 
Journal of Clinical Pathology  1995;48(2):147-150.
AIMS--To study the patterns of expression of topoisomerase II-alpha in primary invasive ductal breast carcinomas; to correlate this expression with clinicopathological data and prognosis. METHODS--Cryostat sections from 63 primary invasive ductal breast carcinomas were stained immunohistochemically for topoisomerase II-alpha. Nuclear immunoreactivity was quantified by counting at least 500 cells in different random fields and results were expressed as per cent of cells staining positively for topoisomerase II-alpha. RESULTS--Topoisomerase II-alpha nuclear immunoreactivity (median 14% of nuclei; range 2-62%) was detected in all tumours with highly variable intertumour and intratumour nuclear reactivity. Higher levels of topoisomerase II-alpha expression were strongly related to higher tumour grade, larger tumour size, nodal status, and the presence of distant metastases at diagnosis. No correlation was found with menopausal status, steroid hormone receptor status, disease free survival, or overall survival. CONCLUSIONS--Expression of topoisomerase II-alpha is related to the presence of poor prognostic factors. Immunohistochemical assessment of topoisomerase II-alpha expression in breast cancer could be potentially useful for tailoring chemotherapy with topoisomerase II inhibitors.
PMCID: PMC502388  PMID: 7745115

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