Chapter 7: Description of MISCAN-lung, the Erasmus MC Lung Cancer microsimulation model for evaluating cancer control interventions.

The MISCAN-lung model was designed to simulate population trends in lung cancer (LC) for comprehensive surveillance of the disease, to relate past exposure to risk factors to (observed) LC incidence and mortality, and to estimate the impact of cancer-control interventions. MISCAN-lung employs the technique of stochastic microsimulation of life histories affected by risk factors. It includes the two-stage clonal expansion model for carcinogenesis and a detailed LC progression model; the latter is specifically intended for the evaluation of screenings. This article elucidates further the principles of MISCAN-lung and describes its application to a comparative study within the CISNET Lung Working Group on the impact of tobacco control on U.S. LC mortality. MISCAN-lung yields an estimate of the number of LC deaths avoided during 1975-2000. The potential number of avoidable LC deaths, had everybody quit smoking in 1965, is 2.2 million; 750,000 deaths (30%) were avoided in the United States due to actual tobacco control interventions. The model fits in the actual tobacco-control scenario, providing credibility to the estimates of other scenarios, although considering survey-reported smoking trends alone has limitations.

Solid ion-exchange electrode selective for calcium ion.

A calcium-selective electrode with solid ion exchanger was prepared from a solution of the calcium salt of a dialkylphosphoric acid in collodion. The electrode responds rapidly and reproducibly to activity of calcium ion and demonstrates a selective response for calcium ion in the presence of alkaline earth and alkali metal cations.

Dosemeter readings and effective dose to the cardiologist with protective clothing in a simulated interventional procedure.

A personal dosemeter issued for individual monitoring is calibrated in terms of personal dose equivalent, usually H(P)(10). In general it yields a reasonable estimate of effective dose (E) when the exposed person does not wear protective clothing. In interventional cardiology, however, a lead equivalent apron is worn and often a thyroid collar. A correction factor will then be necessary to convert a dosemeter reading to E. To explore this factor an interventional cardiology procedure is simulated based on exposure conditions typical for a modern hospital in the BENELUX area. The dose to the cardiologist is investigated using Monte Carlo simulation of radiation transport. It is concluded that a personal dosemeter may best be worn outside the apron at a central position high on the chest for least dependence on the beam direction. It will overestimate E by roughly a factor of 20 (apron and thyroid collar of 0.25 mm Pb).

Results of a European survey on patient doses in paediatric radiology.

Paediatric patients represent a very specific group within the radiology department. Compared to adult patients, they are more sensitive to radiation. As they are sometimes submitted to several radiology procedures, dose and image quality should be well balanced. Nowadays, only a few centres specialize in paediatric imaging, and knowledge of paediatric patient doses is, therefore, very scattered. The effect of the introduction of digital technology on paediatric patient doses remains largely undocumented. Data collected in the present survey illustrate that there is a clear need for standardisation in this domain. The proposal of a European diagnostic reference level (DRL) is quite difficult. Preliminary DRLs, based on typically 5-7 radiology centres per examination are proposed. The 'effective dose' may or may not be a very rigorous parameter, but it still remains useful nowadays to calculate a parameter that summarises the possible radiation-induced detriment to these young patients. However, conversion factors for calculation of the effective dose should be harmonised. Future studies should include an image quality evaluation study, using criteria that account for digital equipment. Data collection would be straightforward and could be performed in a systematic and automatic way if DICOM headers of digital images would include appropriate as well as relevant information for the particular case of paediatric examinations.

Quality control measurements for fluoroscopy systems in eight countries participating in the SENTINEL EU coordination action.

Quality control (QC) is becoming increasingly important in relation to the introduction of digital medical imaging systems using X rays. It was, therefore, decided to organise and perform a trial on image quality and physical measurements. The SENTINEL toolkit for QC measurements of fluoroscopy systems containing equipment and instructions for their use in the assessment of dose and image quality circulated among participants in the trial. The participants reported on their results. In the present contribution, the impact of the trial on the selected protocols is presented. The Medical Physics and Bioengineering protocol appeared to be useful for QC, and also for digital systems. The protocol needs an additional section, or an addition to each section, to state compliance with the requirements. The circular cross-sections of the Leeds test objects need adaptation for rectangular flat panel detector (FPD) systems. Only one participant was able to perform the monitor test using MoniQA. This is due to the fact that assistance is required from the suppliers of the X-ray systems. This problem needs to be solved to apply MoniQA in practice.

Analysis of the CONRAD computational problems expressing only stochastic uncertainties: neutrons and protons.

Within the scope of CONRAD (A Coordinated Action for Radiation Dosimetry) Work Package 4 on Computational Dosimetry jointly collaborated with the other research actions on internal dosimetry, complex mixed radiation fields at workplaces and medical staff dosimetry. Besides these collaborative actions, WP4 promoted an international comparison on eight problems with their associated experimental data. A first set of three problems, the results of which are herewith summarised, dealt only with the expression of the stochastic uncertainties of the results: the analysis of the response function of a proton recoil telescope detector, the study of a Bonner sphere neutron spectrometer and the analysis of the neutron spectrum and dosimetric quantity H(p)(10) in a thermal neutron facility operated by IRSN Cadarache (the SIGMA facility). A second paper will summarise the results of the other five problems which dealt with the full uncertainty budget estimate. A third paper will present the results of a comparison on in vivo measurements of the (241)Am bone-seeker nuclide distributed in the knee. All the detailed papers will be presented in the WP4 Final Workshop Proceedings.

Estimating effective dose for a cardiac catheterisation procedure with single or double personal dosemeters.

In most countries of the European Union legislation requires individual determination and registration of the dose to radiological workers exposed to ionising radiation to check whether dose limits are exceeded. To assess stochastic risk, ideally effective dose (E) should be known. In practice, personal dose equivalent [H(P)(10)] is used as it can be measured with a personal dosemeter. The dosemeter reading may provide a reasonable assessment of H(P)(10), but it may deviate strongly from E, in particular in radiology procedures for medical diagnosis or intervention when protective clothing like lead-equivalent apron and thyroid collar is worn. In the literature various correction factors and algorithms to convert readings of single or dual dosemeters to an estimate of E can be found. An illustrative example of a cardiac catheterisation procedure, in which dose calculations are made by Monte Carlo simulation of radiation transport, shows that such corrections may still yield considerable overestimation.

The contribution of residual leukemic cells in the graft to leukemia relapse after autologous bone marrow transplantation: mathematical considerations.

A hypothetical model for estimating the probability of leukemia development, supported by experimental evidence, provides a basis on which the conclusion can be drawn that residual leukemic cells in the graft will not contribute significantly to the occurrence of a leukemia relapse after autologous bone marrow transplantation.

Monitoring of leukemia growth in a rat model using a highly sensitive assay for the detection of LacZ marked leukemic cells.

A very sensitive assay for the detection of LacZ marked cells of an in vitro growing subline of the brown Norway rat myelocytic leukemia (BNML) model was developed. By combining cytochemical X-gal staining with D-galactose mediated suppression of endogenous background beta-galactose activity, a detection sensitivity of one leukemic cell per 10(8) normal bone marrow cells could be achieved. A detailed analysis of the in vivo growth pattern and kinetics of this cell line is presented. Also, it is shown that after cyclophosphamide treatment of leukemic rats no leukemic colonies are formed in an agar-colony assay, whereas the leukemic cells remain detectable in the bone marrow for a considerable time period. Eventually, however, all leukemic cells disappear from the marrow. These findings are discussed in the light of prolonged detection of rare leukemic cells in patients in continuing remission.

Dose conversion coefficients for interventional procedures.

Effective dose (E) is a convenient quantity to estimate the stochastic risk of radiation applied to patients in interventional procedures and can be used for optimisation. Relatively long exposure times may cause deterministic effects. Hence it is necessary to know the (maximum local) doses in organs owing to the interventional procedure. In practice, organ doses cannot be measured directly. They are derived by applying a conversion coefficient to a measurable quantity, e.g. dose-area product (DAP) or entrance skin dose. For a number of interventional procedures, dose conversion coefficients (DCCs) can be found in the literature. Various DCCs are stated for nominally equal procedures, e.g. for percutaneous transluminal coronary angioplasty both 0.18 and 0.27 mSv Gy(-1) cm(-2) were reported to convert DAP to effective dose. Dependence of DCC on protocol and equipment parameters, as demonstrated through Monte Carlo simulation in this paper, makes it hazardous to simply adopt a literature value.

Optimisation strategies and justification: an example in uterine artery embolisation for fibroids.

Radiation risk has to be justified and optimised. This study discusses the radiation risk of uterine artery embolisation (UAE) for the treatment of fibroids. A total of 70 consecutive UAE dosimetry parameters were assessed. Using Monte Carlo simulation, organ and effective doses and dose conversion coefficients (DCCs) (mSv Gy cm(-2)) were calculated. During UAE optimisation, avoidance of oblique views and use of last-image-hold (LIH) documentation instead of digital subtraction angiography (DSA) were investigated. Mean dose-area product (DAP) was 37.1 Gy cm2 (median 23.7 Gy cm2) and mean fluoroscopy time was 18.4 min (median 16.6 min). Dose values decreased as the study progressed: mean DAP for patients 1-21, 68.5 Gy cm2; patients 22-43, 35.7 Gy cm2; and patients 44-69, 13.0 Gy cm2. Average DCC for DSA image procedures was 0.572, yielding a mean effective dose of 29.6 mSv (median 17.1 mSv). For LIH-only procedures, an average DCC of 0.813 was estimated [using mean effective dose: 10.6 mSv (median 8.1 mSv)].

Glycogen accumulation of the aging human brain.

We describe light- and electron-microscopically a new type of intracytoplasmatic inclusions within cell processes of the cerebral cortex and the underlying white matter. These structures measure 5-50 micron in diameter and consist almost exclusively of densely packed alpha- or beta-glycogen granules, which never occur together in any single structure. Within their periphery, electron-dense amorphous spots and cell organelles, especially mitochondria, were seen. No membrane-bound glycogen was observed. We propose to call them granular glycogen bodies. They occur in 4 of 7 examined postmortem specimens of the cerebral cortex of people older than 60 years of age. They were not found in 4 younger controls aged 26-48. Their appearance may reflect a distinct turnover disorder of carbohydrate metabolism, which becomes manifest under diverse pathologic conditions and in the normal aging process.

Methylphenidate treatment of hyperactive children: effects on the hypothalamic-pituitary-somatomedin axis.

To further define the influence of methylphenidate on the growth hormone-somatomedin axis and prolactin secretion, serum growth hormone and prolactin concentrations were assessed over 24 hours and in response to provocative stimuli. The nine hyperactive subjects were all studied during methylphenidate therapy and after drug discontinuation, Diurnal patterns of growth hormone and prolactin concentrations were assessed using an ambulatory, continuous blood withdrawal procedure to ensure that activity, caloric intake, and sleep patterns mimicked normal schedules. No significant difference in integrated concentration of growth hormone, fasting somatomedin concentration, or prolactin integrated concentration was detected between subjects receiving or not receiving methylphenidate. There was a significant increase in peak growth hormone response to arginine stimulation among subjects receiving methylphenidate therapy; however, this appeared to correlate with acute methylphenidate administration. These data do not support the hypothesis that growth defects in hyperactive children treated with methylphenidate are caused by alteration in the hypothalamic-pituitary-somatomedin axis.

Dynamic pressure transmission through agarose gels.

In biomedical research, agarose gel is widely used in tissue culture systems because it permits growing cells and tissues in a three-dimensional suspension. This is especially important in the application of tissue engineering concepts to cartilage repair because it supports the cartilage phenotype. Mechanical loading, especially compression, plays a fundamental role in the development and repair of cartilage. It would be advantageous to develop a system where cells and tissues could be subjected to compression so that their responses can be studied. There is currently no information on the pressure response of agarose gel when pressure is applied to the gas phase of a culture system. To understand the transmission of pressure through the gel, we set up an apparatus that would mimic an agarose suspension tissue culture system. This consisted of a sealed metal cylinder containing air as well as a layer of agarose submerged in culture medium. Pressure responses were recorded in the air, fluid, gel center, and gel periphery using various frequencies, pressures, gel volumes, and viscosities. Regression analyses show an almost perfect linear relation between gas and gel pressures (r(2) = 0.99987, p < 0.0001, f(x) = 0.9982 x - 0.0286). The pressure transmission was complete and immediate, throughout the range of the applied pressures, frequencies, volumes, and viscosities tested. Applying dynamic pressure to the gas phase results in reproducible pressure in the agarose and, therefore, validates the use of agarose tissue culture systems in studies employing dynamic pressurization in cartilage tissue engineering.

Fetal lung maturatio. III. Amniotic fluid phosphatidic acid phosphohydrolase (PAPase) and its relation to the lecithin/sphingomyelin ratio.

The purpose of this study was to establish 1) the sequential changes in specific activity of phosphatidic acid phosphohydrolase (PAPase) in amniotic fluid and its relation to the lecithin/sphingomyelin (L/S) ratio; and 2) the origin of amniotic fluid PAPase. the increase in the amniotic fluid L/S ratio is preceded by an increase in PAPase activity, rising from 15 nmoles of phosphate released per milligram of protein per hour at 30 weeks to 100 nmoles at 37 weeks. The mean PAPase activity in the nasopharyngeal fluid of the infant is 456 nmoles of phosphate released per ml per hour, the amniotic fluid mean PAPase activity at delivery being 129 nmoles (P less than 0.01). These findings are consistent with the view that amniotic fluid PAPase originates, in part, from the fetal lung and likely participates in the regulation of the synthesis of lecithin.

Initiation of human parturition. III. Fetal membrane content of prostaglandin E2 and F2alpha precursor.

Unesterified arachidonic acid is the obligatory precursor of the prostaglandins (PG), PGF2alpha and PGE2. In order to ascertain whether or not the human fetal membranes could represent a storage site for prostaglandin(s) precursor, the fatty acid content of human fetal membranes was measured. Approximately 20% of the fatty acids found in fetal membranes obtained from near-term, non-laboring women was arachidonic acid, whereas only 0.4% of the fatty acids of the parietal peritoneum of the mother is arachidonic acid. A small but significant decrease in the arachidonic acid concentration was found in the fetal membranes obtained from laboring women compared to that found prior to labor. On the other hand, the concentration of palmitic acid was increased in membranes obtained during labor while no significant changes in concentration in the remaining fatty acids were observed in membranes from laboring compared to non-laboring near-term gravidas. The significance of these observations in relation to the availability of prostaglandin precursor and the initiation of human parturition is considered.

Pharmacokinetics of methotrexate and 7-hydroxy-methotrexate in plasma and bone marrow of children receiving low-dose oral methotrexate.

The absorption, distribution, and elimination kinetics of low-dose p.o. methotrexate (MTX) were repeatedly studied in 19 children during maintenance treatment of childhood acute lymphoblastic leukemia. Plasma concentrations, urinary elimination, and bone marrow concentrations of MTX and 7-hydroxymethotrexate (7-OH-MTX) were monitored during 24 h following a routine p.o. dose (30 mg/m2) using high-pressure liquid chromatography. Significant interindividual variability was found in time to peak concentration (30-180 min), peak concentration (0.41-2.77 microM), and to a lesser extent the half-lives (t1/2 alpha: 32.8-86.1 min; t1/2 beta: 43.6-350.0 min; t1/2 absorption: 25.2-60.3 min) and plasma area under the concentration-time curve from zero to infinity (195.6-818.5 microM.min). Significant amounts of 7-OH-MTX were detected in plasma, with a mean area under the concentration-time curve from zero to infinity of 208 microM.min compared with 365.6 microM.min for MTX. High concentrations of 7-OH-MTX were present in bone marrow 24 h after oral MTX (15/19 patients) and were at least five fold those in plasma and three fold the concentration of MTX in bone marrow. In four patients occasionally neither MTX nor metabolite could be detected. Repeated examination of these pharmacokinetic parameters in plasma and bone marrow showed that the intraindividual variability was small.

Repeated daunomycin administration in rats. Pharmacokinetics and bone marrow toxicity.

In the experiments described here, rats received three IV bolus injections (7.5 mg/kg) of daunomycin. The plasma data obtained after a single IV injection could be described by a two-compartment open model with t1/2 alpha and t1/2 beta values of 18.4 and 472.1 min. Of the tissues, the lungs contained the most daunomycin per gram of tissue, followed by the kidneys, liver, heart, and spleen. Daunomycinol was the main metabolic product and no substantial differences were found in daunomycinol content among the different organs. For all tissues and plasma, higher drug concentration values than would be expected on the basis of accumulation alone were observed after the second but not after the third injection. The cumulative urine excretion of daunomycin and daunomycinol remained essentially unchanged after one, two, and three daunomycin injections. However, the cumulative bile excretion increased after repeated daunomycin administration. The experiments in which the myelotoxicity was assessed by CFU-S survival after daunomycin treatment showed that three successive daunomycin administrations lead to a proportional reduction in stem cells.

Tendons attached to prostheses by tendon-bone block fixation: an experimental study in dogs.

To develop a method of tendon attachment to a metallic endoprosthesis, we evaluated fixation strength, clinical function of the tendon, and morphological changes in an experimental model. The canine supraspinatus tendon was removed from the greater tubercle of the humerus and attached to a titanium prosthesis. In 12 animals, the bone block underlying the tendon insertion was preserved and attached in one limb; the soft part of the tendon was attached directly to the prosthesis in the contralateral limb. Fixation strength was evaluated after 16 weeks of in vivo implantation (12 specimens) and compared with the in vitro fixation strength (12 specimens) and with intact normal controls (six specimens from cadavera). Function of the tendon in vivo was evaluated by force-plate analysis (at 3-week intervals). All specimens were evaluated histologically. Sixteen weeks after surgery, the tendon-bone block attachment was significantly stronger (mean, 16%) than the direct tendon attachment and not significantly different from the normal control, and the direct tendon attachment was significantly weaker (mean, 68%) than the normal control. There was significantly more weight-bearing on the limbs with a tendon-bone block attachment than on the limbs with a direct tendon attachment at both 3 and 6 weeks postoperatively. Both front legs showed increased weight-bearing with time, but the differences were not statistically significant. Anchorage by tissue ingrowth to the titanium prosthesis was found consistently--there was bone ingrowth in the tendon-bone block attachments and fibrous tissue ingrowth in the direct tendon attachments. When a bone block was preserved, the strength and stiffness were comparable with those of a normal tendon insertion.(ABSTRACT TRUNCATED AT 250 WORDS)

Tensile properties of the supraspinatus tendon.

The tensile properties of the supraspinatus tendon were investigated in 11 shoulders from fresh cadavers. The tendon was divided into three longitudinal strips: anterior, middle, and posterior. Each specimen was mounted on a materials testing machine, with four fluorescent markers placed on both surfaces of the tendon strip. The positions of these markers were recorded during the test by two synchronized video cameras. Load-deformation and strain curves were determined, and the stress-strain curve, strength, and modulus of elasticity were calculated. The posterior strip was thinner in cross section than the others (p = 0.0355). The ultimate load and ultimate stress were significantly greater in the anterior strip (16.5 +/- 7.1 MPa) than in the middle (6.0 +/- 2.6 MPa) and posterior (4.1 +/- 1.3 MPa) strips (p < 0.0001). The modulus of elasticity also was significantly greater in the anterior strip (p < 0.0001), but there was no significant difference between the superficial and deep surfaces. It is concluded that the anterior portion of the supraspinatus tendon is mechanically stronger than the other portions, and it seems to perform the main functional role of the tendon.