Exploration of clinical preferences in treatment planning of radiotherapy for prostate cancer using Pareto fronts and clinical grading analysis.

INTRODUCTION: Radiotherapy treatment planning is a multi-criteria problem. Any optimization of the process produces a set of mathematically optimal solutions. These optimal plans are considered mathematically equal, but they differ in terms of the trade-offs involved. Since the various objectives are conflicting, the choice of the best plan for treatment is dependent on the preferences of the radiation oncologists or the medical physicists (decision makers).We defined a clinically relevant area on a prostate Pareto front which better represented clinical preferences and determined if there were differences among radiation oncologists and medical physicists. METHODS AND MATERIALS: Pareto fronts of five localized prostate cancer patients were used to analyze and visualize the trade-off between the rectum sparing and the PTV under-dosage. Clinical preferences were evaluated with Clinical Grading Analysis by asking nine radiation oncologists and ten medical physicists to rate pairs of plans presented side by side. A choice of the optimal plan on the Pareto front was made by all decision makers. RESULTS: The plans in the central region of the Pareto front (1-4% PTV under-dosage) received the best evaluations. Radiation oncologists preferred the organ at risk (OAR) sparing region (2.5-4% PTV under-dosage) while medical physicists preferred better PTV coverage (1-2.5% PTV under-dosage). When the Pareto fronts were additionally presented to the decisions makers they systematically chose the plan in the trade-off region (0.5-1% PTV under-dosage). CONCLUSION: We determined a specific region on the Pareto front preferred by the radiation oncologists and medical physicists and found a difference between them.

A critical evaluation of secondary cancer risk models applied to Monte Carlo dose distributions of 2-dimensional, 3-dimensional conformal and hybrid intensity-modulated radiation therapy for breast cancer.

The comparison of radiotherapy techniques regarding secondary cancer risk has yielded contradictory results possibly stemming from the many different approaches used to estimate risk. The purpose of this study was to make a comprehensive evaluation of different available risk models applied to detailed whole-body dose distributions computed by Monte Carlo for various breast radiotherapy techniques including conventional open tangents, 3D conformal wedged tangents and hybrid intensity modulated radiation therapy (IMRT). First, organ-specific linear risk models developed by the International Commission on Radiological Protection (ICRP) and the Biological Effects of Ionizing Radiation (BEIR) VII committee were applied to mean doses for remote organs only and all solid organs. Then, different general non-linear risk models were applied to the whole body dose distribution. Finally, organ-specific non-linear risk models for the lung and breast were used to assess the secondary cancer risk for these two specific organs. A total of 32 different calculated absolute risks resulted in a broad range of values (between 0.1% and 48.5%) underlying the large uncertainties in absolute risk calculation. The ratio of risk between two techniques has often been proposed as a more robust assessment of risk than the absolute risk. We found that the ratio of risk between two techniques could also vary substantially considering the different approaches to risk estimation. Sometimes the ratio of risk between two techniques would range between values smaller and larger than one, which then translates into inconsistent results on the potential higher risk of one technique compared to another. We found however that the hybrid IMRT technique resulted in a systematic reduction of risk compared to the other techniques investigated even though the magnitude of this reduction varied substantially with the different approaches investigated. Based on the epidemiological data available, a reasonable approach to risk estimation would be to use organ-specific non-linear risk models applied to the dose distributions of organs within or near the treatment fields (lungs and contralateral breast in the case of breast radiotherapy) as the majority of radiation-induced secondary cancers are found in the beam-bordering regions.

Calculation of correction factors for ionization chamber measurements with small fields in low-density media.

The quantity of interest for high-energy photon beam therapy recommended by most dosimetric protocols is the absorbed dose to water. Thus, ionization chambers are calibrated in absorbed dose to water, which is the same quantity as what is calculated by most treatment planning systems (TPS). However, when measurements are performed in a low-density medium, the presence of the ionization chamber generates a perturbation at the level of the secondary particle range. Therefore, the measured quantity is close to the absorbed dose to a volume of water equivalent to the chamber volume. This quantity is not equivalent to the dose calculated by a TPS, which is the absorbed dose to an infinitesimally small volume of water. This phenomenon can lead to an overestimation of the absorbed dose measured with an ionization chamber of up to 40% in extreme cases. In this paper, we propose a method to calculate correction factors based on the Monte Carlo simulations. These correction factors are obtained by the ratio of the absorbed dose to water in a low-density medium □D(w,Q,V1)(low) averaged over a scoring volume V1 for a geometry where V1 is filled with the low-density medium and the absorbed dose to water □D(w,QV2)(low) averaged over a volume V2 for a geometry where V2 is filled with water. In the Monte Carlo simulations, □D(w,QV2)(low) is obtained by replacing the volume of the ionization chamber by an equivalent volume of water, according to the definition of the absorbed dose to water. The method is validated in two different configurations which allowed us to study the behavior of this correction factor as a function of depth in phantom, photon beam energy, phantom density and field size.

Variability of a peripheral dose among various linac geometries for second cancer risk assessment.

Second cancer risk assessment for radiotherapy is controversial due to the large uncertainties of the dose-response relationship. This could be improved by a better assessment of the peripheral doses to healthy organs in future epidemiological studies. In this framework, we developed a simple Monte Carlo (MC) model of the Siemens Primus 6 MV linac for both open and wedged fields that we then validated with dose profiles measured in a water tank up to 30 cm from the central axis. The differences between the measured and calculated doses were comparable to other more complex MC models and never exceeded 50%. We then compared our simple MC model with the peripheral dose profiles of five different linacs with different collimation systems. We found that the peripheral dose between two linacs could differ up to a factor of 9 for small fields (5 × 5 cm2) and up to a factor of 10 for wedged fields. Considering that an uncertainty of 50% in dose estimation could be acceptable in the context of risk assessment, the MC model can be used as a generic model for large open fields (≥10 × 10 cm2) only. The uncertainties in peripheral doses should be considered in future epidemiological studies when designing the width of the dose bins to stratify the risk as a function of the dose.

A Monte Carlo-based procedure for independent monitor unit calculation in IMRT treatment plans.

Intensity-modulated radiotherapy (IMRT) treatment plan verification by comparison with measured data requires having access to the linear accelerator and is time consuming. In this paper, we propose a method for monitor unit (MU) calculation and plan comparison for step and shoot IMRT based on the Monte Carlo code EGSnrc/BEAMnrc. The beamlets of an IMRT treatment plan are individually simulated using Monte Carlo and converted into absorbed dose to water per MU. The dose of the whole treatment can be expressed through a linear matrix equation of the MU and dose per MU of every beamlet. Due to the positivity of the absorbed dose and MU values, this equation is solved for the MU values using a non-negative least-squares fit optimization algorithm (NNLS). The Monte Carlo plan is formed by multiplying the Monte Carlo absorbed dose to water per MU with the Monte Carlo/NNLS MU. Several treatment plan localizations calculated with a commercial treatment planning system (TPS) are compared with the proposed method for validation. The Monte Carlo/NNLS MUs are close to the ones calculated by the TPS and lead to a treatment dose distribution which is clinically equivalent to the one calculated by the TPS. This procedure can be used as an IMRT QA and further development could allow this technique to be used for other radiotherapy techniques like tomotherapy or volumetric modulated arc therapy.

Shielding requirements in helical tomotherapy.

Helical tomotherapy is a relatively new intensity-modulated radiation therapy (IMRT) treatment for which room shielding has to be reassessed for the following reasons. The beam-on-time needed to deliver a given target dose is increased and leads to a weekly workload of typically one order of magnitude higher than that for conventional radiation therapy. The special configuration of tomotherapy units does not allow the use of standard shielding calculation methods. A conventional linear accelerator must be shielded for primary, leakage and scatter photon radiations. For tomotherapy, primary radiation is no longer the main shielding issue since a beam stop is mounted on the gantry directly opposite the source. On the other hand, due to the longer irradiation time, the accelerator head leakage becomes a major concern. An analytical model based on geometric considerations has been developed to determine leakage radiation levels throughout the room for continuous gantry rotation. Compared to leakage radiation, scatter radiation is a minor contribution. Since tomotherapy units operate at a nominal energy of 6 MV, neutron production is negligible. This work proposes a synthetic and conservative model for calculating shielding requirements for the Hi-Art II TomoTherapy unit. Finally, the required concrete shielding thickness is given for different positions of interest.

[Prospective study of accelerated postoperative radiation therapy in patients with squamous-cell carcinoma of the head and neck]. / Radiothérapie externe accélérée postopératoire des carcinomes épidermoïdes localement évolués de la sphère ORL: étude prospective de phase II.

PURPOSE: To assess the feasibility and efficacy of accelerated postoperative radiation therapy (RT) in patients with squamous-cell carcinoma of the head and neck (SCCHN). PATIENTS AND METHODS: Between December 1997 and July 2001, 68 patients (male to female ratio: 52/16; median age: 60-years (range: 43-81) with pT1-pT4 and/or pN0-pN3 SCCHN (24 oropharynx, 19 oral cavity, 13 hypopharynx, 5 larynx, 3 unknown primary, 2 maxillary sinus, and 2 salivary gland) were included in this prospective study. Postoperative RT was indicated because extracapsular infiltration (ECI) was observed in 20 (29%), positive surgical margins (PSM) in 20 (29%) or both in 23 patients (34%). Treatment consisted of external beam RT 66 Gy in 5 weeks and 3 days. Median follow-up was 15 months. RESULTS: According to CTC 2.0, acute morbidity was acceptable: grade 3 mucositis was observed in 15 (22%) patients, grade 3 dysphagia in 19 (28%) patients, grade 3 skin erythema in 21 (31%) patients with a median weight loss of 3.1 kg (range: 0-16). No grade 4 toxicity was observed. Median time to relapse was 13 months; we observed only three (4%) local and four (6%) regional relapses, whereas eight (12%) patients developed distant metastases without any evidence of locoregional recurrence. The 2 years overall-, disease-free survival, and actuarial locoregional control rates were 85, 73 and 83% respectively. CONCLUSION: The reduction of the overall treatment time using postoperative accelerated RT with weekly concomitant boost (six fractions per week) is feasible with local control rates comparable to that of published data. Acute RT-related morbidity is acceptable.

Objective comparison of image quality and dose between conventional and synchrotron radiation mammography.

The shape of the energy spectrum produced by an x-ray tube has a great importance in mammography. Many anode-filtration combinations have been proposed to obtain the most effective spectrum shape for the image quality-dose relationship. On the other hand, third generation synchrotrons such as the European Synchrotron Radiation Facility in Grenoble are able to produce a high flux of monoenergetic radiation. It is thus a powerful tool to study the effect of beam energy on image quality and dose in mammography. An objective method was used to evaluate image quality and dose in mammography with synchrotron radiation and to compare them to standard conventional units. It was performed systematically in the energy range of interest for mammography through the evaluation of a global image quality index and through the measurement of the mean glandular dose. Compared to conventional mammography units, synchrotron radiation shows a great improvement of the image quality-dose relationship, which is due to the beam monochromaticity and to the high intrinsic collimation of the beam, which allows the use of a slit instead of an anti-scatter grid for scatter rejection.

Survey on image quality and dose levels used in Europe for mammography.

Quality assurance programmes are becoming a common practice in the field of mammography. At the present time several recommendations exist and different test objects are used to optimize this radiological procedure. The goal of this study was to check if geographically distant centres using different quality control procedures were comparable when using a common objective way of assessing image quality. The results show that consensus still needs to be found among radiologists to reach a satisfactory level of harmony between patient doses and image quality in Europe.

Seroprevalence of antibody to hepatitis E virus among Chinese subjects in Taiwan.

Recently, with an available serological hepatitis E virus diagnostic kit, the prevalence of IgG antibody to hepatitis E virus among Chinese subjects in Taiwan was evaluated by means of a solid-phase enzyme-linked immunoassay based on two recombinant hepatitis E virus antigens. The overall prevalence of hepatitis E virus antibody was 10.7% among 384 healthy subjects older than 20 yr but only 0.3% among 600 schoolchildren and young adolescents younger than 20 yr (p < 0.0001). Serial serum samples from 32 hepatitis E virus antibody-positive healthy subjects showed 84% of them to have antibodies persisting more than 3 to 8 yr. Among patients with viral hepatitis, IgG hepatitis E virus antibody was detected in 10% of 10 patients with acute hepatitis A, in 9.5% of 63 patients with acute hepatitis B and in 13.9% of 36 patients with acute posttransfusion hepatitis C. Of 77 patients with sporadic non-A, non-B hepatitis, IgG hepatitis E virus antibody was detected in 18.9% of 53 patients positive for antibody to hepatitis C virus and in 45.8% of 24 patients negative for hepatitis C virus antibody (p < 0.03). Most of our hepatitis E virus antibody-positive normal subjects and patients had never been abroad. These findings demonstrate that sporadic or subclinical hepatitis E virus infections also exist among the Chinese subjects in Taiwan. Hepatitis E virus infection may play an important role in patients with hepatitis C virus antibody-negative sporadic non-A, non-B hepatitis. IgG hepatitis E virus antibody in the sera of normal subjects may last for more than 8 yr.

A case of acute hepatitis E in Victoria.

OBJECTIVE: To report a case of acute hepatitis E in Victoria, confirmed by laboratory investigations. CLINICAL FEATURES: A 10-year-old boy presented for medical attention with a seven-day history of anorexia and jaundice, 17 days after arriving from Pakistan. The diagnosis of acute hepatitis E was suspected after exclusion of the known causes of viral hepatitis, and was further established by specific antibody testing and identification of hepatitis E virus-like particles in a faecal sample collected three weeks after the onset of illness. INTERVENTION AND OUTCOME: The patient was managed at home, treated symptomatically and made a complete recovery. CONCLUSION: In patients who arrive from countries where hepatitis E is endemic, and who develop non-A, non-B, non-C viral hepatitis, hepatitis E should be considered as a possible diagnosis.

Seroepidemiological survey of hepatitis E in Hong Kong by recombinant-based enzyme immunoassays.

The agent that causes the enterally transmitted form of non-A, non-B hepatitis has been cloned and called hepatitis E virus (HEV). We have carried out a seroepidemiological survey on the prevalence of hepatitis E in Hong Kong. In a retrospective study, serum from 394 patients with acute viral hepatitis and 355 healthy subjects was tested for antibodies to HEV (anti-HEV) with a recombinant-based enzyme immunoassay. 65 (16.5%) patients with hepatitis were positive for IgM anti-HEV and 23 (5.8%) were also positive for IgM anti-HEV. Of 18 patients diagnosed as having acute non-A, non-B, non-C hepatitis, 6 were IgM anti-HEV positive. 17 (6%) patients in whom acute hepatitis A was diagnosed were also infected with HEV. None of 70 patients with acute hepatitis B or C or exacerbation of chronic hepatitis B was IgM anti-HEV positive. 57 (16.1%) of the healthy subjects were positive for IgG anti-HEV. The prevalence of IgG anti-HEV was higher in subjects over 20 years old than in younger subjects (24% vs 4%, p < 0.0001). IgG anti-HEV was detected in 26% of subjects who were positive for IgG antibody to HAV and in 7% of those negative for that antibody (p < 0.0001). We demonstrated the validity of the recombinant-based enzyme immunoassays for the diagnosis of hepatitis E. Our results suggest that hepatitis E accounts for a third of non-A, non-B, non-C hepatitis in Hong Kong and that coinfection of hepatitis A and E can occur.

Determination of a unique and immunodominant epitope of human T cell lymphotropic virus type I.

The identification and isolation of unique and immunogenic recombinant epitopes for human T cell lymphotrophic virus (HTLV) type I might allow the development of an antibody-based assay to differentiate between HTLV-I and HTLV-II infections. To test the feasibility of this approach, an HTLV-I envelope epitope was isolated by immunoscreening of a lambda gt11 recombinant HTLV-I DNA library with a human monoclonal antibody to HTLV-I. This recombinant epitope. MTA-4, when tested with sera from HTLV-I- or HTLV-II-infected individuals, was reactive with all HTLV-I and nonreactive with all HTLV-II antisera. These results indicate that MTA-4 is a unique and immunodominant epitope on HTLV-I and confirm the usefulness of human-derived monoclonal antibodies in an experimental approach to dissect the human humoral response to a viral pathogen.

Cultivation of pathogenic treponema in tissue cultures of SflEp cells.

Recently, the successful in vitro cultivation of the Nichols strain of Treponema pallidum was achieved. Afterward, attempts were made to cultivate three other strains of T. pallidum and two strains of T. pertenue. The cultivation of the KKJ, Mexico A, and Bosnia A strains of T. pallidum was somewhat successful; the average increases were 10.8, 9.1, and 7.5-fold, respectively. The range of growth for each of these strains varied dramatically from experiment to experiment. The KKJ strain varied from 14.4 to 8.0-fold; the Mexico A strain from 12.8 to 5.4-fold; and the Bosnia A strain from 11.3 to 3.6-fold. However, the attempts to cultivate the Gauthier and the FB strains of T. pertenue were unsuccessful. The average increases were 1.7 and 1.9-fold, respectively. Although the maximum growth observed was about threefold with either of these strains of T. pertenue, over 50% of the treponemes remained motile for 10 d. These results suggest that although each of these strains of T. pallidum and T. pertenue has been shown to be genetically identical, they are very diverse biologically even among strains of the same species.

Enumeration of Treponema pallidum cells cultivated in vitro by an enzyme-linked immunosorbent assay.

An enzyme-linked immunosorbent assay was developed to enumerate Treponema pallidum cells. The assay could detect from 2 X 10(7) to 4 X 10(8) treponemes per ml. Reactive rabbit serum and goat anti-rabbit immunoglobulin G (peroxidase conjugate) were used in the assay. Optimum results were obtained when 2,2'-azino-di(ethylbenzthiazolinesulfonic acid) was used as the dye for the enzyme reaction and the reactions were allowed to run for 45 min. Interestingly, assays in which in vivo-cultivated T. pallidum was used produced lower absorbance values than those in which T. pallidum was cultivated in vitro.

Further studies on replication of virulent Treponema pallidum in tissue cultures of Sf1Ep cells.

A number of parameters aimed at optimizing culture conditions for both Sf1Ep cells and Treponema pallidum have been investigated. Optimum temperature for replication of T. pallidum ranged between 33 and 35 degrees C. At 33 degrees C, replication occurred in the presence of atmospheric oxygen concentrations of less than 0.3 to 10%, the optimum range being 1.5 to 5%. No replication occurred in the presence of 12.5% oxygen. When both temperature and oxygen concentrations were varied between 33 and 35 degrees C and 1.5 to 5%, respectively, little differences in replication were noted. Although variation in the oxygen concentration within each temperature group had little or no effect on replication, it did have an effect on motility, which remained greater in the 5% oxygen concentration after 9 to 12 days of cultivation. Optimum concentration of fetal bovine serum in the culture medium was 20%, although replication occurred in concentrations ranging from 5 to 30%. If carefully screened, calf serum could be substituted for fetal bovine serum. Testis extract was an essential component of the culture medium. Although extract obtained from an adult rabbit--either normal or T. pallidum infected--was slightly superior, replication of T. pallidum occurred when rat or hamster testis extract was substituted.

Cultivation of virulent Treponema pallidum in tissue culture.

In a series of seven experiments, the virulent Nichols strain of Treponema pallidum was shown to attach and replicate on the surface of tissue culture cells of cottontail rabbit epithelium (Sf1Ep) growing in conventional monolayer cultures under an atmosphere of 1.5% oxygen. Five days after inoculation of 10(6)T. pallidum, the number of treponemes had increased to between 8 x 10(6) and 2.59 x 10(7). The viability of harvested organisms ranged from 86 to 97%. The number of T. pallidum continued to increase, generally reaching a plateau between days 9 and 12 of incubation, with increases ranging up to 100-fold and averaging 49-fold. There appeared to be a ceiling of multiplication of about 2 x 10(8) irrespective of the inoculum, which ranged from 10(6) to 10(8)T. pallidum. Concurrent deoxyribonucleic acid assays were performed on the cultures containing T. pallidum to obtain further evidence of replication. Significant increases in treponemal deoxyribonucleic acid were observed when the inocula ranged from 10(6) to 10(7), with the greatest increases, as might be expected, being in the former group. There was also excellent correlation in the amount of deoxyribonucleic acid per treponeme; the averages for the 10(6), 2.5 x 10(6), and 10(7) groups were 3.46 x 10(-14), 3.28 x 10(-14), and 2.79 x 10(-14) g per treponeme, respectively (3.14 +/- 0.72 x 10(-14) g per treponeme). In each experiment, organisms were harvested from the group inoculated with 10(6)T. pallidum after 7 days of incubation to test for virulence. In all instances, the organisms were virulent; erythematous, indurated, treponeme-containing lesions were produced from an average of six to seven organisms. Scanning electron microscopy revealed that during the course of replication many microcolonies of treponemes formed on the surface of the cells.