Investigation of pulsed low dose rate radiotherapy using dynamic arc delivery techniques.

There has been no consensus standard of care to treat recurrent cancer patients who have previously been irradiated. Pulsed low dose rate (PLDR) external beam radiotherapy has the potential to reduce normal tissue toxicities while still providing significant tumor control for recurrent cancers. This work investigates the dosimetry feasibility of PLDR treatment using dynamic arc delivery techniques. Five treatment sites were investigated in this study including breast, pancreas, prostate, head and neck, and lung. Dynamic arc plans were generated using the Varian Eclipse system and the RapidArc delivery technique with 6 and 10 MV photon beams. Each RapidArc plan consisted of two full arcs and the plan was delivered five times to achieve a daily dose of 200 cGy. The dosimetry requirement was to deliver approximately 20 cGy/arc with a 3 min interval to achieve an effective dose rate of 6.7 cGy min⁻¹. Monte Carlo simulations were performed to calculate the actual dose delivered to the planning target volume (PTV) per arc taking into account beam attenuation/scattering and intensity modulation. The maximum, minimum and mean doses to the PTV were analyzed together with the dose volume histograms and isodose distributions. The dose delivery for the five plans was validated using solid water phantoms inserted with an ionization chamber and film, and a cylindrical detector array. Two intensity-modulated arcs were used to efficiently deliver the PLDR plans that provided conformal dose distributions for treating complex recurrent cancers. For the five treatment sites, the mean PTV dose ranged from 18.9 to 22.6 cGy/arc. For breast, the minimum and maximum PTV dose was 8.3 and 35.2 cGy/arc, respectively. The PTV dose varied between 12.9 and 27.5 cGy/arc for pancreas, 12.6 and 28.3 cGy/arc for prostate, 12.1 and 30.4 cGy/arc for H&N, and 16.2 and 27.6 cGy/arc for lung. Advanced radiation therapy can provide superior target coverage and normal tissue sparing for PLDR reirradiation of recurrent cancers, which can be delivered using dynamic arc delivery techniques with ten full arcs and an effective dose rate of 6.7 ± 4.0 cGy min⁻¹.

Esophageal motion during radiotherapy: quantification and margin implications.

The purpose was to evaluate interfraction and intrafraction esophageal motion in the right-left (RL) and anterior-posterior (AP) directions using computed tomography (CT) in esophageal cancer patients. Eight patients underwent CT simulation and CT-on-rails imaging before and after radiotherapy. Interfraction displacement was defined as differences between pretreatment and simulation images. Intrafraction displacement was defined as differences between pretreatment and posttreatment images. Images were fused using bone registries, adjusted to the carina. The mean, average of the absolute, and range of esophageal motion were calculated in the RL and AP directions, above and below the carina. Thirty-one CT image sets were obtained. The incidence of esophageal interfraction motion > or =5 mm was 24% and > or =10 mm was 3%; intrafraction motion > or =5 mm was 13% and > or =10 mm was 4%. The average RL motion was 1.8 +/- 5.1 mm, favoring leftward movement, and the average AP motion was 0.6 +/- 4.8 mm, favoring posterior movement. Average absolute motion was 4.2 mm or less in the RL and AP directions. Motion was greatest in the RL direction above the carina. Coverage of 95% of esophageal mobility requires 12 mm left, 8 mm right, 10 mm posterior, and 9 mm anterior margins. In all directions, the average of the absolute interfraction and intrafraction displacement was 4.2 mm or less. These results support a 12 mm left, 8 mm right, 10 mm posterior, and 9 mm anterior margin for internal target volume (ITV) and can guide margins for future intensity modulated radiation therapy (IMRT) trials to account for organ motion and set up error in three-dimensional planning.

Dosimetric verification of modulated electron radiotherapy delivered using a photon multileaf collimator for intact breasts.

Modulated electron radiotherapy (MERT) may potentially be an effective modality for the treatment of shallow tumors, but dose calculation accuracy and delivery efficiency challenges remain. The purpose of this work is to investigate the dose accuracy of MERT delivery using a photon multileaf collimator (pMLC) on a Siemens Primus accelerator. A Monte Carlo (MC)-based inverse treatment planning system was developed for the 3D treatment planning process. Phase space data of 6, 9, 12 and 15 MeV electron beams were commissioned and used as the input source for MC dose calculations. A treatment plan was performed based on the 3D CT data of a heterogeneous 'breast phantom' that mimics a breast cancer patient, and delivered with 22 segments, each associated with a particular energy and Monitor Unit value. Film and ion chamber dosimetry was carefully performed for the conversion from measurement reading to dose, and the results were employed for plan verification using the heterogeneous breast phantom and a solid water phantom. Dose comparisons between measurements and calculations showed agreement within 2% or 1 mm. We conclude that our in-house MC treatment planning system is capable of performing treatment planning and accurate dose calculations for MERT using the pMLC to deliver radiation therapy to the intact breast.

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.

Pitfalls and modelling inconsistencies in computational radiation dosimetry: lessons learnt from the QUADOS intercomparison. Part I: Neutrons and uncertainties.

The QUADOS EU cost shared action conducted an intercomparison on the usage of numerical methods in radiation protection and dosimetry. The eight problems proposed were intended to test the usage of Monte Carlo and deterministic methods by assessing the accuracy with which the codes are applied and also the methods used to evaluate uncertainty in the answer gained through these methods. The overall objective was to spread good practice through the community and give users information on how to assess the uncertainties associated with their calculated results.

Pitfalls and modelling inconsistencies in computational radiation dosimetry: lessons learnt from the QUADOS intercomparison. Part II: Photons, electrons and protons.

'QUADOS', a concerted action of the European Commission, has promoted an intercomparison aimed at evaluating the use of computational codes for dosimetry in radiation protection and medical physics. This intercomparison was open to all users of radiation transport codes. Eight problems were selected for their relevance to the radiation dosimetry community, five of which involved photon and proton transport. This paper focuses on a discussion of lessons learned from the participation in solving the photon and charged particle problems. The lessons learned from the participation in solving the neutron problems are presented in a companion paper (in this issue).

Extreme obesity is associated with attempted suicides: results from a family study.

This study was conducted to explore the association between attempted suicides and body mass index (BMI, kg/m2) in a family sample of 2547 individuals. As a comparison, a national NESARC (the 2001-2002 National Epidemiologic Survey on Alcohol and Related Conditions) sample of 41 589 individuals was included to validate the observed association. Compared to average weight, extreme obesity showed significantly increased odds for attempted suicides both in family sample (odds ratio (OR) = 3.37 and 95% confidence interval (CI) = 1.59-7.13 for BMI = 40- < 50 kg/m2; OR = 3.85 and 95% CI = 1.71-8.66 for BMI > or = 50 kg/m2) and in NESARC sample (OR = 2.11 and 95% CI = 1.59-2.81 for BMI = 40- < 50 kg/m2; OR = 2.56 and 95% CI = 1.34-4.92 for BMI> or = 50 kg/m2) after adjustment for sociodemographic factors. Compared to general population, the risk for attempted suicide was 87 and 122% higher for those with BMI=40- < 50 and > or = 50 kg/m2, respectively. The pattern of results in the family and population studies indicates that extreme obesity is strongly associated with attempted suicide.

Molecular modeling of PepT1--towards a structure.

The proton-coupled uptake of di- and tri-peptides is the major route of dietary nitrogen absorption in the intestine and of reabsorption of filtered protein in the kidney. In addition, the transporters involved, PepT1 (SLC15a1) and PepT2 (SLC15a2), are responsible for the uptake and tissue distribution of a wide range of pharmaceutically important compounds, including beta-lactam antibiotics, angiotensin-converting enzyme inhibitors, anti-cancer and anti-viral drugs. PepT1 and PepT2 are large proteins, with over 700 amino acids, and to date there are no reports of their crystal structures, nor of those of related proteins from lower organisms. Therefore there is virtually no information about the protein 3-D structure, although computer-based approaches have been used to both model the transmembrane domain (TM) layout and to produce a substrate binding template. These models will be discussed, and a new one proposed from homology modeling rabbit PepT1 to the recently crystallized bacterial transporters LacY and GlpT. Understanding the mechanism by which PepT1 and PepT2 bind and transport their substrates is of great interest to researchers, both in academia and in the pharmaceutical industries.

QUADOS intercomparison: a summary of photon and charged particle problems.

QUADOS, a Concerted Action of the European Commission, has promoted an intercomparison aimed at evaluating the use of computational codes for dosimetry in radiation protection and medical physics. This intercomparison was open to all users of radiation transport codes. Eight problems were selected for their relevance to the radiation dosimetry community, five of which involved photon and proton transport. This paper focuses on the analysis of the photon and charged particle problems. The neutron problems were presented in a paper at the NEUDOS9 conference.

Elongated beamlets: a simple technique for segment and MU reduction for sMLC IMRT delivery on accelerators utilizing 5 mm leaf widths.

The focus of this work is to demonstrate the effects of using an elongated beamlet to achieve similar dose conformity as achieved with a square beamlet while reducing the number of segments and subsequent MU required. A series of 10 patients were planned for IMRT delivery to the prostate using minimum beamlet sizes of 5x5 mm2 (default scheme), 10x5 mm2 with the short axis parallel to the prostate-rectum interface (scheme 1), and 10x5 mm2 with the short axis perpendicular to the prostate-rectum interface (scheme 2). All other parameters between plans were left unchanged. Plans were appropriately normalized and evaluated for R65, R40, conformity index, total number of segments and MU. All plans were generated using the Corvus inverse planning system. The average number of segments in this study decreased by approximately 49% for both schemes 1 and 2. The subsequent number of MU required decreased by approximately 34.6%. The resultant modified modulation scaling factor (MSFmod) decreased by approximately 34.3%. Additionally, we found that each isodose distribution using scheme 2 would still meet our clinical acceptance criteria with no visible degradation in the dose distribution as compared with the default scheme. In conclusion, we have demonstrated that it is possible to achieve similar results as those obtained using a 5x5 mm2 beamlet with respect to target coverage and critical structure sparing by using strategically oriented elongated beamlets. This technique directly translates to a decreased MSF(mod) allowing for decreased leakage dose to the patient, a decreased risk of exceeding secondary shielding limits in pre-existing vaults, and shorter treatment times.

Dosimetric evaluation of MRI-based treatment planning for prostate cancer.

The purpose of this study is to evaluate the dosimetric accuracy of MRI-based treatment planning for prostate cancer using a commercial radiotherapy treatment planning system. Three-dimensional conformal plans for 15 prostate patients were generated using the AcQPlan system. For each patient, dose distributions were calculated using patient CT data with and without heterogeneity correction, and using patient MRI data without heterogeneity correction. MR images were post-processed using the gradient distortion correction (GDC) software. The distortion corrected MR images were fused to the corresponding CT for each patient for target and structure delineation. The femoral heads were delineated based on CT. Other anatomic structures relevant to the treatment (i.e., prostate, seminal vesicles, lymph notes, rectum and bladder) were delineated based on MRI. The external contours were drawn separately on CT and MRI. The same internal contours were used in the dose calculation using CT- and MRI-based geometries by directly transferring them between MRI and CT as needed. Treatment plans were evaluated based on maximum dose, isodose distributions and dose-volume histograms. The results confirm previous investigations that there is no clinically significant dose difference between CT-based prostate plans with and without heterogeneity correction. The difference in the target dose between CT- and MRI-based plans using homogeneous geometry was within 2.5%. Our results suggest that MRI-based treatment planning is suitable for radiotherapy of prostate cancer.

Intercomparison on the usage of computational codes in radiation dosimetry.

'QUADOS', a Concerted Action of the European Commission, has run an intercomparison aimed at evaluating the use of computational codes for dosimetry in radiation protection and medical physics. This intercomparison was open to all users of Monte Carlo, analytic and semi-analytic codes or deterministic methods. Its main aim was to provide a snapshot of the methods and codes currently in use. It also intended to furnish information on the methods used to assess the reliability of computational results and disseminate 'good practice' throughout the radiation dosimetry community. Eight problems were selected for their relevance to the radiation dosimetry community, three of which involve neutron transport. This paper focuses on the analysis of the neutron problems.

Optimization of combined electron and photon beams for breast cancer.

Recently, intensity-modulated radiation therapy and modulated electron radiotherapy have gathered a growing interest for the treatment of breast and head and neck tumours. In this work, we carried out a study to combine electron and photon beams to achieve differential dose distributions for multiple target volumes simultaneously. A Monte Carlo based treatment planning system was investigated, which consists of a set of software tools to perform accurate dose calculation, treatment optimization, leaf sequencing and plan analysis. We compared breast treatment plans generated using this home-grown optimization and dose calculation software for different treatment techniques. Five different planning techniques have been developed for this study based on a standard photon beam whole breast treatment and an electron beam tumour bed cone down. Technique 1 includes two 6 MV tangential wedged photon beams followed by an anterior boost electron field. Technique 2 includes two 6 MV tangential intensity-modulated photon beams and the same boost electron field. Technique 3 optimizes two intensity-modulated photon beams based on a boost electron field. Technique 4 optimizes two intensity-modulated photon beams and the weight of the boost electron field. Technique 5 combines two intensity-modulated photon beams with an intensity-modulated electron field. Our results show that technique 2 can reduce hot spots both in the breast and the tumour bed compared to technique 1 (dose inhomogeneity is reduced from 34% to 28% for the target). Techniques 3, 4 and 5 can deliver a more homogeneous dose distribution to the target (with dose inhomogeneities for the target of 22%, 20% and 9%, respectively). In many cases techniques 3, 4 and 5 can reduce the dose to the lung and heart. It is concluded that combined photon and electron beam therapy may be advantageous for treating breast cancer compared to conventional treatment techniques using tangential wedged photon beams followed by a boost electron field.

Monitor unit calculation for Monte Carlo treatment planning.

In this work, we investigate a formalism for monitor unit (MU) calculation in Monte Carlo based treatment planning. By relating MU to dose measured under reference calibration conditions (central axis, depth of dose maximum in water, 10 cm x 10 cm field defined at 100 cm source-to-surface distance) our formalism determines the MU required for a treatment plan based on the prescription dose and Monte Carlo calculated dose distribution. Detailed descriptions and formulae are given for various clinical situations including conventional treatments and advanced techniques such as intensity-modulated radiotherapy (IMRT) and modulated electron radiotherapy (MERT). Analysis is made of the effects of source modelling, beam modifier simulation and patient dose calculation accuracy, all of which are important factors for absolute dose calculations using Monte Carlo simulations. We have tested the formalism through phantom measurements and the predicted MU values were consistent with measured values to within 2%. The formalism has been used for MU calculation and plan comparison for advanced treatment techniques such as MERT, extracranial stereotactic IMRT, MRI-based treatment planning and intensity-modulated laser-proton therapy studies. It is also used for absolute dose calculations using Monte Carlo simulations for treatment verification, which has become part of our comprehensive IMRT quality assurance programme.

Relationship of obesity to depression: a family-based study.

OBJECTIVE: To examine the relationship between obesity and depression in a sample of extremely obese individuals and their siblings and parents. SUBJECTS: A total of 1730 European Americans (558 men, 1172 women, aged 49.29+/-15.42 y, body mass index (BMI) of 35.57+/-11.53 kg/m(2)) and 373 African Americans (103 men, 270 women, aged 44.85+/-15.08 years, BMI of 36.83+/-11.31 kg/m(2)) in a sample of 482 nuclear families segregating extreme obesity and normal weight. MEASUREMENTS: Individual BMI, history of depression treatment and covariates (age, sex, race, education, marital status, socioeconomic status, chronic medical conditions and exercise program). RESULTS: Greater odds for depression were found for the obese, European American, women, the unmarried, the more educated, those with chronic physical disorder(s) and the offspring of depressed parents. A trend test found that the odds ratios for depression increased with BMI and number of chronic medical conditions (P<0.0001). Multivariate logistic regression analyses indicated that BMI, race, marital status, chronic medical conditions and family history were the predicators of depression for both the genders. Hierarchical analyses revealed that BMI significantly increased the risk above that predicated by the combined effects of all other variables. CONCLUSIONS: Extreme obesity was associated with the increased risk for depression across gender and racial groups, even after controlling for chronic physical disease, familial depression and demographic risk factors. More detailed research is needed to determine the underlying mechanisms.

DNA fragmentation in leukocytes following subacute low-dose nerve agent exposure.

The objective of the present study was to determine levels of DNA fragmentation in blood leukocytes from guinea pigs by single-cell gel electrophoresis (comet assay) after exposure to the chemical warfare nerve agent (CWNA), soman, at doses ranging from 0.1 LD50 to 0.4 LD50, once per day for either 5 or 10 days. Post-exposure recovery periods ranged from 0 to 17 days. Leukocytes were imaged from each animal, and the images analyzed by computer. Data obtained for exposure to soman demonstrated significant increases in DNA fragmentation in circulating leukocytes in CWNA-treated guinea pigs compared with saline-injected control animals at all doses and time points examined. Notably, significantly increased DNA fragmentation was observed in leukocytes 17 days after cessation of soman exposure. Our findings demonstrate that leukocyte DNA fragmentation assays may provide a sensitive biomarker for low-dose CWNA exposure.

Central neuro-inflammatory gene response following soman exposure in the rat.

Effective treatments to improve survivability following exposure to the nerve agent soman have been established and are currently available. Unfortunately, electrographic brain seizures, neuroinflammation and brain cell death are still a potential problem even with treatment. In the present study we have characterized the time course of the central neuro-inflammatory gene response using quantitative real time-PCR (TaqMan). Male Sprague-Dawley rats were pre-treated with HI-6 (1-2-hydroxy-iminomethyl-1-pyridino-3-(4-carbamoyl-1-pyridino-2-oxapropane dichloride); 125 mg/kg, i.p.) and exposed 30 min later to 1.6 x LD(50) of soman (pinacolyl methyl-phosphonofluoridate, 180 microg/kg, s.c.) followed at 1 min by atropine methyl nitrate (4 mg/kg, i.m.). Initially, a significant and dramatic upregulation of tumor necrosis factor-alpha and vascular cell adhesion molecule-1 mRNA levels was measured 2 h post-exposure followed at 6 h by upregulation of interleukin-1beta, interleukin-6, E-selectin, and intercellular adhesion molecule-1 with eventual resolution by 24-48 h. In conclusion, an acute and transient upregulation of the inflammatory gene response is activated following soman exposure that may be involved in the soman-induced brain injury process.

The sodium channel blocker RS100642 reverses down-regulation of the sodium channel alpha-subunit Na(v) 1.1 expression caused by transient ischemic brain injury in rats.

In this study we evaluated the expression of five sodium channel (NaCh) Alpha-subunit genes after transient middle cerebral artery occlusion (MCAo) in the rat and the effects of treatment with the NaCh blocker and experimental neuroprotective agent RS100642 as compared to the prototype NaCh blocker mexiletine. The expression of Na(v) 1.1, Na(v) 1.2, Na(v) 1.3, Na(v) 1.7, Na(v) 1.8 and the housekeeping gene beta-actin were studied in vehicle or drug-treated rats at 6, 24 and 48 h post-MCAo using real-time quantitative RT-PCR. RS100642 (1 mg/kg), mexiletine (10 mg/kg), or vehicle (1 ml/kg) was injected (i.v.) at 30 min, 2, 4, and 6 h post-injury. Following MCAo only the Na(v) 1.1 and Na(v) 1.2 genes were significantly down-regulated in the ipsilateral hemisphere of the injured brains. RS100642 treatment significantly reversed the down-regulation of Na(v) 1.1 (but not Na(v) 1.2) at 24-48 h post-injury. Mexiletine treatment, on the other hand, had no significant effect on the down-regulation of either gene. These findings demonstrate that treatment with a neuroprotective dose of RS100642 significantly reverses the down-regulation of Na(v) 1.1 caused by ischemic brain injury and suggests that RS100642 selectively targets the Na(v) 1.1 Alpha-subunit of the NaCh. Furthermore, our findings strengthen the hypothesis that ischemic injury may produce selective depletion of voltage-gated NaChs, and suggest that the Na(v) 1.1 NaCh Alpha-subunit may play a key role in the neuronal injury/recovery process.

Shielding evaluation for IMRT implementation in an existing accelerator vault.

A formalism is developed for evaluating the shielding in an existing vault to be used for IMRT. Existing exposure rate measurements are utilized as well as a newly developed effective modulation scaling factor. Examples are given for vaults housing 6, 10 and 18 MV linear accelerators. The use of an 18 MV Siemens linear accelerator is evaluated for IMRT delivery with respect to neutron production and the effects on individual patients. A modified modulation scaling factor is developed and the risk of the incurrence of fatal secondary malignancies is estimated. The difference in neutron production between 18 MV Varian and Siemens accelerators is estimated using Monte Carlo results. The neutron production from the Siemens accelerator is found to be approximately 4 times less than that of the Varian accelerator resulting in a risk of fatal secondary malignancy occurrence of approximately 1.6% when using the SMLC delivery technique and our measured modulation scaling factors. This compares with a previously published value of 1.6% for routine 3D CRT delivery on the Varian accelerator.