Residual ctDNA after treatment predicts early relapse in patients with early-stage non-small cell lung cancer.

BACKGROUND: Identification of residual disease in patients with localized non-small cell lung cancer (NSCLC) following treatment with curative intent holds promise to identify patients at risk of relapse. New methods can detect circulating tumour DNA (ctDNA) in plasma to fractional concentrations as low as a few parts per million, and clinical evidence is required to inform their use. PATIENTS AND METHODS: We analyzed 363 serial plasma samples from 88 patients with early-stage NSCLC (48.9%/28.4%/22.7% at stage I/II/III), predominantly adenocarcinomas (62.5%), treated with curative intent by surgery (n = 61), surgery and adjuvant chemotherapy/radiotherapy (n = 8), or chemoradiotherapy (n = 19). Tumour exome sequencing identified somatic mutations and plasma was analyzed using patient-specific RaDaR™ assays with up to 48 amplicons targeting tumour-specific variants unique to each patient. RESULTS: ctDNA was detected before treatment in 24%, 77% and 87% of patients with stage I, II and III disease, respectively, and in 26% of all longitudinal samples. The median tumour fraction detected was 0.042%, with 63% of samples <0.1% and 36% of samples <0.01%. ctDNA detection had clinical specificity >98.5% and preceded clinical detection of recurrence of the primary tumour by a median of 212.5 days. ctDNA was detected after treatment in 18/28 (64.3%) of patients who had clinical recurrence of their primary tumour. Detection within the landmark timepoint 2 weeks to 4 months after treatment end occurred in 17% of patients, and was associated with shorter recurrence-free survival [hazard ratio (HR): 14.8, P <0.00001] and overall survival (HR: 5.48, P <0.0003). ctDNA was detected 1-3 days after surgery in 25% of patients yet was not associated with disease recurrence. Detection before treatment was associated with shorter overall survival and recurrence-free survival (HR: 2.97 and 3.14, P values 0.01 and 0.003, respectively). CONCLUSIONS: ctDNA detection after initial treatment of patients with early-stage NSCLC using sensitive patient-specific assays has potential to identify patients who may benefit from further therapeutic intervention.

The radiosensitizing effect of platinum nanoparticles in proton irradiations is not caused by an enhanced proton energy deposition at the macroscopic scale.

Objective.Due to the radiosensitizing effect of biocompatible noble metal nanoparticles (NPs), their administration is considered to potentially increase tumor control in radiotherapy. The underlying physical, chemical and biological mechanisms of the NPs' radiosensitivity especially when interacting with proton radiation is not conclusive. In the following work, the energy deposition of protons in matter containing platinum nanoparticles (PtNPs) is experimentally investigated.Approach.Surfactant-free monomodal PtNPs with a mean diameter of (40 ± 10) nm and a concentration of 300 µg ml-1, demonstrably leading to a substantial production of reactive oxygen species (ROS), were homogeneously dispersed into cubic gelatin samples serving as tissue-like phantoms. Gelatin samples without PtNPs were used as control. The samples' dimensions and contrast of the PtNPs were verified in a clinical computed tomography scanner. Fields from a clinical proton machine were used for depth dose and stopping power measurements downstream of both samples types. These experiments were performed with a variety of detectors at a pencil beam scanning beam line as well as a passive beam line with proton energies from about 56-200 MeV.Main results.The samples' water equivalent ratios in terms of proton stopping as well as the mean proton energy deposition downstream of the samples with ROS-producing PtNPs compared to the samples without PtNPs showed no differences within the experimental uncertainties of about 2%.Significance.This study serves as experimental proof that the radiosensitizing effect of biocompatible PtNPs is not due to a macroscopically increased proton energy deposition, but is more likely caused by a catalytic effect of the PtNPs. Thus, these experiments provide a contribution to the highly discussed radiobiological question of the proton therapy efficiency with noble metal NPs and facilitate initial evidence that the dose calculation in treatment planning is straightforward and not affected by the presence of sensitizing PtNPs.

On the wall perturbation correction for a parallel-plate NACP-02 chamber in clinical electron beams.

PURPOSE: In recent years, several Monte Carlo studies have been published concerning the perturbation corrections of a parallel-plate chamber in clinical electron beams. In these studies, a strong depth dependence of the relevant correction factors (p(wall) and P(cav)) for depth beyond the reference depth is recognized and it has been shown that the variation with depth is sensitive to the choice of the chamber's effective point of measurement. Recommendations concerning the positioning of parallel-plate ionization chambers in clinical electron beams are not the same for all current dosimetry protocols. The IAEA TRS-398 as well as the IPEM protocol and the German protocol DIN 6800-2 interpret the depth of measurement within the phantom as the water equivalent depth, i.e., the nonwater equivalence of the entrance window has to be accounted for by shifting the chamber by an amount deltaz. This positioning should ensure that the primary electrons traveling from the surface of the water phantom through the entrance window to the chamber's reference point sustain the same energy loss as the primary electrons in the undisturbed phantom. The objective of the present study is the determination of the shift deltaz for a NACP-02 chamber and the calculation of the resulting wall perturbation correction as a function of depth. Moreover, the contributions of the different chamber walls to the wall perturbation correction are identified. METHODS: The dose and fluence within the NACP-02 chamber and a wall-less air cavity is calculated using the Monte Carlo code EGSnrc in a water phantom at different depths for different clinical electron beams. In order to determine the necessary shift to account for the nonwater equivalence of the entrance window, the chamber is shifted in steps deltaz around the depth of measurement. The optimal shift deltaz is determined from a comparison of the spectral fluence within the chamber and the bare cavity. The wall perturbation correction is calculated as the ratio between doses for the complete chamber and a wall-less air cavity. RESULTS: The high energy part of the fluence spectra within the chamber strongly varies even with small chamber shifts, allowing the determination of deltaz within micrometers. For the NACP-02 chamber a shift deltaz = -0.058 cm results. This value is independent of the energy of the primary electrons as well as of the depth within the phantom and it is in good agreement with the value recommended in the German dosimetry protocol. Applying this shift, the calculated wall perturbation correction as a function of depth is varying less than 1% from zero up to the half value depth R50 for electron energies in the range of 6-21 MeV. The remaining depth dependence can mainly be attributed to the scatter properties of the entrance window. When neglecting the nonwater equivalence of the entrance window, the variation of p(wall) with depth is up to 10% and more, especially for low electron energies. CONCLUSIONS: The variation of the wall perturbation correction for the NACP-02 chamber in clinical electron beams strongly depends on the positioning of the chamber. Applying a shift deltaz = -0.058 cm toward the focus ensures that the primary electron spectrum within the chamber bears the largest resemblance to the fluence of a wall-less cavity. Hence, the influence of the chamber walls on the perturbation correction can be separated out and the residual variation of p(wall) with depth is minimized.

The relationship between body mass index and number of days spent in hospital in Scotland.

In most countries in the Western world, more than 50% of adults are overweight or obese putting them at increased risk of hypertension, type 2 diabetes, coronary heart disease, stroke and other chronic disorders. It is not clear what impact increasing prevalence of over-weight and obesity has on hospital admissions. The objective of this study was to examine the relationship between body mass index (BMI) and number of days spent in hospital. The study was designed as a retrospective and prospective cohort study using nationally representative Health Survey data linked to NHS hospital admissions data. The study was set in Scotland. The participants were a nationally representative sample of 6968 (45%) men and 8700 (55%) women, of 16-74 years of age, living in private households whose BMI was recorded in the 1995 and 1998 Scottish Health Surveys. The outcome measure was the number of days spent in hospital between 1981 and 2004. The results showed that the proportion of participants in both normal weight (BMI 20-24.9 kg/m(2)) and over-weight (BMI 25-29.9 kg/m(2)) categories was 37%, with 21% in the obese (BMI ≥30 kg/m(2)) and 5% in the under-weight (BMI <20 kg/m(2)) categories. The median number of days spent in hospital between 1981 and 2004 was six. The odds ratios (95% confidence intervals) for spending above the median numbers of days in hospital adjusted for age, sex, socioeconomic status and behavioural factors (i.e. smoking, alcohol drinking and physical activity) were 1.29 (1.06-1.56) for the <20 kg/m(2) group, 1.00 (0.91-1.11) for the 25-29.9 kg/m(2) group and 1.24 (1.10-1.38) for the ≥30 kg/m(2) group compared with the 20-24.9 kg/m(2) group. In conclusion, extremes of BMI category identified at a single point in time are associated with spending above the median number of days in hospital over a 20-year period after adjusting for demographic, behavioural and socioeconomic exposures.

Impact of air gap, range shifter, and delivery technique on skin dose in proton therapy.

OBJECTIVE: Side effects of radiation therapy may include skin damage. The surface dose is of great interest and contains the buildup effect. In particular, the proton therapy community requires further experimental data to quantify doses in the surface region. This specification includes the skin dose, which is defined according to ICRU Report No. 39 at 70 µm water equivalent depth. The aim of this study is to gather more knowledge of the skin dose by varying key parameters defined by the patient treatment plan. This consists of clinical aspects such as the influence of the air gap, the application of a range shifter (RS), or the proton delivery technique. MATERIAL/METHODS: Skin doses were determined with a PTW 23391 extrapolation chamber with three thin Kapton® entrance windows operated as a conventional ionization chamber. The impact on the skin dose for quasi-monoenergetic pencil beam scanning (PBS) proton beams was evaluated for clinical air gaps between 3.5 and 51.1 cm. The differences in skin dose were assessed by irradiating equivalent fields with an RS of 51 mm water equivalent thickness (RS51) and without. Furthermore, the delivery techniques PBS, uniform scanning (US), and double scattering (DS) were compared by defining a spread-out Bragg peak (SOBP). TOPAS (V.3.1.2) was used to model an IBA nozzle with PBS and to score dose to water at the surface of a water phantom. RESULTS: For the monoenergetic fields without the application of the RS the skin dose was constant down to an air gap of 6.2 cm. A lower air gap of 3.5 cm showed a variation in skin dose by up to 2.4% compared to the results obtained with larger air gaps. With the inserted RS51 an increase in the skin dose was found for air gaps smaller than 11.3 cm. Experimentally, a dose difference of 1.4% was recorded for an air gap of 6.2 cm by inserting an RS and none. With the Monte Carlo calculations the largest dose increase was observed at the air gap of 3.5 cm with 1.7% and 4.0% relative to the skin dose results without the RS and to the largest evaluated air gap of 51.1 cm, respectively. The SOBP comparison of the beam modalities at the measuring plane at the isocenter revealed higher skin doses without RS (including RS) by up to +1.9% (+1.5%) for DS and +1.3% (+1.1%) for US compared to PBS. For all three techniques an approx. 2% rise in skin dose was observed for the largest evaluated air gap of 37.7 cm to an air gap of 6.2 cm when using an RS51. CONCLUSION: The study investigated aspects of skin dose of a water equivalent phantom by varying key parameters of a proton treatment plan. Parameters like the RS, the air gap, and the delivery modality have an impact on the order of 4.0% for the skin dose at the depth of 70 µm. The increases in skin dose are the effects of the contribution of the increased electron fluence at small air gaps and the emitted hadronic particles produced by the RS.

Covalent functionalization of polypropylene filters with diazirine-photosensitizer conjugates producing visible light driven virus inactivating materials.

The SARS-CoV-2 pandemic has highlighted the weaknesses of relying on single-use mask and respirator personal protective equipment (PPE) and the global supply chain that supports this market. There have been no major innovations in filter technology for PPE in the past two decades. Non-woven textiles used for filtering PPE are single-use products in the healthcare environment; use and protection is focused on preventing infection from airborne or aerosolized pathogens such as Influenza A virus or SARS-CoV-2. Recently, C-H bond activation under mild and controllable conditions was reported for crosslinking commodity aliphatic polymers such as polyethylene and polypropylene. Significantly, these are the same types of polymers used in PPE filtration systems. In this report, we take advantage of this C-H insertion method to covalently attach a photosensitizing zinc-porphyrin to the surface of a melt-blow non-woven textile filter material. With the photosensitizer covalently attached to the surface of the textile, illumination with visible light was expected to produce oxidizing 1O2/ROS at the surface of the material that would result in pathogen inactivation. The filter was tested for its ability to inactivate Influenza A virus, an enveloped RNA virus similar to SARS-CoV-2, over a period of four hours with illumination of high intensity visible light. The photosensitizer-functionalized polypropylene filter inactivated our model virus by 99.99% in comparison to a control.

Can a ToF-PET photon attenuation reconstruction test stopping-power estimations in proton therapy? A phantom study.

Objective. The aim of the phantom study was to validate and to improve the computed tomography (CT) images used for the dose computation in proton therapy. It was tested, if the joint reconstruction of activity and attenuation images of time-of-flight PET (ToF-PET) scans could improve the estimation of the proton stopping-power.Approach. The attenuation images, i.e. CT images with 511 keV gamma-rays (γCTs), were jointly reconstructed with activity maps from ToF-PET scans. Theß+activity was produced with FDG and in a separate experiment with proton-induced radioactivation. The phantoms contained slabs of tissue substitutes. The use of theγCTs for the prediction of the beam stopping in proton therapy was based on a linear relationship between theγ-ray attenuation, the electron density, and the stopping-power of fast protons.Main results. The FDG based experiment showed sufficient linearity to detect a bias of bony tissue in the heuristic look-up table, which maps between x-ray CT images and proton stopping-power.γCTs can be used for dose computation, if the electron density of one type of tissue is provided as a scaling factor. A possible limitation is imposed by the spatial resolution, which is inferior by a factor of 2.5 compared to the one of the x-ray CT.γCTs can also be derived from off-line, ToF-PET scans subsequent to the application of a proton field with a hypofractionated dose level.Significance. γCTs are a viable tool to support the estimation of proton stopping with radiotracer-based ToF-PET data from diagnosis or staging. This could be of higher potential relevance in MRI-guided proton therapy.γCTs could form an alternative approach to make use of in-beam or off-line PET scans of proton-inducedß+activity with possible clinical limitations due to the low number of coincidence counts.

Determination of surface dose in pencil beam scanning proton therapy.

PURPOSE/OBJECTIVE: Quantification of surface dose within the first few hundred water equivalent µm is challenging. Nevertheless, it is of large interest for the proton therapy community to study dose effects in the skin. The experimental determination is affected by the detector properties, such as the detector volume and material. The International Commission on Radiation Units and Measurements in its report 39 recommends assessing the skin dose at a depth of 0.07 mm. The aim of this study is the estimation of the absorbed dose at and around a depth of 70 µm. We used various dosimetric approaches in conjunction with proton pencil beam scanning delivery to determine the skin dose in a clinical setting. MATERIAL/METHODS: Five different detectors were tested for determining the surface dose in water: EBT3 and HD-V2 GAFCHROMIC™ radiochromic film, LiF:Mg,Ti thermoluminescent dosimeter, IBA PPC05 plane-parallel ionization chamber, and PTW 23391 extrapolation chamber. The irradiation setup consisted of quasi-monoenergetic scanned proton pencil beams with kinetic energies of 100, 150, and 226.7 MeV, respectively. Radiochromic films were placed within a vertical stack and in wedge geometry and were analyzed with FilmQA Pro™ adopting triple channel dosimetry. The extrapolation chamber PTW 23391, which served as a reference in the current work, was used in a conventional ionization chamber setup with a fixed electrode gap of 2 mm. Three Kapton® entrance windows with thicknesses of 25, 50, and 75 µm were employed. Thermoluminescent dosimeters were provided as powder and were pressed onto a sheet of aluminum. Furthermore, the Monte Carlo code TOol for PArticle Simulation (TOPAS) in version 3.1.p2 was used to model an IBA pencil beam scanning nozzle and score dose to water in a water phantom. RESULTS: The resulting depth dose curves were normalized to their 100% dose at the reference depth of 3 cm. We obtained the skin doses with the extrapolation chamber and with TOPAS. For the experimental approach this resulted in 79.7 ± 0.3%, 86.0 ± 0.6%, and 87.1 ± 0.1% for the proton energies 100, 150, and 226.7 MeV, respectively. The results for TOPAS were 80.1 ± 0.2% (100 MeV), 87.1 ± 0.5% (150 MeV), and 86.9 ± 0.4% (226.7 MeV), respectively. Based on the experimental results of the skin dose, we provided a clinically relevant surface extrapolation factor for the common measurement methods. This allows the result of the first measurement depth of a detector to be scaled to the dose at the skin depth. Most practical would be the use of the surface extrapolation factor for the PPC05 chamber, due to its direct reading, the wide availability in clinics and the low uncertainties. The calculated factors were 0.986 ± 0.004 for 100 MeV, 0.961 ± 0.008 for 150 MeV, and 0.963 ± 0.003 for 226.7 MeV. CONCLUSIONS: In this study, dissimilar experimental approaches were evaluated with respect to measurements at depths close to the surface. The experimental depth dose curves are in good agreement with the simulation with TOPAS Monte Carlo. To the author's knowledge this was the first experimental determination of the skin dose according to the International Commission on Radiation Units and Measurements 39 definition in proton pencil beam scanning.

Hurricane Allen's Impact on Jamaican Coral Reefs.

Coral reefs of north Jamaica, normally sheltered, were severely damaged by Hurricane Allen, the strongest Caribbean hurricane of this century. Immediate studies were made at Discovery Bay, where reef populations were already known in some detail. Data are presented to show how damage varied with the position and orientation of the substraturn and with the shape, size, and mechanical properties of exposed organisms. Data collected over succeeding weeks showed striking differences in the ability of organisms to heal and survive.

Positioning of a plane-parallel ionization chamber in clinical electron beams and the impact on perturbation factors.

Current dosimetry protocols recommend the use of plane-parallel ionization chambers for the dosimetry of clinical electron beams. The necessary perturbation corrections p(wall) and p(cav) are assumed to be unity, independent of the depth of measurement and the energy of the primary electrons. To verify these assumptions detailed Monte Carlo studies of a Roos chamber in clinical electron beams with energies in the range of 6-21 MeV are performed at different depths in water and analyzed in terms of Spencer-Attix cavity theory. Separate simulations for the perturbation corrections p(wall) and p(cav) indicate quite different properties of both correction factors with depth. Dose as well as fluence calculations show a nearly depth-independent wall correction factor for a shift of the Roos chamber Deltaz = -0.017 cm toward the focus. This value is in good agreement with the positioning recommendation given in all dosimetry protocols. Regarding the fluence perturbation p(cav) the simulation of the electron fluence inside the air cavity in comparison to water unambiguously reveals an in-scattering of low energy electrons, despite the fact, that the cavity is 'well guarded'. For depths beyond the reference depth z(ref) this effect is superimposed by an increased loss of primary electrons from the beam resulting in p(cav) > 1. This effect is largest for low electron energies but present for all electron energies involved in this study. Based on the different depth dependences of p(wall) and p(cav) it is possible to choose a chamber shift Deltaz in a way to minimize the depth dependence of the overall perturbation factor p. For the Roos chamber this shift is Deltaz = -0.04 cm independent of electron energy.

Stereotactical fields applied in proton spot scanning mode with range shifter and collimating aperture.

Some clinical indications require small fields with sharp lateral dose gradients, which is technically challenging in proton beam therapy. This holds especially true for low-range fields applied with the spot scanning technique, where large beam profiles entering from the beam-line or the insertion of range shifting blocks lead to large lateral gradients. We regard the latter case and solve it by shifting the range shifting block far upstream in conjunction with a collimating aperture close to the patient. The experiments of the current work are based on a commercial proton therapy treatment head designed for several delivery modes. In a research environment of the spot-scanning delivery mode a range shifter is inserted downstream of the scanning magnets in a slot which is usually employed only in a scattering delivery mode. This configuration is motivated by equations assuming a simple model of proton transport. In the experiments lateral dose planes are acquired with a scintillation screen and radiochromic films. Dose distributions are calculated with the Monte Carlo dose engine of the RayStation treatment planning system. We demonstrate that proton fields with 80%-20% lateral dose fall-off values between 1.4 mm and 4.0 mm can be achieved for water equivalent depths between 0 cm and 10 cm. The simulated lateral dose profiles agree with the experimental dose profiles. The sharpening of the field edges is set off by a broadening of the proton spots towards the center of the fields. This limits the clinical application mainly to small fields for which the distal and proximal conformality is of minor importance.

Efficiency improvements for ion chamber calculations in high energy photon beams.

This article presents the implementation of several variance reduction techniques that dramatically improve the simulation efficiency of ion chamber dose and perturbation factor calculations. The cavity user code for the EGSnrc Monte Carlo code system is extended by photon cross-section enhancement (XCSE), an intermediate phase-space storage (IPSS) technique, and a correlated sampling (CS) scheme. XCSE increases the density of photon interaction sites inside and in the vicinity of the chamber and results-in combination with a Russian Roulette game for electrons that cannot reach the cavity volume-in an increased efficiency of up to a factor of 350 for calculating dose in a Farmer type chamber placed at 10 cm depth in a water phantom. In combination with the IPSS and CS techniques, the efficiency for the calculation of the central electrode perturbation factor Pcel can be increased by up to three orders of magnitude for a single chamber location and by nearly four orders of magnitude when considering the Pcel variation with depth or with distance from the central axis in a large field photon beam. The intermediate storage of the phase-space properties of particles entering a volume that contains many possible chamber locations leads to efficiency improvements by a factor larger than 500 when computing a profile of chamber doses in the field of a linear accelerator photon beam. All techniques are combined in a new EGSnrc user code egs_chamber. Optimum settings for the variance reduction parameters are investigated and are reported for a Farmer type ion chamber. A few example calculations illustrating the capabilities of the egs_chamber code are presented.

Monte Carlo calculations of beam quality correction factors kQ for electron dosimetry with a parallel-plate Roos chamber.

Current dosimetry protocols (AAPM, IAEA, DIN) recommend the use of parallel-plate ionization chambers for the measurement of absorbed dose-to-water in clinical electron beams. For well-guarded plane-parallel chambers, it is assumed that the perturbation correction pQ is unity for all electron energies. In this study, we present detailed Monte Carlo simulations with the EGSnrc code for the widely used Roos parallel-plate chamber which is, besides other plane-parallel chamber types, recommended in all protocols. We have calculated the perturbation corrections pcav and pwall for a wide range of electron energies and for 60Co. While our results confirm the recommended value of unity for the cavity perturbation pcav, the wall-correction factor pwall depends on electron energy and decreases with increasing electron energy. For the lowest electron energies in this study (R50 approximately 2 cm), pwall deviates from unity by up to 1.5%. Using the perturbation factors for the different electron energies and those for the reference beam quality, 60Co, we have calculated the beam quality correction factor kQ. For electron energies E0>9 MeV (R50>4 cm), the calculated values are in good agreement with the data published in the IAEA protocol. Deviations in the range of 0.5-0.8% are found for R50<3 cm.

Monte-Carlo-based perturbation and beam quality correction factors for thimble ionization chambers in high-energy photon beams.

This paper presents a detailed investigation into the calculation of perturbation and beam quality correction factors for ionization chambers in high-energy photon beams with the use of Monte Carlo simulations. For a model of the NE2571 Farmer-type chamber, all separate perturbation factors as found in the current dosimetry protocols were calculated in a fixed order and compared to the currently available data. Furthermore, the NE2571 Farmer-type and a model of the PTW31010 thimble chamber were used to calculate the beam quality correction factor kQ. The calculations of kQ showed good agreement with the published values in the current dosimetry protocols AAPM TG-51 and IAEA TRS-398 and a large set of published measurements. Still, some of the single calculated perturbation factors deviate from the commonly used ones; especially prepl deviates more than 0.5%. The influence of various sources of uncertainties in the simulations is investigated for the NE2571 model. The influence of constructive details of the chamber stem shows a negligible dependence on calculated values. A comparison between a full linear accelerator source and a simple collimated point source with linear accelerator photon spectra yields comparable results. As expected, the calculation of the overall beam quality correction factor is sensitive to the mean ionization energy of graphite used. The measurement setup (source-surface distance versus source-axis distance) had no influence on the calculated values.

Thimble ionization chambers in medium-energy x-ray beams and the role of constructive details of the central electrode: Monte Carlo simulations and measurements.

This paper presents investigations of thimble ionization chamber response in medium-energy kilovoltage x-ray beams (70-280 kVp, 0.09-3.40 mm Cu HVL). Two thimble ionization chambers (PTW30015 and PTW30016) were investigated, regarding the influence of the central electrode dimensions made of aluminum. Measurements were carried out in photon fields of different beam quality. Corresponding Monte Carlo simulations employing the EGSnrc Monte Carlo code system were performed. The simulations included the modelling of the x-ray tube and measurement setup for generation of x-ray spectra. These spectra were subsequently used to calculate the absorbed energy in the air cavity of the two thimble ionization chamber models and the air kerma at the reference point of the chambers. Measurements and simulations revealed an optimal diameter of the central electrode, concerning an almost energy-independent response of the ionizaton chamber. The Monte Carlo simulations are in good agreement with the measured values, expressed in beam quality correction factors k(Q). The agreement was generally within 0.6% but could only be achieved with an accurate model of the central electrode including its exact shape. Otherwise, deviations up to 8.5% resulted, decreasing with higher photon energies, which can be addressed to the high yield of the photoelectric effect in the electrode material aluminum at low photon energies.

Collimated proton pencil-beam scanning for superficial targets: impact of the order of range shifter and aperture.

To assess if apertures shall be mounted upstream or downstream of a range shifting block if these field-shaping devices are combined with the pencil-beam scanning delivery technique (PBS). The lateral dose fall-off served as a benchmark parameter. Both options realizing PBS-with-apertures were compared to the uniform scanning mode. We also evaluated the difference regarding the out-of-field dose caused by interactions of protons in beam-shaping devices. The potential benefit of the downstream configuration over the upstream configuration was estimated analytically. Guided by this theoretical evaluation a mechanical adapter was developed which transforms the upstream configuration provided by the proton machine vendor to a downstream configuration. Transversal dose profiles were calculated with the Monte-Carlo based dose engine of the commercial treatment planning system RayStation 6. Two-dimensional dose planes were measured with an ionization chamber array and a scintillation detector at different depths and compared to the calculation. Additionally, a clinical example for the irradiation of the orbit was compared for both PBS options and a uniform scanning treatment plan. Assuming the same air gap the lateral dose fall-off at the field edge at a few centimeter depth is 20% smaller for the aperture-downstream configuration than for the upstream one. For both options of PBS-with-apertures the dose fall-off is larger than in uniform scanning delivery mode if the minimum accelerator energy is 100 MeV. The RayStation treatment planning system calculated the width of the lateral dose fall-off with an accuracy of typically 0.1 mm-0.3 mm. Although experiments and calculations indicate a ranking of the three delivery options regarding lateral dose fall-off, there seems to be a limited impact on a multi-field treatment plan.

Retinoids for preventing the progression of cervical intra-epithelial neoplasia.

BACKGROUND: Invasive cervical carcinoma is preceded by a precancerous phase, cervical intra-epithelial neoplasia (CIN), which can be detected on cervical smears and confirmed by colposcopy and biopsy. Moderate and severe intra-epithelial neoplasia (CIN2 and CIN3) are treated mainly with surgery to prevent progression to invasive carcinoma. Medical methods of preventing the progression or inducing regression of CIN are needed. Retinoids are potent modulators of epithelial cell growth and differentiation and may have potential for the treatment of CIN. OBJECTIVES: To ascertain whether retinoids can cause regression or prevent progression of CIN. SEARCH STRATEGY: Cochrane Gynaecological Cancer Review Group's Specialised Register and Non-Trials Database, Cochrane Central Register of Controlled Trials (CENTRAL) (Issue 2,2007),MEDLINE and EMBASE (June 2007). SELECTION CRITERIA: Randomized controlled trials (RCTs) and non-RCTs of retinoids for treating CIN in women. DATA COLLECTION AND ANALYSIS: Two authors independently assessed trial quality and extracted data from the trials. Adverse effects information was also collected from the trials. MAIN RESULTS: Five RCTs comparing the efficacy of four different retinoids were identified. Two studies examined the effect on CIN2 and CIN3 of retinoids N-(4-hydroxyphenyl)retinamide (fenretinide) (Follen 2001) and 9-cis-retinoic acid (aliretinoin) (Alvarez 2003) given orally and two examined the effect of all-trans-retinoic acid given topically to the cervix (Meyskens 1994; Ruffin 2004). The fifth study investigated the use of 13-cis-retinoic acid (isotretinoin) given orally in HIV positive patients with CIN1 and condyloma (Robinson 2002).Four studies reported no significant effect of retinoids on the progression to higher grades of CIN, whilst the fifth did not report data on progression. In all studies retinoids had no significant effect on regression of CIN3. Two studies reported that retinoids were associated with regression of CIN2. One reported a greater complete regression of CIN2 over placebo, which was of borderline statistical significance, odds ratio(OR) = 0.5 (95% confidence interval (CI) 0.25 to 1.02). The other study reported a non-significant dose-related trend towards increased rates of complete and partial regression compared with placebo. One study reported a significantly worse outcome in women receiving retinoid, OR for regression = 6.00 (95% CI 1.00 to 35.91). In general, the retinoid medications were well tolerated. AUTHORS' CONCLUSIONS: The retinoids studied are not effective at causing regression of CIN3 but may have some effect on CIN2. The data on CIN1 is inadequate. Retinoids are not effective at preventing progression of CIN of any grade. At the doses given and duration of treatment studied, the retinoids were reasonably well-tolerated.

Nonspecific acid esterase activity as a marker for canine T lymphocytes.

Canine T lymphocytes are as yet poorly defined. Since focal paranuclear positivity for nonspecific esterase (alpha-naphthyl acetate esterase--ANAE) has been shown to be a reliable marker for T cells in humans and mice, canine lymphoid tissue sections, and cell suspensions were stained for this enzyme. Sections of five lymph nodes and 11 puppy thymuses displayed the same distribution patterns of focally ANAE-positive cells as were found in humans and mice in both organs: in thymuses only the medulla contained positive cells, and in lymph nodes only the thymus-dependent, paracortical zones, but not central areas of germinal centers, displayed focal ANAE reactivity. Furthermore, 56-78% of peripheral blood mononuclear cells, 60-71% of thoracic duct lymphocytes, and 10-15% of suspended thymus cells were positive for ANAE. It is concluded that focal ANAE reactivity is a marker for a canine T cell subpopulation.

Purified canine monocytes fail to confer concanavalin-A responsiveness to accessory-cell-depleted lymphocytes.

Monocytes were purified from canine peripheral blood by subjecting Ficoll-Hypaque-separated mononuclear cells to either complement-dependent cytolytic treatment with a panlymphocyte antibody (DLy-6) or rosette formation with human red blood cells (RBCs) followed by adherence to fetal-calf-serum-coated plastic dishes, or sedimentation over discontinuous Percoll gradients. These techniques resulted in monocyte enrichment of 83 +/- 3%, 89 +/-6%, and 42 +/- 3%, respectively. Monocytes purified by either the monoclonal antibody method or rosette formation with human RBCs failed to confer concanavalin-A responsiveness to lymphocytes depleted of accessory cells by discontinuous Percoll gradients. The most potent accessory activity was present among cells from low-density fractions of Percoll gradients and populations that did not form rosettes with human RBCs (monocyte-depleted), indicating that cells other than monocytes are involved in accessory function.