Reducing CT radiation dose with iterative reconstruction algorithms: the influence of scan and reconstruction parameters on image quality and CTDIvol

OBJECTIVES In this phantom CT study, we investigated whether images reconstructed using filtered back projection (FBP) and iterative reconstruction (IR) with reduced tube voltage and current have equivalent quality. We evaluated the effects of different acquisition and reconstruction parameter settings on image quality and radiation doses. Additionally, patient CT studies were evaluated to confirm our phantom results. METHODS Helical and axial 256 multi-slice computed tomography scans of the phantom (Catphan(®)) were performed with varying tube voltages (80-140kV) and currents (30-200mAs). 198 phantom data sets were reconstructed applying FBP and IR with increasing iterations, and soft and sharp kernels. Further, 25 chest and abdomen CT scans, performed with high and low exposure per patient, were reconstructed with IR and FBP. Two independent observers evaluated image quality and radiation doses of both phantom and patient scans. RESULTS In phantom scans, noise reduction was significantly improved using IR with increasing iterations, independent from tissue, scan-mode, tube-voltage, current, and kernel. IR did not affect high-contrast resolution. Low-contrast resolution was also not negatively affected, but improved in scans with doses <5mGy, although object detectability generally decreased with the lowering of exposure. At comparable image quality levels, CTDIvol was reduced by 26-50% using IR. In patients, applying IR vs. FBP resulted in good to excellent image quality, while tube voltage and current settings could be significantly decreased. CONCLUSIONS Our phantom experiments demonstrate that image quality levels of FBP reconstructions can also be achieved at lower tube voltages and tube currents when applying IR. Our findings could be confirmed in patients revealing the potential of IR to significantly reduce CT radiation doses.

Deep molecular response is reached by the majority of patients treated with imatinib, predicts survival, and is achieved more quickly by optimized high-dose imatinib: results from the randomized CML-study IV

PURPOSE Deep molecular response (MR(4.5)) defines a subgroup of patients with chronic myeloid leukemia (CML) who may stay in unmaintained remission after treatment discontinuation. It is unclear how many patients achieve MR(4.5) under different treatment modalities and whether MR(4.5) predicts survival. PATIENTS AND METHODS Patients from the randomized CML-Study IV were analyzed for confirmed MR(4.5) which was defined as ≥ 4.5 log reduction of BCR-ABL on the international scale (IS) and determined by reverse transcriptase polymerase chain reaction in two consecutive analyses. Landmark analyses were performed to assess the impact of MR(4.5) on survival. RESULTS Of 1,551 randomly assigned patients, 1,524 were assessable. After a median observation time of 67.5 months, 5-year overall survival (OS) was 90%, 5-year progression-free-survival was 87.5%, and 8-year OS was 86%. The cumulative incidence of MR(4.5) after 9 years was 70% (median, 4.9 years); confirmed MR(4.5) was 54%. MR(4.5) was reached more quickly with optimized high-dose imatinib than with imatinib 400 mg/day (P = .016). Independent of treatment approach, confirmed MR(4.5) at 4 years predicted significantly higher survival probabilities than 0.1% to 1% IS, which corresponds to complete cytogenetic remission (8-year OS, 92% v 83%; P = .047). High-dose imatinib and early major molecular remission predicted MR(4.5). No patient with confirmed MR(4.5) has experienced progression. CONCLUSION MR(4.5) is a new molecular predictor of long-term outcome, is reached by a majority of patients treated with imatinib, and is achieved more quickly with optimized high-dose imatinib, which may provide an improved therapeutic basis for treatment discontinuation in CML.

High-Dose Benzodiazepine Dependence: A Qualitative Study of Patients' Perceptions on Initiation, Reasons for Use, and Obtainment

BACKGROUND High-dose benzodiazepine (BZD) dependence is associated with a wide variety of negative health consequences. Affected individuals are reported to suffer from severe mental disorders and are often unable to achieve long-term abstinence via recommended discontinuation strategies. Although it is increasingly understood that treatment interventions should take subjective experiences and beliefs into account, the perceptions of this group of individuals remain under-investigated. METHODS We conducted an exploratory qualitative study with 41 adult subjects meeting criteria for (high-dose) BZD-dependence, as defined by ICD-10. One-on-one in-depth interviews allowed for an exploration of this group's views on the reasons behind their initial and then continued use of BZDs, as well as their procurement strategies. Mayring's qualitative content analysis was used to evaluate our data. RESULTS In this sample, all participants had developed explanatory models for why they began using BZDs. We identified a multitude of reasons that we grouped into four broad categories, as explaining continued BZD use: (1) to cope with symptoms of psychological distress or mental disorder other than substance use, (2) to manage symptoms of physical or psychological discomfort associated with somatic disorder, (3) to alleviate symptoms of substance-related disorders, and (4) for recreational purposes, that is, sensation-seeking and other social reasons. Subjects often considered BZDs less dangerous than other substances and associated their use more often with harm reduction than as recreational. Specific obtainment strategies varied widely: the majority of participants oscillated between legal and illegal methods, often relying on the black market when faced with treatment termination. CONCLUSIONS Irrespective of comorbidity, participants expressed a clear preference for medically related explanatory models for their BZD use. We therefore suggest that clinicians consider patients' motives for long-term, high-dose BZD use when formulating treatment plans for this patient group, especially since it is known that individuals are more compliant with approaches they perceive to be manageable, tolerable, and effective.

Attitudes towards a maintenance (-agonist) treatment approach in high-dose benzodiazepine-dependent patients: a qualitative study

BACKGROUND High-dose benzodiazepine dependence constitutes a major clinical concern. Although withdrawal treatment is recommended, it is unsuccessful for a significant proportion of affected patients. More recently, a benzodiazepine maintenance approach has been suggested as an alternative for patients' failing discontinuation treatment. While there is some data supporting its effectiveness, patients' perceptions of such an intervention have not been investigated. METHODS An exploratory qualitative study was conducted among a sample of 41 high-dose benzodiazepine (BZD)-dependent patients, with long-term use defined as doses equivalent to more than 40 mg diazepam per day and/or otherwise problematic use, such as mixing substances, dose escalation, recreational use, or obtainment by illegal means. A qualitative content analysis approach was used to evaluate findings. RESULTS Participants generally favored a treatment discontinuation approach with abstinence from BZD as its ultimate aim, despite repeated failed attempts at withdrawal. A maintenance treatment approach with continued prescription of a slow-onset, long-acting agonist was viewed ambivalently, with responses ranging from positive and welcoming to rejection. Three overlapping themes of maintenance treatment were identified: "Only if I can try to discontinue…and please don't call it that," "More stability and less criminal activity…and that is why I would try it," and "No cure, no brain and no flash…and thus, just for everybody else!" CONCLUSIONS Some patients experienced slow-onset, long-acting BZDs as having stabilized their symptoms and viewed these BZDs as having helped avoid uncontrolled withdrawal and abstain from criminal activity. We therefore encourage clinicians to consider treatment alternatives if discontinuation strategies fail.

Metal Artifact Reduction in Pelvic Computed Tomography With Hip Prostheses: Comparison of Virtual Monoenergetic Extrapolations From Dual-Energy Computed Tomography and an Iterative Metal Artifact Reduction Algorithm in a Phantom Study.

OBJECTIVE The aim of this study was to directly compare metal artifact reduction (MAR) of virtual monoenergetic extrapolations (VMEs) from dual-energy computed tomography (CT) with iterative MAR (iMAR) from single energy in pelvic CT with hip prostheses. MATERIALS AND METHODS A human pelvis phantom with unilateral or bilateral metal inserts of different material (steel and titanium) was scanned with third-generation dual-source CT using single (120 kVp) and dual-energy (100/150 kVp) at similar radiation dose (CT dose index, 7.15 mGy). Three image series for each phantom configuration were reconstructed: uncorrected, VME, and iMAR. Two independent, blinded radiologists assessed image quality quantitatively (noise and attenuation) and subjectively (5-point Likert scale). Intraclass correlation coefficients (ICCs) and Cohen κ were calculated to evaluate interreader agreements. Repeated measures analysis of variance and Friedman test were used to compare quantitative and qualitative image quality. Post hoc testing was performed using a corrected (Bonferroni) P < 0.017. RESULTS Agreements between readers were high for noise (all, ICC ≥ 0.975) and attenuation (all, ICC ≥ 0.986); agreements for qualitative assessment were good to perfect (all, κ ≥ 0.678). Compared with uncorrected images, VME showed significant noise reduction in the phantom with titanium only (P < 0.017), and iMAR showed significantly lower noise in all regions and phantom configurations (all, P < 0.017). In all phantom configurations, deviations of attenuation were smallest in images reconstructed with iMAR. For VME, there was a tendency toward higher subjective image quality in phantoms with titanium compared with uncorrected images, however, without reaching statistical significance (P > 0.017). Subjective image quality was rated significantly higher for images reconstructed with iMAR than for uncorrected images in all phantom configurations (all, P < 0.017). CONCLUSIONS Iterative MAR showed better MAR capabilities than VME in settings with bilateral hip prosthesis or unilateral steel prosthesis. In settings with unilateral hip prosthesis made of titanium, VME and iMAR performed similarly well.

Dose-painting intensity-modulated proton therapy for intermediate- and high-risk meningioma.

BACKGROUND Newly diagnosed WHO grade II-III or any WHO grade recurrent meningioma exhibit an aggressive behavior and thus are considered as high- or intermediate risk tumors. Given the unsatisfactory rates of disease control and survival after primary or adjuvant radiation therapy, optimization of treatment strategies is needed. We investigated the potential of dose-painting intensity-modulated proton beam-therapy (IMPT) for intermediate- and high-risk meningioma. MATERIAL AND METHODS Imaging data from five patients undergoing proton beam-therapy were used. The dose-painting target was defined using [68]Ga-[1,4,7,10-tetraazacyclododecane tetraacetic acid]- d-Phe(1),Tyr(3)-octreotate ([68]Ga-DOTATATE)-positron emission tomography (PET) in target delineation. IMPT and photon intensity-modulated radiation therapy (IMRT) treatment plans were generated for each patient using an in-house developed treatment planning system (TPS) supporting spot-scanning technology and a commercial TPS, respectively. Doses of 66 Gy (2.2 Gy/fraction) and 54 Gy (1.8 Gy/fraction) were prescribed to the PET-based planning target volume (PTVPET) and the union of PET- and anatomical imaging-based PTV, respectively, in 30 fractions, using simultaneous integrated boost. RESULTS Dose coverage of the PTVsPET was equally good or slightly better in IMPT plans: dose inhomogeneity was 10 ± 3% in the IMPT plans vs. 13 ± 1% in the IMRT plans (p = 0.33). The brain Dmean and brainstem D50 were small in the IMPT plans: 26.5 ± 1.5 Gy(RBE) and 0.002 ± 0.0 Gy(RBE), respectively, vs. 29.5 ± 1.5 Gy (p = 0.001) and 7.5 ± 11.1 Gy (p = 0.02) for the IMRT plans, respectively. The doses delivered to the optic structures were also decreased with IMPT. CONCLUSIONS Dose-painting IMPT is technically feasible using currently available planning tools and resulted in dose conformity of the dose-painted target comparable to IMRT with a significant reduction of radiation dose delivered to the brain, brainstem and optic apparatus. Dose escalation with IMPT may improve tumor control and decrease radiation-induced toxicity.

A novel treatment planning methodology for high dose 166Ho-DOTMP therapy in patients with multiple myeloma

Bone marrow ablation, i.e., the complete sterilization of the active bone marrow, followed by bone marrow transplantation (BMT) is a comment treatment of hematological malignancies. The use of targeted bone-seeking radiopharmaceuticals to selectively deliver radiation to the adjacent bone marrow cavities while sparing normal tissues is a promising technique. Current radiopharmaceutical treatment planning methods do not properly compensate for the patient-specific variable distribution of radioactive material within the skeleton. To improve the current method of internal dosimetry, novel methods for measuring the radiopharmaceutical distribution within the skeleton were developed. 99mTc-MDP was proven as an adequate surrogate for measuring 166Ho-DOTMP skeletal uptake and biodistribution, allowing these measures to be obtained faster, safer, and with higher spatial resolution. This translates directly into better measurements of the radiation dose distribution within the bone marrow. The resulting bone marrow dose-volume histograms allow prediction of the patient disease response where conventional organ scale dosimetry failed. They indicate that complete remission is only achieved when greater than 90% of the bone marrow receives at least 30 Gy. ^ Comprehensive treatment planning requires combining target and non-target organ dosimetry. Organs in the urinary tract were of special concern. The kidney dose is primarily dependent upon the mean transit time of 166 Ho-DOTMP through the kidney. Deconvolution analysis of renograms predicted a mean transit time of 2.6 minutes for 166Ho-DOTMP. The radiation dose to the urinary bladder wall is dependent upon numerous factors including patient hydration and void schedule. For beta-emitting isotopes such as 166Ho, reduction of the bladder wall dose is best accomplished through good patient hydration and ensuring a partially full bladder at the time of injection. Encouraging the patient to void frequently, or catheterizing the patient without irrigation, will not significantly reduce the bladder wall dose. ^ The results from this work will produce the most advanced treatment planning methodology for bone marrow ablation therapy using radioisotopes currently available. Treatments can be tailored specifically for each patient, including the addition of concomitant total body irradiation for patients with unfavorable dose distributions, to deliver a desired patient disease response, while minimizing the dose or toxicity to non-target organs. ^

Reduction of setup uncertainties and tumor motion in the radiation therapy of lung tumors

Because the goal of radiation therapy is to deliver a lethal dose to the tumor, accurate information on the location of the tumor needs to be known. Margins are placed around the tumor to account for variations in the daily position of the tumor. If tumor motion and patient setup uncertainties can be reduced, margins that account for such uncertainties in tumor location in can be reduced allowing dose escalation, which in turn could potentially improve survival rates. ^ In the first part of this study, we monitor the location of fiducials implanted in the periphery of lung tumors to determine the extent of non-gated and gated fiducial motion, and to quantify patient setup uncertainties. In the second part we determine where the tumor is when different methods of image-guided patient setup and respiratory gating are employed. In the final part we develop, validate, and implement a technique in which patient setup uncertainties are reduced by aligning patients based upon fiducial locations in projection images. ^ Results from the first part indicate that respiratory gating reduces fiducial motion relative to motion during normal respiration and setup uncertainties when the patients were aligned each day using externally placed skin marks are large. The results from the second part indicate that current margins that account for setup uncertainty and tumor motion result in less than 2% of the tumor outside of the planning target volume (PTV) when the patient is aligned using skin marks. In addition, we found that if respiratory gating is going to be used, it is most effective if used in conjunction with image-guided patient setup. From the third part, we successfully developed, validated, and implemented on a patient a technique for aligning a moving target prior to treatment to reduce the uncertainties in tumor location. ^ In conclusion, setup uncertainties and tumor motion are a significant problem when treating tumors located within the thoracic region. Image-guided patient setup in conjunction with treatment delivery using respiratory gating reduces these uncertainties in tumor locations. In doing so, margins around the tumor used to generate the PTV can be reduced, which may allow for dose escalation to the tumor. ^

Inverse radiation dose-rate effects on somatic and germ-line mutations and DNA damage rates

The mutagenic effect of low linear energy transfer ionizing radiation is reduced for a given dose as the dose rate (DR) is reduced to a low level, a phenomenon known as the direct DR effect. Our reanalysis of published data shows that for both somatic and germ-line mutations there is an opposite, inverse DR effect, with reduction from low to very low DR, the overall dependence of induced mutations being parabolically related to DR, with a minimum in the range of 0.1 to 1.0 cGy/min (rule 1). This general pattern can be attributed to an optimal induction of error-free DNA repair in a DR region of minimal mutability (MMDR region). The diminished activation of repair at very low DRs may reflect a low ratio of induced (“signal”) to spontaneous background DNA damage (“noise”). Because two common DNA lesions, 8-oxoguanine and thymine glycol, were already known to activate repair in irradiated mammalian cells, we estimated how their rates of production are altered upon radiation exposure in the MMDR region. For these and other abundant lesions (abasic sites and single-strand breaks), the DNA damage rate increment in the MMDR region is in the range of 10% to 100% (rule 2). These estimates suggest a genetically programmed optimatization of response to radiation in the MMDR region.

Regulation of number and size of digits by posterior Hox genes: A dose-dependent mechanism with potential evolutionary implications

The proper development of digits, in tetrapods, requires the activity of several genes of the HoxA and HoxD homeobox gene complexes. By using a variety of loss-of-function alleles involving the five Hox genes that have been described to affect digit patterning, we report here that the group 11, 12, and 13 genes control both the size and number of murine digits in a dose-dependent fashion, rather than through a Hox code involving differential qualitative functions. A similar dose–response is observed in the morphogenesis of the penian bone, the baculum, which further suggests that digits and external genitalia share this genetic control mechanism. A progressive reduction in the dose of Hox gene products led first to ectrodactyly, then to olygodactyly and adactyly. Interestingly, this transition between the pentadactyl to the adactyl formula went through a step of polydactyly. We propose that in the distal appendage of polydactylous short-digited ancestral tetrapods, such as Acanthostega, the HoxA complex was predominantly active. Subsequent recruitment of the HoxD complex contributed to both reductions in digit number and increase in digit length. Thus, transition through a polydactylous limb before reaching and stabilizing the pentadactyl pattern may have relied, at least in part, on asynchronous and independent changes in the regulation of HoxA and HoxD gene complexes.

Estimativa de dose nos pulmões para procedimentos de tomografia computadorizada

Desde o seu desenvolvimento na década de 1970 a tomografia computadorizada (TC) passou por grandes mudanças tecnológicas, tornando-se uma importante ferramenta diagnóstica para a medicina. Consequentemente o papel da TC em diagnóstico por imagem expandiu-se rapidamente, principalmente devido a melhorias na qualidade da imagem e tempo de aquisição. A dose de radiação recebida por pacientes devido a tais procedimentos vem ganhando atenção, levando a comunidade científica e os fabricantes a trabalharem juntos em direção a determinação e otimização de doses. Nas últimas décadas muitas metodologias para dosimetria em pacientes têm sido propostas, baseadas especialmente em cálculos utilizando a técnica Monte Carlo ou medições experimentais com objetos simuladores e dosímetros. A possibilidade de medições in vivo também está sendo investigada. Atualmente as principais técnicas para a otimização da dose incluem redução e/ou modulação da corrente anódica. O presente trabalho propõe uma metodologia experimental para estimativa de doses absorvidas pelos pulmões devido a protocolos clínicos de TC, usando um objeto simulador antropomórfico adulto e dosímetros termoluminescentes de Fluoreto de Lítio (LiF). Sete protocolos clínicos diferentes foram selecionados, com base em sua relevância com respeito à otimização de dose e frequência na rotina clínica de dois hospitais de grande porte: Instituto de Radiologia do Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo (InRad) e Instituto do Câncer do Estado de São Paulo Octávio Frias de Oliveira (ICESP). Quatro protocolos de otimização de dose foram analisados: Auto mA, Auto + Smart mA, Baixa Dose (BD) e Ultra Baixa Dose (UBD). Os dois primeiros protocolos supracitados buscam redução de dose por meio de modulação da corrente anódica, enquanto os protocolos BD e UBD propõem a redução do valor da corrente anódica, mantendo-a constante. Os protocolos BD e UBD proporcionaram redução de dose de 72,7(8) % e 91(1) %, respectivamente; 16,8(1,3) % e 35,0(1,2) % de redução de dose foram obtidas com os protocolos Auto mA e Auto + Smart mA, respectivamente. As estimativas de dose para os protocolos analisados neste estudo são compatíveis com estudos similares publicados na literatura, demonstrando a eficiência da metodologia para o cálculo de doses absorvidas no pulmão. Sua aplicabilidade pode ser estendida a diferentes órgãos, diferentes protocolos de CT e diferentes tipos de objetos simuladores antropomórficos (pediátricos, por exemplo). Por fim, a comparação entre os valores de doses estimadas para os pulmões e valores de estimativas de doses dependentes do tamanho (Size Specific Dose Estimates SSDE) demonstrou dependência linear entre as duas grandezas. Resultados de estudos similares exibiram comportamentos similares para doses no reto, sugerindo que doses absorvidas pelos uma órgãos podem ser linearmente dependente dos valores de SSDE, com coeficientes lineares específicos para cada órgão. Uma investigação mais aprofundada sobre doses em órgãos é necessária para avaliar essa hipótese.

Reduction of β-Endorphin-Containing Immune Cells in Inflamed Paw Tissue Corresponds with a Reduction in Immune-Derived Antinociception: Reversible by Donor Activated Lymphocytes

The functional integrity of the immune system is essential for peripheral antinociception. Previous studies have demonstrated that immune cells elicit potent antinociception in inflamed tissues and that corticotropin-releasing factor-induced antinociception is significantly inhibited in animals that have undergone cyclosporin A (CsA)-induced immunosuppression. In this study, we examined the effect of a single bolus of CsA on inflammatory nociception. CsA-treated rats had substantially increased nociception compared with nonimmunosuppressed rats, consistent with a reduction in circulating and infiltrating lymphocytes. Furthermore, CsA-treated rats had inhibition of corticotropin-releasing factor-induced immune-derived antinociception, which was dose-dependently reversed by IV injection of concanavalin A-activated donor lymphocytes (1.0-7.0 X 10(6) cells/0.1 mL). In conclusion, our findings provided further evidence that opioid-containing immune cells are essential for peripheral analgesia. It is evident from these findings that control of inflammatory pain relies heavily on a functioning immune system.

Synthetic ceramides inhibit CD36 expression in U937 cells through a reduction in cytosolic peroxide

Ceramide (a sphingolipid) and reactive oxygen species (ROS) are each partly responsible for the intracellular signal transduction of a variety of physiological, pharmacological or environmental agents. It has been reported that synthesis of ceramide and ROS are intimately linked, and show reciprocal regulation. The levels of ceramide are reported to be elevated in atherosclerotic plaques providing circumstantial evidence for a pro-atherogenic role for ceramide. Indeed, LDL may be important sources of ceramide from sphingomyelin, where it promotes LDL aggregation. Using synthetic, short chain ceramides to mimic the cellular responses to fluctuations in natural endogenous ceramides, we have investigated ceramide effects on both intracellular redox state (as glutathione and ROS) and redox-sensitive gene expression, specifically the scavenger receptor CD36 (using RT-PCR and flow cytometry), in U937 monocytes and macrophages. We describe that the principal redox altering properties of ceramide are to lower cytosolic peroxide and to increase mitochondrial ROS formation, where growth arrest of U937 monocytes is also observed. In addition, cellular glutathione was depleted, which was independent of an increase in glutathione peroxidase activity. Examination of the effects of ceramide on stress induced CD36 expression in macrophages, revealed a dose dependent reduction in CD36 mRNA and protein levels, which was mimicked by N-acetyl cysteine. Taken together, these data suggest that ceramides differentially affect ROS within different cellular compartments, and that loss of cytosolic peroxide inhibits expression of the redox sensitive gene, CD36. This may attenuate both the uptake of oxidised LDL and the interaction of HDL with macrophages. The resulting sequelae in vivo remain to be determined.

Consistent reduction of postprandial glucagon and insulin by lixisenatide in the GetGoal clinical trial programme

Background and aims: Glucagon-like peptide-1 (GLP-1) receptor agonists improve islet function and delay gastric emptying in subjects with type 2 diabetes mellitus. We evaluated 2-hour glucose, glucagon and insulin changes following a standardized mixed-meal tolerance test before and after 24 weeks of treatment with the once-daily prandial GLP-1 receptor agonist lixisenatide (approved for a therapeutic dose of 20 μg once daily) in six randomized, placebo-controlled studies within the lixisenatide Phase III GetGoal programme. In the studies, the mixed-meal test was conducted before and after: (1) lixisenatide treatment in patients insufficiently controlled despite diet and exercise (GetGoal-Mono), (2) lixisenatide treatment in combination with oral antidiabetic drugs (OADs) (GetGoal-M and GetGoal-S), or (3) lixisenatide treatment in combination with basal insulin ± OAD (GetGoal-Duo 1, GetGoal-L and GetGoal-L-Asia).Materials and methods: A meta-analysis was performed (lixisenatide n=1124 vs placebo n=707) combining ANCOVA least squares (LS) mean values using an inverse variance weighted analysis. Results: Lixisenatide significantly reduced 2-hour postprandial glucose from baseline (LS mean difference vs placebo: -4.9 mmol/L, p<0.0001, Figure) and glucose excursions (LS mean difference vs placebo: -4.5 mmol/L, p<0.0001). As measured in two studies, lixisenatide also reduced postprandial glucagon (LS mean difference vs placebo: -19.0 ng/L, p<0.0001) and insulin (LS mean difference vs placebo: -64.8 pmol/L, p<0.0001), although the glucagon/insulin ratio was increased (LS mean difference vs placebo: 0.15, p=0.02) compared with placebo. Conclusion: The results show that lixisenatide potently reduces the glucose excursion after meal ingestion in subjects with type 2 diabetes, in association with marked reductions in glucagon and insulin levels. It is suggested that diminished glucagon secretion and slower gastric emptying contribute to reduced hepatic glucose production and delayed glucose absorption, enabling postprandial glycaemia to be controlled with less demand on beta-cell insulin secretion. Clinical Trial Registration Number: NCT00688701; NCT00712673; NCT00713830; NCT00975286; NCT00715624; NCT00866658 Supported by: Sanofi

Radiation Dose to the Lens of the Eye from Computed Tomography Scans of the Head

While it is well known that exposure to radiation can result in cataract formation, questions still remain about the presence of a dose threshold in radiation cataractogenesis. Since the exposure history from diagnostic CT exams is well documented in a patient’s medical record, the population of patients chronically exposed to radiation from head CT exams may be an interesting area to explore for further research in this area. However, there are some challenges in estimating lens dose from head CT exams. An accurate lens dosimetry model would have to account for differences in imaging protocols, differences in head size, and the use of any dose reduction methods.

The overall objective of this dissertation was to develop a comprehensive method to estimate radiation dose to the lens of the eye for patients receiving CT scans of the head. This research is comprised of a physics component, in which a lens dosimetry model was derived for head CT, and a clinical component, which involved the application of that dosimetry model to patient data.

The physics component includes experiments related to the physical measurement of the radiation dose to the lens by various types of dosimeters placed within anthropomorphic phantoms. These dosimeters include high-sensitivity MOSFETs, TLDs, and radiochromic film. The six anthropomorphic phantoms used in these experiments range in age from newborn to adult.

First, the lens dose from five clinically relevant head CT protocols was measured in the anthropomorphic phantoms with MOSFET dosimeters on two state-of-the-art CT scanners. The volume CT dose index (CTDIvol), which is a standard CT output index, was compared to the measured lens doses. Phantom age-specific CTDIvol-to-lens dose conversion factors were derived using linear regression analysis. Since head size can vary among individuals of the same age, a method was derived to estimate the CTDIvol-to-lens dose conversion factor using the effective head diameter. These conversion factors were derived for each scanner individually, but also were derived with the combined data from the two scanners as a means to investigate the feasibility of a scanner-independent method. Using the scanner-independent method to derive the CTDIvol-to-lens dose conversion factor from the effective head diameter, most of the fitted lens dose values fell within 10-15% of the measured values from the phantom study, suggesting that this is a fairly accurate method of estimating lens dose from the CTDIvol with knowledge of the patient’s head size.

Second, the dose reduction potential of organ-based tube current modulation (OB-TCM) and its effect on the CTDIvol-to-lens dose estimation method was investigated. The lens dose was measured with MOSFET dosimeters placed within the same six anthropomorphic phantoms. The phantoms were scanned with the five clinical head CT protocols with OB-TCM enabled on the one scanner model at our institution equipped with this software. The average decrease in lens dose with OB-TCM ranged from 13.5 to 26.0%. Using the size-specific method to derive the CTDIvol-to-lens dose conversion factor from the effective head diameter for protocols with OB-TCM, the majority of the fitted lens dose values fell within 15-18% of the measured values from the phantom study.

Third, the effect of gantry angulation on lens dose was investigated by measuring the lens dose with TLDs placed within the six anthropomorphic phantoms. The 2-dimensional spatial distribution of dose within the areas of the phantoms containing the orbit was measured with radiochromic film. A method was derived to determine the CTDIvol-to-lens dose conversion factor based upon distance from the primary beam scan range to the lens. The average dose to the lens region decreased substantially for almost all the phantoms (ranging from 67 to 92%) when the orbit was exposed to scattered radiation compared to the primary beam. The effectiveness of this method to reduce lens dose is highly dependent upon the shape and size of the head, which influences whether or not the angled scan range coverage can include the entire brain volume and still avoid the orbit.

The clinical component of this dissertation involved performing retrospective patient studies in the pediatric and adult populations, and reconstructing the lens doses from head CT examinations with the methods derived in the physics component. The cumulative lens doses in the patients selected for the retrospective study ranged from 40 to 1020 mGy in the pediatric group, and 53 to 2900 mGy in the adult group.

This dissertation represents a comprehensive approach to lens of the eye dosimetry in CT imaging of the head. The collected data and derived formulas can be used in future studies on radiation-induced cataracts from repeated CT imaging of the head. Additionally, it can be used in the areas of personalized patient dose management, and protocol optimization and clinician training.