Segmented field electron conformal therapy with an electron multi-leaf collimator

Purpose: The purpose of this work was to investigate the potential of a prototype electron multi-leaf collimator (eMLC) to deliver segmented-field electron conformal therapy (ECT) and to improve dose homogeneity to the planning target volume (PTV) by feathering the abutting edge of the higher energy electron fields. Methods: Software was developed to define the eMLC leaf positions that most closely fit a general field shape. Electron beams (6-20 MeV) using a prototype eMLC were commissioned for the pencil beam dose algorithm in the Pinnacle treatment planning system. A discrete (5-step) Gaussian edge spread function was used to match electron dose penumbras of differing energies at a specified depth in a water phantom. The effect of 1D edge feathering on dose homogeneity was computed and measured for segmented-field ECT treatment plans for three 2D PTVs in a water phantom (depths varied along axis parallel to leaf motion) and one 3D PTV (depth varied along both axes normal to beam). Additionally, the effect of 2D edge feathering was computed for the 3D PTV. Results: 1D discrete Gaussian edge feathering reduced the standard deviation of dose in the 2D PTVs by 34, 34, and 39%. In the 3D PTV, 1D discrete Gaussian edge feathering reduced the standard deviation of dose by 19%. The physical constraints (1-cm leaf width) of the eMLC hindered the 2D application of the feathering solution to the 3D PTV, and the standard deviation of dose increased by 10%. However, 2D discrete Gaussian edge feathering with a smooth-aperture (infinitesimal leaf width) reduced the standard deviation of dose in the 3D PTV by 33%. Conclusions: A 5-step discrete Gaussian edge spread function applied in 2D improves the abutment dosimetry but requires an eMLC leaf resolution better than 1 cm

Scanned Ion Beam Therapy for Thoracic Tumors

Although frequently cured of Hodgkin lymphoma, adolescents and young adults can develop radiation induced second cancers. These patients could potentially benefit from scanned ion radiotherapy yet likely would require motion mitigation strategies. In theory, four-dimensional (4D) optimization of ion beam fields for individual motion states of respiration can enable superior sparing of healthy tissue near moving targets, compared to other motion mitigation strategies. Furthermore, carbon-ion therapy can sometimes provide greater relative biological effectiveness (RBE) for cell sterilization in a target but nearly equivalent RBE in tissue upstream of the target, compared to proton therapy. Thus, we expected that for some patients with Hodgkin lymphoma, carbon-ion therapy would reduce the predicted risk of second cancer incidence in the breast compared with proton therapy. The purpose of this work was to determine whether 4D-optimized carbon-ion therapy would significantly reduce the predicted risk of radiation induced second cancers in the breast for female Hodgkin lymphoma patients while preserving tumor control compared with proton therapy. To achieve our goals, we first investigated whether 4D-optimized carbon beam tracking could reduce dose to volumes outside a moving target compared with 3D-optimized carbon beam tracking while preserving target dose coverage. To understand the reliability of scanned carbon beam tracking, we studied the robustness of dose distributions in thoracic targets to uncertainties in patient motion. Finally, we investigated whether using carbon-ion therapy instead of proton therapy would significantly reduce the predicted risk of second cancer in the breast for a sample of Hodgkin lymphoma patients. We found that 4D-optimized ion beam tracking therapy can reduce the maximum dose to critical structures near a moving target by as much as 53%, compared to 3D-optimized ion beam tracking therapy. We validated these findings experimentally using a scanned carbon ion synchrotron and a motion phantom. We found scanned carbon beam tracking to be sensitive to a number of motion uncertainties, most notably phase delays in tracking, systematic spatial errors, and interfractional motion changes. Our findings indicate that a lower risk of second cancer in the breast might be expected for some Hodgkin lymphoma patients using carbon-ion therapy instead of proton therapy. For our reference scenario, we found the ratio of risk to be 0.77 ± 0.35 for radiogenic breast cancer after carbon-ion therapy versus proton therapy. Our findings were dependent on the RBE values for tumor induction and the radiosensitivity of breast tissue, as well as the physical dose distribution

Radiation therapy with orthovoltage X-ray minibeams

A method for delivering therapeutic radiation to a target includes positioning a multi-aperture collimator on the skin within a trajectory of orthovoltage x-rays directed at the target, thus generating an array of minibeams, each of width between 0.1 mm to 0.6 mm. The skin is irradiated with the array. An effective beam of therapeutic radiation, which may be a solid beam, is delivered to the target at a predetermined tissue depth by merging adjacent orthovoltage x-ray minibeams sufficiently to form the effective beam. The effective beam may be formed proximal to the target. The depth at which the effective, preferably, solid, beam is formed is controlled by varying one or more of the spacing of the minibeams in the array, the minibeam width, the distance from the x-ray source to the collimator, and the x-ray source spot size. Planar minibeams can be arc-scanned while continuously modulating beam shape and intensity.Board of Regents, University of Texas Syste

Robustness of target dose coverage to motion uncertainties for scanned carbon ion beam tracking therapy of moving tumors

Beam tracking with scanned carbon ion radiotherapy achieves highly conformal target dose by steering carbon pencil beams to follow moving tumors using real-time magnetic deflection and range modulation. The purpose of this study was to evaluate the robustness of target dose coverage from beam tracking in light of positional uncertainties of moving targets and beams. To accomplish this, we simulated beam tracking for moving targets in both water phantoms and a sample of lung cancer patients using a research treatment planning system. We modeled various deviations from perfect tracking that could arise due to uncertainty in organ motion and limited precision of a scanned ion beam tracking system. We also investigated the effects of interfractional changes in organ motion on target dose coverage by simulating a complete course of treatment using serial (weekly) 4DCTs from six lung cancer patients. For perfect tracking of moving targets, we found that target dose coverage was high (V¯95 was 94.8% for phantoms and 94.3% for lung cancer patients, respectively) but sensitive to changes in the phase of respiration at the start of treatment and to the respiratory period. Phase delays in tracking the moving targets led to large degradation of target dose coverage (up to 22% drop for a 15° delay). Sensitivity to technical uncertainties in beam tracking delivery was minimal for a lung cancer case. However, interfractional changes in anatomy and organ motion led to large decreases in target dose coverage (target coverage dropped approximately 8% due to anatomy and motion changes after 1 week). Our findings provide a better understand of the importance of each of these uncertainties for beam tracking with scanned carbon ion therapy and can be used to inform the design of future scanned ion beam tracking systems

Comprehensive molecular characterization of gastric adenocarcinoma

Gastric cancer is a leading cause of cancer deaths, but analysis of its molecular and clinical characteristics has been complicated by histological and aetiological heterogeneity. Here we describe a comprehensive molecular evaluation of 295 primary gastric adenocarcinomas as part of The Cancer Genome Atlas (TCGA) project. We propose a molecular classification dividing gastric cancer into four subtypes: tumours positive for Epstein–Barr virus, which display recurrent PIK3CA mutations, extreme DNA hypermethylation, and amplification of JAK2, CD274 (also known as PD-L1) and PDCD1LG2 (also knownasPD-L2); microsatellite unstable tumours, which show elevated mutation rates, including mutations of genes encoding targetable oncogenic signalling proteins; genomically stable tumours, which are enriched for the diffuse histological variant and mutations of RHOA or fusions involving RHO-family GTPase-activating proteins; and tumours with chromosomal instability, which show marked aneuploidy and focal amplification of receptor tyrosine kinases. Identification of these subtypes provides a roadmap for patient stratification and trials of targeted therapies

Genome-wide interaction study of a proxy for stress-sensitivity and its prediction of major depressive disorder

Individual response to stress is correlated with neuroticism and is an important predictor of both neuroticism and the onset of major depressive disorder (MDD). Identification of the genetics underpinning individual differences in response to negative events (stress-sensitivity) may improve our understanding of the molecular pathways involved, and its association with stress-related illnesses. We sought to generate a proxy for stress-sensitivity through modelling the interaction between SNP allele and MDD status on neuroticism score in order to identify genetic variants that contribute to the higher neuroticism seen in individuals with a lifetime diagnosis of depression compared to unaffected individuals. Meta-analysis of genome-wide interaction studies (GWIS) in UK Biobank (N = 23,092) and Generation Scotland: Scottish Family Health Study (N = 7,155) identified no genome-wide significance SNP interactions. However, gene-based tests identified a genome-wide significant gene, ZNF366, a negative regulator of glucocorticoid receptor function implicated in alcohol dependence (p = 1.48x10-7; Bonferroni-corrected significance threshold p < 2.79x10-6). Using summary statistics from the stress-sensitivity term of the GWIS, SNP heritability for stress-sensitivity was estimated at 5.0%. In models fitting polygenic risk scores of both MDD and neuroticism derived from independent GWAS, we show that polygenic risk scores derived from the UK Biobank stress-sensitivity GWIS significantly improved the prediction of MDD in Generation Scotland. This study may improve interpretation of larger genome-wide association studies of MDD and other stress-related illnesses, and the understanding of the etiological mechanisms underpinning stress-sensitivity

Hair Cortisol in Twins : Heritability and Genetic Overlap with Psychological Variables and Stress-System Genes

A. Palotie on työryhmän jäsen.Hair cortisol concentration (HCC) is a promising measure of long-term hypothalamus-pituitary-adrenal (HPA) axis activity. Previous research has suggested an association between HCC and psychological variables, and initial studies of inter-individual variance in HCC have implicated genetic factors. However, whether HCC and psychological variables share genetic risk factors remains unclear. The aims of the present twin study were to: (i) assess the heritability of HCC; (ii) estimate the phenotypic and genetic correlation between HPA axis activity and the psychological variables perceived stress, depressive symptoms, and neuroticism; using formal genetic twin models and molecular genetic methods, i.e. polygenic risk scores (PRS). HCC was measured in 671 adolescents and young adults. These included 115 monozygotic and 183 dizygotic twin-pairs. For 432 subjects PRS scores for plasma cortisol, major depression, and neuroticism were calculated using data from large genome wide association studies. The twin model revealed a heritability for HCC of 72%. No significant phenotypic or genetic correlation was found between HCC and the three psychological variables of interest. PRS did not explain variance in HCC. The present data suggest that HCC is highly heritable. However, the data do not support a strong biological link between HCC and any of the investigated psychological variables.Peer reviewe

Dissecting the Shared Genetic Architecture of Suicide Attempt, Psychiatric Disorders, and Known Risk Factors

Background Suicide is a leading cause of death worldwide, and nonfatal suicide attempts, which occur far more frequently, are a major source of disability and social and economic burden. Both have substantial genetic etiology, which is partially shared and partially distinct from that of related psychiatric disorders. Methods We conducted a genome-wide association study (GWAS) of 29,782 suicide attempt (SA) cases and 519,961 controls in the International Suicide Genetics Consortium (ISGC). The GWAS of SA was conditioned on psychiatric disorders using GWAS summary statistics via multitrait-based conditional and joint analysis, to remove genetic effects on SA mediated by psychiatric disorders. We investigated the shared and divergent genetic architectures of SA, psychiatric disorders, and other known risk factors. Results Two loci reached genome-wide significance for SA: the major histocompatibility complex and an intergenic locus on chromosome 7, the latter of which remained associated with SA after conditioning on psychiatric disorders and replicated in an independent cohort from the Million Veteran Program. This locus has been implicated in risk-taking behavior, smoking, and insomnia. SA showed strong genetic correlation with psychiatric disorders, particularly major depression, and also with smoking, pain, risk-taking behavior, sleep disturbances, lower educational attainment, reproductive traits, lower socioeconomic status, and poorer general health. After conditioning on psychiatric disorders, the genetic correlations between SA and psychiatric disorders decreased, whereas those with nonpsychiatric traits remained largely unchanged. Conclusions Our results identify a risk locus that contributes more strongly to SA than other phenotypes and suggest a shared underlying biology between SA and known risk factors that is not mediated by psychiatric disorders.Peer reviewe

The Somatic Genomic Landscape of Glioblastoma

We describe the landscape of somatic genomic alterations based on multi-dimensional and comprehensive characterization of more than 500 glioblastoma tumors (GBMs). We identify several novel mutated genes as well as complex rearrangements of signature receptors including EGFR and PDGFRA. TERT promoter mutations are shown to correlate with elevated mRNA expression, supporting a role in telomerase reactivation. Correlative analyses confirm that the survival advantage of the proneural subtype is conferred by the G-CIMP phenotype, and MGMT DNA methylation may be a predictive biomarker for treatment response only in classical subtype GBM. Integrative analysis of genomic and proteomic profiles challenges the notion of therapeutic inhibition of a pathway as an alternative to inhibition of the target itself. These data will facilitate the discovery of therapeutic and diagnostic target candidates, the validation of research and clinical observations and the generation of unanticipated hypotheses that can advance our molecular understanding of this lethal cancer

The Somatic Genomic Landscape of Chromophobe Renal Cell Carcinoma

We describe the landscape of somatic genomic alterations of 66 chromophobe renal cell carcinomas (ChRCCs) based on multidimensional and comprehensive characterization, including mitochondrial DNA (mtDNA) and whole genome sequencing. The result is consistent that ChRCC originates from the distal nephron compared to other kidney cancers with more proximal origins. Combined mtDNA and gene expression analysis implicates changes in mitochondrial function as a component of the disease biology, while suggesting alternative roles for mtDNA mutations in cancers relying on oxidative phosphorylation. Genomic rearrangements lead to recurrent structural breakpoints within TERT promoter region, which correlates with highly elevated TERT expression and manifestation of kataegis, representing a mechanism of TERT up-regulation in cancer distinct from previously-observed amplifications and point mutations