| 1. |
- Abdollahi, Sara, et al.
(författare)
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A dose planning study for cardiac and lung dose sparing techniques in left breast cancer radiotherapy : Can free breathing helical tomotherapy be considered as an alternative for deep inspiration breath hold?
- 2023
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Ingår i: Technical Innovations and Patient Support in Radiation Oncology. - : Elsevier BV. - 2405-6324. ; 25
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Tidskriftsartikel (refereegranskat)abstract
- Purpose: To investigate the possibility to be able to offer left sided breast cancer patients, not suitable for DIBH, an organ at risk saving treatment. Materials and Methods: Twenty patients receiving radiotherapy for left breast cancer in DIBH were enrolled in the study. Planning CT scans were acquired in the same supine treatment position in FB and DIBH. 3DCRT_DIBH plans were designed and optimized using two parallel opposed tangent beams (with some additional segments) for the breast and chest wall and anterior-posterior fields for regional lymph nodes irradiation. Additionally, FB helical tomotherapy plans were optimized to minimize heart and lung dose. All forty plans were optimized with at least 95% of the total CTV covered by the 95% of prescribed dose of 50 Gy in 25 fractions. Results: HT_FB plans showed significantly better dose homogeneity and conformity compared to the 3DCRT_DIBH specially for regional nodal irradiation. The heart mean dose was almost comparable in 3DCRT_DIBH and HT_FB while the volume (%) of the heart receiving 25 Gy had a statistically significant reduction from 7.90 ± 3.33 in 3DCRT_DIBH to 0.88 ± 0.66 in HT_FB. HT_FB was also more effective in left descending artery (LAD) mean dose reduction about 100% from 30.83 ± 9.2 Gy to 9.7 ± 3.1. The ipsilateral lung volume receiving 20 Gy has a further reduction of 43 % in HT_FB compared with 3DCRT_DIBH. For low dose comparison, 3DCRT_DIBH was superior for contralateral organ sparing compared to the HT_FB due to the limited angle for dose delivery. Conclusion: For patients who cannot be a candidate for DIBH for any reason, HT in free breathing may be a good alternative and provides heart and ipsilateral lung dose sparing, however with the cost of increased dose to contralateral breast and lung.
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| 2. |
- Abdollahi, Sara, et al.
(författare)
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Dynamic anthropomorphic thorax phantom for quality assurance of motion management in radiotherapy
- 2024
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Ingår i: Physics and imaging in radiation oncology. - 2405-6316. ; 30
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Tidskriftsartikel (refereegranskat)abstract
- Background and purpose: Motion management techniques are important to spare the healthy tissue adequately. However, they are complex and need dedicated quality assurance. The aim of this study was to create a dynamic phantom designed for quality assurance and to replicate a patient's size, anatomy, and tissue density. Materials and methods: A computed tomography (CT) scan of a cancer patient was used to create molds for the lungs, heart, ribs, and vertebral column via additive manufacturing. A pump system and software were developed to simulate respiratory dynamics. The extent of respiratory motion was quantified using a 4DCT scan. End-to-end tests were conducted to evaluate two motion management techniques for lung stereotactic body radiotherapy (SBRT). Results: The chest wall moved between 4 mm and 13 mm anteriorly and 2 mm to 7 mm laterally during the breathing. The diaphragm exhibited superior-inferior movement ranging from 5 mm to 16 mm in the left lung and 10 mm to 36 mm in the right lung. The left lung tumor displaced ± 7 mm superior-inferiorly and anterior-posteriorly. The CT numbers were for lung: −716 ± 108 HU (phantom) and −713 ± 70 HU (patient); bone: 460 ± 20 HU (phantom) and 458 ± 206 HU (patient); soft tissue: 92 ± 9 HU (phantom) and 60 ± 25 HU (patient). The end-to-end testing showed an excellent agreement between the measured and the calculated dose for ion chamber and film dosimetry. Conclusions: The phantom is recommended for quality assurance, evaluating the institution's specific planning and motion management strategies either through end-to-end testing or as an external audit phantom.
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| 3. |
- Abdollahi, Sara, et al.
(författare)
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Surface guided 3DCRT in deep-inspiration breath-hold for left sided breast cancer radiotherapy : implementation and first clinical experience in Iran
- 2022
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Ingår i: Reports of Practical Oncology and Radiotherapy. - 1507-1367. ; 27:5, s. 881-896
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Tidskriftsartikel (refereegranskat)abstract
- Background: The aim of the study is to evaluate the overall accuracy of the surface-guided radiotherapy (SGRT) workflow through a comprehensive commissioning and quality assurance procedures and assess the potential benefits of deep-inspiration breath-hold (DIBH) radiotherapy as a cardiac and lung dose reduction approach for left-sided breast cancer irradiation. Materials and methods: Accuracy and reproducibility of the optical surface scanner used for DIBH treatment were evaluated using different phantoms. Patient positioning accuracy and reproducibility of DIBH treatment were evaluated. Twenty patients were studied for treatment plan quality in target dose coverage and healthy organ sparing for the two different treatment techniques. Results: Reproducibility tests for the surface scanner showed good stability within 1 mm in all directions. The maximum position variation between applied shifts on the couch and the scanner measured offsets is 1 mm in all directions. The clinical study of 200 fractions showed good agreement between the surface scanner and portal imaging with the isocenter position deviation of less than 3 mm in each lateral, longitudinal, and vertical direction. The standard deviation of the DIBH level showed a value of < 2 mm during all evaluated DIBHs. Compared to the free breathing (FB) technique, DIBH showed significant reduction of 48% for heart mean dose, 43% for heart V25, and 20% for ipsilateral lung V20. Conclusion: Surface-guided radiotherapy can be regarded as an accurate tool for patient positioning and monitoring in breast radiotherapy. DIBH treatment are considered to be effective techniques in heart and ipsilateral lung dose reductions for left breast radiotherapy.
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| 4. |
- Hadizadeh, Fatemeh, et al.
(författare)
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Effects of oral contraceptives and menopausal hormone therapy on the risk of rheumatoid arthritis : a prospective cohort study.
- 2023
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Ingår i: Rheumatology. - 1462-0324 .- 1462-0332.
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVES: Oral contraceptives (OC) and menopausal hormone therapy (MHT) contain exogenous sex hormones and are used by millions of women around the world. However, their effect on development of rheumatoid arthritis (RA) is still debated and the current literature suggests that they may exert opposite effects on the risk of RA. The present study aimed to estimate the effects of exogenous hormones on development of RA, both during the reproductive lifespan and later in life.METHODS: The association between OC and RA, as well as between MHT and late-onset RA (LORA), was investigated using time-dependent Cox regression modelling in white British women from the UK Biobank (N = 236 602 and N = 102 466, respectively) and replicated in women from all ethnic groups.RESULTS: OC use was associated with a decreased risk of RA in ever-users (hazard ratio [HR]=0.89; 95% CI = 0.82-0.96), as well as in current (HR = 0.81; 0.73-0.91) and former users (HR = 0.92; 0.84 -1.00), compared with never-users. In contrast, MHT use was associated with an increased risk of LORA in ever-users (HR = 1.16; 1.06-1.26) as well as in former users (HR = 1.13; 1.03-1.24) compared with never-users.CONCLUSION: OC use appears to protect against RA, while MHT may increase the risk of LORA. This study provides new insights into the possible inverse effect of exposure to different exogenous sex hormones on the risk of RA.
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| 5. |
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| 6. |
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| 7. |
- Hadizadeh, Fatemeh
(författare)
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Understanding the interplay between gut microbiota, gut function and host genes in the generation of gastrointestinal symptoms and disease
- 2017
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Irritable bowel syndrome (IBS) is a multifactorial and complex disease categorized in the functional gastrointestinal disorders (FGIDs) with an intricate pathogenesis yet far from understood. The prevalence and burden of the FGIDs has urged the need to improve our understanding of them and recent findings have led us to realize that there are biochemical and structural alterations playing roles in their etiology. This thesis has concentrated on a number of factors including altered intestinal motility, pain perception, genetic predisposition, and gut microbiota in order to obtain a better understanding of the interplay between these factors in the generation of gastrointestinal (GI) symptoms. To achieve this, we have carried out five studies exploiting data from a Swedish data-rich general population-based cohort, namely PopCol, and some other cohorts. In the first study, to investigate the link between gut microbiota and gut transit time (as an objective means to quantify GI functional abnormalities) we studied the association between different indices of fecal microbiota composition with stool consistency and stool frequency (as surrogates for gut transit time) in the PopCol cohort. The obtained results provide more support for the already reported association between gut microbiota and stool consistency and also revealed an even stronger association between the composition of fecal microbiota and stool frequency. To study the association between one of the most common symptoms of FGIDs, i.e. abdominal pain, and gut microbiota in the second study, data of 159 individuals from PopCol cohort (including 52 individuals who reported pain) was inspected. Results indicated an association between fecal microbiota composition and abdominal pain occurrence as well as its frequency, duration, and severity. Also, we could provide more evidence for the negative association of Prevotella with pain in the general population. In the third study, to investigate the genetic biology of stool frequency, we exploited data from two general population-based cohorts, PopCol and LifeLines-Deep, and carried out a genome-wide association study (GWAS) followed by a meta-analysis. Gene set enrichment analysis was performed on the resulting gene list. Although, possibly due to limited sample size, none of the association tests revealed genome-wide significant results, we could identify excellent functional candidate genes and more interestingly, the results from the post-GWAS analysis suggested xenobiotic metabolism and ion channel activity as two plausible underlying mechanisms for regulation of the stool frequency. This result pointing at the link between ion channel activity and bowel function in addition to the results of another study which revealed that 2.2% of IBS patients carry a mutation in a voltage-gated channel gene (SCN5A), led us to the fourth study. In this study, 14 single nucleotide polymorphisms (SNPs) spread over TRPM8 (a gene involved in GI-related ion channel activity) were investigated in association to IBS and its subtypes in a cohort of IBS cases and controls followed by a meta-analysis of the results of this study and the GWAS of IBS (already published by our lab). Subsequently, PopCol data was used to study the association between TRPM8 genotype variants and stool consistency. Logistic regression analysis revealed significant associations between different variants of TRPM8 gene and predisposition to IBS, which was restricted to the constipation-related subtypes of IBS (IBS-C and IBS-M). This result was confirmed by the meta-analysis. Moreover, a negative correlation between all IBS-C/M predisposing risk alleles and stool consistency was obtained from investigating the PopCol cohort. Finally, considering the importance of genes and diet in the susceptibility to IBS, in a nutrigenetic approach, we studied the sucrase-isomaltase (SI) gene variants (congenital defective form of this gene results from rare mutations and is characterized by abdominal pain, diarrhea, and bloating) for their potential relevance to IBS in the fifth study. To do this, the four most known congenital sucrase-isomaltase deficiency (CSID) mutations in addition to a SI coding SNP (p.Val15Phe) were screened in a multicenter cohort of IBS cases and controls. The effect of this SNP on the function of SI was also inspected in vitro. Finally, we analyzed p.Val15Phe genotype in association to fecal microbiota and stool frequency in PopCol cohort. Our results indicated that the four CSID mutations and the common variant were more common in patients than asymptomatic controls. The in vitro study indicated 35% reduced enzymatic activity for the SI protein with 15Phe compared to 15Val. Investigating PopCol samples, 15Phe copies correlated with stool frequency and the abundance of fecal Parabacteroides. In summary, in this thesis we succeeded in providing additional strong evidence for the importance of human genes (TRPM8 and SI) in the development of IBS and its symptoms. Moreover, we demonstrated a link between some of the important IBS symptoms, i.e. abdominal pain and altered stool frequency with gut microbiota composition in the general population. Taken together, this thesis contributes to a better understanding of the interplay between several factors in the generation of GI symptoms. The information we report here may contribute to translational opportunities for the stratification and eventual management of individuals with IBS and other FGIDs
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| 8. |
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| 9. |
- Höglund, Julia, et al.
(författare)
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Gene-based variant analysis of whole-exome sequencing in relation to eosinophil count
- 2022
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Ingår i: Frontiers in Immunology. - : Frontiers Media S.A.. - 1664-3224. ; 13
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Tidskriftsartikel (refereegranskat)abstract
- Eosinophils play important roles in the release of cytokine mediators in response to inflammation. Many associations between common genetic variants and eosinophils have already been reported, using single nucleotide polymorphism (SNP) array data. Here, we have analyzed 200,000 whole-exome sequences (WES) from the UK Biobank cohort and performed gene-based analyses of eosinophil count. We defined five different variant weighting schemes to incorporate information on both deleteriousness and frequency. A total of 220 genes in 55 distinct (>10 Mb apart) genomic regions were found to be associated with eosinophil count, of which seven genes (ALOX15, CSF2RB, IL17RA, IL33, JAK2, S1PR4, and SH2B3) are driven by rare variants, independent of common variants identified in genome-wide association studies. Two additional genes, NPAT and RMI1, have not been associated with eosinophil count before and are considered novel eosinophil loci. These results increase our knowledge about the effect of rare variants on eosinophil count, which can be of great value for further identification of therapeutic targets.
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| 12. |
- Johansson, Åsa, et al.
(författare)
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Investigating the Effect of Estradiol Levels on the Risk of Breast, Endometrial, and Ovarian Cancer
- 2022
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Ingår i: Journal of the Endocrine Society. - : The Endocrine Society. - 2472-1972. ; 6:8
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Tidskriftsartikel (refereegranskat)abstract
- Background: High levels of estrogen are associated with increased risk of breast and endometrial cancer and have been suggested to also play a role in the development of ovarian cancer. Cancerogenic effects of estradiol, the most prominent form of estrogen, have been highlighted as a side effect of estrogen-only menopausal hormone therapy. However, whether high levels of endogenous estrogens, produced within the body, promote cancer development, has not been fully established.Objective: We aimed to examine causal effects of estradiol on breast, endometrial, and ovarian cancer.Methods: Here we performed a two-sample Mendelian randomization (MR) to estimate the effect of endogenous estradiol on the risk of developing breast, endometrial, and ovarian cancer, using the UK Biobank as well as 3 independent cancer cohorts.Results: Using 3 independent instrumental variables, we showed that higher estradiol levels significantly increase the risk for ovarian cancer (OR = 3.18 [95% CI, 1.47-6.87], P = 0.003). We also identified a nominally significant effect for ER-positive breast cancer (OR = 2.16 [95% CI, 1.09-4.26], P = 0.027). However, we could not establish a clear link to the risk of endometrial cancer (OR = 1.93 [95% CI, 0.77-4.80], P = 0.160).Conclusion: Our results suggest that high estradiol levels promote the development of ovarian and ER-positive breast cancer.
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| 13. |
- Karlsson, Torgny, et al.
(författare)
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Body Mass Index and the Risk of Rheumatic Disease : Linear and Nonlinear Mendelian Randomization Analyses
- 2023
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Ingår i: Arthritis & Rheumatology. - : John Wiley & Sons. - 2326-5191 .- 2326-5205. ; 75:11, s. 2027-2035
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE: While the association between obesity and risk of rheumatic disease is well established, the precise causal relation has not been conclusively proved. Here, we estimate the causal effect of body mass index (BMI) on the risk of developing five different rheumatic diseases.METHODS: Linear and nonlinear mendelian randomization (MR) were used to estimate the effect of BMI on risk of rheumatic disease, and sex-specific effects were identified. Analyses were performed in 361,952 participants from the UK Biobank cohort for the five rheumatic diseases: rheumatoid arthritis (N=8,381 cases), osteoarthritis (N=87,430), psoriatic arthropathy (N=933), gout (N=13,638), and inflammatory spondylitis (N=4,328).RESULTS: Using linear MR, we found that one standard deviation higher BMI increases the incidence rate for rheumatoid arthritis (IRR=1.52; 95% CI=1.36-1.69), osteoarthritis (IRR=1.49; 1.43-1.55), psoriatic arthropathy (IRR=1.80; 1.31-2.48), gout (IRR=1.73; 1.56-1.92), and inflammatory spondylitis (IRR=1.34; 1.14-1.57) in all individuals. BMI was found to be a stronger risk factor in women compared to men for psoriatic arthropathy (sex-interaction P=3.3×10-4 ) and gout (P=4.3×10-3 ), and the effect on osteoarthritis was stronger in premenopausal compared to postmenopausal women (P=1.8×10-3 ). Nonlinear effects of BMI were identified for osteoarthritis and gout in men, and for gout in women. The nonlinearity for gout was also more extreme in men compared to women (P=0.03).CONCLUSION: Higher BMI causes an increased risk for rheumatic disease, an effect that is more pronounced in women for both gout and psoriatic arthropathy. The novel sex- and BMI-specific causal effects identified here, give further insight into rheumatic-disease etiology and mark an important step towards personalized medicine.
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| 14. |
- Lo Faro, Valeria, et al.
(författare)
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Polygenic risk scores and risk stratification in deep vein thrombosis.
- 2023
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Ingår i: Thrombosis Research. - 0049-3848 .- 1879-2472. ; 228, s. 151-162
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Tidskriftsartikel (refereegranskat)abstract
- INTRODUCTION: Deep vein thrombosis (DVT) is a complex disease, where 60 % of risk is due to genetic factors, such as the Factor V Leiden (FVL) variant. DVT is either asymptomatic or manifests with unspecific symptoms and, if left untreated, DVT leads to severe complications. The impact is dramatic and currently, there is still a research gap in DVT prevention. We characterized the genetic contribution and stratified individuals based on genetic makeup to evaluate if it favorably impacts risk prediction.METHODS: In the UK Biobank (UKB), we performed gene-based association tests using exome sequencing data, as well as a genome-wide association study. We also constructed polygenic risk scores (PRS) in a subset of the cohort (Number of cases = 8231; Number of controls = 276,360) and calculated the impact on the prediction capacity of the PRS in a non-overlapping part of the cohort (Number of cases = 4342; Number of controls = 142,822). We generated additional PRSs that excluded the known causative variants.RESULTS: We discovered and replicated a novel common variant (rs11604583) near the region where are located the TRIM51 and LRRC55 genes and identified a novel rare variant (rs187725533) located near the CREB3L1 gene, associated with 2.5-fold higher risk of DVT. In one of the PRS models constructed, the top decile of risk is associated with 3.4-fold increased risk, an effect that is 2.3-fold when excluding FVL carriers. In the top PRS decile, the cumulative risk of DVT at the age of 80 years is 10 % for FVL carriers, contraposed to 5 % for non-carriers. The population attributable fractions of having a high polygenic risk on the rate of DVT was estimated to be around 20 % in our cohort.CONCLUSION: Individuals with a high polygenic risk of DVT, and not only carriers of well-studied variants such as FVL, may benefit from prevention strategies.
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