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Sökning: WFRF:(Halle Martin)

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  • Danielsson, Daniel, et al. (författare)
  • Influence of genetic background and oxidative stress response on risk of mandibular osteoradionecrosis after radiotherapy of head and neck cancer
  • 2016
  • Ingår i: Head and Neck. - 1043-3074 .- 1097-0347. ; 38:3, s. 387-393
  • Tidskriftsartikel (refereegranskat)abstract
    • Background: Osteoradionecrosis (ORN) of the mandible is a severe complication of head and neck radiotherapy (RT) treatment, where the impact of individual radiosensitivity has been a suggested explanation. Methods: A cohort of patients with stage II/III ORN was compared to matched controls. Blood was collected and irradiated in vitro to study the capacity to handle radiation-induced oxidative stress. Patients were also genotyped for 8 single-nucleotide polymorphisms (SNPs) in genes involved in the oxidative stress response. Results: A difference in 8-oxo-7,8-dihydro-2-deoxyguanosine (8-oxo-dG) levels was found between the patient cohorts (p = 0.01). The SNP rs1695 in glutathione s-transferase p1 (GSTP1) was also found to be more frequent in the patients with ORN (p = .02). Multivariate analysis of the clinical and biological factors revealed concomitant brachytherapy plus the 2 biomarkers to be significant factors which influense risk of mandibular osteoradionecrosis after radiotherapy of head and neck cancer. Conclusion: The current study indicates that oxidative stress response contributes to individual radiosensitivity and healthy tissue damage caused by RT and may be predicted by biomarker analysis.
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  • Drobin, Kimi, et al. (författare)
  • Molecular Profiling for Predictors of Radiosensitivity in Patients with Breast or Head-and-Neck Cancer
  • 2020
  • Ingår i: Cancers. - : MDPI AG. - 2072-6694. ; 12:3
  • Tidskriftsartikel (refereegranskat)abstract
    • Nearly half of all cancers are treated with radiotherapy alone or in combination with other treatments, where damage to normal tissues is a limiting factor for the treatment. Radiotherapy-induced adverse health effects, mostly of importance for cancer patients with long-term survival, may appear during or long time after finishing radiotherapy and depending on the patient's radiosensitivity. Currently, there is no assay available that can reliably predict the individual's response to radiotherapy. We profiled two study sets from breast (n = 29) and head-and-neck cancer patients (n = 74) that included radiosensitive patients and matched radioresistant controls. We studied 55 single nucleotide polymorphisms (SNPs) in 33 genes by DNA genotyping and 130 circulating proteins by affinity-based plasma proteomics. In both study sets, we discovered several plasma proteins with the predictive power to find radiosensitive patients (adjusted p < 0.05) and validated the two most predictive proteins (THPO and STIM1) by sandwich immunoassays. By integrating genotypic and proteomic data into an analysis model, it was found that the proteins CHIT1, PDGFB, PNKD, RP2, SERPINC1, SLC4A, STIM1, and THPO, as well as the VEGFA gene variant rs69947, predicted radiosensitivity of our breast cancer (AUC = 0.76) and head-and-neck cancer (AUC = 0.89) patients. In conclusion, circulating proteins and a SNP variant of VEGFA suggest that processes such as vascular growth capacity, immune response, DNA repair and oxidative stress/hypoxia may be involved in an individual's risk of experiencing radiation-induced toxicity.
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  • Danielsson, Daniel, et al. (författare)
  • Reduced oxidative stress response as a risk factor for normal tissue damage after radiotherapy: a study on mandibular osteoradionecrosis
  • Annan publikation (övrigt vetenskapligt)abstract
    • BackgroundThe use of radiotherapy (RT) to treat cancer involves exposure of normal tissues. Factors that promote the development of normal tissue damage are poorly understood. An increased individual sensitivity to ionizing radiation is a likely candidate, but general phenotypes for late adverse effects of RT are difficult to define. We have found osteoradionecrosis (ORN) in the mandible as a well-defined model phenotype for an in-depth study of clinical and biological risk factors for developing late adverse effects to RT.MethodsA cohort of patients with stage 2/3 ORN following RT for head and neck cancer (HCN) was studied and compared to a closely matched control group. Blood samples from the patients were collected and irradiated in vitro and the capacity to handle radiation-induced oxidative stress was investigated by measuring the level of 8-oxo-dG in serum 60 min post exposure. The patients were also genotyped for eight SNPs in genes involved in the oxidative stress response and previously studied in the context of individual radiosensitivity. Results from these endpoints were analyzed in conjunction with clinical data using multivariate analysis and an ORN risk model was constructed. FindingsA significant difference in 8-oxo-dG levels was found between the patient cohorts, indicating a heterogeneous response to oxidative stress induced by the in vitro γ-radiation. The SNP rs1695 in GSTP1 was found to be significantly more frequent in the ORN+ compared to ORN- group. Multivariate analysis of the clinical and biological factors revealed concomitant brachytherapy plus the two biomarkers to be the most significant. Interpretation: The current study indicates that patient-related factors are a major source of individual variation in normal tissue response to RT. Two of the studied genetic biomarkers are strong factors in the described risk model of ORN.
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  • Halle, Martin (författare)
  • Vascular inflammation : Implications for microvascular reconstructive surgery after irradiation
  • 2010
  • Doktorsavhandling (övrigt vetenskapligt)abstract
    • Better treatment has led to a rapidly increasing population of cancer survivors. A growing body of clinical evidence has shown that radiotherapy is associated with adverse effects on the cardiovascular system, such as myocardial infarction and stroke, depending on the previous treatment site. However, there is a paucity of experimental evidence linked to these clinical findings since the pathology, not evident until years after exposure, precludes adequate investigation through cell- and animal-experiments. We present a differential global gene expression strategy, by comparing irradiated with nonirradiated conduit arteries and veins, harvested simultaneously from the same patient during microvascular free tissue transfers for cancer reconstruction. We could thereby benefit from the true advantages of microarray technology, bypassing the common problem of inter-individual variability and furthermore exclude the influence of other risk factors and study the effect of irradiation only. Surgery at different time-points after radiotherapy did furthermore give us the opportunity to study temporal aspects, a key-factor for the understanding of delayed vascular disease. Temporal aspects of vascular alterations caused by irradiation are furthermore of importance for the timing of surgery in relation to radiotherapy, since there has been a debate about treatment order and timing between the two. In paper I, we could demonstrate that preoperative, compared to postoperative, radiotherapy was associated with microvascular occlusion after autologous free tissue transfers for head and neck reconstructions, and furthermore increased with the time elapsed from last radiotherapy session to surgery. In paper II, we utilized Affymetrix® microarray technology to unravel gene expression patterns in irradiated, compared to non-irradiated, arteries. Based on Gene Ontology Tree Machine®- analysis, target genes were selected and further confirmed with RT-PCR and immunohistochemistry. A major part of differentially expressed genes related to increased NF-kappaB activation, confined to cells within the arterial wall. The observed NF-kappaB activation, together with invading macrophages and T-cells, was evident even years after radiation exposure. Since microvascular occlusions after free tissue transfers are more likely to occur on the venous side, further analyses were performed in veins in paper III, utilizing a Taqman® tissue low density array, including 45 selected target-genes involved in inflammation and coagulation. An acute NF-kappaB activation was detected in irradiated veins, confined to the endothelium, whereas in contrast to arteries, no sustained NF-kappaB activity was observed more than 15 weeks from last radiotherapy session. Neither was any detectable invasion of inflammatory cells observed. Immunohistochemistry indicated decreased staining of endothelial nitric oxide synthase (eNOS) in irradiated veins, compared to controls, in further support for an endothelial dysfunction caused by irradiation. A sustained activation was detected for plasminogen activator-1 (PAI-1) in irradiated veins. In study IV, we detected a decreased eNOS activity in endothelial cells after incubation with the free fatty acids (FFAs) palmitic and oleic, but not linolenic, acid, whereas a triglyceride-rich fat emulsion increased the eNOS activity. This is interesting since FFAs are markedly elevated during surgery. With support from clinical and experimental data, we clearly advocate postoperative radiotherapy for microvascular reconstructive surgery, whenever possible for oncological reasons. Vascular inflammation may, together with increased PAI-1 gene expression observed in radiated veins, explain the increased risk for vascular complications when radiotherapy is administered prior to microvascular surgery. Moreover, the finding of a sustained NF-kappaB activation, together with presence of macrophages and T-cells, in irradiated arteries supports radiotherapy as an independent risk factor for cardiovascular disease and contributes to the search for therapeutic adjuncts to cope with the adverse effects of radiotherapy.
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  • Njingu, Atabong Emmanuel, et al. (författare)
  • Incidence, risk factors, clinical presentation and treatment of ectopic pregnancy in the Limbe and Buea Regional Hospital in Cameroon
  • 2020
  • Ingår i: Pan African Medical Journal. ; 2:95
  • Tidskriftsartikel (refereegranskat)abstract
    • Introduction: ectopic pregnancy (EP) is the leading cause of maternal mortality in the first trimester of pregnancy in our environment. This study aimed at evaluating the incidence, risk factors, clinical presentation and treatment of ectopic pregnancy in the Limbe and Buea Regional Hospitals in Cameroon. Methods: this was a retrospective nested case control study carried out from December 2006 to December 2016. A ratio for control vs cases of 3:1 was obtained. Any pregnancy implanted outside the normal uterine cavity was considered as an ectopic pregnancy. Student's t-test was used to compare continuous variables and Pearson's Chi-square test for categorical variables. The association between EP and the demographical and clinical variables was estimated using logistic regression. Statistical significance was set at p-values<0.05. Results: a total of 247 cases of EP were registered out of 17221 deliveries giving an incidence of 1.43% in ten years. History of pelvic inflammatory disease (OR = 3.10, CI (1.76-5.44), p < 0.001), previous EP (OR = 10.22, CI (2.61-14.82), p < 0.001), History of induced abortion (OR = 2.68, CI (3.32-9.73), p< 0.001), history of adnexa surgery (OR = 4.37, CI (2.17-10.32), p < 0.001) and history of appendectomy (OR = 2.16, CI (0.99-6.64) p< 0.001), were also found to be associated with increased risk of EP. More than five percent (5.52%) of the patients were in shock at presentation. Diagnosis was confirmed mainly by use of ultrasound (78.53%) and treatment was principally by laparotomy (97.55%) with salpingectomy (95.60%). Most (90.18%) of ectopic pregnancies were ruptured at presentation. Only 2.45% of cases were manage medically with the use of methotrexate. Conclusion: the incidence of ectopic pregnancy (EP) in our environment is within the global range (hospital-based incidence of 1.43%) and is rising. Late presentation, lack of modern diagnostic and management tools have made laparotomy with salpingectomy the principal method of management of ectopic pregnancy in our environment.
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