| 1. |
- Micke, Patrick, et al.
(författare)
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The prognostic impact of the tumour stroma fraction : A machine learning-based analysis in 16 human solid tumour types
- 2021
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Ingår i: EBioMedicine. - : Elsevier. - 2352-3964. ; 65
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Tidskriftsartikel (refereegranskat)abstract
- Background: The development of a reactive tumour stroma is a hallmark of tumour progression and pronounced tumour stroma is generally considered to be associated with clinical aggressiveness. The variability between tumour types regarding stroma fraction, and its prognosis associations, have not been systematically analysed.Methods: Using an objective machine-learning method we quantified the tumour stroma in 16 solid cancer types from 2732 patients, representing retrospective tissue collections of surgically resected primary tumours. Image analysis performed tissue segmentation into stromal and epithelial compartment based on pan-cytokeratin staining and autofluorescence patterns.Findings: The stroma fraction was highly variable within and across the tumour types, with kidney cancer showing the lowest and pancreato-biliary type periampullary cancer showing the highest stroma proportion (median 19% and 73% respectively). Adjusted Cox regression models revealed both positive (pancreato-biliary type periampullary cancer and oestrogen negative breast cancer, HR(95%CI)=0.56(0.34-0.92) and HR (95%CI)=0.41(0.17-0.98) respectively) and negative (intestinal type periampullary cancer, HR(95%CI)=3.59 (1.49-8.62)) associations of the tumour stroma fraction with survival.Interpretation: Our study provides an objective quantification of the tumour stroma fraction across major types of solid cancer. Findings strongly argue against the commonly promoted view of a general associations between high stroma abundance and poor prognosis. The results also suggest that full exploitation of the prognostic potential of tumour stroma requires analyses that go beyond determination of stroma abundance.
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| 2. |
- Olander, Susanne, et al.
(författare)
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Angiosarcoma in the breast: a population-based cohort from Sweden
- 2023
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Ingår i: British Journal of Surgery. - : Oxford University Press. - 0007-1323 .- 1365-2168. ; 110:12, s. 1850-1856
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Tidskriftsartikel (refereegranskat)abstract
- Background: Breast angiosarcoma is a rare disease mostly observed in breast cancer (BC) patients who have previously received radiotherapy (RT). Little is known about angiosarcoma aetiology, management, and outcome. The study aim was to estimate risk and to characterize breast angiosarcoma in a Swedish population-based cohort. Methods: The Swedish Cancer Registry was searched for breast angiosarcoma between 1992 and 2018 in three Swedish healthcare regions (population 5.5 million). Information on previous BC, RT, management, and outcome were retrieved from medical records. Results: Overall, 49 angiosarcomas located in the breast, chest wall, or axilla were identified, 8 primary and 41 secondary to BC treatment. Median age was 51 and 73 years, respectively. The minimum latency period of secondary angiosarcoma after a BC diagnosis was 4 years (range 4–21 years). The cumulative incidence of angiosarcoma after breast RT increased continuously, reaching 1.4‰ after 20 years. Among 44 women with angiosarcoma treated by surgery, 29 developed subsequent local recurrence. Median recurrence-free survival was 3.4 and 1.8 years for primary and secondary angiosarcoma, respectively. The 5-year overall survival probability for the whole cohort was 50 per cent (95 per cent c.i., 21 per cent–100 per cent) for primary breast angiosarcoma and 35 per cent (95 per cent c.i., 23 per cent–54 per cent) for secondary angiosarcoma. Conclusion: Breast angiosarcoma is a rare disease strongly associated with a history of previous BC RT. Overall survival is poor with high rates of local recurrences and distant metastasis.
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| 3. |
- Devarajan, Raman, et al.
(författare)
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Targeting collagen XVIII improves the efficiency of ErbB inhibitors in breast cancer models
- 2023
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Ingår i: Journal of Clinical Investigation. - : American Society for Clinical Investigation. - 0021-9738 .- 1558-8238. ; 133:18
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Tidskriftsartikel (refereegranskat)abstract
- The tumor extracellular matrix (ECM) critically regulates cancer progression and treatment response. Expression of the basement membrane component collagen XVIII (ColXVIII) is induced in solid tumors, but its involvement in tumorigenesis has remained elusive. We show here that ColXVIII was markedly upregulated in human breast cancer (BC) and was closely associated with a poor prognosis in high-grade BCs. We discovered a role for ColXVIII as a modulator of epidermal growth factor receptor tyrosine kinase (ErbB) signaling and show that it forms a complex with ErbB1 and -2 (also known as EGFR and human epidermal growth factor receptor 2 [HER2]) and α6-integrin to promote cancer cell proliferation in a pathway involving its N-terminal portion and the MAPK/ERK1/2 and PI3K/AKT cascades. Studies using Col18a1 mouse models crossed with the mouse mammary tumor virus-polyoma virus middle T antigen (MMTV-PyMT) mammary carcinogenesis model showed that ColXVIII promoted BC growth and metastasis in a tumor cell-autonomous manner. Moreover, the number of mammary cancer stem cells was significantly reduced in the MMTV-PyMT and human cell models upon ColXVIII inhibition. Finally, ablation of ColXVIII substantially improved the efficacy of ErbB-targeting therapies in both preclinical models. In summary, ColXVIII was found to sustain the stemness properties of BC cells and tumor progression and metastasis through ErbB signaling, suggesting that targeting ColXVIII in the tumor milieu may have important therapeutic potential.
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| 4. |
- Devarajan, R., et al.
(författare)
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Targeting collagen XVIII improves the efficiency of ErbB inhibitors in breast cancer models
- 2023
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Ingår i: Journal of Clinical Investigation. - 0021-9738. ; 133:18
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Tidskriftsartikel (refereegranskat)abstract
- The tumor extracellular matrix (ECM) critically regulates cancer progression and treatment response. Expression of the basement membrane component collagen XVIII (ColXVIII) is induced in solid tumors, but its involvement in tumorigenesis has remained elusive. We show here that ColXVIII was markedly upregulated in human breast cancer (BC) and was closely associated with a poor prognosis in high-grade BCs. We discovered a role for ColXVIII as a modulator of epidermal growth factor receptor tyrosine kinase (ErbB) signaling and show that it forms a complex with ErbB1 and-2 (also known as EGFR and human epidermal growth factor receptor 2 [HER2]) and alpha 6-integrin to promote cancer cell proliferation in a pathway involving its N-terminal portion and the MAPK/ERK1/2 and PI3K/AKT cascades. Studies using Col18a1 mouse models crossed with the mouse mammary tumor virus-polyoma virus middle T antigen (MMTV-PyMT) mammary carcinogenesis model showed that ColXVIII promoted BC growth and metastasis in a tumor cell-autonomous manner. Moreover, the number of mammary cancer stem cells was significantly reduced in the MMTV-PyMT and human cell models upon ColXVIII inhibition. Finally, ablation of ColXVIII substantially improved the efficacy of ErbB-targeting therapies in both preclinical models. In summary, ColXVIII was found to sustain the stemness properties of BC cells and tumor progression and metastasis through ErbB signaling, suggesting that targeting ColXVIII in the tumor milieu may have important therapeutic potential.
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| 5. |
- Gümüscü, Rojda, et al.
(författare)
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National long-term patient-reported outcomes following mastectomy with or without breast reconstruction : The Swedish Breast Reconstruction Outcome Study Part 2 (SweBRO 2)
- 2024
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Ingår i: BJS Open. - : Oxford University Press. - 2474-9842. ; 8:1
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Tidskriftsartikel (refereegranskat)abstract
- Background: The Swedish Breast Reconstruction Outcome Study (SweBRO) initiative is a nationwide study with the primary aim of assessing long-term outcomes after mastectomy with and without breast reconstruction (BR). The current part (SweBRO 2) is designed to evaluate health-related quality of life (HRQoL), with the hypothesis that BR has a positive impact on patient-reported HRQoL in the long-term.Methods: Women who underwent mastectomy in Sweden in 2000, 2005, or 2010 and were alive at the time of the survey were identified through the National Breast Cancer Registry. Eligible participants received formal invitation letters to take part in a survey evaluating their HRQoL at 5 , 10, or 15 years post-mastectomy. The EORTC QLQ-C30, EORTC QLQ-BR23, and EQ-5D-3L questionnaires were employed.Results: Of 2904 respondents (50% of 5853 invited), 895 (31%) had received BR. Among them, 516 (58%) were reconstructed with implants and 281 (31%) with autologous tissue. Women with BR scored significantly better in the EORCT QLQ-C30 physical functioning domain (mean 90 versus 81 points), fatigue (mean 21 versus 25), and dyspnoea (mean 16 versus 22) compared to non-reconstructed women. The EORTC QLQ-BR23 revealed that women with BR experienced favourable sexual functioning compared with non-reconstructed women (mean 26 versus 14). The EQ-5D-3L visual analogue scale score was similar between groups.Conclusion: The current study underscores the benefits of BR for long-term well-being, for example, in terms of physical and sexual functioning. These underline the importance of informing women undergoing mastectomy about BR alternatives and its potential benefits in enhancing long-term well-being. The Swedish Breast Reconstruction Outcome Study (SweBRO) initiative is a nationwide study with the primary aim of assessing long-term outcomes after mastectomy with and without breast reconstruction (BR). Women who had undergone mastectomy in Sweden in 2000, 2005, or 2010 and were alive at the time of the survey were identified through the National Breast Cancer Registry. The current study underscores the benefits of BR for long-term well-being, for example, in terms of physical and sexual functioning.
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| 6. |
- Jansson, Malin, et al.
(författare)
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Prognostic Value of Stromal Type IV Collagen Expression in Small Invasive Breast Cancers
- 2022
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Ingår i: Frontiers in Molecular Biosciences. - : Frontiers Media SA. - 2296-889X. ; 9
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Tidskriftsartikel (refereegranskat)abstract
- Breast cancer is the most common cause of cancer death among women worldwide. Localized breast cancer can be cured by surgery and adjuvant therapy, but mortality remains high for tumors that metastasize early. Type IV collagen is a basement membrane protein, and breach of this extracellular matrix structure is the first step of cancer invasion. Type IV collagen is found in the stroma of many cancers, but its role in tumor biology is unclear. Here, expression of type IV collagen in the stroma of small breast cancers was analyzed, correlated to clinically used prognostic biomarkers and patient survival. The findings were further validated in an independent gene expression data cohort. Tissue samples from 1,379 women with in situ and small invasive breast cancers (<= 15 mm) diagnosed in 1986-2004 were included. Primary tumor tissue was collected into tissue microarrays. Type IV collagen expression in tissues was visualized using immunohistochemistry. Gene expression data was extracted from the Cancer Genome Atlas database. Out of 1,379 women, 856 had an invasive breast cancer and type IV collagen staining was available for 714 patients. In Kaplan-Meier analysis high type IV collagen expression was significantly associated (p = 0.026) with poorer breast cancer specific survival. There was no correlation of type IV collagen expression to clinically used prognostic biomarkers. High type IV collagen expression was clearly associated to distant metastasis (p = 0.002). In an external validation cohort (n = 1,104), high type IV collagen mRNA expression was significantly (p = 0.041) associated with poorer overall survival, with overexpression of type IV collagen mRNA in metastatic tissue. Stromal type IV collagen expression in the primary tumor correlates to poor breast cancer specific survival most likely due to a higher risk of developing distant metastasis. This ECM protein may function as biomarker to predict the risk of future metastatic disease in patients with breast cancers.
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| 7. |
- Jansson, Malin, 1978-, et al.
(författare)
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Stromal type I collagen in breast cancer : correlation to prognostic biomarkers and prediction of chemotherapy response
- 2024
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Ingår i: Clinical Breast Cancer. - : Elsevier. - 1526-8209 .- 1938-0666.
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Tidskriftsartikel (refereegranskat)abstract
- Introduction: Fibrillar collagens accumulate in the breast cancer stroma and appear as poorly defined spiculated masses in mammography imaging. The prognostic value of tissue type I collagen remains elusive in treatment-naïve and chemotherapy-treated breast cancer patients. Here, type I collagen mRNA and protein expression were analysed in 2 large independent breast cancer cohorts. Levels were related to clinicopathological parameters, prognostic biomarkers, and outcome.Method: COL1A1 mRNA expression was analysed in 2509 patients with breast cancer obtained from the cBioPortal database. Type I collagen protein expression was studied by immunohistochemistry in 1395 women diagnosed with early invasive breast cancer.Results: Low COL1A1 mRNA and protein levels correlated with poor prognosis features, such as hormone receptor negativity, high histological grade, triple-negative subtype, node positivity, and tumour size. In unadjusted analysis, high stromal type I collagen protein expression was associated with improved overall survival (OS) (HR = 0.78, 95% CI = 0.61-0.99, p = .043) and trended towards improved breast cancer–specific survival (BCSS) (HR = 0.65, 95% CI = 0.42-1.01, P = 0.053), although these findings were lost after adjustment for other clinical variables. In unadjusted analysis, high expression of type I collagen was associated with better OS (HR = 0.70, 95% CI = 0.55-0.90, P = .006) and BCSS (HR = 0.55, 95% CI = 0.34-0.88, P = .014) among patients not receiving chemotherapy. Strikingly, the opposite was observed among patients receiving chemotherapy. There, high expression of type I collagen was instead associated with worse OS (HR = 1.83, 95% CI = 0.65-5.14, P = .25) and BCSS (HR = 1.72, 95% CI = 0.54-5.50, P = .357).Conclusion: Low stromal type I collagen mRNA and protein expression are associated with unfavourable tumour characteristics in breast cancer. Stromal type I collagen might predict chemotherapy response.
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| 8. |
- Lidström, Anna-Karin, et al.
(författare)
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Work at inpatient care units is associated with an increased risk of SARS-CoV-2 infection; a cross-sectional study of 8679 healthcare workers in Sweden.
- 2020
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Ingår i: Upsala Journal of Medical Sciences. - : Uppsala Medical Society. - 0300-9734 .- 2000-1967. ; 125:4, s. 305-310
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: During the Covid-19 pandemic, the protection of healthcare workers has been in focus throughout the world, but the availability and quality of personal protective equipment has at times and in some settings been suboptimal.MATERIALS AND METHODS: A total of 8679 healthcare workers and healthcare support staff in the county of Uppsala, north of Stockholm, were included in this cross-sectional study. All subjects were analysed for IgG anti-SARS-CoV-2, and predictors for positive serostatus were analysed in a logistic regression model including demographic parameters and self-reported employment characteristics.RESULTS: Overall, 577 (6.6%) were classified as seropositive, with no statistically significant differences between healthcare workers and support staff. Among healthcare workers, age (OR 0.987 per year, 95% CI 0.980-0.995), time to sampling (OR 1.019 per day, 95% CI 1.004-1.035), and employment at an outpatient care unit (OR 0.620, 95% CI 0.487-0.788) were statistically significantly associated with risk of infection. Covid-19 specific units were not at particular risk, compared to other units with comparable characteristics and staff demography.CONCLUSION: Our findings indicate that SARS-CoV-2 transmission is related to inpatient healthcare work, and illustrate the need for a high standard of basic hygiene routines in all inpatient care settings.
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| 9. |
- Rask, Gunilla, et al.
(författare)
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Correlation of tumour subtype with long-term outcome in small breast carcinomas: a Swedish population-based retrospective cohort study
- 2022
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Ingår i: Breast Cancer Research and Treatment. - : Springer Science and Business Media LLC. - 0167-6806 .- 1573-7217. ; 195:3, s. 367-377
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Tidskriftsartikel (refereegranskat)abstract
- Purpose To investigate if molecular subtype is associated with outcome in stage 1 breast cancer (BC). Methods Tissue samples from 445 women with node-negative BC <= 15 mm, treated in 1986-2004, were classified into surrogate molecular subtypes [Luminal A-like, Luminal B-like (HER2-), HER2-positive, and triple negative breast cancer (TNBC)]. Information on treatment, recurrences, and survival were gathered from medical records. Results Tumour subtype was not associated with overall survival (OS). Luminal B-like (HER2-) and TNBC were associated with higher incidence of distant metastasis at 20 years (Hazard ratio (HR) 2.26; 95% CI 1.08-4.75 and HR 3.24; 95% CI 1.17-9.00, respectively). Luminal B-like (HER2-) and TNBC patients also had worse breast cancer-specific survival (BCSS), although not statistically significant (HR 1.53; 95% CI 0.70-3.33 and HR 1.89; 95% CI 0.60-5.93, respectively). HER2-positive BC was not associated with poor outcome despite no patient receiving HER2-targeted therapy, with most of these tumours being ER+. Conclusions Stage 1 TNBC or Luminal B-like (HER2-) tumours behave more aggressively. Women with HER2+/ER+ tumours do not have an increased risk of distant metastasis or death, absent targeted treatment.
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| 10. |
- Rask, Gunilla, et al.
(författare)
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Immune cell infiltrate in ductal carcinoma in situ and the risk of dying from breast cancer : case-control study
- 2024
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Ingår i: British Journal of Surgery. - : Oxford University Press. - 0007-1323 .- 1365-2168. ; 111:2
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Tidskriftsartikel (refereegranskat)abstract
- Background: Studies identifying risk factors for death from breast cancer after ductal carcinoma in situ (DCIS) are rare. In this retrospective nested case-control study, clinicopathological factors in women treated for DCIS and who died from breast cancer were compared with those of patients with DCIS who were free from metastatic disease.Methods: The study included patients registered with DCIS without invasive carcinoma in Sweden between 1992 and 2012. This cohort was linked to the National Cause of Death Registry. Of 6964 women with DCIS, 96 were registered with breast cancer as cause of death (cases). For each case, up to four controls (318; women with DCIS, alive and without metastatic breast cancer at the time of death of the corresponding case) were selected randomly by incidence density sampling. Whole slides of tumour tissue were evaluated for DCIS grade, comedo necrosis, and intensity of periductal lymphocytic infiltrate. Composition of the immune cell infiltrate, expression of oestrogen receptor, progesterone receptor, human epidermal growth factor receptor 2, and proliferation marker Ki-67 were scored on tissue microarrays. Clinical information was obtained from medical records. Information on date, site, and histological characteristics of local and distant recurrences was obtained from medical records for both cases and controls.Results: Tumour tissue was analysed from 65 cases and 195 controls. Intense periductal lymphocytic infiltrate around DCIS was associated with an increased risk of later dying from breast cancer (OR 2.21. 95% c.i. 1.01 to 4.84). Tumours with more intense lymphocytic infiltrate had a lower T cell/B cell ratio. None of the other biomarkers correlated with increased risk of breast cancer death.Conclusion: The immune response to DCIS may influence the risk of dying from breast cancer.
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| 11. |
- Söderberg, Emma, et al.
(författare)
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Association of clinicopathologic variables and patient preference with the choice of surgical treatment for early-stage breast cancer : A registry-based study
- 2024
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Ingår i: Breast. - : Elsevier. - 0960-9776 .- 1532-3080. ; 73
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Tidskriftsartikel (refereegranskat)abstract
- Introduction: Observational studies suggest that breast conserving surgery (BCS) and radiotherapy (RT) offers superior survival compared to mastectomy. The aim was to compare patient and tumour characteristics in women with invasive breast cancer <= 30 mm treated with either BCS or mastectomy, and to explore the underlying reason for choosing mastectomy.Methods: Women registered with breast cancer <= 30 mm and <= 4 positive axillary lymph nodes in the Swedish National Breast Cancer Register 2013-2016 were included. Logistic regression analyses were performed to assess the association of tumour and patient characteristics with receiving a mastectomy vs. BCS.Results: Of 1860 breast cancers in 1825 women, 1346 were treated by BCS and 514 by mastectomy. Adjuvant RT was given to 1309 women (97.1 %) after BCS and 146 (27.6 %) after mastectomy. Variables associated with receiving a mastectomy vs. BCS included clinical detection (Odds Ratio (OR) 4.15 (95 % Confidence Interval (CI) 3.35-5.14)) and clinical stage (T2 vs. T1 (OR 3.68 (95 % CI 2.90-4.68)), N1 vs. N0 (OR 2.02 (95 % CI 1.38-2.96)). Women receiving mastectomy more often had oestrogen receptor negative, HER2 positive tumours of higher histological grade. The most common reported reason for mastectomy was large or multifocal tumours (53.5 %), followed by patient preference (34.5 %).Conclusion: Choice of surgery is strongly associated with key prognostic factors among women undergoing BCS with RT compared to mastectomy. Failure to control for all relevant confounders may bias results in outcome studies in favour of BCS.
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| 12. |
- Unukovych, Dmytro, et al.
(författare)
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Breast reconstruction patterns from a Swedish nation-wide survey
- 2020
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Ingår i: European Journal of Surgical Oncology. - : Elsevier BV. - 0748-7983 .- 1532-2157. ; 46:10, s. 1867-1873
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Tidskriftsartikel (refereegranskat)abstract
- ObjectivesThe overall aim of the Swedish Breast Reconstruction Outcome Study was to investigate national long-term outcomes after mastectomy with or without breast reconstruction. The current report evaluates breast reconstruction (BR) patterns in Sweden over time.Materials and methodsThis is a cross-sectional, registry-based study where all women operated with mastectomy 2000, 2005, 2010 were identified (N = 5853). Geographical differences in type of BR were investigated using heatmaps. Distribution of continuous variables were compared using the Mann-Whitney U test, categorical variables were compared using the chi-square test.ResultsMean age at survey was 69 years (SD=±11.4) and response rate was 50%, responders were on average six years younger than the non-responders and had a more favourable tumor stage (both p < 0.01). Of the 2904 responders, 31% (895/2904) had received a BR: implant-based in 58% (516/895)autologous in 31% (281/895). BR was immediate in 20% (176/895) and delayed in 80% (719/895) women.Women with BR were on average one year older, more often had a normal BMI, reported to be married or had a partner, had a higher educational level and a higher annual income when compared to those without BR (all p < 0.001). The independent factors of not receiving BR were older age and given radiotherapy.ConclusionsTo our knowledge, this is the first national long-term follow-up study on women undergoing mastectomy with and without BR. Around 30% of the survey responders have had a BR with a significant geographical variation highlighting the importance of information, availability and standardisation of indications for BR.
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| 13. |
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| 14. |
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| 15. |
- Westman, Gabriel, 1977-, et al.
(författare)
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Cerebrospinal fluid biomarkers of brain injury, inflammation and synaptic autoimmunity predict long-term neurocognitive outcome in herpes simplex encephalitis.
- 2021
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Ingår i: Clinical Microbiology and Infection. - : Elsevier. - 1198-743X .- 1469-0691. ; 27:8, s. 1131-1136
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVES: The aim was to investigate the correlation between biomarkers of brain injury and long-term neurocognitive outcome, and the interplay with intrathecal inflammation and neuronal autoimmunity, in patients with herpes simplex encephalitis (HSE).METHODS: A total of 53 adult/adolescent HSE patients were included from a prospective cohort in a randomized placebo-controlled trial investigating the effect of a 3-month follow-up treatment with valaciclovir. Study subjects underwent repeated serum/cerebrospinal fluid (CSF) sampling and brain magnetic resonance imaging in the first 3 months along with cognitive assessment using the Mattis Dementia Rating Scale (MDRS) at 24 months. CSF samples were analysed for biomarkers of brain injury, inflammation and synaptic autoimmunity. The predefined primary analysis was the correlation between peak CSF neurofilament protein (NFL), a biomarker of neuronal damage, and MDRS at 24 months.RESULTS: Impaired cognitive performance significantly correlated with NFL levels (rho = -0.36, p = 0.020). Development of IgG anti-N-methyl-D-aspartate receptor (NDMAR) antibodies was associated with a broad and prolonged proinflammatory CSF response. In a linear regression model, lower MDRS at 24 months was associated with previous development of IgG anti-N-methyl-D-aspartate receptor (NMDAR) (beta = -0.6249, p = 0.024) and age (z-score beta = -0.2784, p = 0.024), but not CSF NFL, which however significantly correlated with subsequent NMDAR autoimmunization (p = 0.006).DISCUSSION: Our findings show that NFL levels are predictive of long-term neurocognitive outcome in HSE, and suggest a causative chain of events where brain tissue damage increases the risk of NMDAR autoimmunisation and subsequent prolongation of CSF inflammation. The data provides guidance for a future intervention study of immunosuppressive therapy administered in the recovery phase of HSE.
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