| 1. |
- Hardell, Elin, et al.
(författare)
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Case-control study on perfluorinated alkyl acids (PFAAs) and the risk of prostate cancer
- 2014
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Ingår i: Environment International. - : Elsevier. - 0160-4120 .- 1873-6750. ; 63, s. 35-39
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Tidskriftsartikel (refereegranskat)abstract
- Perfluorinated alkyl acids (PFAAs) are emerging environmental contaminants. Possible health effects for humans include increased risk for cancer but the knowledge is limited. In this study serum concentrations of certain perfluorinated sulfonates (PFHxS and PFOS) and carboxylates (PFOA, PFNA, PFDA, PFUnDA) were analyzed among 201 cases with prostate cancer and 186 population based control subjects. All blood samples were collected during 2007-2011 and no case had been treated with radio- or chemotherapy before enrolment in the study. The blood concentrations did not differ statistically significant between cases and controls except for PFDA with higher concentration among the cases (p = 0.03). Analyses based on Gleason score and prostate specific antigen (PSA) level did not change the results. Heredity was a risk factor for prostate cancer yielding odds ratio (OR) = 1.8, 95% confidence interval (CI) = 1.01-3.1. The analyzed PFAAs yielded statistically significant higher ORs in cases with a first degree relative reporting prostate cancer, e.g., PFOA gave OR = 2.6, 95% CI = 1.2-6.0 and PFOS gave OR = 2.7,95% CI = 1.04-6.8. The results showed a higher risk for prostate cancer in cases with heredity as a risk factor. In further studies interaction between gene and environment should be considered. (C) 2013 Elsevier Ltd. All rights reserved.
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| 2. |
- Binzer-Panchal, Amrei, et al.
(författare)
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Integrated Molecular Analysis of Undifferentiated Uterine Sarcomas Reveals Clinically Relevant Molecular Subtypes
- 2019
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Ingår i: Clinical Cancer Research. - : AMER ASSOC CANCER RESEARCH. - 1078-0432 .- 1557-3265. ; 25:7, s. 2155-2165
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Tidskriftsartikel (refereegranskat)abstract
- Purpose: Undifferentiated uterine sarcomas (UUS) are rare, extremely deadly, sarcomas with no effective treatment. The goal of this study was to identify novel intrinsic molecular UUS subtypes using integrated clinical, histopathologic, and molecular evaluation of a large, fully annotated, patient cohort.Experimental Design: Fifty cases of UUS with full clinicopathologic annotation were analyzed for gene expression (n = 50), copy-number variation (CNV, n = 40), cell morphometry (n = 39), and protein expression (n = 22). Gene ontology and network enrichment analysis were used to relate over-and underexpressed genes to pathways and further to clinicopathologic and phenotypic findings.Results: Gene expression identified four distinct groups of tumors, which varied in their clinicopathologic parameters. Gene ontology analysis revealed differential activation of pathways related to genital tract development, extracellular matrix (ECM), muscle function, and proliferation. A multivariable, adjusted Cox proportional hazard model demonstrated that RNA group, mitotic index, and hormone receptor expression influence patient overall survival (OS). CNV arrays revealed characteristic chromosomal changes for each group. Morphometry demonstrated that the ECM group, the most aggressive, exhibited a decreased cell density and increased nuclear area. A cell density cutoff of 4,300 tumor cells per mm(2) could separate ECM tumors from the remaining cases with a sensitivity of 83% and a specificity of 94%. IHC staining of MMP-14, Collagens 1 and 6, and Fibronectin proteins revealed differential expression of these ECM-related proteins, identifying potential new biomarkers for this aggressive sarcoma subgroup. Conclusions: Molecular evaluation of UUS provides novel insights into the biology, prognosis, phenotype, and possible treatment of these tumors.
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| 3. |
- Gremel, Gabriela, et al.
(författare)
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A prognosis based classification of undifferentiated uterine sarcomas : Identification of mitotic index, hormone receptors and YWHAE-FAM22 translocation status as predictors of survival
- 2015
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Ingår i: International Journal of Cancer. - : Wiley. - 0020-7136 .- 1097-0215. ; 136:7, s. 1608-1618
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Tidskriftsartikel (refereegranskat)abstract
- Undifferentiated uterine sarcomas (UUS) are rare tumors with a heterologous biology and a poor prognosis. The goal of this study was to examine clinicopathology, biomarkers and YWHAE-FAM22 translocation status, in the prognosis of these tumors. Twenty-six cases of UUS were included. All original slides were rereviewed and age at diagnosis, tumor stage, Kurihara diagnosis, mitotic index, presence of necrosis and grade of nuclear atypia were recorded. Additionally, a tissue microarray was constructed from 22 of the cases, and the protein biomarkers P53, P16, Ki-67, Cyclin-D1, ER, PR and ANLN were evaluated by immunohistochemistry. All tumors were evaluated for the presence of a YWHAE-FAM translocation; the translocation was demonstrated in the three Cyclin-D1 positive tumors. Follow-up data in the form of overall survival were available on all patients. These tumors could be divided into two prognostic groups, a high mitotic index group (10 cases, M=36.8, SD=5.4) and a low mitotic index group (16 cases, M=8.7, SD=5.8). These two groups showed a statistically significant difference in prognosis. The expression of ER, PR or presence of the YWHAE-FAM22 translocation correlated with low mitotic index and an additionally improved prognosis, although the number of cases was small. These results indicate that UUS can be divided into two prognostic groups using mitotic index as a primary criteria, followed by expression of either ER, PR or the presence of a YWHAE-FAM22 translocation as a secondary criteria. This study demonstrates the presence of statistically significant prognostic subgroups within UUS, and provides treatment insights.
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| 4. |
- Gultekin, Okan, et al.
(författare)
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FOXP3+ T cells in uterine sarcomas are associated with favorable prognosis, low extracellular matrix expression and reduced YAP activation
- 2021
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Ingår i: npj Precision Oncology. - : Springer Nature. - 2397-768X. ; 5:1
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Tidskriftsartikel (refereegranskat)abstract
- Uterine sarcomas are rare but deadly malignancies without effective treatment. Immunotherapy is a promising new approach to treat these tumors but has shown heterogeneous effects in sarcoma patients. With the goal of identifying key factors for improved patient treatment, we characterized the tumor immune landscape in 58 uterine sarcoma cases with full clinicopathological annotation. Immune cell characterization revealed the overall prevalence of FOXP3+ cells and pro-tumor M2-like macrophages. Hierarchical clustering of patients showed four tumor type-independent immune signatures, where infiltration of FOXP3+ cells and M1-like macrophages associated with favorable prognosis. High CD8+/FOXP3+ ratio in UUS and ESS correlated with poor survival, upregulation of immunosuppressive markers, extracellular matrix (ECM)-related genes and proteins, and YAP activation. This study shows that uterine sarcomas present distinct immune signatures with prognostic value, independent of tumor type, and suggests that targeting the ECM could be beneficial for future treatments.
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| 5. |
- Hardell, Elin
(författare)
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Prognosis based classification and tumor biology of uterine sarcomas
- 2020
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Uterine stromal sarcomas are a heterogenous group of tumors ranging from low-grade stromal sarcomas with a relatively good survival but high risk of recurrence, to undifferentiated uterine sarcomas with a far worse prognosis. Little is known about their biology, and prognostic markers are lacking. The treatment options are limited mainly to surgery. Chemotherapy and radiotherapy have little or no effect on survival. Recent success with immunotherapy has opened a promising research field with potential to gain new insights into the biology, prognosis and therapy of uterine stromal sarcomas. In paper I we examined the correlation of clinicopathological factors, biomarkers and YWHAE-FAM22 translocation with prognosis in undifferentiated uterine sarcomas. Twenty-six cases from the Karolinska University Hospital’s archive were included, out of which 22 of them had paraffin blocks for translocation status and immunohistochemical analysis of p53, p16, Ki67, Cyclin-D1, estrogen receptor, progesterone receptor and Anillin. Our findings show that the cases could be divided into two prognostic groups based on mitotic index; the high mitotic index group with a statistically significant worse prognosis than the group with low mitotic index. In paper II we wanted to validate the results from paper I in an independent cohort of cases. A total of 40 cases of undifferentiated uterine sarcomas were included from the Norwegian Radium Hospital, the Mayo Clinic and Skåne University Hospital. Mitotic index was recorded and the cases were divided into high and low mitotic index groups based on the cut-off from paper I. The analysis showed that one-third of the patients survived beyond five years. In the adjusted survival analysis, mitotic index group and tumor stage were prognostic factors. In paper III we identified molecular subgroups of undifferentiated uterine sarcomas and evaluated the possible correlation with different clinicopathological parameters. The cohort of paper III consisted of 50 cases with undifferentiated uterine sarcomas from six different institutions. All cases had formalin-fixed paraffin-embedded tumor material used for isolation of DNA and RNA. In total 50 cases were analyzed for gene expression, copy number variation, cell morphometry and protein expression. Four groups with different mRNA expression pattern were identified. Gene ontology analysis showed an activation of pathways related to genital tract development, extracellular matrix, muscle function and proliferation in the different groups. The result of the chromosomal copy number analysis showed a spectrum of variation, from cases that were diploid or near diploid to cases with extensive chromosomal aberrations. The adjusted Cox Proportional Hazard model showed that the mitotic index group, the hormone receptor expression and the mRNA group had a statistically significant impact on overall survival. In the ontology analysis, the mRNA group with the worst prognosis showed overexpressed pathways related to the extracellular matrix (ECM). When further analyzed by image analysis the ECM group was characterized by reduced cell density and increased nuclear size compared to the other groups. The ECM group also showed higher expression of the four ECM related proteins matrix metalloproteinase 14, collagen 1, collagen 6 and fibronectin, when evaluated with immunohistochemistry. In paper IV we analyzed the prognostic significance of different immune markers in lowgrade endometrial stromal sarcomas (LGESS). The cohort consisted of 21 cases identified by searching the pathological database at the Karolinska University hospital and the Stockholm region cancer registry. All cases had formalin-fixed paraffin-embedded tumor material and follow-up data. Tissue microarrays consisting of two biopsies of tumor material from each case were constructed. Multiplex fluorescent immunohistochemistry in combination with digital image analysis in QuPath was used to quantitatively assess the expression of different immune markers, including CD8, FOXP3, CD68, CD163, IDO1, B7-H4 and PD-L1. A low ratio of CD8+/FOXP3+ cells was significantly associated with a favorable prognosis in LGESS. For patients with a high quantity of CD8+ T cells and B7- H4, a trend towards better survival was seen. The expression of B7-H4 is also a potential therapeutic target.
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| 6. |
- Hardell, Elin, et al.
(författare)
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Time trends of persistent organic pollutants in Sweden during 1993-2007 and relation to age, gender, body mass index, breast-feeding and parity
- 2010
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Ingår i: Science of the Total Environment. - : Elsevier BV. - 0048-9697 .- 1879-1026. ; 408:20, s. 4412-4419
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Tidskriftsartikel (refereegranskat)abstract
- Background: Persistent organic pollutants (POPs) are lipophilic chemicals that bioaccumulate. Most of them were resticted or banned in the 1970s and 1980s to protect human health and the environment. The main source for humans is dietary intake of dairy products, meat and fish. Little data exist on changes of the concentration of POPs in the Swedish population over time. Objective: To study if the concentrations of polychlorinated biphenyls (PCBs). DDE, hexachlorobenzene (HCB) and chlordanes have changed in the Swedish population during 1993-2007, and certain factors that may influence the concentrations. Methods: During 1993-2007 samples from 537 controls in different human cancer studies were collected and analysed. Background information such as body mass index, breast-feeding and parity was assessed by questionaires. Wilcoxon rank-sum test was used to analyse the explanatory factors specimen (blood or adipose tissue), gender, BMI, total breast-feeding and parity in relation to POPs. Time trends for POPs were analysed using linear regression analysis, adjusted for specimen, gender, BMI and age. Results: The concentration decreased for all POPs during 1993-2007. The annual change was statistically significant for the sum of PCBs -7.2%, HCB -8.8%, DDE -13.5% and the sum of chlordanes -10.3%. BMI and age were determinants of the concentrations. Cumulative breast-feeding >8 months gave statistically significantly lower concentrations for the sum of PCBs. DDE and the sum of chlordanes. Parity with >2 children yielded statistically significantly lower sum of PCBs. Conclusions: All the studied POPs decreased during the time period, probably due to restrictions of their use. (c) 2010 Elsevier BM. All rights reserved.
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| 7. |
- Hardell, Elin, et al.
(författare)
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Validation of a Mitotic Index Cutoff as a Prognostic Marker in Undifferentiated Uterine Sarcomas
- 2017
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Ingår i: American Journal of Surgical Pathology. - 0147-5185 .- 1532-0979. ; 41:9, s. 1231-1237
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Tidskriftsartikel (refereegranskat)abstract
- Undifferentiated uterine sarcomas (UUS) are a heterogenous group of high-grade mesenchymal tumors. Although these tumors are highly aggressive, a subset of patients may experience long-term survival. These tumors have previously been divided morphologically into uniform and pleomorphic types. A previous study demonstrated that a mitotic index cutoff of 25 mitoses/10 high-power fields (corresponding to 11.16 mitotic figures/mm) could successfully divide tumors into 2 prognostic groups with significantly different overall survival. The goals of the current study were to (1) validate this mitotic index cutoff in an independent, multicenter cohort and (2) explore the prognostic value of the mitotic index groups in relation to other clinicopathologic variables. Cases were included from 3 independent institutions: The Norwegian Radium Hospital, The Mayo Clinic, and Skåne University Hospital. A total of 40 tumors were included after central review. All cases were negative for the YWHAE-FAM22A/B and JAZF1-JJAZ1 translocations. Survival data were available on all patients. In this study, one-third of patients with UUS survived beyond 5 years. The crude (unadjusted) Cox Proportional Hazards model revealed a number of parameters that significantly impacted overall survival, including mitotic index group, patient age, stage, and the presence of tumor necrosis. Classification into the uniform and pleomorphic types was not prognostic. Combining these parameters into an adjusted model revealed that only the mitotic index group and stage were prognostic. On the basis of these findings, it is proposed that UUS be subdivided into “mitogenic” and “not otherwise specified” types.
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