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1.	Bagge, R. Olofsson, et al. (författare) Comment on "factors affecting sentinel node metastasis in thin (T1) cutaneous melanomas : Development and external validation of a predictive nomogram" 2020 Ingår i: Journal of Clinical Oncology. - 0732-183X. ; 38:27, s. 3233-3234 Tidskriftsartikel (refereegranskat)
2.	Bagge, Roger Olofsson, et al. (författare) Population-Based Validation of the MIA and MSKCC Tools for Predicting Sentinel Lymph Node Status 2024 Ingår i: JAMA Surgery. - : AMER MEDICAL ASSOC. - 2168-6254 .- 2168-6262. Tidskriftsartikel (refereegranskat)abstract Importance Patients with melanoma are selected for sentinel lymph node biopsy (SLNB) based on their risk of a positive SLN. To improve selection, the Memorial Sloan Kettering Cancer Center (MSKCC) and Melanoma Institute Australia (MIA) developed predictive models, but the utility of these models remains to be tested.Objective To determine the clinical utility of the MIA and MSKCC models.Design, Setting, and Participants This was a population-based comparative effectiveness research study including 10 089 consecutive patients with cutaneous melanoma undergoing SLNB from the Swedish Melanoma Registry from January 2007 to December 2021. Data were analyzed from May to August 2023.Main Outcomes and Measures, The predicted probability of SLN positivity was calculated using the MSKCC model and a limited MIA model (using mitotic rate as absent/present instead of count/mm(2) and excluding the optional variable lymphovascular invasion) for each patient. The operating characteristics of the models were assessed and compared. The clinical utility of each model was assessed using decision curve analysis and compared with a strategy of performing SLNB on all patients.Results Among 10 089 included patients, the median (IQR) age was 64.0 (52.0-73.0) years, and 5340 (52.9%) were male. The median Breslow thickness was 1.8 mm, and 1802 patients (17.9%) had a positive SLN. Both models were well calibrated across the full range of predicted probabilities and had similar external area under the receiver operating characteristic curves (AUC; MSKCC: 70.8%; 95% CI, 69.5-72.1 and limited MIA: 69.7%; 95% CI, 68.4-71.1). At a risk threshold of 5%, decision curve analysis indicated no added net benefit for either model compared to performing SLNB for all patients. At risk thresholds of 10% or higher, both models added net benefit compared to SLNB for all patients. The greatest benefit was observed in patients with T2 melanomas using a threshold of 10%; in that setting, the use of the nomograms led to a net reduction of 8 avoidable SLNBs per 100 patients for the MSKCC nomogram and 7 per 100 patients for the limited MIA nomogram compared to a strategy of SLNB for all.Conclusions and Relevance This study confirmed the statistical performance of both the MSKCC and limited MIA models in a large, nationally representative data set. However, decision curve analysis demonstrated that using the models only improved selection for SLNB compared to biopsy in all patients when a risk threshold of at least 7% was used, with the greatest benefit seen for T2 melanomas at a threshold of 10%. Care should be taken when using these nomograms to guide selection for SLNB at the lowest thresholds.
3.	Bartuma, Hammurabi, et al. (författare) Gene expression and single nucleotide polymorphism array analyses of spindle cell lipomas and conventional lipomas with 13q14 deletion. 2011 Ingår i: Genes, Chromosomes and Cancer. - : Wiley. - 1045-2257. ; 50, s. 619-632 Tidskriftsartikel (refereegranskat)abstract Spindle cell lipomas (SCL) are circumscribed, usually s.c. tumors that typically occur on the posterior neck, shoulder, and back of middle aged men. Cytogenetically, almost all SCL are characterized by deletions of chromosome arm 13q, often in combination with loss of 16q. Deletions of 13q are seen also in approximately 15% of conventional lipomas. Through single nucleotide polymorphism (SNP) array analyses, we identified two minimal deleted regions (MDR) in 13q14 in SCL. In MDR1, four genes were located, including the tumor suppressor gene RB1. MDR1 in SCL overlapped with the MDR detected in conventional lipomas with 13q14 deletion. In MDR2 in SCL there were 34 genes and the two microRNA (miRNA) genes miR-15a and miR-16-1. Global gene expression analysis was used to study the impact of the deletions on genes mapping to the two SCL-associated MDR. Five genes (C13orf1, DHRS12, ATP7B, ALG11, and VPS36) in SCL and one gene (C13orf1) in conventional lipomas with 13q-deletions were found to be significantly underexpressed compared with control tissues. Quantitative real-time PCR showed that miR-16-1 was expressed at lower levels in SCL than in the control samples. No mutations were found at sequencing of RB1, miR-15a, and miR-16-1. Our findings further delineate the target region for the 13q deletion in SCL and conventional lipomas and show that the deletions are associated with down-regulated expression of several genes, notably C13orf1, which was the only gene to be significantly down-regulated in both tumor types. © 2011 Wiley-Liss, Inc.
4.	Bauden, Monika, et al. (författare) Novel anti-adhesive barrier Biobarrier reduces growth of colon cancer cells. 2014 Ingår i: Journal of Surgical Research. - : Elsevier BV. - 1095-8673 .- 0022-4804. ; 191:1, s. 196-202 Tidskriftsartikel (refereegranskat)abstract Postoperative peritoneal carcinomatosis together with adhesion formation are considered as two major clinical complications after resection of malignant abdominal tumors, jeopardizing the beneficial effect of the curative surgery. Biobarrier is a novel anti-adhesive barrier fulfilling the criteria for a good adhesion preventive agent, possessing biochemical properties that may enable it to function as a dual efficient device, reducing both adhesion and tumor development. This study aims to evaluate the effect of novel anti-adhesive device Biobarrier on intra-abdominal tumor progression.
5.	Bradbury, Kathryn E., et al. (författare) Circulating insulin-like growth factor I in relation to melanoma risk in the European prospective investigation into cancer and nutrition 2019 Ingår i: International Journal of Cancer. - : John Wiley & Sons. - 0020-7136 .- 1097-0215. ; 144:5, s. 957-966 Tidskriftsartikel (refereegranskat)abstract Insulin-like growth factor-I (IGF-I) regulates cell proliferation and apoptosis, and is thought to play a role in tumour development. Previous prospective studies have shown that higher circulating concentrations of IGF-I are associated with a higher risk of cancers at specific sites, including breast and prostate. No prospective study has examined the association between circulating IGF-I concentrations and melanoma risk. A nested case-control study of 1,221 melanoma cases and 1,221 controls was performed in the European Prospective Investigation into Cancer and Nutrition cohort, a prospective cohort of 520,000 participants recruited from 10 European countries. Conditional logistic regression was used to estimate odds ratios (ORs) for incident melanoma in relation to circulating IGF-I concentrations, measured by immunoassay. Analyses were conditioned on the matching factors and further adjusted for age at blood collection, education, height, BMI, smoking status, alcohol intake, marital status, physical activity and in women only, use of menopausal hormone therapy. There was no significant association between circulating IGF-I concentration and melanoma risk (OR for highest vs lowest fifth = 0.93 [95% confidence interval [CI]: 0.71 to 1.22]). There was no significant heterogeneity in the association between IGF-I concentrations and melanoma risk when subdivided by gender, age at blood collection, BMI, height, age at diagnosis, time between blood collection and diagnosis, or by anatomical site or histological subtype of the tumour (Pheterogeneity≥0.078). We found no evidence for an association between circulating concentrations of IGF-I measured in adulthood and the risk of melanoma.
6.	Cabrita, Rita, et al. (författare) Tertiary lymphoid structures improve immunotherapy and survival in melanoma 2020 Ingår i: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 577:7791, s. 561-565 Tidskriftsartikel (refereegranskat)abstract Checkpoint blockade therapies that reactivate tumour-associated T cells can induce durable tumour control and result in the long-term survival of patients with advanced cancers1. Current predictive biomarkers for therapy response include high levels of intratumour immunological activity, a high tumour mutational burden and specific characteristics of the gut microbiota2,3. Although the role of T cells in antitumour responses has thoroughly been studied, other immune cells remain insufficiently explored. Here we use clinical samples of metastatic melanomas to investigate the role of B cells in antitumour responses, and find that the co-occurrence of tumour-associated CD8+ T cells and CD20+ B cells is associated with improved survival, independently of other clinical variables. Immunofluorescence staining of CXCR5 and CXCL13 in combination with CD20 reveals the formation of tertiary lymphoid structures in these CD8+CD20+ tumours. We derived a gene signature associated with tertiary lymphoid structures, which predicted clinical outcomes in cohorts of patients treated with immune checkpoint blockade. Furthermore, B-cell-rich tumours were accompanied by increased levels of TCF7+ naive and/or memory T cells. This was corroborated by digital spatial-profiling data, in which T cells in tumours without tertiary lymphoid structures had a dysfunctional molecular phenotype. Our results indicate that tertiary lymphoid structures have a key role in the immune microenvironment in melanoma, by conferring distinct T cell phenotypes. Therapeutic strategies to induce the formation of tertiary lymphoid structures should be explored to improve responses to cancer immunotherapy.
7.	Cabrita, Rita, et al. (författare) Tertiary lymphoid structures improve immunotherapy and survival in melanoma. 2020 Ingår i: Nature. - : Nature Publishing Group. - 1476-4687 .- 0028-0836. ; 577:7791, s. 561-565 Tidskriftsartikel (refereegranskat)abstract Checkpoint blockade therapies that reactivate tumour-associated T cells can induce durable tumour control and result in the long-term survival of patients with advanced cancers1. Current predictive biomarkers for therapy response include high levels of intratumour immunological activity, a high tumour mutational burden and specific characteristics of the gut microbiota2,3. Although the role of T cells in antitumour responses has thoroughly been studied, other immune cells remain insufficiently explored. Here we use clinical samples of metastatic melanomas to investigate the role of B cells in antitumour responses, and find that the co-occurrence of tumour-associated CD8+ T cells and CD20+ B cells is associated with improved survival, independently of other clinical variables. Immunofluorescence staining of CXCR5 and CXCL13 in combination with CD20 reveals the formation of tertiary lymphoid structures in these CD8+CD20+ tumours. We derived a gene signature associated with tertiary lymphoid structures, which predicted clinical outcomes in cohorts of patients treated with immune checkpoint blockade. Furthermore, B-cell-rich tumours were accompanied by increased levels of TCF7+ naive and/or memory T cells. This was corroborated by digital spatial-profiling data, in which T cells in tumours without tertiary lymphoid structures had a dysfunctional molecular phenotype. Our results indicate that tertiary lymphoid structures have a key role in the immune microenvironment in melanoma, by conferring distinct T cell phenotypes. Therapeutic strategies to induce the formation of tertiary lymphoid structures should be explored to improve responses to cancer immunotherapy.
8.	Cabrita, Rita, et al. (författare) The Role of PTEN Loss in Immune Escape, Melanoma Prognosis and Therapy Response 2020 Ingår i: Cancers. - : MDPI AG. - 2072-6694. ; 12:3 Tidskriftsartikel (refereegranskat)abstract Checkpoint blockade therapies have changed the clinical management of metastatic melanoma patients considerably, showing survival benefits. Despite the clinical success, not all patients respond to treatment or they develop resistance. Although there are several treatment predictive biomarkers, understanding therapy resistance and the mechanisms of tumor immune evasion is crucial to increase the frequency of patients benefiting from treatment. The PTEN gene is thought to promote immune evasion and is frequently mutated in cancer and melanoma. Another feature of melanoma tumors that may affect the capacity of escaping T-cell recognition is melanoma cell dedifferentiation characterized by decreased expression of the microphtalmia-associated transcription factor (MITF) gene. In this study, we have explored the role of PTEN in prognosis, therapy response, and immune escape in the context of MITF expression using immunostaining and genomic data from a large cohort of metastatic melanoma. We confirmed in our cohort that PTEN alterations promote immune evasion highlighted by decreased frequency of T-cell infiltration in such tumors, resulting in a worse patient survival. More importantly, our results suggest that dedifferentiated PTEN negative melanoma tumors have poor patient outcome, no T-cell infiltration, and transcriptional properties rendering them resistant to targeted- and immuno-therapy.
9.	Cervenka, Iris, et al. (författare) Exogenous hormone use and cutaneous melanoma risk in women : The European Prospective Investigation into Cancer and Nutrition 2020 Ingår i: International Journal of Cancer. - : John Wiley & Sons. - 0020-7136 .- 1097-0215. ; 146:12, s. 3267-3280 Tidskriftsartikel (refereegranskat)abstract Evidence suggests an influence of sex hormones on cutaneous melanoma risk, but epidemiologic findings are conflicting. We examined the associations between use of oral contraceptives (OCs) and menopausal hormone therapy (MHT) and melanoma risk in women participating in the European Prospective Investigation into Cancer and Nutrition (EPIC). EPIC is a prospective cohort study initiated in 1992 in 10 European countries. Information on exogenous hormone use at baseline was derived from country‐specific self‐administered questionnaires. We used Cox proportional hazards regression models to calculate hazard ratios (HRs) and 95% confidence intervals (CIs). Over 1992–2015, 1,696 melanoma cases were identified among 334,483 women, whereof 770 cases among 134,758 postmenopausal women. There was a positive, borderline‐significant association between OC use and melanoma risk (HR = 1.12, 95% CI = 1.00–1.26), with no detected heterogeneity across countries (phomogeneity = 0.42). This risk increased linearly with duration of use (ptrend = 0.01). Among postmenopausal women, ever use of MHT was associated with a nonsignificant increase in melanoma risk overall (HR = 1.14, 95% CI = 0.97–1.43), which was heterogeneous across countries (phomogeneity = 0.05). Our findings do not support a strong and direct association between exogenous hormone use and melanoma risk. In order to better understand these relations, further research should be performed using prospectively collected data including detailed information on types of hormone, and on sun exposure, which may act as an important confounder or effect modifier on these relations.
10.	Chandran, Vineesh Indira, et al. (författare) Hypoxia Attenuates Trastuzumab Uptake and Trastuzumab-Emtansine (T-DM1) Cytotoxicity through Redistribution of Phosphorylated Caveolin-1 2020 Ingår i: Molecular Cancer Research. - 1541-7786 .- 1557-3125. ; 18:4, s. 644-656 Tidskriftsartikel (refereegranskat)abstract The antibody-drug conjugate trastuzumab-emtansine (T-DM1) offers an additional treatment option for patients with HER2-amplified tumors. However, primary and acquired resistance is a limiting factor in a significant subset of patients. Hypoxia, a hallmark of cancer, regulates the trafficking of several receptor proteins with potential implications for tumor targeting. Here, we have investigated how hypoxic conditions may regulate T-DM1 treatment efficacy in breast cancer. The therapeutic effect of T-DM1 and its metabolites was evaluated in conjunction with biochemical, flow cytometry, and high-resolution imaging studies to elucidate the functional and mechanistic aspects of hypoxic regulation. HER2 and caveolin-1 expression was investigated in a well-annotated breast cancer cohort. Wefind that hypoxia fosters relative resistance to T-DM1 in HER2(+) cells (SKBR3 and BT474). This effect was not a result of deregulated HER2 expression or resistance to emtansine and its metabolites. Instead, we show that hypoxia-induced translocation of caveolin-1 from cytoplasmic vesicles to the plasma membrane contributes to deficient trastuzumab internalization and T-DM1 chemosensitivity. Caveolin-1 depletion mimicked the hypoxic situation, indicating that vesicular caveolin-1 is indispensable for trastuzumab uptake and T-DM1 cytotoxicity. In vitro studies suggested that HER2 and caveolin-1 are not coregulated, which was supported by IHC analysis in patient tumors. We find that phosphorylation-deficient caveolin-1 inhibits trastuzumab internalization and T-DM1 cytotoxicity, suggesting a specific role for caveolin-1 phosphorylation in HER2 trafficking.
11.	da Silva, Marisa, et al. (författare) Cohort profile : The Obesity and Disease Development Sweden (ODDS) study, a pooled cohort 2024 Ingår i: BMJ Open. - 2044-6055. ; 14:7 Tidskriftsartikel (refereegranskat)abstract PURPOSE: The Obesity and Disease Development Sweden (ODDS) study was designed to create a large cohort to study body mass index (BMI), waist circumference (WC) and changes in weight and WC, in relation to morbidity and mortality.PARTICIPANTS: ODDS includes 4 295 859 individuals, 2 165 048 men and 2 130 811 women, in Swedish cohorts and national registers with information on weight assessed once (2 555 098 individuals) or more (1 740 761 individuals), in total constituting 7 733 901 weight assessments at the age of 17-103 years in 1963-2020 (recalled weight as of 1911). Information on WC is available in 152 089 men and 212 658 women, out of whom 108 795 have repeated information on WC (in total 512 273 assessments). Information on morbidity and mortality was retrieved from national registers, with follow-up until the end of 2019-2021, varying between the registers.FINDINGS TO DATE: Among all weight assessments (of which 85% are objectively measured), the median year, age and BMI (IQR) is 1985 (1977-1994) in men and 2001 (1991-2010) in women, age 19 (18-40) years in men and 30 (26-36) years in women and BMI 22.9 (20.9-25.4) kg/m 2 in men and 23.2 (21.2-26.1) kg/m 2 in women. Normal weight (BMI 18.5-24.9 kg/m 2) is present in 67% of assessments in men and 64% in women and obesity (BMI≥30 kg/m 2) in 5% of assessments in men and 10% in women. The median (IQR) follow-up time from the first objectively measured or self-reported current weight assessment until emigration, death or end of follow-up is 31.4 (21.8-40.8) years in men and 19.6 (9.3-29.0) years in women. During follow-up, 283 244 men and 123 457 women died. FUTURE PLANS: The large sample size and long follow-up of the ODDS Study will provide robust results on anthropometric measures in relation to risk of common diseases and causes of deaths, and novel findings in subgroups and rarer outcomes.
12.	Eriksson, H., et al. (författare) The Proportion Cured of Patients with Resected Stage II-III Cutaneous Melanoma in Sweden 2021 Ingår i: Cancers. - : MDPI AG. - 2072-6694. ; 13:10 Tidskriftsartikel (refereegranskat)abstract Simple summary Patients diagnosed with stage II-III cutaneous melanoma (CM) are at high risk of recurrences, but the CM-specific survival ranges from approximately 40-70%. Here, the cure proportions and survival among uncured stage II-III CM patients were estimated. The 1- and 5-year relative survival ratios, cure proportions and the median survival times of uncured stage II-III CM patients in Sweden (n = 6466) were calculated based on data from the nationwide population-based Swedish Melanoma Register 2005-2013 with a follow-up through 2018. Proportions cured by surgery are low for sub-groups of stage II-III cutaneous melanoma showing that cure analyses can serve as a complement to established survival analyses. Background: Cure proportion represents the proportion of patients who experience the same mortality rate as the general population and can be estimated together with the survival of the proportion experiencing excess mortality (the uncured). The aim was to estimate the cure proportions and survival among uncured stage II-III cutaneous melanoma (CM) patients. Methods: 1- and 5-year relative survival ratios, cure proportions and the median survival times of uncured stage II-III CM patients in Sweden (n = 6466) were calculated based on data from the nationwide population-based Swedish Melanoma Register 2005-2013 with a follow-up through 2018. Results: Stages IIB and IIC showed significant differences in standardized cure proportions vs. stage IIA CM (0.80 (95% CI 0.77-0.83) stage IIA; 0.62 (95% CI 0.59-0.66) stage IIB; 0.42 (95% CI 0.37-0.46) for stage IIC). Significant differences in standardized cure proportions were found for stages IIIB and IIIC-D CM vs. stage IIIA (0.76 (95% CI 0.68-0.84) stage IIIA; 0.52 (95% CI 0.45-0.59) stage IIIB; 0.35 (95% CI 0.30-0.39) for stage IIIC-D). Conclusions: The results are emphasizing the poor prognosis with low proportions cured by surgery only for sub-groups of stage II-III CM, specifically within stages IIB-C CM.
13.	Eriksson, Hanna, et al. (författare) Trend shifts in age-specific incidence for in situ and invasive cutaneous melanoma in sweden 2021 Ingår i: Cancers. - : MDPI AG. - 2072-6694. ; 13:11 Tidskriftsartikel (refereegranskat)abstract Background: The incidence of invasive cutaneous melanoma (CM) is increasing in Sweden. The aim was to present age-and sex-specific trends of the age-standardised incidence and the average annual percentage change (AAPC) for in situ and invasive CM. Methods: Joinpoint regression models were used to analyse data from the Swedish Cancer Register and the Swedish Melanoma Registry 1997–2018 (N = 35,350 in situ CM; 59,932 CM). Results: The AAPC of CM for women was 4.5 (4.1–5.0; p < 0.001) for the period 1997–2018. For men, the APCC was 4.2 (3.0–5.4; p < 0.001), with a significantly higher annual percentage change (APC) for the period 2000–2018 (5.0; 4.6–5.4; p < 0.001) compared to 1997–1999. An increasing annual incidence of CM ≤ 0.6 mm and 0.7 mm Breslow tumour thickness was found for men with a significant incidence shift for the period 2006–2015, respectively. Similarly for women, with a significantly higher APC for CM ≤ 0.6 mm from 2005. The incidence of intermediate thick CM (2.1–4.0 mm) has not increased since 2011. The incidence of CM > 4.0 mm has been increasing among both sexes, with a significantly lower APC among women from 2005. Conclusions: The incidence of in situ and low-risk CM ≤ 1.0 mm in tumour thickness has been rising among both sexes since the 2000s.
14.	Gisslander, Karl, et al. (författare) Can active sun exposure decrease the risk of giant cell arteritis and polymyalgia rheumatica in women? 2023 Ingår i: Rheumatology Advances in Practice. - 2514-1775. ; 7:3 Tidskriftsartikel (refereegranskat)abstract ObjectivesTo study if active sun exposure among women affects the risk of developing GCA or PMR in a prospective cohort study with restricted latitudinal variability.MethodsWe linked the response to questions relating to sun exposure from the Melanoma Inquiry in Southern Sweden (MISS) prospective cohort study in women to the risk of developing GCA or PMR. Healthcare data were gathered from the Skåne Healthcare Register (SHR), covering all public healthcare consultations. The direct effect of active sun exposure on the risk of developing GCA or PMR was assessed using Cox proportional hazards models adjusted for covariates based on a directed acyclic graph.ResultsA total of 14 574 women were included in the study; 601 women were diagnosed with GCA or PMR (144 and 457, respectively) during the follow-up time. Women with moderate or high sun exposure were not less likely to develop GCA or PMR compared with women that indicated they avoided sun exposure [hazard ratio (HR) 1.2 (CI 0.9, 1.6) and 1.3 (0.9, 1.9), respectively] when adjusted for diabetes, hyperlipidaemia, hypertension, smoking, obesity and stratified by age. Similar patterns were observed when studying only GCA [HR 1.2 (CI 0.7, 2.3) and 1.3 (0.7, 2.6)] and only PMR [HR 1.3 (CI 0.9, 1.8) and 1.4 (0.9, 2.0)].ConclusionActive sun exposure did not affect the risk of developing GCA or PMR in women in a cohort with restricted latitudinal variability.
15.	Godina, Christopher, et al. (författare) Caveolin-1 gene expression provides additional prognostic information combined with PAM50 risk of recurrence (ROR) score in breast cancer 2024 Ingår i: Scientific Reports. - : Springer Nature. - 2045-2322. ; 14 Tidskriftsartikel (refereegranskat)abstract Combining information from the tumor microenvironment (TME) with PAM50 Risk of Recurrence (ROR) score could improve breast cancer prognostication. Caveolin-1 (CAV1) is a marker of an active TME. CAV1 is a membrane protein involved in cell signaling, extracellular matrix organization, and tumor-stroma interactions. We sought to investigate CAV1 gene expression in relation to PAM50 subtypes, ROR score, and their joint prognostic impact. CAV1 expression was compared between PAM50 subtypes and ROR categories in two cohorts (SCAN-B, n = 5326 and METABRIC, n = 1980). CAV1 expression was assessed in relation to clinical outcomes using Cox regression and adjusted for clinicopathological predictors. Effect modifications between CAV1 expression and ROR categories on clinical outcome were investigated using multiplicative and additive two-way interaction analyses. Differential gene expression and gene set enrichment analyses were applied to compare high and low expressing CAV1 tumors. All samples expressed CAV1 with the highest expression in the Normal-like subtype. Gene modules consistent with epithelial-mesenchymal transition (EMT), hypoxia, and stromal activation were associated with high CAV1 expression. CAV1 expression was inversely associated with ROR category. Interactions between CAV1 expression and ROR categories were observed in both cohorts. High expressing CAV1 tumors conferred worse prognosis only within the group classified as ROR high. ROR gave markedly different prognostic information depending on the underlying CAV1 expression. CAV1, a potential mediator between the malignant cells and TME, could be a useful biomarker that enhances and further refines PAM50 ROR risk stratification in patients with ROR high tumors and a potential therapeutic target.
16.	Godina, Christopher, et al. (författare) Caveolin-1 genotypes as predictor for locoregional recurrence and contralateral disease in breast cancer 2023 Ingår i: Breast Cancer Research and Treatment. - : Springer. - 0167-6806 .- 1573-7217. ; 199:2, s. 335-347 Tidskriftsartikel (refereegranskat)abstract PurposeCaveolin-1 (CAV1) has been implicated in breast cancer oncogenesis and metastasis and may be a potential prognosticator, especially for non-distant events. CAV1 functions as a master regulator of membrane transport and cell signaling. Several CAV1 SNPs have been linked to multiple cancers, but the prognostic impact of CAV1 SNPs in breast cancer remains unclear. Here, we investigated CAV1 polymorphisms in relation to clinical outcomes in breast cancer.MethodsA cohort of 1017 breast cancer patients (inclusion 2002–2012, Sweden) were genotyped using Oncoarray by Ilumina. Patients were followed for up to 15 years. Five out of six CAV1 SNPs (rs10256914, rs959173, rs3807989, rs3815412, and rs8713) passed quality control and were used for haplotype construction. CAV1 genotypes and haplotypes in relation to clinical outcomes were assessed with Cox regression and adjusted for potential confounders (age, tumor characteristics, and adjuvant treatments).ResultsOnly one SNP was associated with lymph node status, no other SNPs or haplotypes were associated with tumor characteristics. The CAV1 rs3815412 CC genotype (5.8% of patients) was associated with increased risk of contralateral breast cancer, adjusted hazard ratio (HRadj) 4.26 (95% CI 1.86–9.73). Moreover, the TTACA haplotype (13% of patients) conferred an increased risk for locoregional recurrence HRadj 2.24 (95% CI 1.24–4.04). No other genotypes or haplotypes were associated with clinical outcome.ConclusionCAV1 polymorphisms were associated with increased risk for locoregional recurrence and contralateral breast cancer. These findings may identify patients that could derive benefit from more tailored treatment to prevent non-distant events, if confirmed.
17.	Godina, Christopher, et al. (författare) High Caveolin-1 mRNA expression in triple-negative breast cancer is associated with an aggressive tumor microenvironment, chemoresistance, and poor clinical outcome 2024 Ingår i: PLoS ONE. - 1932-6203. ; 19:7, s. 1-21 Tidskriftsartikel (refereegranskat)abstract BACKGROUND: Currently, there are few treatment-predictive and prognostic biomarkers in triple-negative breast cancer (TNBC). Caveolin-1 (CAV1) is linked to chemoresistance and several important processes involved in tumor progression and metastasis, such as epithelial-mesenchymal transition (EMT). Herein, we report that high CAV1 gene expression is an independent factor of poor prognosis in TNBC.METHODS: CAV1 gene expression was compared across different molecular features (e.g., PAM50 subtypes). CAV1 expression was assessed in relation to clinical outcomes using Cox regression adjusted for clinicopathological predictors. Differential gene expression and gene set enrichment analyses were applied to compare high- and low-expressing CAV1 tumors. Tumor microenvironment composition of high- and low-expressing CAV1 tumors was estimated using ECOTYPER. Tumor tissue microarrays were used to evaluate CAV1 protein levels in stromal and malignant cells.RESULTS: In the SCAN-B (n = 525) and GSE31519 (n = 327) cohorts, patients with CAV1-high tumors had an increased incidence of early recurrence adjusted HR 1.78 (95% CI 1.12-2.81) and 2.20 (95% CI 1.39-3.47), respectively. In further analysis, high CAV1 gene expression was associated with a molecular profile indicating altered metabolism, neovascularization, chemoresistance, EMT, suppressed immune response, and active tumor microenvironment. Protein levels of CAV1 in malignant and stromal cells were not correlated with CAV1 gene expression.CONCLUSION: CAV1 gene expression in TNBC is a biomarker that merits further investigation in clinical trials and as a therapeutic target.
18.	Godina, Christopher, et al. (författare) Interplay between Caveolin-1 and body and tumor size affects clinical outcomes in breast cancer 2022 Ingår i: Translational Oncology. - : Elsevier. - 1944-7124 .- 1936-5233. ; 22 Tidskriftsartikel (refereegranskat)abstract Background: Caveolin-1 (CAV1) is associated with cholesterol-rich membrane raft domains and is a master regulator of cell signaling and membrane transport. Here, we investigated CAV1's role in cellular compartments of breast cancer in relation to signaling pathways, clinicopathological features, and clinical outcomes.Methods: CAV1 levels were evaluated with immunohistochemistry in cytoplasm of invasive tumor cells and stromal cells in tumor tissue microarrays from a cohort of 1018 breast cancer patients (inclusion 2002-2012, Sweden). Cytoplasmic and stromal CAV1 were categorized as positive/negative and strong/not strong, respectively. CAV1 expression in relation to clinical outcomes was assessed with Cox regression. Investigations into CAV1 functional pathways was conducted in the STRING, GOBO, and TCGA databases.Results: CAV1 expression was associated with non-luminal subtypes, cell cycle control, inflammation, epithelialmesenchymal transition, and the IGF/Insulin system. Generally, CAV1 was not associated with recurrence risk. Stromal CAV1's impact on recurrence risk was modified by BMI > 25 kg/m(2) (P-interaction = 0.002), waist > 80 cm (P-interaction = 0.005), and invasive tumor size (pT2/3/4) (P-interaction = 0.028). In low-risk patients only, strong stromal CAV1 significantly increased recurrence risk (HRs(adj) > 1.61). In all patients, positive cytoplasmic CAV1 conferred > 2-fold risk for contralateral disease HRadj 2.63 (95% CI 1.36-5.10). Strong stromal CAV1 conferred nearly 2-fold risk for locoregional recurrence HRadj 1.88 (95% CI 1.09-3.24).Conclusions: CAV1's prognostic impact depended on its localization, anthropometric, and tumor factors. Stromal CAV1 predicted high recurrence risk in a group of supposedly "low-risk' patients. Cytoplasmic CAV1 predicted metachronous contralateral disease. If confirmed, CAV1 could be used as treatment target and for risk stratification.
19.	Godina, Christopher, et al. (författare) Prognostic Impact of Menopausal Hormone Therapy in Breast Cancer Differs According to Tumor Characteristics and Treatment 2020 Ingår i: Frontiers in Oncology. - : Frontiers Media SA. - 2234-943X. ; 10 Tidskriftsartikel (refereegranskat)abstract This study investigated how a history of menopausal hormone therapy (MHT) impacts clinical outcomes overall and in different subgroups of breast cancer patients. The study included 814 primary breast cancer patients aged ≥50 years in Sweden (2002–2012) with follow-up until 2016. Associations between patient- and tumor characteristics, recurrences, and overall survival were analyzed in relation to MHT. After a median follow-up of 7 years, 119 recurrences, and 111 deaths occurred. Ever MHT (n = 433, 53.2%) was associated with a lower BMI, frequency of alcohol abstinence, and histological grade, higher frequency of oral contraceptive use, and lobular cancer. Overall, MHT was not associated with prognosis, but there were significant effect modifications by estrogen receptor (ER) status, node status, main histological type, and aromatase inhibitor (AI) treatment on recurrence-risk (all Pinteractions≤ 0.017). MHT conferred an increased recurrence-risk in patients with ER- tumors, adjusted Hazard Ratio (HRadj) 3.99 (95% Confidence Interval (CI) 1.40–11.33), in node-negative patients HRadj 1.88 (95% CI 1.11–3.17), and in non-AI-treated patients HRadj 1.81 (95% CI 1.01–3.24), but decreased recurrence-risk in AI-treated patients HRadj 0.46 (95% CI 0.25–0.84) and in patients with lobular cancer HRadj 0.15 (95% CI 0.04–0.64). MHT was associated with lower risk of death in node-positive patients HRadj of 0.48 (95% CI 0.27–0.86) and in AI-treated patients HRadj of 0.41 (95% CI 0.22–0.77), but not in other patients (both Pinteractions≤ 0.027). A history of MHT may have prognostic value for certain subgroups of breast cancer patients such as AI-treated or node-negative patients.
20.	Godina, Christopher, et al. (författare) Prognostic impact of tumor-specific insulin-like growth factor binding protein 7 (IGFBP7) levels in breast cancer : A prospective cohort study 2021 Ingår i: Carcinogenesis. - : Oxford University Press (OUP). - 0143-3334 .- 1460-2180. ; 42:11, s. 1314-1325 Tidskriftsartikel (refereegranskat)abstract The prognostic impact of insulin-like growth factor binding protein 7 (IGFBP7) in breast cancer is unclear. Host factors, including lifestyle, anthropometry and metabolic profile, might influence tumor-specific IGFBP7. This study aimed to investigate whether IGFBP7 levels and messenger ribonucleic acid (mRNA) expression are associated with the patient and tumor characteristics and prognosis in breast cancer. Patients with primary breast cancer in Lund, Sweden, were included preoperatively in the study between 2002 and 2012 (n = 1018). Tumor-specific IGFBP7 protein levels were evaluated with immunohistochemistry using tissue microarrays in tumors from 878 patients. IGFBP7 mRNA expression and its corresponding clinical data were obtained from The Cancer Genome Atlas and analyzed for 809 patients. Tumor-specific IGFBP7 protein levels were categorized based on Histo 300 scores into IGFBP7low (6.2%), IGFBP7intermediate (75.7%) and IGFBP7high (18.1%). Both low IGFBP7 protein levels and mRNA expression were associated with less aggressive tumor characteristics. Overall, IGFBP7low conferred low recurrence risk. The prognostic impact of IGFBP7high varied according to any alcohol consumption and tamoxifen treatment. IGFBP7high was associated with low recurrence risk in alcohol consumers but high recurrence risk in alcohol abstainers (Pinteraction= 0.039). Moreover, the combination of IGFBP7high and estrogen receptor-positive tumors was associated with low recurrence risk only in tamoxifen-treated patients (Pinteraction= 0.029). To conclude, IGFBP7low might be a good, independent prognosticator in breast cancer. The prognostic impact of IGFBP7high depends on host factors and treatment. IGFBP7 merits further investigation to confirm whether it could be a suitable biomarker for treatment selection.
21.	Hansén Nord, Karolin, et al. (författare) Concomitant deletions of tumor suppressor genes MEN1 and AIP are essential for the pathogenesis of the brown fat tumor hibernoma. 2010 Ingår i: Proceedings of the National Academy of Sciences. - : Proceedings of the National Academy of Sciences. - 1091-6490 .- 0027-8424. ; Dec, s. 21122-21127 Tidskriftsartikel (refereegranskat)abstract Hibernomas are benign tumors with morphological features resembling brown fat. They consistently display cytogenetic rearrangements, typically translocations, involving chromosome band 11q13. Here we demonstrate that these aberrations are associated with concomitant deletions of AIP and MEN1, tumor suppressor genes that are located 3 Mb apart and that underlie the hereditary syndromes pituitary adenoma predisposition and multiple endocrine neoplasia type I. MEN1 and AIP displayed a low expression in hibernomas whereas the expression of genes up-regulated in brown fat-PPARA, PPARG, PPARGC1A, and UCP1-was high. Thus, loss of MEN1 and AIP is likely to be pathogenetically essential for hibernoma development. Simultaneous loss of two tumor suppressor genes has not previously been shown to result from a neoplasia-associated translocation. Furthermore, in contrast to the prevailing assumption that benign tumors harbor relatively few genetic aberrations, the present analyses demonstrate that a considerable number of chromosome breaks are involved in the pathogenesis of hibernoma.
22.	Harbst, Katja, et al. (författare) Multiregion whole-exome sequencing uncovers the genetic evolution and mutational heterogeneity of early-stage metastatic melanoma 2016 Ingår i: Cancer Research. - 0008-5472. ; 76:16, s. 4765-4774 Tidskriftsartikel (refereegranskat)abstract Cancer genome sequencing has shed light on the underlying genetic aberrations that drive tumorigenesis. However, current sequencing-based strategies, which focus on a single tumor biopsy, fail to take into account intratumoral heterogeneity. To address this challenge and elucidate the evolutionary history of melanoma, we performed whole-exome and transcriptome sequencing of 41 multiple melanoma biopsies from eight individual tumors. This approach revealed heterogeneous somatic mutations in the range of 3%-38% in individual tumors. Known mutations in melanoma drivers BRAF and NRAS were always ubiquitous events. Using RNA sequencing, we found that the majority of mutations were not expressed or were expressed at very low levels, and preferential expression of a particular mutated allele did not occur frequently. In addition, we found that the proportion of ultraviolet B (UVB) radiation-induced C>T transitions differed significantly (P <0.001) between early and late mutation acquisition, suggesting that different mutational processes operate during the evolution of metastatic melanoma. Finally, clinical history reports revealed that patients harboring a high degree of mutational heterogeneity were associated with more aggressive disease progression. In conclusion, our multiregion tumor-sequencing approach highlights the genetic evolution and non-UVB mutational signatures associated with melanoma development and progression, and may provide a more comprehensive perspective of patient outcome.
23.	Helgadottir, Hildur, et al. (författare) Multiple primary melanoma incidence trends over five decades, a nation-wide population-based study 2021 Ingår i: Journal of the National Cancer Institute. - : Oxford University Press (OUP). - 1460-2105 .- 0027-8874. ; 113:3, s. 318-328 Tidskriftsartikel (refereegranskat)abstract BACKGROUND: Over the past decades many regions have experienced a steady increase in the incidence of cutaneous melanoma. Here, we report on incidence trends for subsequent primary melanoma.METHODS: In this nationwide population-based study, patients diagnosed with a first primary cutaneous melanoma reported to the Swedish Cancer Registry, were followed for up to ten years for a diagnosis of subsequent primary melanoma. Patients were grouped with patients diagnosed with first melanoma in the same decade (1960s, 1970s, 1980s, 1990s and 2000s, respectively). Frequencies, incidence rates (IRs), standardized incidence ratios (SIRs) and 95% confidence intervals (CIs) for second melanomas were calculated. All tests of statistical significance were two-sided.RESULTS: 54,884 patients with melanoma were included and 2,469 were diagnosed, within ten years, with subsequent melanomas. Over the five decades there was a statistically significant steady increase in the frequency, IR and SIR for second primary melanoma. For example, in the 1960s cohort, <1% (1.0 (95% CI = 0.5-1.7) and 1.1 (95% CI = 0.5-1.9) per 1,000 person-years in women and men, respectively) had second primary melanoma and this rose to 6.4% (7.5 (95% CI = 6.8-8.3) per 1,000 person-years) in the women and 7.9% (10.3 (95% CI = 9.3-11.2) per 1,000 person-years) in the men in the 2000s cohort. This rise was seen, independent of age, sex, invasiveness or site of the melanoma. Further, in patients diagnosed with a second melanoma, the frequency of those having >2 melanomas increased statistically significantly and was 0.0% in the 1960s and rose to 18.0% in the 2000s (P <.001).CONCLUSIONS: This is the first study to evaluate and report on a rising trend for subsequent primary melanoma. Additional primary melanomas worsen the patients' survival and precautions are needed to turn this steep upgoing trend.
24.	Helkkula, Teo, et al. (författare) Acral Melanoma Incidence and Survival Trends in 1990–2020: A Nationwide, Population-based Study 2024 Ingår i: Acta Dermato-Venereologica. - 1651-2057. ; 104 Tidskriftsartikel (refereegranskat)abstract Acral melanoma is a clinical subtype of melanoma with high mortality, on which research is limited in scope. This study aimed to assess incidence trends and melanoma-specific survival rates for acral melanoma in the Swedish population from 1990 to 2020.This cross-sectional study included patients with an acral melanoma diagnosis from 1990 to 2020 from the nationwide, population-based Swedish Melanoma Registry. Analyses on acral melanoma melanoma-specific survival rates were adjusted for age, sex, histopathological subtype, and tumour thickness. Clinicopathological features and melanoma-specific survival rates were compared between diagnostic periods: 1990–1999, 2000–2009, and 2010–2020, respectively. Changes in standardized incidence rates in 1996–2020 were evaluated separately for males and females. In total, 1,000 acral melanomas in 999 patients were included in the study. No significant yearly change in standardized incidence rates for either males or females was observed, even though the absolute number of cases increased. Factors such as male sex, age ≥ 70 years, and Breslow thickness > 1.0 were independently linked to lower melanoma-specific survival. The 5-year melanoma-specific survival across the studied period ranged from 75.8% to 77.9% for females, and from 62.4% to 71.7% for males.
25.	Helkkula, Teo, et al. (författare) BioMEL : a translational research biobank of melanocytic lesions and melanoma 2024 Ingår i: BMJ Open. - 2044-6055. ; 14:2 Tidskriftsartikel (refereegranskat)abstract Introduction Diagnosing invasive cutaneous melanoma (CM) can be challenging due to subjectivity in distinguishing equivocal nevi, melanoma in situ and thin CMs. The underlying molecular mechanisms of progression from nevus to melanoma must be better understood. Identifying biomarkers for treatment response, diagnostics and prognostics is crucial. Using biomedical data from biobanks and population-based healthcare data, translational research can improve patient care by implementing evidence-based findings. The BioMEL biobank is a prospective, multicentre, large-scale biomedical database on equivocal nevi and all stages of primary melanoma to metastases. Its purpose is to serve as a translational resource, enabling researchers to uncover objective molecular, genotypic, phenotypic and structural differences in nevi and all stages of melanoma. The main objective is to leverage BioMEL to significantly improve diagnostics, prognostics and therapy outcomes of patients with melanoma. Methods and analysis The BioMEL biobank contains biological samples, epidemiological information and medical data from adult patients who receive routine care for melanoma. BioMEL is focused on primary and metastatic melanoma, but equivocal pigmented lesions such as clinically atypical nevi and melanoma in situ are also included. BioMEL data are gathered by questionnaires, blood sampling, tumour imaging, tissue sampling, medical records and histopathological reports. Ethics and dissemination The BioMEL biobank project is approved by the national Swedish Ethical Review Authority (Dnr. 2013/101, 2013/339, 2020/00469, 2021/01432 and 2022/02421-02). The datasets generated are not publicly available due to regulations related to the ethical review authority. Trial registration number NCT05446155.
26.	Holmberg, Carl Jacob, et al. (författare) ASO Visual Abstract: Prognostic Significance ofSentinelLymphNodeStatusinThick Primary Melanomas (> 4mm) 2023 Ingår i: Annals of surgical oncology. - 1534-4681. ; 30:13, s. 8034-8035 Tidskriftsartikel (refereegranskat)
27.	Holmberg, Carl Jacob, et al. (författare) Prognostic Significance of Sentinel Lymph Node Status in Thick Primary Melanomas (> 4 mm) 2023 Ingår i: Annals of Surgical Oncology. - : SPRINGER. - 1068-9265 .- 1534-4681. ; 30:13, s. 8026-8033 Tidskriftsartikel (refereegranskat)abstract BackgroundThe key prognostic factors for staging patients with primary cutaneous melanoma are Breslow thickness, ulceration, and sentinel lymph node (SLN) status. The multicenter selective lymphadenectomy trial (MSLT-I) verified SLN status as the most important prognostic factor for patients with intermediate-thickness melanoma (Breslow thickness, 1-4 mm). Although most international guidelines recommend SLN biopsy (SLNB) also for patients with thick (> 4 mm, pT4) melanomas, its prognostic role has been questioned. The primary aim of this study was to establish whether SLN status is prognostic in T4 melanoma tumors.MethodsData for all patients with a diagnosis of primary invasive cutaneous melanoma of Breslow thickness greater than 1 mm in Sweden between 2007 and 2020 were retrieved from the Swedish Melanoma Registry, a large prospective population-based registry. A multivariable Cox proportional hazard model for melanoma-specific survival (MSS) was constructed based on Breslow thickness stratified for SLN status.ResultsThe study enrolled 10,491 patients, 1943 of whom had a Breslow thickness greater than 4 mm (pT4). A positive SLN was found for 34% of these pT4 patients. The 5-year MSS was 71%, and the 10-year MSS was 62%. There was a statistically significant difference in MSS between the patients with a positive SLN and those with a negative SLN (hazard ratio of 2.4 (95% confidence interval CI 1.6-3.5) for stage T4a and 2.0 (95% CI 1.6-2.5) for satage T4b.ConclusionSentinel lymph node status gives important prognostic information also for patients with thick (> 4 mm) melanomas, and the authors thus recommend that clinical guidelines be updated to reflect this.
28.	Holmberg, Carl Jacob, et al. (författare) Surgery of metastatic melanoma after systemic therapy - the SUMMIST trial : study protocol for a randomized controlled trial 2021 Ingår i: Acta Oncologica. - : Taylor & Francis. - 0284-186X .- 1651-226X. ; 60:1, s. 52-55 Tidskriftsartikel (refereegranskat)
29.	Huss, Linnea, et al. (författare) The Vitamin D Receptor as a Prognostic Marker in Breast Cancer-A Cohort Study 2024 Ingår i: Nutrients. - 2072-6643. ; 16:7, s. 1-15 Tidskriftsartikel (refereegranskat)abstract Previous research has indicated an association between the presence of the vitamin D receptor (VDR) in breast cancer tissue and a favorable prognosis. This study aimed to further evaluate the prognostic potential of VDR located in the nuclear membrane or nucleus (liganded). The VDR protein levels were analyzed using immunohistochemistry in tumor samples from 878 breast cancer patients from Lund, Sweden, included in the Breast Cancer and Blood Study (BCBlood) from October 2002 to June 2012. The follow-up for breast cancer events and overall survival was recorded until 30 June 2019. Univariable and multivariable survival analyses were conducted, both with complete case data and with missing data imputed using multiple imputation by chained equations (MICE). Tumor-specific positive nuclear membrane VDR(num) staining was associated with favorable tumor characteristics and a longer breast cancer free interval (BCFI; HR: 0.64; 95% CI: 0.44-0.95) and overall survival (OS; HR: 0.52; 95% CI: 0.34-0.78). Further analyses indicated that VDRnum status also was predictive of overall survival when investigated in relation to ER status. There were significant interactions between VDR and invasive tumor size (Pinteraction = 0.047), as well as mode of detection (Pinteraction = 0.049). VDRnum was associated with a longer BCFI in patients with larger tumors (HR: 0.36; 95% CI: 0.14-0.93) or clinically detected tumors (HR: 0.28; 95% CI: 0.09-0.83), while no association was found for smaller tumors and screening-detected tumors. Further studies are suggested to confirm our results and to evaluate whether VDR should and could be used as a prognostic and targetable marker in breast cancer diagnostics.
30.	Ingvar, Åsa M, et al. (författare) Participation in a Prospective Cohort Study on Melanoma did not Affect the Incidence and Mortality of the Studied Disease 2020 Ingår i: Acta Dermato-Venereologica. - : Medical Journals Sweden AB. - 1651-2057 .- 0001-5555. ; 100:1 Tidskriftsartikel (refereegranskat)abstract Prospective observational studies have shown previously that study participants have lower morbidity and mortality than non-participants. The aim of the current study was to determine whether participants in a prospective cohort study on melanoma have a different incidence and mortality of melanoma compared with non-participants and the background population. Information was collected from Swedish National Registers on participants (n = 30,501) and non-participants (n = 10,499) in the "Melanoma In Southern Sweden" (MISS) study and the background population (n = 243,032). Hazard ratios were calculated for overall incidence of cancer and melanoma, and all-cause and melanoma-specific mortality, using Cox regression. Participants had a lower overall incidence of cancer and all-cause mortality than non-participants and the background population. There was no difference in incidence of melanoma or melanoma-specific characteristics between participants and the background population. In conclusion, participants in the MISS study have a slightly better general health, but are a representative sample of the population with regard to studies of melanoma risk factors.
31.	Isaksson, Karolin, et al. (författare) A Population-Based Comparison of the AJCC 7th and AJCC 8th Editions for Patients Diagnosed with Stage III Cutaneous Malignant Melanoma in Sweden. 2019 Ingår i: Annals of surgical oncology. - : Springer Science and Business Media LLC. - 1534-4681 .- 1068-9265. ; 26:9, s. 2839-2845 Tidskriftsartikel (refereegranskat)abstract Cutaneous melanoma is steadily increasing worldwide. The new AJCC 8th edition was recently launched and introduced several changes in melanoma staging, particularly for stage III. We conducted a population-based registry study with the purpose to evaluate the impact and prognostic accuracy of the new classification in Sweden.Consecutive patients diagnosed with stage III melanoma between January 2005 and September 2017 were identified by the Swedish Melanoma Registry (SMR) and included for analyses. Patients with multiple primary melanomas were excluded. Patients were classified according to the AJCC 7th as well as the 8th edition. Melanoma-specific survival (MSS) was retrieved from the Swedish Cause of Death Registry.A total of 2067 eligible patients were identified from the SMR; 1150 patients (57%) changed stage III subgroup when reclassified according to the AJCC 8th edition. The median 5- and 10-year MSS for the whole cohort of stage III melanoma patients was 59% and 51% respectively. The MSS for substage IIIA, B, and C were all improved when patients were reclassified by using to the AJCC 8th edition. The newly defined substage IIID had the worst prognosis with a 10-year MSS of 16%.A high proportion of patients diagnosed with stage III melanoma in Sweden between 2005 and 2017 was restaged to another subgroup, when they were reclassified according to the AJCC 8th of staging manual. We established an improved MSS for all substages compared with the former AJCC 7th edition. This may have implications on decisions about adjuvant treatment.
32.	Isaksson, Karolin, et al. (författare) Cationic polypeptides in a concept of oppositely charged polypeptides as prevention of postsurgical intraabdominal adhesions 2011 Ingår i: Journal of Biomedical Science and Engineering. - : Scientific Research Publishing, Inc.. - 1937-6871 .- 1937-688X. ; 4:3, s. 200-206 Tidskriftsartikel (populärvet., debatt m.m.)abstract Two differently charged polypeptides, α-poly-L-lysine and poly-L-glutamate, have previ- ously been shown to effectively reduce postoperative intraabdominal adhesions. Though α-poly-L-lysine showed toxicity in doses too close to the lowest the-rapeutic dose, the aim in the present study was to investigate the possible antiadhesive effect of another four cationic polypeptides.
33.	Isaksson, Karolin, et al. (författare) In vivo toxicity and biodistribution of intraperitoneal and intravenous poly-L-lysine and poly-L-lysine/poly-L-glutamate in rats. 2014 Ingår i: Journal of Materials Science: Materials in Medicine. - : Springer Science and Business Media LLC. - 1573-4838 .- 0957-4530. ; 25:5, s. 1293-1299 Tidskriftsartikel (refereegranskat)abstract The combination of two differently charged polypeptides, poly-L-lysine (PL) and poly-L-glutamate (PG), has shown excellent postsurgical antiadhesive properties. However, the high molecular, positively charged PL is toxic in high doses, proposed as lysis of red blood cells. This study aims to elucidate the in vivo toxicity and biodistribution of PL and complex bound PLPG comparing intravenous and intraperitoneal administration. Fifty-six Sprague-Dawley rats were used in a model with repeated blood samples within 30 min examining blood gases and blood smears. Similarly, FITC labelled PL were used to track bio distribution and clearance of PL, given as single dose and complex bound to PG after intravenous and intraperitoneal administration. Tissue for histology and immunohistochemistry was collected. Blood gases and blood smears as well as histology points to a toxic effect of high dose PL given intravenously but not after intraperitoneal administration. The toxic effect is exerted through endothelial disruption and subsequent bleeding in the lungs, provoking sanguineous lung edema. FITC-labelled PL experiments reveal a rapid clearance with differences between routes and complex binding. This study advocates a new theory of the toxic effects in vivo of high molecular PL. PLPG complex is safe to use as antiadhesive prevention based on this toxicity study given that PL is always intraperitoneally administered in combination with PG and that the dose is adequate.
34.	Isaksson, Karolin, et al. (författare) Long-term Follow-up for Adhesive Small Bowel Obstruction After Open Versus Laparoscopic Surgery for Suspected Appendicitis. 2014 Ingår i: Annals of Surgery. - 1528-1140. ; 259:6, s. 1173-1177 Tidskriftsartikel (refereegranskat)abstract The aim of the present study was to compare the frequency of readmissions due to small bowel obstruction (SBO) after open versus laparoscopic surgery performed for suspected acute appendicitis.
35.	Isaksson, Karolin, et al. (författare) Sentinel lymph node biopsy in patients with thin melanomas : Frequency and predictors of metastasis based on analysis of two large international cohorts 2018 Ingår i: Journal of Surgical Oncology. - : Wiley. - 0022-4790 .- 1096-9098. ; 118:4, s. 599-605 Tidskriftsartikel (refereegranskat)abstract Background: Sentinel lymph node (SLN) metastasis in patients with thin melanomas (≤1 mm) is uncommon but adverse prognostic factors may indicate an increased risk. We sought to determine how often SLN biopsy (SLNB) was performed in patients with thin melanomas, establish the frequency of SLN metastasis and evaluate the predictive value of ulceration, tumor mitotic rate, and thickness for SLN involvement. Methods: Melanoma patients with a Breslow thickness greater than or equal to 0.5 to less than or equal to 1 mm, diagnosed 2009-2016, were identified in the Swedish Melanoma Register (SMR) and the Melanoma Institute Australia (MIA) Database. Results: In total 8165 patients were included from the SMR and 1603 from MIA. SLNB was performed in 9.5% and 16.2% of patients, respectively. Corresponding figures for T1b (American Joint Committee on Cancer [AJCC] 7th Edition) were 19.5% and 24.6%. The SLN positivity rate were 4.4% (Sweden) and 5.8% (MIA). SLN metastasis was more frequent in tumors with ulceration, mitoses, and Breslow thickness greater than or equal to 0.9 mm but none were statistically significant. Younger age was identified as a significant risk factor for SLN positivity at MIA. Conclusions: A minority of patients with thin melanomas had SLNB performed and the SLN positivity rate was low. This study did not confirm tumor ulceration, mitoses, or thickness as statistically significant predictors for SLN metastasis.
36.	Isaksson, Karolin (författare) Small bowel obstruction and toxicity of a new model of adhesion prevention 2014 Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract Abstract Background: Small bowel obstruction (SBO) is a common surgical diagnosis. If no signs of strangulation are evident, the majority of the patients can be conservatively managed. Approximately one third of the patients need surgical treatment and there is a need for early parameters that can predict operative intervention. The etiology of SBO in most cases is postoperative abdominal adhesions. Laparoscopic surgery generates less surgical trauma and thereby possibly less adhesion formation and subsequent decreased risk of SBO. The burden of postoperative adhesions is substantial and there is a need for an adhesion preventive agent that can be used in different clinical situations and reduce the clinical complications caused by adhesions, ie SBO, infertility and chronic abdominal pain. Previous experimental studies have reported promising anti adhesive effect of intraabdominally installed differently charged polypeptides in different clinical settings. However, there was observed toxicity of the cationic polypeptide when administered alone. Aims/methods: The aims of the retrospective clinical studies were to identify early parameters predicting surgical intervention in patients with SBO (I) and to determine whether there is a difference in the incidence of SBO after open versus laparoscopic surgery for suspected appendicitis (II). In the experimental studies the aims were to establish the lowest anti adhesive dose of α-polylysine (PL) in combination with polyglutamate (PG) and determine the toxic dose of α-PL (III), to investigate the possible anti adhesive effect of another four cationic polypeptides in combination with PG (IV). Furthermore, explore the mechanism of toxicity as well as the biodistribution of α-PL, alone or in combination with PG, after intravenous and intraperitoneal administration (V). Results/conclusions: 109 patients were included, 65 were conservatively managed and 44 were surgically treated. We identified five parameters, possible to retrieve within 4 hours from hospital admission, that were more frequent in the patients that were surgically treated for SBO. These parameters can possibly be used to advance the selection of patients for operation (I). The incidence of SBO after open and laparoscopic surgery for suspected appendicitis was low in both groups, 1% (24/2333) and 0,4% (10/2372) respectively. The difference was minor but significant, favoring the laparoscopic approach (II). We could show that the anti adhesive effect of α-PL/PG was dose dependent and the lowest effective dose for α-PL was established. The toxic dose of α-PL was determined and the gap between the lowest effective dose and the toxic dose is probably too narrow (III). All four alternative cationic polypeptides (polyarginine, lactoferrin, lysozyme,ε-PL) investigated in the fourth study showed anti adhesive effect. ε-PL, another isoform of PL, was superior to the other three and showed less toxicity than α-PL (IV). High doses of intravenous α-PL caused a damage to endothelial cells with subsequent edema and extravasation of blood in lung and liver. The biodistribution and accumulation of α-PL and α-PL/PG in blood and organs is lower and slower after intraperitoneal than intravenous administration (V).
37.	Isaksson, Karolin, et al. (författare) Small bowel obstruction: early parameters predicting the need for surgical intervention 2011 Ingår i: European Journal of Trauma and Emergency Surgery. - : Springer Science and Business Media LLC. - 1863-9933 .- 1863-9941. ; 37:2, s. 155-159 Tidskriftsartikel (refereegranskat)abstract To study and identify early clinical and radiological findings that could help to predict operative intervention for small bowel obstruction. One hundred and nine consecutive patients with small bowel obstruction who underwent small bowel follow-through examination with Gastrografin(A (R)) during 2005-2006. The patients were divided into an operative group and a non-operative group, n = 44 and 65, respectively. Findings primarily noted were those which were possible to register within 1-4 h from hospital arrival. In univariate analyses, factors found to be significantly associated with surgical intervention were no prior abdominal surgery, the presence of radiological differential air fluid levels, and absence of flatulence 24 h prior to admission, CRP > 10 mg/L and dehydration at admission. In multivariate analyses, the presence of dehydration and radiological differentiated air fluid levels were independent predictive factors of significance. Absence of all factors significantly favored non-operative treatment, while operative treatment was significantly favored when two or more factors were present. The presence of two or more early predictive factors as defined above, available at admission, significantly correlates with a likelihood of complete obstruction and the need of surgical intervention.
38.	Isaksson, Karolin, et al. (författare) Toxicity and Dose Response of Intra-Abdominally Administered Poly-L-alpha-Lysine and Poly-L-Glutamate for Postoperative Adhesion Protection. 2010 Ingår i: European Surgical Research. - : S. Karger AG. - 0014-312X .- 1421-9921. ; 44:1, s. 17-22 Tidskriftsartikel (refereegranskat)abstract Background/Aims: Two differently charged polypeptides, poly-L-lysine (PL) and poly-L-glutamate (PG), have previously been shown to reduce postoperative intra-abdominal adhesions. This study aims to investigate the possible toxic effects and to establish a lowest effective antiadhesive dose. Methods: 152 mice were investigated with a well-known adhesion model and given different concentrations of the two differently charged polypeptides as well as only the cationic PL. Results: For the first time, a probable toxic level of PL given intraperitoneally (40 mg/kg) and the lowest significant concentration of PL and PG for antiadhesive purposes (1.6 mg/kg) could be established. Conclusion: The gap between the possible toxicity level of PL and the lowest efficient antiadhesive dose is probably too narrow, and the shape and charge of PL warrant continuous research for another polycation in the concept of differently charged polypeptides used as antiadhesive agents.
39.	Katsarelias, Dimitrios, et al. (författare) ASO Author Reflections: Effects of the Updated AJCC Classification for Patients with Stage III Melanoma. 2019 Ingår i: Annals of surgical oncology. - : Springer Science and Business Media LLC. - 1534-4681 .- 1068-9265. ; 26, s. 713-4 Forskningsöversikt (refereegranskat)
40.	Khazaei, Somayeh, et al. (författare) Research Paper Impact of combining vitamin C with radiation therapy in human breast cancer : Does it matter? 2022 Ingår i: Oncotarget. - 1949-2553. ; 13:1, s. 439-453 Tidskriftsartikel (refereegranskat)abstract Vitamin C may impact the efficiency of radiation therapy (RT) in breast cancer. The effects of RT alone or in combination with vitamin C in SKBR3, MDA-MB-231, and MCF7 cells were compared using clonogenic assay, proliferation assay (MTT), cell cycle analysis, and Western blot. Vitamin C use was assessed in 1803 breast cancer patients 2002–2017 in relation to clinicopathological features and recurrences after RT. Vitamin C combined with RT resulted in non-significant increases in colony formation and minor differences in cell cycle arrest and expression of studied proteins, compared to RT alone. Lower vitamin C doses alone or in combination with RT, resulted in higher proliferation with MTT than higher vitamin C doses in a cell line-dependent manner. Vitamin C use was associated with lower histological grade and BMI but not recurrence risk in RT-treated patients (LogRank P = 0.54). Vitamin C impacted RT efficiency differently depending on breast cancer subtype and vitamin C concentration. Lower doses of vitamin C, achievable with oral administration, might increase breast cancer cell proliferation and decrease radiosensitivity. Despite vitamin C users having less aggressive tumors than non-users, the recurrence risk in RT-treated patients was similar in vitamin C users and non-users.
41.	Kimbung, Siker, et al. (författare) CYP27A1 expression is associated with risk of late lethal estrogen receptor-positive breast cancer in postmenopausal patients 2020 Ingår i: Breast Cancer Research. - : Springer Science and Business Media LLC. - 1465-5411 .- 1465-542X. ; 22:1 Tidskriftsartikel (refereegranskat)abstract Background: 27-Hydroxycholesterol (27HC) stimulates estrogen receptor-positive (ER+) breast cancer (BC) progression. Inhibiting the sterol 27-hydroxylase (CYP27A1) abrogates these growth-promoting effects of 27HC in mice. However, the significance of CYP27A1 expression on BC biology and prognosis is unclear. Methods: Intratumoral CYP27A1 expression in invasive BC was measured by immunohistochemistry in two Swedish population-based cohorts (n = 645 and n = 813, respectively). Cox proportional hazards models were used to evaluate the association between CYP27A1 expression and prognosis. Results: CYP27A1 was highly expressed in less than 1/3 of the tumors. High CYP27A1 expression was more frequent among high-grade tumors lacking hormone receptor expression and with larger tumor sizes. Over a median of 12.2 years follow-up in cohort 1, high CYP27A1 expression was associated with impaired survival, specifically after 5 years from diagnosis among all patients [overall survival (OS), HRadjusted = 1.93, 95%CI = 1.26–2.97, P = 0.003; breast cancer-specific survival (BCSS), HRadjusted = 2.33, 95%CI = 1.28–4.23, P = 0.006] and among patients ≥ 55 years presenting with ER+ tumors [OS, HRadjusted = 1.99, 95%CI = 1.24–3.21, P = 0.004; BCSS, HRadjusted = 2.78, 95%CI = 1.41–5.51, P = 0.003]. Among all patients in cohort 2 (median follow-up of 7.0 years), CYP27A1 expression was significantly associated with shorter OS and RFS in univariable analyses across the full follow-up period. However after adjusting for tumor characteristics and treatments, the association with survival after 5 years from diagnosis was non-significant among all patients [OS, HRadjusted = 1.08, 95%CI = 0.05–2.35, P = 0.83 and RFS, HRadjusted = 1.22, 95%CI = 0.68–2.18, P = 0.50] as well as among patients ≥ 55 years presenting with ER+ tumors [OS, HRadjusted = 0.46 95% CI = 0.11–1.98, P = 0.30 and RFS, HRadjusted = 0.97 95% CI = 0.44–2.10, P = 0.93]. Conclusion: CYP27A1 demonstrated great potentials as a biomarker of aggressive tumor biology and late lethal disease in postmenopausal patients with ER+ BC. Future studies should investigate if the benefits of prolonged endocrine therapy and cholesterol-lowering medication in BC are modified by CYP27A1 expression.
42.	Lauss, Martin, et al. (författare) Molecular patterns of resistance to immune checkpoint blockade in melanoma 2024 Ingår i: Nature Communications. - 2041-1723. ; 15:1 Tidskriftsartikel (refereegranskat)abstract Immune checkpoint blockade (ICB) has improved outcome for patients with metastatic melanoma but not all benefit from treatment. Several immune- and tumor intrinsic features are associated with clinical response at baseline. However, we need to further understand the molecular changes occurring during development of ICB resistance. Here, we collect biopsies from a cohort of 44 patients with melanoma after progression on anti-CTLA4 or anti-PD1 monotherapy. Genetic alterations of antigen presentation and interferon gamma signaling pathways are observed in approximately 25% of ICB resistant cases. Anti-CTLA4 resistant lesions have a sustained immune response, including immune-regulatory features, as suggested by multiplex spatial and T cell receptor (TCR) clonality analyses. One anti-PD1 resistant lesion harbors a distinct immune cell niche, however, anti-PD1 resistant tumors are generally immune poor with non-expanded TCR clones. Such immune poor microenvironments are associated with melanoma cells having a de-differentiated phenotype lacking expression of MHC-I molecules. In addition, anti-PD1 resistant tumors have reduced fractions of PD1+ CD8+ T cells as compared to ICB naïve metastases. Collectively, these data show the complexity of ICB resistance and highlight differences between anti-CTLA4 and anti-PD1 resistance that may underlie differential clinical outcomes of therapy sequence and combination.
43.	Lindgren, Hampus, et al. (författare) Potential interplay between tumor size and vitamin D receptor (VDR) polymorphisms in breast cancer prognosis : a prospective cohort study Ingår i: Cancer Causes and Control. - 0957-5243. Tidskriftsartikel (refereegranskat)abstract Purpose: Vitamin D has some anticancer properties that may decrease breast cancer risk and improve prognosis. The aim was to investigate associations between four previously studied VDR SNPs (Taq1, Tru91, Bsm1, and Fok1) and prognosis in different groups of breast cancer patients. Methods: VDR genotyping of 1,017 breast cancer patients included 2002–2012 in Lund, Sweden, was performed using Oncoarray. Follow-up was until June 30, 2019. Clinical data and patient information were collected from medical records and questionnaires. Cox regression was used for survival analyses. Results: Genotype frequencies were as follows: Fok1 (AA 15.7%, AG 49.1%, GG 35.1%), Bsm1 (CC 37.2%, CT 46.1%, TT 16.7%), Tru91 (CC 77.8%, CT 20.7%, TT 1.5%), and Taq1 (AA 37.2%, AG 46.2%, GG 16.6%). During follow-up there were 195 breast cancer events. The homozygous variants of Taq1 and Bsm1 were associated with reduced risk of breast cancer events (adjusted HR = 0.59, 95% CI 0.38–0.92 for Taq1 and adjusted HR = 0.61, 95% CI 0.40–0.94 for Bsm1). The G allele of the Fok1 was associated with increased risk of breast cancer events in small tumors (pT1, adjusted HR = 1.83, 95% CI 1.04–3.23) but not in large tumors (pT2/3/4, adjusted HR = 0.80, 95% CI 0.41–1.59) with a borderline interaction (Pinteraction = 0.058). No interactions between VDR genotypes and adjuvant treatments regarding breast cancer prognosis were detected. Conclusion: VDR genotypes were associated with breast cancer prognosis and the association might be modified by tumor size. Further research is needed to confirm the findings and elucidate their potential clinical implications.
44.	Lyth, Johan, et al. (författare) Population-based prognostic instrument (SweMR 2.0) for melanoma- specific survival- An ideal tool for individualised treatment decisions for Swedish patients 2023 Ingår i: European Journal of Surgical Oncology. - : ELSEVIER SCI LTD. - 0748-7983 .- 1532-2157. ; 49:10 Tidskriftsartikel (refereegranskat)abstract Introduction: The prognosis for patients with melanoma has improved due to better treatments in recent years and updated tools to accurately predict an individual's risk are warranted. This study aims to describe a prognostic instrument for patients with cutaneous melanoma and its potential as a clinical device for treatment decisions.Methods: Patients with localised invasive cutaneous melanoma diagnosed in 1990-2021 with data on tumour thickness were identified from the population-based Swedish Melanoma Registry. The parametric Royston-Parmar (RP) method was used to estimate melanoma-specific survival (MSS) probabilities. Separate models were constructed for patients (<= 1 mm) and (>1 mm) and prognostic groups were created based on all combinations of age, sex, tumour site, tumour thickness, absence/presence of ulceration, histopathologic type, Clark's level of invasion, mitoses and sentinel lymph node (SLN) status.Results: In total, 72 616 patients were identified, 41 764 with melanoma <= 1 mm and 30 852 with melanoma >1 mm. The most important variable was tumour thickness for both (<= 1 mm) and (>1 mm), that explained more than 50% of the survival. The second most important variables were mitoses (<= 1 mm) and SLN status (>1 mm). The prognostic instrument successfully created probabilities for >30 000 prognostic groups.Conclusions: The Swedish updated population-based prognostic instrument, predicts MSS survival up to 10 years after diagnosis. The prognostic instrument gives more representative and up-to-date prognostic information for Swedish patients with primary melanoma than the present AJCC staging. Additional to clinical use and the adjuvant setting, the information retrieved could be used to plan future studies.
45.	Mboya, Innocent B, et al. (författare) Time trends of the association of body mass index with mortality in 3.5 million young Swedish adults 2024 Ingår i: Annals of Epidemiology. - : Elsevier. - 1047-2797 .- 1873-2585. ; 97, s. 23-32 Tidskriftsartikel (refereegranskat)abstract Purpose: We investigated time trends of the obesity-mortality association, accounting for age, sex, and cause-specific deaths.Methods: We analysed pooled nationwide data in Sweden for 3,472,310 individuals aged 17–39 years at baseline in 1963–2016. Cox regression and flexible parametric survival models investigated BMI-mortality associations in sub-groups of sex and baseline calendar years (men: <1975, 1975–1985, ≥1985 and women: <1985, 1985–1994, ≥1995).Results: Comparing men with obesity vs. normal weight, all-cause and “other-cause” mortality associations decreased over periods; HR (95% CI) 1.92 (1.83–2.01) and 1.70 (1.58–1.82) for all-cause and 1.72 (1.58–1.87) and 1.40 (1.28–1.53) for “other-cause” mortality in <1975 and ≥1985, but increased for CVD mortality; HR 2.71 (2.51–2.94) and 3.91 (3.37–4.53). Higher age at death before 1975 coincided with more obesity-related deaths at higher ages. Furthermore, the all-cause mortality association for different ages in men showed no clear differences between periods (p-interaction=0.09), suggesting no calendar effect after accounting for attained age. Similar, but less pronounced, results were observed in women. Associations with cancer mortality showed no clear trends in men or in women.Conclusions: Accounting for differences in age and death causes between calendar periods when investigating BMI-mortality time trends may avoid misinterpreting the risks associated with obesity over time.
46.	Middha, Pooja K., et al. (författare) A genome-wide gene-environment interaction study of breast cancer risk for women of European ancestry 2023 Ingår i: Breast Cancer Research. - : BioMed Central (BMC). - 1465-5411 .- 1465-542X. ; 25:1 Tidskriftsartikel (refereegranskat)abstract Background Genome-wide studies of gene-environment interactions (GxE) may identify variants associated with disease risk in conjunction with lifestyle/environmental exposures. We conducted a genome-wide GxE analysis of similar to 7.6 million common variants and seven lifestyle/environmental risk factors for breast cancer risk overall and for estrogen receptor positive (ER +) breast cancer. Methods Analyses were conducted using 72,285 breast cancer cases and 80,354 controls of European ancestry from the Breast Cancer Association Consortium. Gene-environment interactions were evaluated using standard unconditional logistic regression models and likelihood ratio tests for breast cancer risk overall and for ER + breast cancer. Bayesian False Discovery Probability was employed to assess the noteworthiness of each SNP-risk factor pairs. Results Assuming a 1 x 10(-5) prior probability of a true association for each SNP-risk factor pairs and a Bayesian False Discovery Probability < 15%, we identified two independent SNP-risk factor pairs: rs80018847(9p13)-LINGO2 and adult height in association with overall breast cancer risk (ORint = 0.94, 95% CI 0.92-0.96), and rs4770552(13q12)-SPATA13 and age at menarche for ER + breast cancer risk (ORint = 0.91, 95% CI 0.88-0.94). Conclusions Overall, the contribution of GxE interactions to the heritability of breast cancer is very small. At the population level, multiplicative GxE interactions do not make an important contribution to risk prediction in breast cancer.
47.	Mitra, Shamik, et al. (författare) Analysis of DNA methylation patterns in the tumor immune microenvironment of metastatic melanoma 2020 Ingår i: Molecular Oncology. - : Wiley. - 1574-7891 .- 1878-0261. ; 14:5, s. 933-950 Tidskriftsartikel (refereegranskat)abstract The presence of immune cells in the tumor microenvironment has been associated with response to immunotherapies across several cancer types, including melanoma. Despite its therapeutic relevance, characterization of the melanoma immune microenvironments remains insufficiently explored. To distinguish the immune microenvironment in a cohort of 180 metastatic melanoma clinical specimens, we developed a method using promoter CpG methylation of immune cell type-specific genes extracted from genome-wide methylation arrays. Unsupervised clustering identified three immune-methylation clusters with varying levels of immune CpG methylation that are related to patient survival. Matching protein and gene expression data further corroborated the identified epigenetic characterization. Exploration of the possible immune exclusion mechanisms at play revealed likely dependency on MITF protein level and PTEN loss-of-function events for melanomas unresponsive to immunotherapies (immune-low). To understand if melanoma tumors resemble other solid tumors in terms of immune-methylation characteristics, we explored 15 different solid tumor cohorts from TCGA. Low-dimensional projection based on immune cell type-specific methylation revealed grouping of the solid tumors in line with melanoma immune-methylation clusters rather than tumor types. Association of survival outcome with immune cell type-specific methylation differed across tumor and cell types. However, in melanomas immune-cell type-specific methylation was associated with inferior patient survival. Exploration of the immune-methylation patterns in a pan-cancer context suggested that specific immune-microenvironments might occur across the cancer spectrum. Together, our findings underscore the existence of diverse immune microenvironments, which may be informative for future immunotherapeutic applications.
48.	Naeser, Ylva, et al. (författare) Patients with thin cutaneous malignant melanoma have similar survival as the general population. A Swedish population-based matched cohort study Annan publikation (övrigt vetenskapligt/konstnärligt)
49.	Naeser, Ylva, et al. (författare) TRIM study protocol - a prospective randomized multicenter Trial to assess the Role of Imaging during follow-up after radical surgery of stage IIB-C and III cutaneous malignant Melanoma 2020 Ingår i: BMC Cancer. - : Springer Science and Business Media LLC. - 1471-2407. ; 20:1 Tidskriftsartikel (refereegranskat)abstract BackgroundThe incidence of cutaneous malignant melanoma (CMM) is increasing worldwide. In Sweden, over 4600 cases were diagnosed in 2018. The prognosis after radical surgery varies considerably with tumor stage. In recent years, new treatment options have become available for metastatic CMM. Early onset of treatment seems to improve outcome, which suggests that early detection of recurrent disease should be beneficial. Consequently, in several countries imaging is a part of the routine follow-up program after surgery of high risk CMM. However, imaging has drawbacks, including resources required (costs, personnel, equipment) and the radiation exposure. Furthermore, many patients experience anxiety in waiting for the imaging results and investigations of irrelevant findings is another factor that also could cause worry and lead to decreased quality of life. Hence, the impact of imaging in this setting is important to address and no randomized study has previously been conducted. The Swedish national guidelines stipulate follow-up for 3years by clinical examinations only.MethodsThe TRIM study is a prospective randomized multicenter trial evaluating the potential benefit of imaging and blood tests during follow-up after radical surgery for high-risk CMM, compared to clinical examinations only. Primary endpoint is overall survival (OS) at 5years. Secondary endpoints are survival from diagnosis of relapse and health-related quality of life (HRQoL). Eligible for inclusion are patients radically operated for CMM stage IIB-C or III with sufficient renal function for iv contrast-enhanced CT and who are expected to be fit for treatment in case of recurrence. The planned number of patients is >1300. Patients are randomized to clinical examinations for 3years +/- whole-body imaging with CT or FDG-PET/CT and laboratory tests including S100B protein and LDH. This academic study is supported by the Swedish Melanoma Study Group.DiscussionThis is the first randomized prospective trial on the potential benefit of imaging as a part of the follow-up scheme after radical surgery for high-risk CMM.ResultsThe first patient was recruited in June 2017 and as of April 2020, almost 500 patients had been included at 19 centers in Sweden.Trial registrationClinicalTrials.gov, NCT 03116412. Registered 17 April 2017, https://clinicaltrials.gov/ct2/show/study/NCT03116412
50.	Nilsson, Linn, et al. (författare) Patient Characteristics Influence Activated Signal Transducer and Activator of Transcription 3 (STAT3) Levels in Primary Breast Cancer—Impact on Prognosis 2020 Ingår i: Frontiers in Oncology. - : Frontiers Media SA. - 2234-943X. ; 10 Tidskriftsartikel (refereegranskat)abstract Background: Activated signal transducer and activator of transcription 3 (pSTAT3) is often present in breast cancer, but its prognostic impact is still unclear. We investigated how breast tumor-specific pSTAT3Y705 levels are associated with patient and tumor characteristics and risk of recurrence. Materials and Methods: Primary breast cancer patients without preoperative treatment were included preoperatively. The patients were treated in Lund, Sweden, in 2002–2012 and followed until 2016. Levels of pSTAT3Y705 were evaluated in 867 tumors using tissue microarrays with immunohistochemistry and categorized according to the H-score as negative (0–9; 24.2%), intermediate (10–150; 69.9%), and high (160–300; 5.9%). Results: Patients were followed for up to 13 years, and 137 recurrences (88 distant) were recorded. Higher pSTAT3Y705 levels were associated with patient characteristics including younger age, any alcohol consumption, higher age at first child birth, and smaller body size, as well as tumor characteristics including smaller tumor size, lower histological grade, lymph node negativity, progesterone receptor positivity, and HER2 negativity (all Ptrends ≤ 0.04). Higher pSTAT3Y705 levels were associated with lower risk of early recurrences (LogRank Ptrend = 0.10; 5-year LogRank Ptrend = 0.004) and distant metastases (LogRank Ptrend = 0.045; 5-year LogRank Ptrend = 0.0007), but this was not significant in the multivariable models. There was significant effect modification between tamoxifen treatment and pSTAT3Y705 negativity on the recurrence risk in chemonaïve patients with estrogen receptor positive tumors [adjusted hazard ratio (HR) 0.38; Pinteraction = 0.046]. Conclusion: Higher pSTAT3Y705 levels were associated with several patient and tumor characteristics that are mainly associated with good prognosis and a tendency toward lower risk for early recurrences. In the future, these results may help guide the selection of patients for trials with drugs targeting the STAT3 pathway.

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