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  • 1.
    Aaltonen, Kristina E.
    et al.
    Lund University, Sweden.
    Rosendahl, Ann H.
    Lund University, Sweden; Skåne University Hospital, Sweden.
    Olsson, Hans
    Linköping University, Department of Clinical and Experimental Medicine, Division of Inflammation Medicine. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Center for Diagnostics, Department of Clinical Pathology and Clinical Genetics.
    Malmstrom, Per
    Lund University, Sweden; Skåne University Hospital, Sweden.
    Hartman, Linda
    Lund University, Sweden; Regional Cancer Centre South, Sweden.
    Ferno, Marten
    Lund University, Sweden.
    Association between insulin-like growth factor-1 receptor (IGF1R) negativity and poor prognosis in a cohort of women with primary breast cancer2014In: BMC Cancer, ISSN 1471-2407, E-ISSN 1471-2407, Vol. 14, no 794Article in journal (Refereed)
    Abstract [en]

    Background: Resistance towards endocrine therapy is a great concern in breast cancer treatment and may partly be explained by the activation of compensatory signaling pathways. The aim of the present study was to investigate if the insulin-like growth factor-1 receptor (IGF1R) signaling pathway was activated or deregulated in breast cancer patients and to explore if any of the markers were prognostic, with or without adjuvant tamoxifen. This signaling pathway has been suggested to cause estrogen independent cell growth and thus contribute to resistance to endocrine treatment in estrogen receptor (ER) positive breast cancer. Methods: The protein expression of IGF1R, phosphorylated Mammalian Target of Rapamycin (p-mTOR) and phosphorylated S6 ribosomal protein (p-S6rp) were investigated by immunohistochemistry using tissue microarrays in two patient cohorts. Cohort I (N = 264) consisted of mainly postmenopausal women with stage II breast cancer treated with tamoxifen for 2 years irrespective of ER status. Cohort II (N = 206) consisted of mainly medically untreated, premenopausal patients with node-negative breast cancer. Distant disease-free survival (DDFS) at 5 years was used as end-point for survival analyses. Results: We found that lower IGF1R expression was associated with worse prognosis for tamoxifen treated, postmenopausal women (HR = 0.70, 95% CI = 0.52 - 0.94, p = 0.016). The effect was seen mainly in ER-negative patients where the prognostic effect was retained after adjustment for other prognostic markers (adjusted HR = 0.49, 95% CI = 0.29 - 0.82, p = 0.007). Expression of IGF1R was associated with ER positivity (p less than 0.001) in the same patient cohort. Conclusions: Our results support previous studies indicating that IGF1R positivity reflects a well differentiated tumor with low metastatic capacity. An association between lack of IGF1R expression and worse prognosis was mainly seen in the ER-negative part of Cohort I. The lack of co-activation of downstream markers (p-mTOR and p-S6rp) in the IGF1R pathway suggested that the prognostic effect was not due to complete activation of this pathway. Thus, no evidence could be found for a compensatory function of IGF1R signaling in the investigated cohorts.

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  • 2.
    Asowed, Mustafa
    et al.
    Linköping University, Department of Biomedical and Clinical Sciences. Linköping University, Faculty of Medicine and Health Sciences.
    Elander, Nils
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Surgery, Orthopedics and Oncology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Oncology.
    Pettersson, Linn
    Ryhov Cty Hosp, Sweden.
    Ekholm, Maria
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Surgery, Orthopedics and Oncology. Linköping University, Faculty of Medicine and Health Sciences. Ryhov Cty Hosp, Sweden.
    Papantoniou, Dimitrios
    Ryhov Cty Hosp, Sweden; Uppsala Univ, Sweden.
    Activity and safety of KEES-an oral multi-drug chemo-hormonal metronomic combination regimen in metastatic castration-resistant prostate cancer2023In: BMC Cancer, ISSN 1471-2407, E-ISSN 1471-2407, Vol. 23, no 1, article id 309Article in journal (Refereed)
    Abstract [en]

    BackgroundMetastatic castration-resistant prostate cancer (mCRPC) remains a therapeutic challenge and evidence for late-line treatments in real-life is limited. The present study investigates the efficacy and safety of an oral metronomic chemo-hormonal regimen including cyclophosphamide, etoposide, estramustine, ketoconazole and prednisolone (KEES) administered in a consecutive biweekly schedule.MethodsA retrospective cohort study in two Swedish regions was conducted. Overall (OS) and progression-free survival (PFS), biochemical response rate (bRR) and toxicities were analyzed.ResultsOne hundred and twenty-three patients treated with KEES after initial treatment with at least a taxane or an androgen-receptor targeting agents (ARTA) were identified. Of those, 95 (77%) had received both agents and were the primary analysis population. Median (95% CI) OS and PFS in the pre-treated population were 12.3 (10.1-15.0) and 4.4 (3.8-5.5) months, respectively. Biochemical response, defined as >= 50% prostate-specific antigen (PSA) reduction, occurred in 26 patients (29%), and any PSA reduction in 59 (65%). PFS was independent of prior treatments used, and KEES seemed to be effective in late treatment lines. The bRR was higher compared to historical data of metronomic treatments in docetaxel and ARTA pre-treated populations. In multivariable analyses, performance status (PS) >= 2 and increasing alkaline phosphatase (ALP) predicted for worse OS. Nausea, fatigue, thromboembolic events and bone marrow suppression were the predominant toxicities.ConclusionsKEES demonstrated meaningful efficacy in heavily pre-treated CRPC patients, especially those with PS 0-1 and lower baseline ALP, and had an acceptable toxicity profile.

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  • 3.
    Berger, Karoline
    et al.
    Univ Gothenburg, Sweden.
    Rhost, Sara
    Univ Gothenburg, Sweden.
    Rafnsdottir, Svanheidur
    Univ Gothenburg, Sweden; Natl Univ Hosp Iceland, Iceland.
    Hughes, Eamon
    Univ Gothenburg, Sweden.
    Magnusson, Ylva
    Univ Gothenburg, Sweden.
    Ekholm, Maria
    Linköping University, Department of Biomedical and Clinical Sciences. Linköping University, Faculty of Medicine and Health Sciences. Lund Univ, Sweden; Department of Oncology, Region Jönköping County, Jönköping, Sweden.
    Stål, Olle
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Surgery, Orthopedics and Oncology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Oncology. 3 Department of Oncology, Region Jönköping County, Jönköping, Sweden.
    Ryden, Lisa
    Lund Univ, Sweden.
    Landberg, Goran
    Univ Gothenburg, Sweden.
    Tumor co-expression of progranulin and sortilin as a prognostic biomarker in breast cancer2021In: BMC Cancer, ISSN 1471-2407, E-ISSN 1471-2407, Vol. 21, no 1, article id 185Article in journal (Refereed)
    Abstract [en]

    Background The growth factor progranulin has been implicated in numerous biological processes such as wound healing, inflammation and progressive tumorigenesis. Both progranulin and its receptor sortilin are known to be highly expressed in subgroups of breast cancer and have been associated with various clinical properties including tamoxifen resistance. Recent data further suggest that progranulin, via its receptor sortilin, drives breast cancer stem cell propagation in vitro and increases metastasis formation in an in vivo breast cancer xenograft model. In this retrospective biomarker analysis, we aimed to determine whether tumor co-expression of progranulin and sortilin has prognostic and treatment predictive values for breast cancer patients. Methods We explored how co-expression of progranulin and sortilin was associated with established clinical markers by analyzing a tissue microarray including 560 randomized premenopausal breast cancer patients receiving either 2 years of tamoxifen treatment or no adjuvant treatment, with a median follow-up time of 28 years. Breast cancer-specific survival was analyzed using Kaplan-Meier and Cox Proportional Hazards regression models to assess the prognostic and predictive value of progranulin and sortilin in relation to known clinical markers. Results Co-expression of progranulin and sortilin was observed in 20% of the breast cancer samples. In untreated patients, prognostic considerations could be detailed separately from treatment prediction and the high progranulin and sortilin expressing subgroup was significantly associated with breast cancer-specific death in multivariable analyses (HR=2.188, CI: 1.317-3.637, p=0.003) along with tumor size, high tumor grade and lymph node positivity. When comparing the untreated patients with tamoxifen treated patients in the ER alpha positive subgroup, co-expression of progranulin and sortilin was not linked to tamoxifen resistance. Conclusion Data suggest that co-expression of progranulin and its receptor sortilin is a novel prognostic biomarker combination identifying a highly malignant subgroup of breast cancer. Importantly, this subpopulation could potentially be targeted with anti-sortilin based therapies.

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  • 4.
    Berntsen, Sveinung
    et al.
    Uppsala University, Sweden; University of Agder, Norway.
    Aaronson, Neil K.
    Netherlands Cancer Institute, Netherlands.
    Buffart, Laurien
    Vrije University of Amsterdam Medical Centre, Netherlands; Vrije University of Amsterdam Medical Centre, Netherlands.
    Börjeson, Sussanne
    Linköping University, Department of Medical and Health Sciences, Division of Nursing Science. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Oncology.
    Demmelmaier, Ingrid
    Uppsala University, Sweden.
    Hellbom, Maria
    Lund University, Sweden.
    Hojman, Pernille
    Copenhagen University Hospital, Denmark.
    Igelstrom, Helena
    Uppsala University, Sweden.
    Johansson, Birgitta
    Uppsala University, Sweden.
    Pingel, Ronnie
    Uppsala University, Sweden.
    Raastad, Truls
    Norwegian School Sport Science, Norway.
    Velikova, Galina
    University of Leeds, England.
    Asenlof, Pernilla
    Uppsala University, Sweden.
    Nordin, Karin
    Uppsala University, Sweden; University of Agder, Norway.
    Design of a randomized controlled trial of physical training and cancer ( Phys-Can) the impact of exercise intensity on cancer related fatigue, quality of life and disease outcome2017In: BMC Cancer, ISSN 1471-2407, E-ISSN 1471-2407, Vol. 17, article id 218Article in journal (Refereed)
    Abstract [en]

    Background: Cancer-related fatigue is a common problem in persons with cancer, influencing health-related quality of life and causing a considerable challenge to society. Current evidence supports the beneficial effects of physical exercise in reducing fatigue, but the results across studies are not consistent, especially in terms of exercise intensity. It is also unclear whether use of behaviour change techniques can further increase exercise adherence and maintain physical activity behaviour. This study will investigate whether exercise intensity affects fatigue and health related quality of life in persons undergoing adjuvant cancer treatment. In addition, to examine effects of exercise intensity on mood disturbance, adherence to oncological treatment, adverse effects from treatment, activities of daily living after treatment completion and return to work, and behaviour change techniques effect on exercise adherence. We will also investigate whether exercise intensity influences inflammatory markers and cytokines, and whether gene expressions following training serve as mediators for the effects of exercise on fatigue and health related quality of life. Methods/design: Six hundred newly diagnosed persons with breast, colorectal or prostate cancer undergoing adjuvant therapy will be randomized in a 2 x 2 factorial design to following conditions; A) individually tailored low-to-moderate intensity exercise with or without behaviour change techniques or B) individually tailored high intensity exercise with or without behaviour change techniques. The training consists of both resistance and endurance exercise sessions under the guidance of trained coaches. The primary outcomes, fatigue and health related quality of life, are measured by self-reports. Secondary outcomes include fitness, mood disturbance, adherence to the cancer treatment, adverse effects, return to activities of daily living after completed treatment, return to work as well as inflammatory markers, cytokines and gene expression. Discussion: The study will contribute to our understanding of the value of exercise and exercise intensity in reducing fatigue and improving health related quality of life and, potentially, clinical outcomes. The value of behaviour change techniques in terms of adherence to and maintenance of physical exercise behaviour in persons with cancer will be evaluated.

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  • 5.
    Blomstrand, Hakon
    et al.
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Surgery, Orthopedics and Oncology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Clinical pathology.
    Green, Henrik
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Drug Research. Linköping University, Faculty of Medicine and Health Sciences. Natl Board Forens Med, Dept Forens Genet & Forens Toxicol, S-58758 Linkoping, Sweden.
    Fredrikson, Mats
    Linköping University, Faculty of Medicine and Health Sciences, Forum Östergötland.
    Gransmark, Emma
    Kalmar Cty Hosp, Sweden.
    Björnsson, Bergthor
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Surgery, Orthopedics and Oncology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Surgery in Linköping.
    Elander, Nils
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Surgery, Orthopedics and Oncology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Oncology.
    Clinical characteristics and blood/serum bound prognostic biomarkers in advanced pancreatic cancer treated with gemcitabine and nab-paclitaxel2020In: BMC Cancer, ISSN 1471-2407, E-ISSN 1471-2407, Vol. 20, no 1, article id 950Article in journal (Refereed)
    Abstract [en]

    Background

    In recent years treatment options for advanced pancreatic cancer have markedly improved, and a combination regimen of gemcitabine and nab-paclitaxel is now considered standard of care in Sweden and elsewhere. Nevertheless, a majority of patients do not respond to treatment. In order to guide the individual patient to the most beneficial therapeutic strategy, simple and easily available prognostic and predictive markers are needed.

    Methods

    The potential prognostic value of a range of blood/serum parameters, patient-, and tumour characteristics was explored in a retrospective cohort of 75 patients treated with gemcitabine/nab-paclitaxel (Gem/NabP) for advanced pancreatic ductal adenocarcinoma (PDAC) in the South Eastern Region of Sweden. Primary outcome was overall survival (OS) while progression free survival (PFS) was the key secondary outcome.

    Result

    Univariable Cox regression analysis revealed that high baseline serum albumin (> 37 g/L) and older age (> 65) were positive prognostic markers for OS, and in multivariable regression analysis both parameters were confirmed to be independent prognostic variables (HR 0.48, p = 0.023 and HR = 0.47, p = 0.039,). Thrombocytopenia at any time during the treatment was an independent predictor for improved progression free survival (PFS) but not for OS (HR 0.49, p = 0.029, 0.54, p = 0.073), whereas thrombocytopenia developed under cycle 1 was neither related with OS nor PFS (HR 0.87, p = 0.384, HR 1.04, p = 0.771). Other parameters assessed (gender, tumour stage, ECOG performance status, myelosuppression, baseline serum CA19–9, and baseline serum bilirubin levels) were not significantly associated with survival.

    Conclusion

    Serum albumin at baseline is a prognostic factor with palliative Gem/NabP in advanced PDAC, and should be further assessed as a tool for risk stratification. Older age was associated with improved survival, which encourages further studies on the use of Gem/NabP in the elderly.

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  • 6.
    Blomstrand, Hakon
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Surgery, Orthopedics and Oncology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Clinical pathology. Ryhov Cty Hosp, Sweden.
    Scheibling, Ursula
    Ryhov Cty Hosp, Sweden.
    Bratthall, Charlotte
    Kalmar Cty Hosp, Sweden.
    Green, Henrik
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Medicine and Health Sciences. Natl Board Forens Med, Dept Forens Genet and Forens Toxicol, S-58758 Linkoping, Sweden.
    Elander, Nils
    Linköping University, Department of Clinical and Experimental Medicine, Division of Surgery, Orthopedics and Oncology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Oncology.
    Real world evidence on gemcitabine and nab-paclitaxel combination chemotherapy in advanced pancreatic cancer2019In: BMC Cancer, ISSN 1471-2407, E-ISSN 1471-2407, Vol. 19, article id 40Article in journal (Refereed)
    Abstract [en]

    BackgroundIn the recent phase III trial MPACT the combination of gemcitabine and nab-paclitaxel (Gem/NabP) showed increased overall survival compared to gemcitabine alone in the treatment of advanced pancreatic ductal adenocarcinoma (aPDA). Until now there has been limited information on the clinical benefit and toxicity of the combination regimen in a real world setting. In addition the value for patients with locally advanced rather than metastatic aPDA has been unclear, since the former category of patients was not included in the MPACT trial.MethodsA multicentre retrospective observational study in the South Eastern Region of Sweden was performed, with the first 75 consecutive patients diagnosed with aPDA (both locally advanced and metastatic disease) who received first-line treatment with Gem/NabP.ResultsIn the overall population median progression free survival (PFS) and overall survival (OS) were 5.2 (3.4-7.0 95% CI) and 10.9 (7.8-14.0 95% CI) months, respectively. Patients with metastatic disease displayed a median OS of 9.4 (4.9-13.9) and a median PFS of 4.5 (3.3-5.7) months whereas the same parameters in the locally advanced subgroup were 17.1 (7.6-26.6) and 6.8 (5.2-8.4) months, respectively. Grade 3-4 hematologic toxicity was recorded: Neutropenia, leukopenia, thrombocytopenia, and anaemia were observed in 23, 20, 5, and 4% of patients, respectively. Dose reductions were performed in 80% of the patients.ConclusionThis study confirms the effectiveness and safety of first-line Gem/NabP in both locally advanced and metastatic PDA in a real world setting.

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  • 7.
    Borgfeldt, Christer
    et al.
    Lund Univ, Sweden.
    Holmberg, Erik
    Reg Canc Ctr West, Sweden.
    Marcickiewicz, Janusz
    Halland Hosp, Sweden.
    Stålberg, Karin
    Uppsala Univ, Sweden.
    Tholander, Bengt
    Uppsala Univ Hosp, Sweden.
    Åvall Lundqvist, Elisabeth
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Surgery, Orthopedics and Oncology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Oncology.
    Flöter-Rådestad, Angelique
    Karolinska Univ Hosp, Sweden.
    Bjurberg, Maria
    Lund Univ, Sweden; Lund Univ, Sweden.
    Dahm-Kähler, Pernilla
    Sahlgrens Acad, Sweden.
    Hellman, Kristina
    Karolinska Univ Hosp, Sweden.
    Hjerpe, Elisabet
    Visby Hosp, Sweden.
    Kjölhede, Preben
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Children's and Women's Health. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center of Paediatrics and Gynaecology and Obstetrics, Department of Gynaecology and Obstetrics in Linköping.
    Rosenberg, Per
    Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Oncology. Linköping University, Faculty of Medicine and Health Sciences. Linköping University, Department of Biomedical and Clinical Sciences, Division of Surgery, Orthopedics and Oncology.
    Högberg, Thomas
    Lund Univ, Sweden.
    Survival in endometrial cancer in relation to minimally invasive surgery or open surgery: a Swedish Gynecologic Cancer Group (SweGCG) study2021In: BMC Cancer, ISSN 1471-2407, E-ISSN 1471-2407, Vol. 21, no 1, article id 658Article in journal (Refereed)
    Abstract [en]

    BackgroundThe aim of this study was to analyze overall survival in endometrial cancer patients FIGO stages I-III in relation to surgical approach; minimally invasive (MIS) or open surgery (laparotomy).MethodsA population-based retrospective study of 7275 endometrial cancer patients included in the Swedish Quality Registry for Gynecologic Cancer diagnosed from 2010 to 2018. Cox proportional hazard models were used in univariable and multivariable survival analyses.ResultsIn univariable analysis open surgery was associated with worse overall survival compared with MIS hazard ratio, HR, 1.39 (95% CI 1.18-1.63) while in the multivariable analysis, surgical approach (MIS vs open surgery) was not associated with overall survival after adjustment for known risk factors (HR 1.12, 95% CI 0.95-1.32). Higher FIGO stage, non-endometrioid histology, non-diploid tumors, lymphovascular space invasion and increasing age were independent risk factors for overall survival.ConclusionThe minimal invasive or open surgical approach did not show any impact on survival for patients with endometrial cancer stages I-III when known prognostic risk factors were included in the multivariable analyses.

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  • 8.
    Elsharif, Mohamed
    et al.
    Leeds Teaching Hosp NHS Trust, England.
    Roche, Matthew
    Leeds Teaching Hosp NHS Trust, England.
    Wilson, Daniel
    Leeds Teaching Hosp NHS Trust, England.
    Basak, Susmita
    Univ Leeds, England.
    Rowe, Ian
    Leeds Teaching Hosp NHS Trust, England.
    Vijayanand, Dhakshina
    Leeds Teaching Hosp NHS Trust, England.
    Feltbower, Richard
    Univ Leeds, England.
    Treanor, Darren
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Inflammation and Infection. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Clinical pathology. Leeds Teaching Hosp NHS Trust, England; St James Univ Hosp, England.
    Roberts, Lee
    Univ Leeds, England.
    Guthrie, Ashley
    Leeds Teaching Hosp NHS Trust, England.
    Prasad, Raj
    Leeds Teaching Hosp NHS Trust, England.
    Gilthorpe, Mark S.
    Leeds Teaching Hosp NHS Trust, England.
    Attia, Magdy
    Leeds Teaching Hosp NHS Trust, England.
    Sourbron, Steven
    IICD Sheffield, England.
    Hepatectomy risk assessment with functional magnetic resonance imaging (HEPARIM)2021In: BMC Cancer, ISSN 1471-2407, E-ISSN 1471-2407, Vol. 21, no 1, article id 1139Article in journal (Refereed)
    Abstract [en]

    Background: Post hepatectomy liver failure (PHLF) remains a significant risk in patients undergoing curative liver resection for cancer, however currently available PHLF risk prediction investigations are not sufficiently accurate. The Hepatectomy risk assessment with functional magnetic resonance imaging trial (HEPARIM) aims to establish if quantitative MRI biomarkers of liver function & perfusion can be used to more accurately predict PHLF risk and FLR function, measured against indocyanine green (ICG) liver function test. Methods: HEPARIM is an observational cohort study recruiting patients undergoing liver resection of 2 segments or more, prior to surgery patients will have both Dynamic Gadoxetate-enhanced (DGE) liver MRI and ICG testing. Day one post op ICG testing is repeated and R15 compared to the Gadoxetate Clearance (GC) of the future liver remnant (FLR-GC) as measure by preoperative DGE- MRI which is the primary outcome, and preoperative ICG R15 compared to GC of whole liver (WL-GC) as a secondary outcome. Data will be collected from medical records, biochemistry, pathology and radiology reports and used in a multi-variate analysis to the value of functional MRI and derive multivariant prediction models for future validation. Discussion: If successful, this test will potentially provide an efficient means to quantitatively assess FLR function and PHLF risk enabling surgeons to push boundaries of liver surgery further while maintaining safe practice and thereby offering chance of cure to patients who would previously been deemed inoperable. MRI has the added benefit of already being part of the routine diagnostic pathway and as such would have limited additional burden on patients time or cost to health care systems. (Hepatectomy Risk Assessment With Functional Magnetic Resonance Imaging - Full Text View -, n.d.)

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  • 9.
    Forsare, Carina
    et al.
    Lund Univ, Sweden.
    Bak, Martin
    Odense Univ Hosp, Denmark.
    Falck, Anna-Karin
    Helsingborg Hosp, Sweden.
    Grabau, Dorthe
    Lund Univ, Sweden.
    Killander, Fredrika
    Lund Univ, Sweden; Skane Univ Hosp, Sweden.
    Malmstrom, Per
    Lund Univ, Sweden; Skane Univ Hosp, Sweden.
    Ryden, Lisa
    Lund Univ, Sweden; Skane Univ Hosp, Sweden.
    Stål, Olle
    Linköping University, Department of Clinical and Experimental Medicine, Division of Surgery, Orthopedics and Oncology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Oncology.
    Sundqvist, Marie
    Cty Hosp, Sweden.
    Bendahl, Par-Ola
    Lund Univ, Sweden.
    Ferno, Marten
    Lund Univ, Sweden.
    Non-linear transformations of age at diagnosis, tumor size, and number of positive lymph nodes in prediction of clinical outcome in breast cancer2018In: BMC Cancer, ISSN 1471-2407, E-ISSN 1471-2407, Vol. 18, article id 1226Article in journal (Refereed)
    Abstract [en]

    BackgroundPrognostic factors in breast cancer are often measured on a continuous scale, but categorized for clinical decision-making. The primary aim of this study was to evaluate if accounting for continuous non-linear effects of the three factors age at diagnosis, tumor size, and number of positive lymph nodes improves prognostication. These factors will most likely be included in the management of breast cancer patients also in the future, after an expected implementation of gene expression profiling for adjuvant treatment decision-making.MethodsFour thousand four hundred forty seven and 1132 women with primary breast cancer constituted the derivation and validation set, respectively. Potential non-linear effects on the log hazard of distant recurrences of the three factors were evaluated during 10years of follow-up. Cox-models of successively increasing complexity: dichotomized predictors, predictors categorized into three or four groups, and predictors transformed using fractional polynomials (FPs) or restricted cubic splines (RCS), were used. Predictive performance was evaluated by Harrells C-index.ResultsUsing FP-transformations, non-linear effects were detected for tumor size and number of positive lymph nodes in univariable analyses. For age, non-linear transformations did, however, not improve the model fit significantly compared to the linear identity transformation. As expected, the C-index increased with increasing model complexity for multivariable models including the three factors. By allowing more than one cut-point per factor, the C-index increased from 0.628 to 0.674. The additional gain, as measured by the C-index, when using FP- or RCS-transformations was modest (0.695 and 0.696, respectively). The corresponding C-indices for these four models in the validation set, based on the same transformations and parameter estimates from the derivation set, were 0.675, 0.700, 0.706, and 0.701.ConclusionsCategorization of each factor into three to four groups was found to improve prognostication compared to dichotomization. The additional gain by allowing continuous non-linear effects modeled by FPs or RCS was modest. However, the continuous nature of these transformations has the advantage of making it possible to form risk groups of any size.

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  • 10.
    Garvin, Stina
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Oncology . Linköping University, Faculty of Health Sciences.
    Dabrosin, Charlotta
    Linköping University, Department of Clinical and Experimental Medicine, Oncology . Linköping University, Faculty of Health Sciences.
    In vivo measurement of tumor estradiol and Vascular Endothelial Growth Factor in breast cancer patients2008In: BMC Cancer, ISSN 1471-2407, E-ISSN 1471-2407, Vol. 73, no 8Article in journal (Refereed)
    Abstract [en]

    Background: Angiogenesis, crucial for tumor progression, is a process regulated in the tissue micro-environment. Vascular endothelial growth factor (VEGF) is a potent stimulatory factor of angiogenesis and a negative prognostic indicator of breast cancer. VEGF is biologically active in the extracellular space and hitherto, there has been a lack of techniques enabling sampling of angiogenic molecules such as VEGF in situ. The majority of breast cancers are estrogen-dependent, and estrogen has been shown to regulate VEGF in normal breast tissue and experimental breast cancer. We investigated if microdialysis may be applicable in human breast cancer for sampling of extracellular VEGF in situ and to explore if there is an association with local estradiol and VEGF levels in normal and cancerous breast tissue.

    Methods: Microdialysis was used to sample VEGF and estradiol in tumors and adjacent normal breast tissue in postmenopausal breast cancer patients. VEGF and estradiol were also measured in plasma, and immunohistochemical staining for VEGF was performed on tumor sections.

    Results: We show that in vivo levels of extracellular VEGF were significantly higher in breast cancer tumors than in normal adjacent breast tissue. There was a significant positive correlation between estradiol and extracellular VEGF in normal breast tissue. However, no correlation was detected between estradiol and VEGF in tumors or between tumor VEGF and plasma VEGF.

    Conclusion: We conclude that VEGF and estradiol correlates significantly in normal breast tissue. Microdialysis may be used to provide novel insight in breast tumor biology and the regulation of molecules in the extracellular space of human breast tumors in vivo.

  • 11.
    Holmqvist, Annica
    et al.
    Linköping University, Department of Health, Medicine and Caring Sciences. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Oncology.
    Lindahl, Gabriel
    Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Oncology. Linköping University, Department of Biomedical and Clinical Sciences, Division of Surgery, Orthopedics and Oncology.
    Mikivier, Rasmus
    Linköping University, Department of Health, Medicine and Caring Sciences. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Regionledningskontoret, Regional Cancer Center.
    Uppugunduri, Srinivas
    Linköping University, Department of Health, Medicine and Caring Sciences. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Regionledningskontoret, Regional Cancer Center.
    Age as a potential predictor of acute side effects during chemoradiotherapy in primary cervical cancer patients2022In: BMC Cancer, ISSN 1471-2407, E-ISSN 1471-2407, Vol. 22, no 1, article id 371Article in journal (Refereed)
    Abstract [en]

    Background

    Toxicity during chemoradiotherapy (CRT) in cervical cancer patients might limit the chances of receiving an optimal treatment and to be cured. Few studies have shown relationships between acute side effects and patients age. Here, the association between age and acute side effects such as nausea/vomiting, diarrhea and weight loss during CRT was analysed in cervical cancer patients.

    Methods

    This study included 93 patients with primary cervical cancer stage IBI to IVA who received CRT from 2013 to 2019. The frequency of symptoms/toxicity grade was analysed by using the Common Terminology Criteria for Adverse Events (CTCAE) version 5.0.

    Results

    Patients ≥ 52 years had a significantly higher frequency of nausea/vomiting and increased grade  ≥ 3 toxicity during CRT compared to younger patients (p<0.001, p = 0.001). Toxicity grade ≥ 3 of nausea/vomiting was associated with increased frequency of weight loss (p = 0.001), reduced ADL (p = 0.001) and dose modifications of both radiotherapy (RT) (p = 0.020) and chemotherapy (CT) (p = 0.030) compared to toxicity grade 2. The frequency of diarrhea (p = 0.015) and weight loss (p = 0.020) was higher in older patients compared to younger.

    Conclusions

    Older patients have an increased risk of acute side effects as nausea/vomiting, diarrhea and weight loss. Age could be useful in predicting acute side effects in primary cervical cancer patients with CRT.

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  • 12.
    Holmqvist Knutsen, Annica
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Oncology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Surgery, Orthopaedics and Cancer Treatment, Department of Oncology UHL.
    Gao, Jing-Fang
    Linköping University, Department of Clinical and Experimental Medicine, Oncology. Linköping University, Faculty of Health Sciences.
    Holmlund, Birgitta
    Linköping University, Department of Clinical and Experimental Medicine, Oncology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Surgery, Orthopaedics and Cancer Treatment, Department of Oncology UHL.
    Adell, Gunnar
    Linköping University, Department of Clinical and Experimental Medicine, Oncology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Surgery, Orthopaedics and Cancer Treatment, Department of Oncology UHL.
    Carstensen, John
    Linköping University, Department of Medical and Health Sciences, Health and Society. Linköping University, Faculty of Arts and Sciences.
    Sun, Xiao-Feng
    Linköping University, Department of Clinical and Experimental Medicine, Oncology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Surgery, Orthopaedics and Cancer Treatment, Department of Oncology UHL.
    PINCH is an independent prognostic factor in rectal cancer patients without preoperative radiotherapy: A study in a Swedish rectal cancer trial of preoperative radiotherapy2012In: BMC Cancer, ISSN 1471-2407, E-ISSN 1471-2407, Vol. 12, no 65Article in journal (Refereed)
    Abstract [en]

    Background and Purpose: The clinical significance between particularly interesting new cysteine-histidine rich protein (PINCH) expression and radiotherapy (RT) in tumours is not known. In this study, the expression of PINCH and its relationship to RT, clinical, pathological and biological factors were studied in rectal cancer patients.

    Material and Methods: PINCH expression determined by immunohistochemistry was analysed at the invasive margin and inner tumour area in 137 primary rectal adenocarcinomas (72 cases without RT and 65 cases with RT). PINCH expression in colon fibroblast cell line (CCD-18 Co) was determined by Western blot.

    Results: In patients without RT, strong PINCH expression at the invasive margin of primary tumours was related to worse survival, compared to patients with weak expression, independent of TNM stage and differentiation (p = 0.03). No survival relationship in patients with RT was observed (p = 0.64). Comparing the non-RT with RT subgroup, there was no difference in PINCH expression in primary tumours (invasive margin (p = 0.68)/inner tumour area (p = 0.49).

    Conclusions: PINCH expression at the invasive margin was an independent prognostic factor in patients without RT. RT does not seem to directly affect the PINCH expression.

     

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  • 13.
    Karlsson, Anneli
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
    Nordigården, Amanda
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
    Jönsson, Jan-Ingvar
    Linköping University, Department of Clinical and Experimental Medicine, Experimental Hematology . Linköping University, Faculty of Health Sciences.
    Söderkvist, Peter
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
    Bcl11b mutations identified in murine lymphomas increase the proliferation rate in hematopoietic progenitor cells2007In: BMC Cancer, ISSN 1471-2407, E-ISSN 1471-2407, Vol. 7, no 195, p. 195-Article in journal (Refereed)
    Abstract [en]

    Background: The telomeric region of mouse chromosome 12 has previously shown frequent allelic loss in murine lymphoma. The Bcl11b gene has been identified and suggested as a candidate tumor suppressor gene within this region. In this study, we aimed to elucidate whether Bcl11b is mutated in lymphomas with allelic loss, and whether the mutations we detected conferred any effect on cell proliferation and apoptosis.

    Methods: Mouse lymphomas induced by 1,3-butadiene or 2',3'-dideoxycytidine were analysed for mutations in the Bcl11b gene using single strand conformation analysis and direct DNA sequencing. Effects on cell proliferation by the detected mutations were studied by expressing wild-type and mutant Bcl11b in the cytokine-dependent hematopoietic progenitor cell line FDC-P1, lacking endogenous Bcl11b expression.

    Results: Missense and frameshift (FS) mutations were identified in 7 of 47 tumors (15%). Interestingly, all mutations were found between amino acids 778–844 which encode the three C-terminal DNA-binding zinc fingers. In FDC-P1 cells, wild-type Bcl11b suppressed cell proliferation, whereas the mutated versions (S778N, K828T, Y844C and FS823) enhanced proliferation several-fold.

    Conclusion: The genetic alterations detected in this study suggest that the three C-terminal zinc fingers of Bcl11b are important for the DNA-binding. Cell proliferation was suppressed by overexpression of wild-type Bcl11b but enhanced by mutant Bcl11b, indicating that these mutations may be an important contributing factor to lymphomagenesis in a subset of tumors.

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  • 14.
    Lagergren, A
    et al.
    Lund University.
    Manetopoulos, C
    Lund University.
    Axelson, H
    Lund University.
    Sigvardsson, Mikael
    Lund University.
    Neuroblastoma and pre-B lymphoma cells share expression of key transcription factors but display tissue restricted target gene expression2004In: BMC Cancer, ISSN 1471-2407, E-ISSN 1471-2407, Vol. 4, no 80Article in journal (Refereed)
    Abstract [en]

    Background: Transcription factors are frequently involved in the process of cellular transformation, and many malignancies are characterized by a distinct genetic event affecting a specific transcription factor. This probably reflects a tissue specific ability of transcription factors to contribute to the generation of cancer but very little is known about the precise mechanisms that governs these restricted effects. Methods: To investigate this selectivity in target gene activation we compared the overall gene expression patterns by micro-array analysis and expression of target genes for the transcription factor EBF in lymphoma and neuroblastoma cells by RT-PCR. The presence of transcription factors in the different model cell lines was further investigated by EMSA analysis. Results: In pre-B cells mb-1 and CD19 are regulate by EBF-1 in collaboration with Pax-5 and E-proteins. We here show that neuroblastoma cells express these three, for B cell development crucial transcription factors, but nevertheless fail to express detectable levels of their known target genes. Expression of mb-1 could, however, be induced in neuroblastoma cells after disruption of the chromatin structure by treatment with 5-azacytidine and Trichostatin A. Conclusion: These data suggest that transcription factors are able to selectively activate target genes in different tissues and that chromatin structure plays a key role in the regulation of this activity.

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  • 15.
    Lehn, Sophie
    et al.
    Lund University, Sweden .
    Tobin, Nicholas P.
    Karolinska Institute, Sweden St Gorans University Hospital, Sweden .
    Sims, Andrew H.
    University of Edinburgh, Scotland .
    Stål, Olle
    Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Oncology.
    Jirstrom, Karin
    Lund University, Sweden .
    Axelson, Hakan
    Lund University, Sweden .
    Landberg, Goran
    University of Gothenburg, Sweden University of Manchester, England .
    Decreased expression of Yes-associated protein is associated with outcome in the luminal A breast cancer subgroup and with an impaired tamoxifen response2014In: BMC Cancer, ISSN 1471-2407, E-ISSN 1471-2407, Vol. 14, no 119Article in journal (Refereed)
    Abstract [en]

    Background: Yes-associated protein (YAP1) is frequently reported to function as an oncogene in many types of cancer, but in breast cancer results remain controversial. We set out to clarify the role of YAP1 in breast cancer by examining gene and protein expression in subgroups of patient material and by downregulating YAP1 in vitro and studying its role in response to the widely used anti-estrogen tamoxifen. Methods: YAP1 protein intensity was scored as absent, weak, intermediate or strong in two primary breast cancer cohorts (n = 144 and n = 564) and mRNA expression of YAP1 was evaluated in a gene expression dataset (n = 1107). Recurrence-free survival was analysed using the log-rank test and Cox multivariate analysis was used to test for independence. WST-1 assay was employed to measure cell viability and a luciferase ERE (estrogen responsive element) construct was used to study the effect of tamoxifen, following downregulation of YAP1 using siRNAs. Results: In the ER+ (Estrogen Receptor a positive) subgroup of the randomised cohort, YAP1 expression was inversely correlated to histological grade and proliferation (p = 0.001 and p = 0.016, respectively) whereas in the ER-(Estrogen Receptor a negative) subgroup YAP1 expression correlated positively to proliferation (p = 0.005). Notably, low YAP1 mRNA was independently associated with decreased recurrence-free survival in the gene expression dataset, specifically for the luminal A subgroup (p less than 0.001) which includes low proliferating tumours of lower grade, usually associated with a good prognosis. This subgroup specificity led us to hypothesize that YAP1 may be important for response to endocrine therapies, such as tamoxifen, extensively used for luminal A breast cancers. In a tamoxifen randomised patient material, absent YAP1 protein expression was associated with impaired tamoxifen response which was significant upon interaction analysis (p = 0.042). YAP1 downregulation resulted in increased progesterone receptor (PgR) expression and a delayed and weaker tamoxifen in support of the clinical data. Conclusions: Decreased YAP1 expression is an independent prognostic factor for recurrence in the less aggressive luminal A breast cancer subgroup, likely due to the decreased tamoxifen sensitivity conferred by YAP1 downregulation.

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  • 16.
    Lindemann, Kristina
    et al.
    Oslo University Hospital, Norway .
    Malander, Susanne
    University of Lund Hospital, Sweden .
    Christensen, Rene D.
    University of Southern Denmark, Denmark .
    Mirza, Mansoor R.
    University of Copenhagen Hospital, Denmark .
    Kristensen, Gunnar B.
    Oslo University Hospital, Norway Oslo University Hospital, Norway .
    Åvall-Lundqvist, Elisabeth
    Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Oncology. Karolinska University Hospital, Sweden .
    Vergote, Ignace
    University Hospital Leuven, Belgium University Hospital Leuven, Belgium .
    Rosenberg, Per
    Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Oncology.
    Boman, Karin
    University Hospital, Sweden .
    Nordstrom, Britta
    Karolinska University Hospital, Sweden .
    Examestane in advanced or recurrent endometrial carcinoma: a prospective phase II study by the Nordic Society of Gynecologic Oncology (NSGO)2014In: BMC Cancer, ISSN 1471-2407, E-ISSN 1471-2407, Vol. 14, no 68Article in journal (Refereed)
    Abstract [en]

    Background: We evaluated the efficacy and safety of the aromatase inhibitor exemestane in patients with advanced, persistent or recurrent endometrial carcinoma. Methods: We performed an open-label one-arm, two-stage, phase II study of 25 mg of oral exemestane in 51 patients with advanced (FIGO stage III-IV) or relapsed endometrioid endometrial cancer. Patients were stratified into subsets of estrogen receptor (ER) positive and ER negative patients. Results: Recruitment to the ER negative group was stopped prematurely after 12 patients due to slow accrual. In the ER positive patients, we observed an overall response rate of 10%, and a lack of progression after 6 months in 35% of the patients. No responses were registered in the ER negative patients, and all had progressive disease within 6 months. For the total group of patients, the median progression free survival (PFS) was 3.1 months (95% CI: 2.0-4.1). In the ER positive patients the median PFS was 3.8 months (95% CI: 0.7-6.9) and in the ER negative patients it was 2.6 months (95% CI: 2.1-3-1). In the ER positive patients the median overall survival (OS) time was 13.3 months (95% CI: 7.7-18.9), in the ER negative patients the corresponding numbers were 6.1 months (95% CI: 4.1-8.2). Treatment with exemestane was well tolerated. Conclusion: Treatment of estrogen positive advanced or recurrent endometrial cancer with exemestane, an aromatase inhibitor, resulted in a response rate of 10% and lack of progression after 6 months in 35% of the patients.

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  • 17.
    Naeser, Ylva
    et al.
    Uppsala Univ, Sweden; Uppsala Univ Hosp, Sweden.
    Helgadottir, Hildur
    Karolinska Univ Hosp Solna, Sweden.
    Brandberg, Yvonne
    Karolinska Inst, Sweden.
    Hansson, Johan
    Karolinska Univ Hosp Solna, Sweden.
    Bagge, Roger Olofsson
    Univ Gothenburg, Sweden; Sahlgrens Univ Hosp, Sweden; Univ Gothenburg, Sweden.
    Elander, Nils
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Surgery, Orthopedics and Oncology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Oncology.
    Ingvar, Christian
    Lund Univ, Sweden.
    Isaksson, Karolin
    Cent Hosp Kristianstad, Sweden; Lund Univ, Sweden.
    Flygare, Petra
    Sundsvall Cty Hosp, Sweden.
    Nilsson, Cecilia
    Hosp Vastmanland Vasteras, Sweden.
    Jakobsson, Frida
    Orebro Univ Hosp, Sweden.
    del Val Munoz, Olga
    Gavle Cty Hosp, Sweden.
    Valachis, Antonis
    Orebro Univ, Sweden.
    Jansson, Malin
    Umea Univ, Sweden; Umea Univ Hosp, Sweden.
    Sparring, Charlotte
    Skaraborg Cty Hosp, Sweden.
    Ohlsson, Lars
    Karlstad Cty Hosp, Sweden.
    Dyrke, Ulf
    Falun Cty Hosp, Sweden.
    Papantoniou, Dimitrios
    Ryhov Cty Hosp, Sweden.
    Sundin, Anders
    Uppsala Univ, Sweden.
    Ullenhag, Gustav J.
    Uppsala Univ, Sweden; Uppsala Univ Hosp, Sweden.
    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 Melanoma2020In: BMC Cancer, ISSN 1471-2407, E-ISSN 1471-2407, Vol. 20, no 1, article id 1197Article in journal (Refereed)
    Abstract [en]

    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 &gt;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

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  • 18.
    Ofverholm, Anna
    et al.
    Univ Gothenburg, Sweden.
    Toerngren, Therese
    Lund Univ, Sweden.
    Rosen, Anna
    Umea Univ, Sweden.
    Arver, Brita
    Karolinska Inst, Sweden.
    Einbeigi, Zakaria
    Univ Gothenburg, Sweden; Southern Alvsborg Hosp, Sweden.
    Haraldsson, Karin
    Lund Univ, Sweden.
    Stahlbom, Anne Kinhult
    Karolinska Univ Hosp Solna, Sweden.
    Kuchinskaya, Ekaterina
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Clinical genetics. Region Östergötland, Center for Diagnostics, Clinical pathology. Karolinska Inst, Sweden.
    Lindblom, Annika
    Karolinska Inst, Sweden; Karolinska Univ Hosp, Sweden.
    Melin, Beatrice
    Umea Univ, Sweden.
    Paulsson-Karlsson, Ylva
    Uppsala Univ Hosp, Sweden.
    Stenmark Askmalm, Marie
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Clinical genetics. Region Östergötland, Center for Diagnostics, Clinical pathology. Off Med Serv Reg Skane, Sweden.
    Tham, Emma
    Karolinska Inst, Sweden; Karolinska Univ Hosp, Sweden.
    von Wachenfeldt, Anna
    Karolinska Inst, Sweden; Soder Sjukhuset, Sweden.
    Kvist, Anders
    Lund Univ, Sweden.
    Borg, Ake
    Lund Univ, Sweden.
    Ehrencrona, Hans
    Off Med Serv Reg Skane, Sweden; Lund Univ, Sweden.
    Extended genetic analysis and tumor characteristics in over 4600 women with suspected hereditary breast and ovarian cancer2023In: BMC Cancer, E-ISSN 1471-2407, Vol. 23, no 1, article id 738Article in journal (Refereed)
    Abstract [en]

    BackgroundGenetic screening for pathogenic variants (PVs) in cancer predisposition genes can affect treatment strategies, risk prediction and preventive measures for patients and families. For decades, hereditary breast and ovarian cancer (HBOC) has been attributed to PVs in the genes BRCA1 and BRCA2, and more recently other rare alleles have been firmly established as associated with a high or moderate increased risk of developing breast and/or ovarian cancer. Here, we assess the genetic variation and tumor characteristics in a large cohort of women with suspected HBOC in a clinical oncogenetic setting.MethodsWomen with suspected HBOC referred from all oncogenetic clinics in Sweden over a six-year inclusion period were screened for PVs in 13 clinically relevant genes. The genetic outcome was compared with tumor characteristics and other clinical data collected from national cancer registries and hospital records.ResultsIn 4622 women with breast and/or ovarian cancer the overall diagnostic yield (the proportion of women carrying at least one PV) was 16.6%. BRCA1/2 PVs were found in 8.9% of women (BRCA1 5.95% and BRCA2 2.94%) and PVs in the other breast and ovarian cancer predisposition genes in 8.2%: ATM (1.58%), BARD1 (0.45%), BRIP1 (0.43%), CDH1 (0.11%), CHEK2 (3.46%), PALB2 (0.84%), PTEN (0.02%), RAD51C (0.54%), RAD51D (0.15%), STK11 (0) and TP53 (0.56%). Thus, inclusion of the 11 genes in addition to BRCA1/2 increased diagnostic yield by 7.7%. The yield was, as expected, significantly higher in certain subgroups such as younger patients, medullary breast cancer, higher Nottingham Histologic Grade, ER-negative breast cancer, triple-negative breast cancer and high grade serous ovarian cancer. Age and tumor subtype distributions differed substantially depending on genetic finding.ConclusionsThis study contributes to understanding the clinical and genetic landscape of breast and ovarian cancer susceptibility. Extending clinical genetic screening from BRCA1 and BRCA2 to 13 established cancer predisposition genes almost doubles the diagnostic yield, which has implications for genetic counseling and clinical guidelines. The very low yield in the syndrome genes CDH1, PTEN and STK11 questions the usefulness of including these genes on routine gene panels.

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  • 19.
    Petersson, Stina
    et al.
    Sahlgrens University Hospital, Sweden.
    Bylander, Anna
    Sahlgrens University Hospital, Sweden.
    Yhr, Maria
    Sahlgrens University Hospital, Sweden.
    Enerbäck, Charlotta
    Sahlgrens University Hospital, Sweden; Sahlgrens University Hospital, Sweden.
    S100A7 (Psoriasin), highly expressed in Ductal Carcinoma In Situ (DCIS), is regulated by IFN-gamma in mammary epithelial cells2007In: BMC Cancer, ISSN 1471-2407, E-ISSN 1471-2407, Vol. 7, no 205Article in journal (Refereed)
    Abstract [en]

    Background: The aim of the present work was to explore signal transduction pathways used in the regulation of S100A7 ( psoriasin). Members of the S100 gene family participate in many important cellular functions. Psoriasin, S100A8 ( calgranulin A) and S100A9 ( calgranulin B) are expressed in ductal carcinoma in situ ( DCIS), as well as in the hyperproliferative skin disease, psoriasis. In the latter condition, a disturbance in the STAT pathway has recently been reported. This pathway is implicated in the regulation of IFN-gamma, widely recognized as a key cytokine in psoriasis. IFN-gamma also exerts anti-tumor action in a number of tumor cell types, including breast cancer. We therefore examined the effect of IFN-gamma and STAT-signaling on the psoriasin expression. Methods: We established a TAC2 mouse mammary epithelial cell line with tetracycline-inducible psoriasin expression (Tet-Off). Viability in cell culture was estimated using MTS assay. Protein and gene expression were evaluated by Western blotting and quantitative real-time PCR. Statistical analyses were assessed using a one-tailed, paired t-test. Results: We report the downregulation of psoriasin by IFN-gamma in the MDA-MB-468 breast cancer cell line, as well as the downregulation of psoriasin induced by anoikis in cell lines derived from different epithelial tissues. In contrast, IFN-gamma had no suppressive effect on calgranulin A or calgranulin B. IFN-gamma is an important activator of the STAT1 pathway and we confirmed an active signaling pathway in the cell lines that responded to IFN-gamma treatment. In contrast, in the SUM190 breast carcinoma cell line, IFN-gamma did not suppress the expression of endogenous psoriasin. Moreover, a reduced phosphorylation of the STAT1 protein was observed. We showed that IFN-gamma treatment and the inhibition of the transcription factor NFkappaB had a synergistic effect on psoriasin levels. Finally, in TAC2 cells with tetracycline-induced psoriasin expression, we observed the increased viability of psoriasin-expressing cells after IFN-gamma treatment. Conclusion: Our data support the possibility that psoriasin expression is transcriptionally suppressed by IFN-gamma and that this effect is likely to be mediated by the activation of the STAT1 signaling pathway. The increased viability of psoriasin-expressing cells after IFN-gamma exposure suggests that psoriasin expression leads to the development of an apoptosis-resistant phenotype.

  • 20.
    Roginski, Mikaela
    et al.
    Linköping University, Department of Health, Medicine and Caring Sciences, Division of Prevention, Rehabilitation and Community Medicine. Linköping University, Faculty of Medicine and Health Sciences.
    Sifaki-Pistolla, Dimitra
    Univ Crete, Greece.
    Stomby, Andreas
    Linköping University, Department of Health, Medicine and Caring Sciences, Division of Prevention, Rehabilitation and Community Medicine. Linköping University, Faculty of Medicine and Health Sciences.
    Velivasaki, Georgia
    Univ Crete, Greece.
    Faresjö, Tomas
    Linköping University, Department of Health, Medicine and Caring Sciences, Division of Prevention, Rehabilitation and Community Medicine. Linköping University, Faculty of Medicine and Health Sciences.
    Lionis, Christos
    Linköping University, Department of Health, Medicine and Caring Sciences, Division of Prevention, Rehabilitation and Community Medicine. Linköping University, Faculty of Medicine and Health Sciences. Univ Crete, Greece.
    Olsen Faresjö, Åshild
    Linköping University, Department of Health, Medicine and Caring Sciences, Division of Society and Health. Linköping University, Faculty of Medicine and Health Sciences.
    Paradoxes of breast cancer incidence and mortality in two corners of Europe2022In: BMC Cancer, ISSN 1471-2407, E-ISSN 1471-2407, Vol. 22, no 1, article id 1123Article in journal (Refereed)
    Abstract [en]

    Background Breast cancer incidence is rising globally, while mortality rates show a geographical heterogenous pattern. Early detection and treatment have been proven to have a profound impact on breast cancer prognosis. The aim of his study was to compare breast cancer incidence, mortality, and survival rates in two contrasting corners of Europe, Sweden and Crete, to better understand cancer determinants with focus on disease burden and sociocultural factors. Methods Breast cancer data from Sweden and Crete was derived from registries. Incidence and mortality were expressed as Age-Standardized Incidence Rates (ASIR), Age-Standardized Mortality Rates (ASMR). Findings Breast cancer incidence has for decades risen in Sweden and on Crete. In 2019, ASIR was 217.5 in Sweden and 58.9 on Crete, (p &lt; 0.001). Mortality rates showed opposite trends. ASMR in Sweden was reduced from 25.5 to 16.8 (2005-2019) while on Crete, ASMR increased from 22.1 to 25.3. A successive rise in survival rate in Sweden with a 5-year survival rate of 92% since 2015, but a converse development on Crete with 85% 5-year survival rate the same year. Interpretation The incidence of breast cancer is slowly rising in both studied regions, but mortality increases on Crete in contrast to Sweden with sinking mortality rates. The interpretation of these findings is that differences in health care systems and health policies including differences in early detection like screening programs and early treatment, as well as sociocultural factors in the two countries might play an important role on the differences found in breast cancer burden.

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  • 21.
    Schmitz, Alexander
    et al.
    Aalborg Univ Hosp, Denmark; Aalborg Univ Hosp, Denmark.
    Brondum, Rasmus Froberg
    Aalborg Univ Hosp, Denmark; Aalborg Univ Hosp, Denmark.
    Johnsen, Hans Erik
    Aalborg Univ Hosp, Denmark; Aalborg Univ Hosp, Denmark; Aalborg Univ, Denmark; Nordic Myeloma Study Grp NMSG, Sweden.
    Mellqvist, Ulf-Henrik
    Nordic Myeloma Study Grp NMSG, Sweden; South Elvsborg Hosp, Sweden.
    Waage, Anders
    Nordic Myeloma Study Grp NMSG, Sweden; Norwegian Univ Sci & Technol, Norway; St Olavs Univ Hosp, Norway.
    Gimsing, Peter
    Nordic Myeloma Study Grp NMSG, Sweden; Univ Copenhagen, Denmark.
    Bruinink, Davine Hofste Op
    Erasmus MC, Netherlands.
    van der Velden, Vincent
    Erasmus MC, Netherlands.
    van der Holt, Bronno
    Erasmus MC, Netherlands; Erasmus MC Canc Inst, Netherlands.
    Hansson, Markus
    Nordic Myeloma Study Grp NMSG, Sweden; Skane Univ Hosp, Sweden.
    Andersen, Niels Frost
    Nordic Myeloma Study Grp NMSG, Sweden; Aarhus Univ Hosp, Denmark.
    Frolund, Ulf Christian
    Nordic Myeloma Study Grp NMSG, Sweden; Sjllands Univ Hosp, Denmark.
    Helleberg, Carsten
    Nordic Myeloma Study Grp NMSG, Sweden; Herlev Hosp, Denmark.
    Schjesvold, Fredrik H.
    Nordic Myeloma Study Grp NMSG, Sweden; Oslo Univ Hosp, Norway; Univ Oslo, Norway.
    Ahlberg, Lucia
    Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Haematology. Nordic Myeloma Study Grp NMSG, Sweden.
    Gulbrandsen, Nina
    Nordic Myeloma Study Grp NMSG, Sweden; Oslo Univ Hosp, Norway; Univ Oslo, Norway.
    Andreasson, Bjorn
    Nordic Myeloma Study Grp NMSG, Sweden; NU Hosp Grp, Sweden.
    Lauri, Birgitta
    Nordic Myeloma Study Grp NMSG, Sweden; Sunderby Hosp, Sweden.
    Haukas, Einar
    Nordic Myeloma Study Grp NMSG, Sweden; Stavanger Univ Hosp, Norway.
    Bodker, Julie Stove
    Aalborg Univ Hosp, Denmark; Aalborg Univ Hosp, Denmark.
    Roug, Anne Stidsholt
    Aalborg Univ Hosp, Denmark; Aalborg Univ, Denmark.
    Bogsted, Martin
    Aalborg Univ Hosp, Denmark; Aalborg Univ Hosp, Denmark; Aalborg Univ, Denmark.
    Severinsen, Marianne T.
    Aalborg Univ Hosp, Denmark; Aalborg Univ, Denmark.
    Gregersen, Henrik
    Aalborg Univ Hosp, Denmark; Aalborg Univ, Denmark; Nordic Myeloma Study Grp NMSG, Sweden.
    Abildgaard, Niels
    Nordic Myeloma Study Grp NMSG, Sweden; Odense Univ Hosp, Denmark.
    Sonneveld, Pieter
    Erasmus MC, Netherlands; European Myeloma Network EMN, Denmark.
    Dybkaer, Karen
    Aalborg Univ Hosp, Denmark; Aalborg Univ Hosp, Denmark; Aalborg Univ, Denmark.
    Longitudinal minimal residual disease assessment in multiple myeloma patients in complete remission: results from the NMSG flow-MRD substudy within the EMN02/HO95 MM trial2022In: BMC Cancer, ISSN 1471-2407, E-ISSN 1471-2407, Vol. 22, no 1, article id 147Article in journal (Refereed)
    Abstract [en]

    Background: Multiple myeloma remains an incurable disease with multiple relapses due to residual myeloma cells in the bone marrow of patients after therapy. Presence of small number of cancer cells in the body after cancer treatment, called minimal residual disease, has been shown to be prognostic for progression-free and overall survival. However, for multiple myeloma, it is unclear whether patients attaining minimal residual disease negativity may be candidates for treatment discontinuation. We investigated, if longitudinal flow cytometry-based monitoring of minimal residual disease (flow-MRD) may predict disease progression earlier and with higher sensitivity compared to biochemical assessments. Methods: Patients from the Nordic countries with newly diagnosed multiple myeloma enrolled in the European-Myeloma-Network-02/Hovon-95 (EMN02/HO95) trial and undergoing bone marrow aspiration confirmation of complete response, were eligible for this Nordic Myeloma Study Group (NMSG) substudy. Longitdudinal flow-MRD assessment of bone marrow samples was performed to identify and enumerate residual malignant plasma cells until observed clinical progression. Results: Minimal residual disease dynamics were compared to biochemically assessed changes in serum free light chain and M-component. Among 20 patients, reaching complete response or stringent complete response during the observation period, and with &gt;= 3 sequential flow-MRD assessments analysed over time, increasing levels of minimal residual disease in the bone marrow were observed in six cases, preceding biochemically assessed disease and clinical progression by 5.5 months and 12.6 months (mean values), respectively. Mean malignant plasma cells doubling time for the six patients was 1.8 months (95% CI, 1.4-2.3 months). Minimal malignant plasma cells detection limit was 4 x 10-5. Conclusions: Flow-MRD is a sensitive method for longitudinal monitoring of minimal residual disease dynamics in multiple myeloma patients in complete response. Increasing minimal residual disease levels precedes biochemically assessed changes and is an early indicator of subsequent clinical progression.

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  • 22.
    Shabo, Ivan
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Surgery in Linköping. Linköping University, Faculty of Medicine and Health Sciences. Karolinska Institute, Sweden; Karolinska University Hospital, Sweden.
    Midtbö, Kristine Maria
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences.
    Andersson, Henrik
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences.
    Åkerlund, Emma
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences.
    Olsson, Hans
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Department of Clinical Pathology and Clinical Genetics.
    Wegman, Pia
    Linköping University, Department of Clinical and Experimental Medicine. Region Östergötland, Center for Diagnostics, Department of Clinical Pathology and Clinical Genetics. Linköping University, Faculty of Medicine and Health Sciences.
    Gunnarsson, Cecilia
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Region Östergötland, Center for Diagnostics, Department of Clinical Pathology and Clinical Genetics. Linköping University, Faculty of Medicine and Health Sciences.
    Lindström, Annelie
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences.
    Macrophage traits in cancer cells are induced by macrophage-cancer cell fusion and cannot be explained by cellular interaction2015In: BMC Cancer, ISSN 1471-2407, E-ISSN 1471-2407, Vol. 15, no 1, p. 922-Article in journal (Refereed)
    Abstract [en]

    Background: Cell fusion is a natural process in normal development and tissue regeneration. Fusion between cancer cells and macrophages generates metastatic hybrids with genetic and phenotypic characteristics from both maternal cells. However, there are no clinical markers for detecting cell fusion in clinical context. Macrophage-specific antigen CD163 expression in tumor cells is reported in breast and colorectal cancers and proposed being caused by macrophages-cancer cell fusion in tumor stroma. The purpose of this study is to examine the cell fusion process as a biological explanation for macrophage phenotype in breast. Methods: Monocytes, harvested from male blood donor, were activated to M2 macrophages and co-cultured in ThinCert transwell system with GFP-labeled MCF-7 cancer cells. MCF7/macrophage hybrids were generated by spontaneous cell fusion, isolated by fluorescence-activated cell sorting and confirmed by fluorescence microscopy, short tandem repeats analysis and flow cytometry. CD163 expression was evaluated in breast tumor samples material from 127 women by immunohistochemistry. Results: MCF-7/macrophage hybrids were generated spontaneously at average rate of 2 % and showed phenotypic and genetic traits from both maternal cells. CD163 expression in MCF-7 cells could not be induced by paracrine interaction with M2-activated macrophages. CD163 positive cancer cells in tumor sections grew in clonal collection and a cutoff point greater than25 % of positive cancer cells was significantly correlated to disease free and overall survival. Conclusions: In conclusion, macrophage traits in breast cancer might be caused by cell fusion rather than explained by paracrine cellular interaction. These data provide new insights into the role of cell fusion in breast cancer and contributes to the development of clinical markers to identify cell fusion.

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  • 23.
    Shubbar, Emman
    et al.
    Sahlgrenska Cancer Center, University of Gothenburg, Sweden.
    Helou, Khalil
    Sahlgrenska Cancer Center, University of Gothenburg, Sweden.
    Kovács, Anikó
    Department of Pathology, Sahlgrenska University Hospital, Gothenburg, Sweden .
    Nemes, Szilárd
    Sahlgrenska Cancer Center, University of Gothenburg, Sweden.
    Hajizadeh, Shahin
    Department of Pathology, Sahlgrenska University Hospital, Gothenburg, Sweden .
    Enerbäck, Charlotta
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Heart and Medicine Center, Department of Dermatology and Venerology.
    Einbeigi, Zakaria
    Sahlgrenska Cancer Center, University of Gothenburg, Sweden.
    High levels of γ-glutamyl hydrolase (GGH) are associated with poor prognosis and unfavorable clinical outcomes in invasive breast cancer2013In: BMC Cancer, ISSN 1471-2407, E-ISSN 1471-2407, Vol. 13, no 47Article in journal (Refereed)
    Abstract [en]

    Background

    Previously, we performed analysis of gene expression in 46 axillary lymph node negative tumors and identified molecular gene signatures that resulted in different clinical outcomes. The aim of this study was to determine the correlation of γ-glutamyl hydrolase (GGH), fatty acid amide hydrolase (FAAH), Pirin (PIR) and TAF5-like RNA polymerase II, p300/CBP-associated factor (PCAF)-associated factor, 65 kDa (TAF5L), selected from identified gene signatures, with clinical outcomes as well as classical clinicopathological characteristics in primary invasive breast cancer patients.

    Methods

    The protein levels of GGH, FAAH, PIR and TAF5L were assessed by immunohistochemistry (IHC) on a panel of 80 primary invasive breast tumors. Quantitative real-time PCR (qRT-PCR) and western blot analysis were performed to verify the expression levels of the candidate biomarkers. Patient disease-specific survival (DSS) and recurrence-free survival (RFS) were evaluated using the Kaplan-Meier method. The prognostic biomarkers were identified by univariate analysis with a log-rank test and by multivariate analysis with Cox proportional hazards regression models.

    Results

    The GGH and FAAH protein levels were significantly up-regulated in invasive breast cancer tumors compared with adjacent non-cancerous tissues. Furthermore, the protein levels of GGH and FAAH were significantly correlated in tumor tissues. Tumoral GGH protein expression was significantly correlated with shorter DSS and RFS. Furthermore, the protein expression of GGH was positively correlated with undifferentiated tumors (BRE grade III) and ER/PR expressing tumors. Multivariate regression analysis showed that only GGH protein expression independently predicts DSS. No such correlations were found for FAAH, PIR and TAF5L protein expression. However, elevated protein levels of FAAH were positively associated with high number of lymph node involvement and upregulated levels of PIR were positively related with lymph node metastasis. The TAF5L was pronouncedly down-regulated in primary invasive breast cancer tissues compared to matched adjacent non-cancerous tissues.

    Conclusion

    These data show for the first time that cytoplasmic GGH might play a relevant role in the development and progression of invasive breast cancer, warranting further investigations. Our findings suggest that GGH serve as a potential biomarker of unfavorable clinical outcomes over short-term follow-up in breast cancer. The GGH may be a very attractive targeted therapy for selected patients.

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  • 24.
    Stiller, Helena Tufvesson
    et al.
    Region Östergötland, Regionledningskontoret, Regional Cancer Center. Umea Univ, Sweden.
    Mikiver, Rasmus
    Region Östergötland, Regionledningskontoret, Regional Cancer Center. Linköping University, Department of Biomedical and Clinical Sciences, Division of Surgery, Orthopedics and Oncology. Linköping University, Faculty of Medicine and Health Sciences.
    Uppugunduri, Srinivas
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Clinical Chemistry and Pharmacology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Regionledningskontoret, Regional Cancer Center.
    Schmitt-Egenolf, Marcus
    Umea Univ, Sweden.
    Perception of information to Swedish melanoma patients in routine clinical practice: a cross-sectional survey2022In: BMC Cancer, ISSN 1471-2407, E-ISSN 1471-2407, Vol. 22, no 1, article id 159Article in journal (Refereed)
    Abstract [en]

    Background Comprehensible, relevant information empowers patients, allowing them to take an active part in their care. We aim to investigate how Swedish melanoma patients perceive information provided in routine clinical practice and explore the correlation between satisfaction with information, symptoms and functioning scales, and quality of life. Methods A cross-sectional study where EORTC QLQ-C30, EORTC QLQ-INFO25 and EQ-5D-3L questionnaires were sent to 1213 patients by post and 792 responded (65%). Results Only 0.5% reported that they wished to have received less information. The amount of information received and the satisfaction with that information was age-dependent, where older patients reported receiving less information than younger patients. Middle-aged patients were more satisfied with the information compared to both younger and older patients. The perception of having received sufficient information correlated negatively with anxiety. Higher satisfaction with the information also correlated positively with scores for functioning scales and negatively with degree of symptoms. No difference was perceived in information levels between disease stage apart from the scale "information about other services", where patients with more severe disease reported receiving more information. Men and women reported equal satisfaction concerning the information received. Conclusions Patients lack sufficient information and age affects the perception of it. It is of utmost importance to tailor the information to suit the individual needs of a given patient, as satisfaction with the information received correlates with the patients well-being.

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  • 25.
    Stratmann, Johannes
    et al.
    Skovde University.
    Wang, Chaojie
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Oncology.
    Gnosa, Sebastian
    Linköping University, Department of Clinical and Experimental Medicine, Oncology. Linköping University, Faculty of Health Sciences.
    Wallin, Åsa
    Linköping University, Department of Clinical and Experimental Medicine, Oncology. Linköping University, Faculty of Health Sciences.
    Hinselwood, David
    Linköping University, Department of Clinical and Experimental Medicine, Oncology. Linköping University, Faculty of Health Sciences.
    Sun, Xiao-Feng
    Linköping University, Department of Clinical and Experimental Medicine, Oncology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Surgery, Orthopaedics and Cancer Treatment, Department of Oncology UHL.
    Zhang, Hong
    Skovde University.
    Dicer and miRNA in relation to clinicopathological variables in colorectal cancer patients2011In: BMC Cancer, ISSN 1471-2407, E-ISSN 1471-2407, Vol. 11, no 345Article in journal (Refereed)
    Abstract [en]

    Background: Dicer is aberrantly expressed in several types of cancers. Applying real-time PCR, we detected the expression of Dicer mRNA in normal mucosa (n = 162), primary colorectal cancer (CRC) (n = 162) and liver metastasis (n = 37), and analysed the relationship between Dicer expression and clinicopathological features. We also correlated the expression of Dicer mRNA to the miRNA expression of miR-141, miR-200a, miR-200b, mir-200c and miR-429 in liver metastases. less thanbrgreater than less thanbrgreater thanMethods: RT-PCR and qPCR were used to analyse the Dicer expression in normal mucosa, primary tumour and liver metastasis by using the High Capacity cDNA Reverse Transcription Kit and TaqMan (TM)(R) Gene Expression assays for Dicer and GAPDH. RT-PCR and qPCR were used to detect miRNA expression in liver metastases by utilizing TaqMan (R) MicroRNA Reverse Transcription Kit and TaqMan (R) miRNA Assays. Statistical analyses were performed with STATISTICA. less thanbrgreater than less thanbrgreater thanResults: Dicer expression in rectal cancer (3.146 +/- 0.953) was higher than in colon cancer (2.703 +/- 1.204, P = 0.018). Furthermore the Dicer expression was increased in primary tumours (3.146 +/- 0.952) in comparison to that in normal mucosa from rectal cancer patients (2.816 +/- 1.009, P = 0.034) but this is not evident in colon cancer patients. Dicer expression in liver metastases was decreased in comparison to that of either normal mucosa or primary tumour in both colon and rectal cancers (P andlt; 0.05). Patients with a high Dicer expression in normal mucosa had a worse prognosis compared to those with a low Dicer expression, independently of gender, age, tumour site, stage and differentiation (P andlt; 0.001, RR 3.682, 95% CI 1.749 - 7.750). In liver metastases, Dicer was positively related to miR-141 (R = 0.419, P = 0.015). less thanbrgreater than less thanbrgreater thanConclusion: Dicer is up-regulated in the early development of rectal cancers. An increased expression of Dicer mRNA in normal mucosa from CRC patients is significantly related to poor survival independently of gender, age, tumour site, stage and differentiation.

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  • 26.
    Vernmark, Karolina
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Oncology.
    Albertsson, Maria
    Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Oncology.
    Björnsson, Bergthor
    Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Surgery in Linköping. Linköping University, Faculty of Medicine and Health Sciences.
    Gasslander, Thomas
    Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Östergötlands Läns Landsting, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Surgery in Östergötland. Linköping University, Faculty of Medicine and Health Sciences.
    Sandström, Per
    Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Surgery in Linköping. Linköping University, Faculty of Medicine and Health Sciences.
    Sun, Xiao-Feng
    Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Oncology.
    Holmqvist, Annica
    Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Oncology. Linköping University, Faculty of Medicine and Health Sciences.
    From palliative to curative treatment - stage IV mucinous adenocarcinoma, successfully treated with metronomic capecitabine in combination with Bevacizumab and surgery- a case report2015In: BMC Cancer, ISSN 1471-2407, E-ISSN 1471-2407, Vol. 15, no 884Article in journal (Refereed)
    Abstract [en]

    Background: Mucinous adenocarcinoma (MAC) represents 6-19 % of all colorectal carcinoma. It is associated with poorer response to chemotherapy and chemoradiotherapy. Case presentation: A 27-year-old Swedish woman presented with stomach pain and weight loss, and was diagnosed with locally advanced MAC in the transverse colon as well as 3 liver metastases. Neoadjuvant treatment with fluorouracil, folinic acid and oxaliplatin (FLOX) failed due to several infections, pulmonary embolism and deteriorated performance status. The patient was therefore considered palliative. Palliative treatment with metronomic capecitabine 500 mg x 2 daily and bevacizumab every other week were initiated. After 4 months of treatment the tumors had regressed and the patient was able to undergo radical surgery, thereby changing the treatment intention from palliative to curative. No adjuvant chemotherapy was given. There were no signs of recurrence 9 months later. Conclusions: The role of the combination of metronomic capecitabine and bevacizumab in patients with MAC merits further investigation.

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  • 27.
    Willander, Kerstin
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Haematology.
    Kumar Dutta, Ravi
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Health Sciences.
    Ungerbäck, Jonas
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Health Sciences.
    Gunnarsson, Rebeqa
    Lund University, Sweden.
    Juliusson, Gunnar
    Lund University, Sweden.
    Fredrikson, Mats
    Linköping University, Department of Clinical and Experimental Medicine, Division of Inflammation Medicine. Linköping University, Faculty of Health Sciences.
    Linderholm, Mats
    Stockholms Sjukhem, Sweden.
    Söderkvist, Peter
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Health Sciences.
    NOTCH1 mutations influence survival in chronic lymphocytic leukemia patients2013In: BMC Cancer, ISSN 1471-2407, E-ISSN 1471-2407, Vol. 13Article in journal (Refereed)
    Abstract [en]

    Background

    NOTCH1 PEST domain mutations in chronic lymphocytic leukemia have recently been shown to be of prognostic relevance. Both NOTCH1 and NOTCH2 are constitutively activated in B-cell CLL but not expressed in normal B cells and may be involved in survival and resistance to apoptosis in CLL. We screened for mutations in different parts of both NOTCH1 and NOTCH2 genes and related the changes to survival and other known risk factors.

    Methods

    In a cohort of 209 CLL patients, we used single strand conformation analysis to determine which of the samples carrying the NOTCH mutations and direct dideoxy sequencing was used to determine the exact nucleotide changes. Kaplan-Meier curves and log rank test were used to determine overall survival for NOTCH1 mutated cases and Cox regression analysis was used to calculate hazardous ratios.

    Results

    In the present study, we found NOTCH1 PEST domain mutations in 6.7% of the cases. A shorter overall survival was found in patients with NOTCH1 mutations compared to wildtype (p = 0.049). Further, we also examined the extracellular and the heterodimerisation domains of the NOTCH1 gene and the PEST domain and heterodimerisation domain of the NOTCH2 gene, but no mutations were found in these regions. NOTCH1 mutations were most commonly observed in patients with unmutated IGHV gene (10/14), and associated with a more aggressive disease course. In addition, NOTCH1 mutations were almost mutually exclusive with TP53 mutations. In the combined group of NOTCH1 (6.7%) or TP53 (6.2%) mutations, a significant difference in overall survival compared to the wildtype NOTCH1 and TP53 was found (p = 0.002).

    Conclusions

    Both NOTCH1 and TP53 mutations seem to be independent predictive markers for worse outcome in CLL-patients and this study emphasizes the contention that NOTCH1 mutations is a novel risk marker.

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  • 28.
    Wintzell, My
    et al.
    Department of Oncology-Pathology, Cancer Center Karolinska CCK R8:03 Karolinska Institutet, Stockholm, S-171 76, Sweden.
    Hjerpe, Elisabet
    Department of Gynecologic Oncology, Karolinska University Hospital, Stockholm, S-171 76, Sweden.
    Åvall Lundqvist, Elisabeth
    Department of Gynecologic Oncology, Karolinska University Hospital, Stockholm, S-171 76, Sweden.
    Shoshan, Maria
    Department of Oncology-Pathology, Cancer Center Karolinska CCK R8:03 Karolinska Institutet, Stockholm, S-171 76, Sweden.
    Protein markers of cancer-associated fibroblasts and tumor-initiating cells reveal subpopulations in freshly isolated ovarian cancer ascites.2012In: BMC Cancer, ISSN 1471-2407, E-ISSN 1471-2407, Vol. 12, no 359Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: In ovarian cancer, massive intraperitoneal dissemination is due to exfoliated tumor cells in ascites. Tumor-initiating cells (TICs or cancer stem cells) and cells showing epithelial-mesenchymal-transition (EMT) are particularly implicated. Spontaneous spherical cell aggregates are sometimes observed, but although similar to those formed by TICs in vitro, their significance is unclear.

    METHODS: Cells freshly isolated from malignant ascites were separated into sphere samples (S-type samples, n=9) and monolayer-forming single-cell suspensions (M-type, n=18). Using western blot, these were then compared for expression of protein markers of EMT, TIC, and of cancer-associated fibroblasts (CAFs).

    RESULTS: S-type cells differed significantly from M-type by expressing high levels of E-cadherin and no or little vimentin, integrin-β3 or stem cell transcription factor Oct-4A. By contrast, M-type samples were enriched for CD44, Oct-4A and for CAF markers. Independently of M- and S-type, there was a strong correlation between TIC markers Nanog and EpCAM. The CAF marker α-SMA correlated with clinical stage IV. This is the first report on CAF markers in malignant ascites and on SUMOylation of Oct-4A in ovarian cancer.

    CONCLUSIONS: In addition to demonstrating potentially high levels of TICs in ascites, the results suggest that the S-type population is the less tumorigenic one. Nanog(high)/EpCAM(high) samples represent a TIC subset which may be either M- or S-type, and which is separate from the CD44(high)/Oct-4A(high) subset observed only in M-type samples. This demonstrates a heterogeneity in TIC populations in vivo which has practical implications for TIC isolation based on cell sorting. The biological heterogeneity will need to be addressed in future therapeutical strategies.

  • 29.
    Zhang, Hong
    et al.
    University of Skovde, Sweden .
    Wang, Da-Wei
    University of Skovde, Sweden Hebei Medical University, Peoples R China .
    Adell, Gunnar
    Karolinska University Hospital, Sweden .
    Sun, Xiao-Feng
    Linköping University, Department of Clinical and Experimental Medicine, Oncology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Surgery, Orthopaedics and Cancer Treatment, Department of Oncology UHL.
    WRAP53 is an independent prognostic factor in rectal cancer- a study of Swedish clinical trial of preoperative radiotherapy in rectal cancer patients2012In: BMC Cancer, ISSN 1471-2407, E-ISSN 1471-2407, Vol. 12, no 294Article in journal (Refereed)
    Abstract [en]

    Background: Expression of WRAP53 protein has oncogenic properties and it is up regulated in several types of tumors. less thanbrgreater than less thanbrgreater thanMethods: We examined expression of WRAP53 protein in rectal cancers and analyzed its relationship to the response to preoperative radiotherapy and patient survival. The WRAP53 protein was examined by immunohistochemistry in normal mucosa, primary tumors and lymph node metastases from 143 rectal cancer patients participated in a Swedish clinical trial of preoperative radiotherapy. less thanbrgreater than less thanbrgreater thanResults: Frequency of WRAP53 protein expression was increased in primary rectal cancer compared to the normal mucosa (p andlt; 0.05). In non-radiotherapy group positive WRAP53 in primary tumors (p = 0.03, RR, 3.73, 95% CI, 1.13-11.89) or metastases (p = 0.01, RR, 4.11, 95% CI, 1.25-13.14), was associated with poor prognosis independently of stages and differentiations. In radiotherapy group, positive WRAP53 in the metastasis correlated with better survival (p = 0.04). An interaction analysis showed that the correlations of WRAP53 with the prognostic significance with and without radiotherapy in the metastasis differed (p = 0.01). In the radiotherapy group, expression of WRAP53 in metastases gave a better outcome (p = 0.02, RR, 0.32, 95% CI, 0.13-0.84), and an interaction analysis showed significance between the two groups (p = 0.01). less thanbrgreater than less thanbrgreater thanConclusion: WRAP53 may be a new biomarker used to predict prognosis and to select suitable patients for preoperative radiotherapy.

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