| 1. |
- Aarnio, Riina, 1971-, et al.
(författare)
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Cost-effectiveness analysis of repeated self-sampling for HPV testing in primary cervical screening: a randomized study
- 2020
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Ingår i: BMC Cancer. - : Springer Science and Business Media LLC. - 1471-2407. ; 20:1
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)abstract
- BackgroundHuman papillomavirus (HPV) testing is recommended in primary cervical screening to improve cancer prevention. An advantage of HPV testing is that it can be performed on self-samples, which could increase population coverage and result in a more efficient strategy to identify women at risk of developing cervical cancer. Our objective was to assess whether repeated self-sampling for HPV testing is cost-effective in comparison with Pap smear cytology for detection of cervical intraepithelial neoplasia grade 2 or more (CIN2+) in increasing participation rate in primary cervical screening.MethodsA cost-effectiveness analysis (CEA) was performed on data from a previously published randomized clinical study including 36 390 women aged 30–49 years. Participants were randomized either to perform repeated self-sampling of vaginal fluid for HPV testing (n = 17 997, HPV self-sampling arm) or to midwife-collected Pap smears for cytological analysis (n = 18 393, Pap smear arm).ResultsSelf-sampling for HPV testing led to 1633 more screened women and 107 more histologically diagnosed CIN2+ at a lower cost vs. midwife-collected Pap smears (€ 228 642 vs. € 781 139). ConclusionsThis study projected that repeated self-sampling for HPV testing increased participation and detection of CIN2+ at a lower cost than midwife-collected Pap smears in primary cervical screening. Offering women a home-based self-sampling may therefore be a more cost-effective alternative than clinic-based screening.
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| 2. |
- Abu-Humaidan, Anas H.A., et al.
(författare)
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EGFR modulates complement activation in head and neck squamous cell carcinoma
- 2020
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Ingår i: BMC Cancer. - : Springer Science and Business Media LLC. - 1471-2407. ; 20:1
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Tidskriftsartikel (refereegranskat)abstract
- Background: The epidermal growth factor receptor (EGFR) is pivotal for growth of epithelial cells and is overexpressed in several epithelial cancers like head and neck squamous cell carcinoma (HNSCC). EGFR signalling is also involved in diverse innate immune functions in epithelia. We previously found a role for EGFR in modulating the complement system in skin, this prompted an investigation into EGFR role in complement modulation in HNSCC. Methods: We used patient derived HNSCC cell lines with varying sensitivities to EGFR inhibitors, and generated EGFR inhibition resistant cell lines to study the role of EGFR in modulating complement in HNSCC. Results: We found that HNSCC cell lines activate the complement system when incubated with human serum. This complement activation was increased in cell lines sensitive to EGFR inhibition following the use of the tyrosine kinase inhibitor Iressa. Sensitive cell line made resistant to EGFR-inhibitors displayed complement activation and a decrease in complement regulatory proteins even in the absence of EGFR-inhibitors. Complement activation did not cause lysis of HNSCC cells, and rather led to increased extracellular signal-regulated kinase (ERK) phosphorylation in one cell line. Conclusion: These data indicate that EGFR has a complement modulatory role in HNSCC, and that a prolonged EGFR-inhibition treatment in sensitive cancer cells increases complement activation. This has implications in understanding the response to EGFR inhibitors, in which resistance and inflammatory skin lesions are two major causes for treatment cessation.
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| 3. |
- Asciutto, Katrin Christine, et al.
(författare)
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14-type HPV mRNA test in triage of HPV DNA-positive postmenopausal women with normal cytology
- 2020
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Ingår i: BMC Cancer. - : Springer Science and Business Media LLC. - 1471-2407. ; 20:1
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Tidskriftsartikel (refereegranskat)abstract
- Background: During 2013 and 2016 the region of Skåne, Sweden started to analyse human papillomavirus (HPV) and cytology in postmenopausal women 60–65 years of age. Our aim was to evaluate high-risk (HR) HPV mRNA testing for the triage of HPV DNA-positive postmenopausal women with normal cytology. Methods: A total of 271 women, 60–65 years of age, underwent liquid-based cytology (LBC) and HPV testing by using the HR-HPV DNA MGP-PCR-Luminex assay. HR-HPV DNA-positive women with normal cytology underwent complimentary HPV mRNA testing (Aptima, Hologic Inc.). Over a period of 49 months (SD 11.0) the women received regular follow-ups at intervals of 12–18 months. Women with abnormal cytology and/or a positive HR-HPV DNA and/or mRNA result at two subsequent visits were scheduled for colposcopy and clinical examination. Results: Over the surveillance period, 3.6% (10/271) of the HR-HPV DNA-positive women developed histologically confirmed high-grade squamous intraepithelial lesions (HSILs) or worse. The cumulative incidence rates (CIR) were 29.7% (CI 24.8–30.1) for HSIL or worse among HPV mRNA-positive women at enrolment (39.5% 107/271) and 0% among HPV mRNA-negative women (60.5%, 164/271), (p = 0.002). Conclusions: Postmenopausal women with normal cytology testing positive for HR-HPV mRNA are at increased risk for the development of high-grade cervical intraepithelial neoplasia (CIN), in contrast to women with a negative HR-HPV mRNA outcome. The HR-HPV mRNA APTIMA assay detecting 14 HR-HPV types may be a useful triage method among HPV DNA-positive postmenopausal women with normal cytology.
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| 4. |
- Blomstrand, Hakon, et al.
(författare)
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Clinical characteristics and blood/serum bound prognostic biomarkers in advanced pancreatic cancer treated with gemcitabine and nab-paclitaxel
- 2020
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Ingår i: BMC Cancer. - : BioMed Central. - 1471-2407. ; 20:1
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Tidskriftsartikel (refereegranskat)abstract
- BackgroundIn 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.MethodsThe 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.ResultUnivariable 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.ConclusionSerum 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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| 5. |
- Corell, Alba, et al.
(författare)
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The clinical significance of the T2-FLAIR mismatch sign in grade II and III gliomas: a population-based study.
- 2020
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Ingår i: BMC cancer. - : Springer Science and Business Media LLC. - 1471-2407. ; 20:1
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Tidskriftsartikel (refereegranskat)abstract
- The T2-FLAIR mismatch sign is an imaging finding highly suggestive of isocitrate dehydrogenase mutated (IDH-mut) 1p19q non-codeleted (non-codel) gliomas (astrocytomas). In previous studies, it has shown excellent specificity but limited sensitivity for IDH-mut astrocytomas. Whether the mismatch sign is a marker of a clinically relevant subtype of IDH-mut astrocytomas is unknown.We included histopathologically verified supratentorial lower-grade gliomas (LGG) WHO grade II-III retrospectively during the period 2010-2016. In the period 2017-2018, patients with suspected LGG radiologically were prospectively included, and in this cohort other diagnoses than glioma could occur. Clinical, radiological and molecular data were collected. For clinical evaluation we included all patients with IDH-mut astrocytomas. In the 2010-2016 cohort DNA methylation analysis with Infinium MethylationEPIC BeadChip (Illumina) was performed for patients withan IDH-mut astrocytomawith available tissue. We aimed to examine the association of the T2-FLAIRmismatch sign with clinical factors and outcomes. Additionally, we evaluated the diagnostic reliability of the mismatch sign and its relation to methylation profiles.Out of 215 patients with LGG, 135 had known IDH-mutation and 1p19q codeletion status. Fifty patients hadan IDH-mut astrocytoma and 12 of these (24.0%) showed a mismatch sign. The sensitivity and specificity of the mismatch sign for IDH-mut detection were 26.4 and 97.6%, respectively. There were no differences between patients withan IDH-mut astrocytoma with or without mismatch sign when grouped according to T2-FLAIR mismatch sign with respect to baseline characteristics, clinical outcomes and methylation profiles. The overall interrater agreement between neuroradiologist and clinical neurosurgeons for the T2-FLAIR mismatch sign was significant when all 215 MRI examination assessed (κ=0.77, p<0.001, N=215).The T2-FLAIR mismatch sign in patients withan IDH-mut astrocytoma is not associated with clinical presentation or outcome. It seems unlikely that the IDH-mut astrocytomas with mismatch sign represent a specific subentity. Finally, we have validated that the T2-FLAIR mismatch sign is a reliable and specific marker of IDH-mut astrocytomas.
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| 6. |
- Dudka, Ilona, et al.
(författare)
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Comprehensive metabolomics analysis of prostate cancer tissue in relation to tumor aggressiveness and TMPRSS2-ERG fusion status
- 2020
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Ingår i: BMC Cancer. - : BioMed Central. - 1471-2407. ; 20:1
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Tidskriftsartikel (refereegranskat)abstract
- Background: Prostate cancer (PC) can display very heterogeneous phenotypes ranging from indolent asymptomatic to aggressive lethal forms. Understanding how these PC subtypes vary in their striving for energy and anabolic molecules is of fundamental importance for developing more effective therapies and diagnostics. Here, we carried out an extensive analysis of prostate tissue samples to reveal metabolic alterations during PC development and disease progression and furthermore between TMPRSS2-ERG rearrangement-positive and -negative PC subclasses.Methods: Comprehensive metabolomics analysis of prostate tissue samples was performed by non-destructive high-resolution magic angle spinning nuclear magnetic resonance (H-1 HR MAS NMR). Subsequently, samples underwent moderate extraction, leaving tissue morphology intact for histopathological characterization. Metabolites in tissue extracts were identified by H-1/P-31 NMR and liquid chromatography-mass spectrometry (LC-MS). These metabolomics profiles were analyzed by chemometric tools and the outcome was further validated using proteomic data from a separate sample cohort.Results: The obtained metabolite patterns significantly differed between PC and benign tissue and between samples with high and low Gleason score (GS). Five key metabolites (phosphocholine, glutamate, hypoxanthine, arginine and alpha-glucose) were identified, who were sufficient to differentiate between cancer and benign tissue and between high to low GS. In ERG-positive PC, the analysis revealed several acylcarnitines among the increased metabolites together with decreased levels of proteins involved in beta-oxidation; indicating decreased acyl-CoAs oxidation in ERG-positive tumors. The ERG-positive group also showed increased levels of metabolites and proteins involved in purine catabolism; a potential sign of increased DNA damage and oxidative stress.Conclusions: Our comprehensive metabolomic analysis strongly indicates that ERG-positive PC and ERG-negative PC should be considered as different subtypes of PC; a fact requiring different, sub-type specific treatment strategies for affected patients.
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| 7. |
- Engelbak Nielsen, Zandra, et al.
(författare)
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Are cancer patients better off if they participate in clinical trials? : A mixed methods study
- 2020
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Ingår i: BMC Cancer. - : Springer Science and Business Media LLC. - 1471-2407. ; 20:1
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Tidskriftsartikel (refereegranskat)abstract
- BackgroundResearch and cancer care are closely intertwined; however, it is not clear whether physicians and nurses believe that clinical trials offer the best treatment for patients and, if so, whether this belief is justified. The aim of this study was therefore: (i) to explore how physicians and nurses perceive the benefits of clinical trial participation compared with standard care and (ii) whether it is justified to claim that clinical trial participation improves outcomes for cancer patients.MethodsA mixed methods approach was used employing semi-structured interviews with 57 physicians and nurses in oncology and haematology and a literature review of the evidence for trial superiority, i.e. the idea that receiving treatment in a clinical trial leads to a better outcome compared with standard care. Inductive thematic analysis was used to examine the interview data. A literature review comprising nine articles was conducted according to a conceptual framework developed by Peppercorn et al. and evaluated recent evidence on trial superiority.ResultsOur findings show that many physicians and nurses make claims supporting trial superiority, however very little evidence is available in the literature comparing outcomes for trial participants and non-participants that supports their assertions.ConclusionsDespite the recent rapid development and use of targeted therapy and immunotherapy, we find no support for trial participation to provide better outcomes for cancer patients than standard care. Hence, our present results are in line with previous results from Peppercorn et al. A weaker version of the superiority claim is that even if a trial does not bring about a direct positive effect, it brings about indirect positive effects. However, as the value of such indirect effects is dependent on the individual’s specific circumstances and preferences, their existence cannot establish the general claim that treatment in trials is superior. Belief in trial superiority is therefore unfounded. Hence, if such beliefs are communicated to patients in a trial recruitment context, it would provide misleading information. Instead emphasis should be on patients volunteering to give an altruistic contribution to the furthering of knowledge and to the potential benefit of future patients.
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| 8. |
- Enríquez Pérez, Julio, et al.
(författare)
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Convection-enhanced delivery of temozolomide and whole cell tumor immunizations in GL261 and KR158 experimental mouse gliomas
- 2020
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Ingår i: BMC Cancer. - : Springer Science and Business Media LLC. - 1471-2407. ; 20
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Glioblastomas (GBM) are therapy-resistant tumors with a profoundly immunosuppressive tumor microenvironment. Chemotherapy has shown limited efficacy against GBM. Systemic delivery of chemotherapeutic drugs is hampered by the difficulty of achieving intratumoral levels as systemic toxicity is a dose-limiting factor. Although some of its effects might be mediated by immune reactivity, systemic chemotherapy can also inhibit induced or spontaneous antitumor immune reactivity. Convection-enhanced delivery of temozolomide (CED-TMZ) can tentatively increase intratumoral drug concentration while reducing systemic side effects. The objective of this study was to evaluate the therapeutic effect of intratumorally delivered temozolomide in combination with immunotherapy and whether such therapy can generate a cellular antitumor immune response. METHODS: Single bolus intratumoral injection and 3-day mini-osmotic pumps (Alzet®) were used to deliver intratumoral TMZ in C57BL6 mice bearing orthotopic gliomas. Immunotherapy consisted of subcutaneous injections of irradiated GL261 or KR158 glioma cells. Tumor size and intratumoral immune cell populations were analyzed by immunohistochemistry. RESULTS: Combined CED-TMZ and immunotherapy had a synergistic antitumor effect in the GL261 model, compared to CED-TMZ or immunotherapy as monotherapies. In the KR158 model, immunization cured a small proportion of the mice whereas addition of CED-TMZ did not have a synergistic effect. However, CED-TMZ as monotherapy prolonged the median survival. Moreover, TMZ bolus injection in the GL261 model induced neurotoxicity and lower cure rate than its equivalent dose delivered by CED. In addition, we found that T-cells were the predominant cells responsible for the TMZ antitumor effect in the GL261 model. Finally, CED-TMZ combined with immunotherapy significantly reduced tumor volume and increased the intratumoral influx of T-cells in both models. CONCLUSIONS: We show that immunotherapy synergized with CED-TMZ in the GL261 model and cured animals in the KR158 model. Single bolus administration of TMZ was effective with a narrower therapeutic window than CED-TMZ. Combined CED-TMZ and immunotherapy led to an increase in the intratumoral influx of T-cells. These results form part of the basis for the translation of the therapy to patients with GBM but the dosing and timing of delivery will have to be explored in depth both experimentally and clinically.
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| 9. |
- Faraz, Mahmood, et al.
(författare)
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LRIG1 gene copy number analysis by ddPCR and correlations to clinical factors in breast cancer
- 2020
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Ingår i: BMC Cancer. - : BioMed Central. - 1471-2407. ; 20:1
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Tidskriftsartikel (refereegranskat)abstract
- Background: Leucine-rich repeats and immunoglobulin-like domains 1 (LRIG1) copy number alterations and unbalanced gene recombination events have been reported to occur in breast cancer. Importantly, LRIG1 loss was recently shown to predict early and late relapse in stage I-II breast cancer.Methods: We developed droplet digital PCR (ddPCR) assays for the determination of relative LRIG1 copy numbers and used these assays to analyze LRIG1 in twelve healthy individuals, 34 breast tumor samples previously analyzed by fluorescence in situ hybridization (FISH), and 423 breast tumor cytosols.Results: Four of the LRIG1/reference gene assays were found to be precise and robust, showing copy number ratios close to 1 (mean, 0.984; standard deviation, +/-0.031) among the healthy control population. The correlation between the ddPCR assays and previous FISH results was low, possibly because of the different normalization strategies used. One in 34 breast tumors (2.9%) showed an unbalanced LRIG1 recombination event. LRIG1 copy number ratios were associated with the breast cancer subtype, steroid receptor status, ERBB2 status, tumor grade, and nodal status. Both LRIG1 loss and gain were associated with unfavorable metastasis-free survival; however, they did not remain significant prognostic factors after adjustment for common risk factors in the Cox regression analysis. Furthermore, LRIG1 loss was not significantly associated with survival in stage I and II cases.Conclusions: Although LRIG1 gene aberrations may be important determinants of breast cancer biology, and prognostic markers, the results of this study do not verify an important role for LRIG1 copy number analyses in predicting the risk of relapse in early-stage breast cancer.
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| 10. |
- Hagerling, Catharina, et al.
(författare)
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LGR5 in breast cancer and ductal carcinoma in situ: a diagnostic and prognostic biomarker and a therapeutic target
- 2020
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Ingår i: Bmc Cancer. - : Springer Science and Business Media LLC. - 1471-2407. ; 20:1
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Tidskriftsartikel (refereegranskat)abstract
- Background Novel biomarkers are required to discern between breast tumors that should be targeted for treatment from those that would never become clinically apparent and/or life threatening for patients. Moreover, therapeutics that specifically target breast cancer (BC) cells with tumor-initiating capacity to prevent recurrence are an unmet need. We investigated the clinical importance of LGR5 in BC and ductal carcinoma in situ (DCIS) to explore LGR5 as a biomarker and a therapeutic target. Methods We stained BC (n = 401) and DCIS (n = 119) tissue microarrays with an antibody against LGR5. We examined anLGR5knockdown ER(-)cell line that was orthotopically transplanted and used for in vitro colony assays. We also determined the tumor-initiating role of Lgr5 in lineage-tracing experiments. Lastly, we transplanted ER(-)patient-derived xenografts into mice that were subsequently treated with a LGR5 antibody drug conjugate (anti-LGR5-ADC). Results LGR5 expression correlated with small tumor size, lower grade, lymph node negativity, and ER-positivity. ER(+)patients with LGR5(high)tumors rarely had recurrence, while high-grade ER(-)patients with LGR5(high)expression recurred and died due to BC more often. Intriguingly, all the DCIS patients who later died of BC had LGR5-positive tumors. Colony assays and xenograft experiments substantiated a role for LGR5 in ER(-)tumor initiation and subsequent growth, which was further validated by lineage-tracing experiments in ER-/triple-negative BC mouse models. Importantly, by utilizing LGR5(high)patient-derived xenografts, we showed that anti-LGR5-ADC should be considered as a therapeutic for high-grade ER-BC. Conclusion LGR5 has distinct roles in ER(-)vs. ER+BC with potential clinical applicability as a biomarker to identify patients in need of therapy and could serve as a therapeutic target for high-grade ER-BC.
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