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Qvick, A., Wirén, A., Rönnqvist, M. & Helenius, G. (2019). Circulating miRNA: a biomarker for classification of lung cancer and benign lung disease. Paper presented at World Congress on Lung Cancer 2019, Barcelona, Spain, September 7-10, 2019. Journal of Thoracic Oncology, 14(10), 311-311, Article ID MA15.07.
Open this publication in new window or tab >>Circulating miRNA: a biomarker for classification of lung cancer and benign lung disease
2019 (English)In: Journal of Thoracic Oncology, ISSN 1556-0864, Vol. 14, no 10, p. 311-311, article id MA15.07Article in journal, Meeting abstract (Other academic) Published
Abstract [en]

Background Circulating biomarkers for cancer have great potential for diagnosis as well as follow up of treatment. MicroRNAs (miRNA) are involved in the expression of a majority of proteins with different cell types having different miRNA expression. The aim of this study was to create a circulating miRNA-based model to discriminate patients with lung cancer from patients with benign lung disease. Methods Samples were collected from patients under investigation for lung cancer at Örebro University hospital. Patients were then divided into groups based on diagnosis, which resulted in NSCLC adenocarcinoma (n=24), NSCLC squamous cell carcinoma (n=13), SCLC (n=4) and a heterogeneous group consisting of different benign lung diseases (n=19). Healthy controls were collected separately (n=17). Circulating miRNA was processed using the extraction-free library preparation miRNA Whole Transcriptome Assay with probes for 2083 human mature miRNAs and analyzed with massive parallel sequencing. Differential expression between groups was estimated using edgeR. MiRNAs that had the highest impact on patient grouping were used in a sPLS discriminant analysis. The resulting classification model was validated using the leave-one-out method. Results The final model for comparison between patients with benign lung disease and patients with lung cancer contained 19 miRNAs. The model had an error rate of 15 % with errors distributed evenly between groups. A sub-analysis of patients with mutations in EGFR (n=5) and KRAS (n=6) was performed showing two distinct patterns in miRNA expression. Conclusion MiRNA shows promise as a circulating biomarker for lung cancer but may not be sufficient as an independent classifier. The predictive power may be improved by using several biomarkers in combination. The difference in expression between tumors with different mutations may be derived from alternate driving processes in these tumors.Sequencing results were standardized as counts per million (cpm), miRNA with cpm < 100 was filtered out and quantile normalization and log2 transformation was performed. Differential expression was analyzed using regression model (R software v. 3.5.1, package edgeR v. 3.24.1) with Benjamini-Hochberg correction. The miRNAs that, after correction, had a significant impact on sample groups were kept and analyzed with sparse partial least squares-regression. The resulting model was validated using leave-one-out method.

Place, publisher, year, edition, pages
Elsevier, 2019
National Category
Cancer and Oncology
Identifiers
urn:nbn:se:oru:diva-77782 (URN)10.1016/j.jtho.2019.08.624 (DOI)000492162201309 ()
Conference
World Congress on Lung Cancer 2019, Barcelona, Spain, September 7-10, 2019
Available from: 2019-11-05 Created: 2019-11-05 Last updated: 2019-11-12Bibliographically approved
Bergengren, L., Lillsunde-Larsson, G., Helenius, G. & Karlsson, M. G. (2019). HPV-based screening for cervical cancer among women 55-59 years of age. PLoS ONE, 14(6), Article ID e0217108.
Open this publication in new window or tab >>HPV-based screening for cervical cancer among women 55-59 years of age
2019 (English)In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 14, no 6, article id e0217108Article in journal (Refereed) Published
Abstract [en]

AIM: Many cervical cancers occurs among women over 65 and prevalence of HPV genotypes in this age cohort is sparingly studied. One aim of this study was to study the prevalence and distribution of HPV genotypes in women 55-59 years, with normal cytology when exiting the screening program. Secondly, HPV clearance as well as the value of HPV genotyping and/or liquid based cytology as triage tests for identifying histological dysplasia among women with persistent HPV was studied.

METHODS: Women that exited the screening program with normal cytology, between the years 2012-2014, in Örebro County, Sweden, were invited to this study. A total of 2946 samples were analyzed with a broad-spectrum assay to detect both hrHPV and lrHPV in order to investigate the distribution of genotypes. In the consent group, women with a positive hrHPV test were offered a follow-up test and a cone biopsy for histological confirmation, and a follow up sample 6 months post cone.

RESULTS: The overall prevalence of hrHPV was 7.4% and 59% of them remained hrHPV positive in a follow-up test after 12 months. A total of 99 women had a cone biopsy done, where 19% showed histological dysplasia. HPV 53 was the most common genotype, and among women with histology confirmed LSIL or HSIL, HPV 31 was most common. A positive hrHPV result showed a PPV of 25% for LSIL+ and 12.5%for HSIL+. Using detection of HPV 16/18 genotypes as a triage test for hrHPV positive tests, indicated FNR for histological LSIL+ and HSIL+ of 94% and 87.5% respectively, whilst triage based on cervical cytology had a FNR of 69% for LSIL+ and 37.5% for HSIL+.

CONCLUSION: The most common hrHPV genotypes among women 55-59 years of age were non HPV16/18 genotypes, and in this population, these genotypes represented most of the histological verified HSIL lesions. This result does not support the proposition of a HPV 16/18 triaging test after a positive hrHPV test as a marker of histological HSIL+ cervical lesions in women over 55 years of age. Similarly, cytological triage after a positive hrHPV showed no additional benefit in this population. Specific triaging tests should be validated to follow post-menopausal women with a positive hrHPV test.

Place, publisher, year, edition, pages
PLOS, 2019
National Category
Cancer and Oncology
Identifiers
urn:nbn:se:oru:diva-74701 (URN)10.1371/journal.pone.0217108 (DOI)000471587000007 ()31199811 (PubMedID)2-s2.0-85067434997 (Scopus ID)
Note

Funding Agencies:

Region Örebro County Research Committee  

Örebro University Hospital Research Foundation  

BBMRI.se 

Available from: 2019-06-17 Created: 2019-06-17 Last updated: 2019-11-14Bibliographically approved
Östling, H., Kruse, R., Helenius, G. & Lodefalk, M. (2019). Placental expression of microRNAs in infants born small for gestational age. Placenta, 81, 46-53
Open this publication in new window or tab >>Placental expression of microRNAs in infants born small for gestational age
2019 (English)In: Placenta, ISSN 0143-4004, E-ISSN 1532-3102, Vol. 81, p. 46-53Article in journal (Refereed) Published
Abstract [en]

INTRODUCTION: The molecular mechanisms behind poor foetal growth are not fully known. The aim of this study was to explore global microRNA expression in placentas of infants born small for gestational age (SGA) compared to infants with a normal birth weight (NBW).

METHODS: Placental biopsies from term infants were identified in a biobank and divided into four groups: infants born SGA with (n = 13) or without (n = 9) exposure to low maternal gestational weight gain (GWG) and infants born with NBWs with (n = 20) or without (n = 26) exposure to low GWG. All women and infants were healthy, and no woman smoked during pregnancy. Only vaginal deliveries were included. Next-generation sequencing was performed with single read sequencing of >9 million reads per sample. Differential microRNA expression was analysed using ANOVA for unequal variances (Welch) with multiple testing corrections through the Benjamini-Hochberg method. A fold change >2 and a corrected p value < 0.05 were considered significant. Adjustments for possible confounding factors were made using a linear regression model.

RESULTS: A total of 1870 known, mature human microRNAs were detected in the sample. MiR-3679-5p and miR-193b-3p were significantly upregulated, and miR-379-3p, miR-335-3p, miR-4532, miR-519e-3p, miR-3065-5p, and miR-105-5p were significantly downregulated after adjustment for potential confounding factors in SGA infants with normal GWG compared to infants with NBWs and normal GWG.

DISCUSSION: Infants born unexplained SGA show differential microRNA expression in their placenta. Important pathways for the differentially expressed microRNAs include inflammation and the insulin-IGF system.

Place, publisher, year, edition, pages
Elsevier, 2019
Keywords
Foetal growth, Inflammation, Placenta, RNA-Sequencing, Small for gestational age, microRNA
National Category
Obstetrics, Gynecology and Reproductive Medicine
Identifiers
urn:nbn:se:oru:diva-74556 (URN)10.1016/j.placenta.2019.05.001 (DOI)000468874700007 ()31138431 (PubMedID)2-s2.0-85065481896 (Scopus ID)
Note

Funding Agency:

Research Committee of Region Örebro County and ALF funding Region Örebro County

Available from: 2019-06-05 Created: 2019-06-05 Last updated: 2019-06-14Bibliographically approved
Helenius, G., Lillsunde-Larsson, G., Bergengren, L., Kaliff, M. & Karlsson, M. (2019). Preliminary data from a Swedish self- sampling study in postmenopausal women. In: : . Paper presented at EUROGIN 2019, Monte Carlo, Monaco, 4-7 December, 2019.
Open this publication in new window or tab >>Preliminary data from a Swedish self- sampling study in postmenopausal women
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2019 (English)Conference paper, Poster (with or without abstract) (Other academic)
Abstract [en]

Background: An updated screening algorithm was introduced in Sweden 2015. Primary HPV test for women >30 years old and a prolonged screening with the last test after 64 years of age were some of the changes. In the region of Örebro County, the previous cut-off age was 60 years and with a screening interval of 5 years, women left their last sample when they were 55-59 years old. In the shift between two screening programs, a group of women, 60-64 years old, that left the program 5-10 years ago were now included in the new screening. For re-inclusion, a two year long program was formed to catch-up this group of women and screen them according to the new screening algorithm. At the same time a research project investigating self-sampling was launched. At the same time as the women were invited for a last screening sample they were also asked to participate in a study where they should take a vaginal self-test up to one week after their ordinary screening sample was taken by a midwife. Method Postmenopausal women between 64-70 years was included in the study. HPV status in samples from midwife sampling (MS) was compared to self-sampling (SS) samples. HPV was analyzed using HPV Aptima and all HPV positive samples, independent of sampling method, was triaged with cytology and followed-up according to national guidelines. Results So far, 585 women with paired samples have been included in the study. In the MS, 4% of the women are positive for hrHPV compared to 11% in the SS group. In 486/585 women, the results of the two samples are concordant. Among the non-concordant samples (13%), 62% were positive in SS and negative in MS. The opposite, negative in SS and positive in MS were seen in 4% of the samples. Among the MS negative samples, 32% were invalid in SS. Cytology was used as a triage test for HPV positive women, both for MS and SS. Of 23 hrHPV positive, 18 had normal cytology, 2 ASCUS, 1 LSIL and 1 HSIL. In the samples with abnormal cytology, 4/5 were hrHPV positive in both SS and MS. One sample was positive in SS but negative in MS. Discussion In this age group, more women are hrHPV positive in SS compared to MS. This is in line with what other have seen. Among the very few hrHPV positive samples with abnormal cytology, the majority was hrHPV positive in both MS and SS. But since cytology is a poor triage marker in this age group clinical follow-up is needed before the effectiveness of the both sampling methods can be concluded.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:oru:diva-77781 (URN)
Conference
EUROGIN 2019, Monte Carlo, Monaco, 4-7 December, 2019
Available from: 2019-11-05 Created: 2019-11-05 Last updated: 2019-11-15
Bergengren, L., Kaliff, M., Lillsunde-Larsson, G., Karlsson, M. & Helenius, G. (2018). Comparison between professional sampling and self-sampling for HPV-based cervical cancer screening among postmenopausal women. International Journal of Gynecology & Obstetrics, 142(3), 359-364
Open this publication in new window or tab >>Comparison between professional sampling and self-sampling for HPV-based cervical cancer screening among postmenopausal women
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2018 (English)In: International Journal of Gynecology & Obstetrics, ISSN 0020-7292, E-ISSN 1879-3479, Vol. 142, no 3, p. 359-364Article in journal (Refereed) Published
Abstract [en]

OBJECTIVE: To investigate whether self-sampling is as reliable as professional sampling for HPV testing and genotype detection among postmenopausal women.

METHODS: In the present prospective cross-sectional study, women in Örebro County, Sweden, who had high-risk HPV (hrHPV) and normal cytology results in exit screening tests conducted in between January 1, 2012, and December 31, 2014, were invited to follow-up screenings between February 24, 2015 and May 15, 2015, that included professional sampling and self-sampling. HPV genotypes were identified by a DNA-based assay that could detect 35 HPV genotypes. Findings between the different sampling methods were compared.

RESULTS: Of 143 women who participated, 119 returned a self-sample. Completely concordant results were observed in 67 of these samples when both hrHPV and low-risk HPV genotypes were analyzed. Overall, 99 (83.2%) women had the same clinically relevant finding from both sampling methods. Twenty women had discordant hrHPV results (hrHPV detected in 10 self-samples vs 10 professionally collected samples; Cohen κ 0.66, 95% confidence interval 0.53-0.80). There was no significant difference between the two sampling methods for clinically significant infections (P>0.99) or extended genotyping (P=0.827).

CONCLUSION: Postmenopausal women could be offered self-sampling devices to increase screening-program coverage while maintaining test quality.

Place, publisher, year, edition, pages
Wiley-Blackwell Publishing Inc., 2018
Keywords
Cervical cancer, HPV, Postmenopausal women, Professional sampling, Screening, Self-sample
National Category
Cancer and Oncology Obstetrics, Gynecology and Reproductive Medicine
Identifiers
urn:nbn:se:oru:diva-67134 (URN)10.1002/ijgo.12538 (DOI)000440652000017 ()29856071 (PubMedID)2-s2.0-85051073715 (Scopus ID)
Note

Funding Agencies:

Region Örebro County Research Committee  

Örebro University Hospital Research Foundation  

BBMRI.se

Available from: 2018-06-04 Created: 2018-06-04 Last updated: 2018-08-30Bibliographically approved
Helenius, G., Ottestig, E., Kaliff, M., Lillsunde-Larsson, G., Karlsson, M. & Bergengren, L. (2018). Distribution of HPV-genotypes in a Swedish screening population. In: : . Paper presented at Eurogin 2018 International multidisciplinary HPV Congress, Lisabon Portugal, December 2-5, 2018.
Open this publication in new window or tab >>Distribution of HPV-genotypes in a Swedish screening population
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2018 (English)Conference paper, Poster (with or without abstract) (Refereed)
National Category
Cancer and Oncology
Identifiers
urn:nbn:se:oru:diva-69348 (URN)
Conference
Eurogin 2018 International multidisciplinary HPV Congress, Lisabon Portugal, December 2-5, 2018
Available from: 2018-10-08 Created: 2018-10-08 Last updated: 2018-10-08Bibliographically approved
Kaliff, M., Sorbe, B., Mordhorst, L. B., Helenius, G., Karlsson, M. G. & Lillsunde-Larsson, G. (2018). Findings of multiple HPV genotypes in cervical carcinoma are associated with poor cancer-specific survival in a Swedish cohort of cervical cancer primarily treated with radiotherapy. OncoTarget, 9(27), 18786-18796
Open this publication in new window or tab >>Findings of multiple HPV genotypes in cervical carcinoma are associated with poor cancer-specific survival in a Swedish cohort of cervical cancer primarily treated with radiotherapy
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2018 (English)In: OncoTarget, ISSN 1949-2553, E-ISSN 1949-2553, Vol. 9, no 27, p. 18786-18796Article in journal (Refereed) Published
Abstract [en]

Cervical cancer (CC) is one of the most common cancers in women and virtually all cases of CC are a result of a persistent infection of human papillomavirus (HPV). For disease detected in early stages there is curing treatment but when diagnosed late with recurring disease and metastasis there are limited possibilities. Here we evaluate HPV impact on treatment resistance and metastatic disease progression. Prevalence and distribution of HPV genotypes and HPV16 variants in a Swedish CC patient cohort (n=209) was evaluated, as well as HPV influence on patient prognosis. Tumor samples suitable for analysis (n=204) were genotyped using two different real-time PCR methods. HPV16 variant analysis was made using pyrosequencing. Results showed that HPV prevalence in the total series was 93%. Of the HPV-positive samples, 13% contained multiple infections, typically with two high-risk HPV together. Primary cure rate for the complete series was 95%. Recurrence rate of the complete series was 28% and distant recurrences were most frequent (20%). Patients with tumors containing multiple HPV-strains and particularly HPV genotypes belonging to the alpha 7 and 9 species together had a significantly higher rate of distant tumor recurrences and worse cancer-specific survival rate.

Place, publisher, year, edition, pages
Impact Journals LLC, 2018
Keywords
HPV, cervical cancer, recurrences, survival
National Category
Cancer and Oncology
Identifiers
urn:nbn:se:oru:diva-71672 (URN)10.18632/oncotarget.24666 (DOI)29721161 (PubMedID)2-s2.0-85045206587 (Scopus ID)
Available from: 2019-01-22 Created: 2019-01-22 Last updated: 2019-01-24Bibliographically approved
Lillsunde-Larsson, G., Kaliff, M., Ottestig, E. & Helenius, G. (2018). HPV genotyping of HPV primary screening positive samples in Örebro, Sweden. In: : . Paper presented at 33rd World congress of Biomedical Laboratory Science (IFBLS), Florens, Italy, 22-26 Sep., 2018.
Open this publication in new window or tab >>HPV genotyping of HPV primary screening positive samples in Örebro, Sweden
2018 (English)Conference paper, Poster (with or without abstract) (Other academic)
National Category
Cancer and Oncology
Identifiers
urn:nbn:se:oru:diva-73851 (URN)
Conference
33rd World congress of Biomedical Laboratory Science (IFBLS), Florens, Italy, 22-26 Sep., 2018
Available from: 2019-04-17 Created: 2019-04-17 Last updated: 2019-04-17Bibliographically approved
Lillsunde-Larsson, G., Kaliff, M., Sorbe, B., Helenius, G. & Karlsson, M. (2018). HPV16 VIRAL CHARACTERISTICS IN PRIMARY AND RECURRENT VULVAR CARCINOMA. In: : . Paper presented at 32nd International Papillomavirus Conference IPVC 2018, Sydney, Australia, 2-6 October, 2018.
Open this publication in new window or tab >>HPV16 VIRAL CHARACTERISTICS IN PRIMARY AND RECURRENT VULVAR CARCINOMA
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2018 (English)Conference paper, Poster (with or without abstract) (Other academic)
National Category
Cancer and Oncology
Identifiers
urn:nbn:se:oru:diva-73753 (URN)
Conference
32nd International Papillomavirus Conference IPVC 2018, Sydney, Australia, 2-6 October, 2018
Available from: 2019-04-15 Created: 2019-04-15 Last updated: 2019-04-16Bibliographically approved
Lillsunde Larsson, G., Kaliff, M., Sorbe, B., Helenius, G. & Karlsson, M. G. (2018). HPV16 viral characteristics in primary, recurrent and metastatic vulvar carcinoma. Papillomavirus research, 6, 63-69
Open this publication in new window or tab >>HPV16 viral characteristics in primary, recurrent and metastatic vulvar carcinoma
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2018 (English)In: Papillomavirus research, ISSN 2405-8521, Vol. 6, p. 63-69Article in journal (Refereed) Published
Abstract [en]

Vulvar carcinoma is the fourth most common gynecological malignancy. Two separate carcinogenic pathways are suggested, where one is associated with the human papillomavirus (HPV) and HPV16 the most common genotype.

The aim of this study was to evaluate HPV-markers in a set of primary tumors, metastases and recurrent lesions of vulvar squamous cell carcinomas (VSCC). Ten HPV16-positive VSCC with metastatic regional lymph nodes, distant lymphoid/hematogenous metastases or local recurrent lesions were investigated for HPV genotype, HPV16 variant, HPV16 viral load, HPV16 integration and HPV16 E2BS3 and 4 methylation.

In all 10 analyzed case series, the same HPV genotype (HPV16), HPV16 variant and level of viral load were detected in all lesions within a patient case. Primary tumors with a high E2/E6 ratio were found to have fewer vulvar recurrences and/or metastases after diagnosis and treatment. Also, a significantly lower viral load was evident in regional lymph nodes compared to primary tumors.

The data presented strengthens the evidence for a clonal HPV-induced pathway for vulvar carcinoma.

Place, publisher, year, edition, pages
Elsevier, 2018
Keywords
Vulvar carcinoma, human papillomavirus, integration, metastases, recurrences, viral load
National Category
Cancer and Oncology Dermatology and Venereal Diseases
Identifiers
urn:nbn:se:oru:diva-69992 (URN)10.1016/j.pvr.2018.10.008 (DOI)000452069800012 ()30391517 (PubMedID)2-s2.0-85056569332 (Scopus ID)
Note

Funding Agency:

Örebro County Council Research Committee

Available from: 2018-11-07 Created: 2018-11-07 Last updated: 2018-12-17Bibliographically approved
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Identifiers
ORCID iD: ORCID iD iconorcid.org/0000-0003-2317-5738

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