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  • 1.
    Bergengren, Lovisa
    et al.
    Örebro universitet, Institutionen för hälsovetenskaper. Department of Women’s Health, Faculty of Health and Medical Sciences, Örebro University, Örebro, Sweden.
    Kaliff, Malin
    Örebro universitet, Institutionen för medicinska vetenskaper. Department of Laboratory Medicine, Faculty of Health and Medical Sciences, Örebro University, Örebro, Sweden.
    Lillsunde-Larsson, Gabriella
    Örebro universitet, Institutionen för hälsovetenskaper. Department of Laboratory Medicine, Faculty of Health and Medical Sciences, Örebro University, Örebro, Sweden.
    Karlsson, Mats
    Örebro universitet, Institutionen för medicinska vetenskaper. Department of Laboratory Medicine, Faculty of Health and Medical Sciences, Örebro University, Örebro, Sweden.
    Helenius, Gisela
    Örebro universitet, Institutionen för medicinska vetenskaper. Department of Laboratory Medicine, Faculty of Health and Medical Sciences, Örebro University, Örebro, Sweden.
    Comparison between professional sampling and self-sampling for HPV-based cervical cancer screening among postmenopausal women2018Ingår i: International Journal of Gynecology & Obstetrics, ISSN 0020-7292, E-ISSN 1879-3479, Vol. 142, nr 3, s. 359-364Artikel i tidskrift (Refereegranskat)
    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.

  • 2.
    Bergengren, Lovisa
    et al.
    Örebro universitet, Institutionen för hälsovetenskaper. Dept. of Women's Health.
    Lillsunde-Larsson, Gabriella
    Örebro universitet, Institutionen för hälsovetenskaper. Dept. of Laboratory Medicine.
    Helenius, Gisela
    Örebro universitet, Institutionen för medicinska vetenskaper. Dept. of Laboratory Medicine.
    Karlsson, Mats G.
    Örebro universitet, Institutionen för medicinska vetenskaper. Dept. of Laboratory Medicine.
    HPV-based screening for cervical cancer among women 55-59 years of age2019Ingår i: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 14, nr 6, artikel-id e0217108Artikel i tidskrift (Refereegranskat)
    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.

  • 3.
    Helenius, Gisela
    et al.
    Örebro universitet, Institutionen för medicinska vetenskaper.
    Lillsunde-Larsson, Gabriella
    Bergengren, Lovisa
    Örebro universitet, Institutionen för hälsovetenskaper.
    Kaliff, Malin
    Örebro universitet, Institutionen för medicinska vetenskaper.
    Karlsson, Mats
    Örebro universitet, Institutionen för medicinska vetenskaper.
    Preliminary data from a Swedish self-sampling study in postmenopausal women2019Konferensbidrag (Övrigt vetenskapligt)
    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.

  • 4.
    Helenius, Gisela
    et al.
    Örebro universitet, Institutionen för medicinska vetenskaper.
    Ottestig, Elin
    Kaliff, Malin
    Örebro universitet, Institutionen för medicinska vetenskaper.
    Lillsunde-Larsson, Gabriella
    Örebro universitet, Institutionen för hälsovetenskaper.
    Karlsson, Mats
    Örebro universitet, Institutionen för medicinska vetenskaper.
    Bergengren, Lovisa
    Örebro universitet, Institutionen för medicinska vetenskaper.
    Distribution of HPV-genotypes in a Swedish screening population2018Konferensbidrag (Refereegranskat)
  • 5.
    Kaliff, Malin
    et al.
    Department of Laboratory Medicine, Faculty of Medicine and Health, Örebro University, Örebro, Sweden.
    Karlsson, Mats
    Department of Laboratory Medicine, Faculty of Medicine and Health, Örebro University, Örebro, Sweden.
    Sorbe, Bengt
    Department of Oncology, Faculty of Medicine and Health, Örebro University, Örebro, Sweden.
    Bohr Mordhorst, Louise
    Department of Oncology, Faculty of Medicine and Health, Örebro University, Örebro, Sweden.
    Helenius, Gisela
    Department of Laboratory Medicine, Faculty of Medicine and Health, Örebro University, Örebro, Sweden.
    Lillsunde-Larsson, Gabriella
    Örebro universitet, Institutionen för hälsovetenskaper. Department of Laboratory Medicine, Faculty of Medicine and Health, Örebro University, Örebro, Sweden.
    HPV-negative Tumors in a Swedish Cohort of Cervical Cancer2019Ingår i: International Journal of Gynecological Pathology, ISSN 0277-1691, E-ISSN 1538-7151Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Despite the common perception that the human papilloma virus (HPV) is a requirement for the development of cervical cancer (CC), a considerable number of CCs test HPV negative. Presently, many countries are shifting to HPV primary CC screening, and it is of importance to increase the knowledge about the group of CCs that test HPV negative. The aim of this study was to reinvestigate a proportion of cervical tumors with a primary negative or invalid test result. Reinvestigation with repeated genotyping (targeting L1) was followed by analysis with an alternative target method (targeting E6/E7) on existing or additional tumor material. Consistently negative tumors were histologically evaluated, and cases with low or lacking tumor cell content, consistent invalid test results, or with suspicion of other than cervical origin were excluded. HPV-negative cases were thereafter subjected to immunohistochemistry (Cytokeratin 5, pan cytokeratin, protein 63, P16, and P53). The HPV-negative proportion could after reinvestigation be reduced by one-half (14%-7%). Additional positive samples were often detected in late polymerase chain reaction cycles, with an alternative (E6/E7) or the same (L1) target, or with a method using shorter amplicon lengths. Confirmed HPV negativity was significantly associated with worse prognosis, high patient age, longer storage time, and adenocarcinoma histology. Some of the HPV-negative cases showed strong/diffuse p16 immunoreactivity, indicating some remaining false-negative cases. False HPV negativity in this cohort was mainly linked to methodological limitations in the analysis of stored CC material. The small proportion of presumably true HPV-negative adenocarcinomas is not a reason for hesitation in revision to CC screening with primary HPV testing.

  • 6.
    Kaliff, Malin
    et al.
    Örebro universitet, Institutionen för medicinska vetenskaper. Department of Laboratory Medicine.
    Sorbe, Bengt
    Department of Oncology, Faculty of Medicine and Health, Örebro University, Örebro, Sweden.
    Mordhorst, Louise Bohr
    Department of Oncology, Faculty of Medicine and Health, Örebro University, Örebro, Sweden.
    Helenius, Gisela
    Örebro universitet, Institutionen för medicinska vetenskaper. Department of Laboratory Medicine.
    Karlsson, Mats G.
    Örebro universitet, Institutionen för medicinska vetenskaper. Department of Laboratory Medicine.
    Lillsunde-Larsson, Gabriella
    Örebro universitet, Institutionen för hälsovetenskaper. Department of Laboratory Medicine.
    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 radiotherapy2018Ingår i: OncoTarget, ISSN 1949-2553, E-ISSN 1949-2553, Vol. 9, nr 27, s. 18786-18796Artikel i tidskrift (Refereegranskat)
    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.

  • 7.
    Kirrander, Peter
    et al.
    Örebro University Hospital, Örebro, Sweden.
    Kolaric, Aleksandra
    Örebro University Hospital, Örebro, Sweden.
    Helenius, Gisela
    Örebro University Hospital, Örebro, Sweden.
    Windahl, Torgny
    Örebro University Hospital, Örebro, Sweden.
    Andrén, Ove
    Örebro University Hospital, Örebro, Sweden.
    Stark, Jennifer Rider
    Örebro University Hospital, Örebro, Sweden; Brigham & Women’s Hospital, Boston MA, USA; Harvard Medical School, Boston MA, USA.
    Lillsunde-Larsson, Gabriella
    Örebro University Hospital, Örebro, Sweden.
    Elgh, Fredrik
    Örebro universitet, Hälsoakademin. Umeå University, Umeå, Sweden.
    Karlsson, Mats G.
    Örebro universitet, Hälsoakademin. Örebro University Hospital, Örebro, Sweden.
    Human papillomavirus prevalence, distribution and correlation to histopathological parameters in a large Swedish cohort of men with penile carcinoma2011Ingår i: BJU International, ISSN 1464-4096, E-ISSN 1464-410X, Vol. 108, nr 3, s. 355-359Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    OBJECTIVE To analyse the overall and type-specific human papillomavirus (HPV) prevalence and distribution in penile carcinoma and determine the correlation to histopathological parameters.

    PATIENTS AND METHODS In this retrospective study, we analysed HPV status in 241 patients with penile carcinoma, treated at Orebro University Hospital, Orebro, Sweden, between 1984 and 2008. Age and date at diagnosis was recorded. The tumour specimens were categorized according to the UICC 2002 TNM classification. A subset of patients was operatively staged with regard to lymph node status. A commercially available Real Time PCR was used to detect 13 different types of HPV (6,11,16,18,31,33,35,45,51,52,56,58 and 59).

    RESULTS We excluded 25 patients due to low DNA quality. Of the remaining 216, 179 (82.9%) tumour specimens were HPV infected. The majority of cases positive for HPV (70.4%) were infected by a single-type. The most frequent type was HPV 16 followed by HPV 18. No significant association between HPV status and pathological tumour stage, grade or lymph node status was found.

    CONCLUSION The HPV prevalence found is higher than in most other studies, further strengthening HPV as an etiological agent in penile carcinoma. Furthermore, the high prevalence of HPV 16 and 18 raises the question of what potential impact current HPV vaccines that target these specific HPV types might have on penile carcinoma. No significant association between HPV status and histopathological parameters was found in the present study. Additional investigations are needed to draw final conclusions on the prognostic value of HPV status in penile carcinoma.

  • 8.
    Kumakech, Edward
    et al.
    Örebro universitet, Institutionen för hälsovetenskap och medicin. Makerere University College of Health Sciences, Kampala, Uganda.
    Berggren, Vanja
    Medical Faculty, Lund University, Lund; Global Health, Karolinska Institute, Stockholm.
    Lillsunde-Larsson, Gabriella
    Örebro universitet, Institutionen för hälsovetenskap och medicin. Department of Laboratory Medicine, Faculty of Medicine and Health, Örebro University, Örebro.
    Helenius, Gisela
    Örebro universitet, Institutionen för läkarutbildning. Department of Laboratory Medicine, Faculty of Medicine and Health, Örebro University, Örebro.
    Kaliff, Malin
    Department of Laboratory Medicine, Faculty of Medicine and Health, Örebro University.
    Karlsson, Mats
    Örebro universitet, Institutionen för hälsovetenskap och medicin. Department of Laboratory Medicine, Faculty of Medicine and Health, Örebro University, Örebro.
    Musubika, Carol
    Makerere University College of Health Sciences, Kampala, Uganda.
    Kirimunda, Samuel
    Makerere University College of Health Sciences, Kampala, Uganda.
    Wabinga, Henry
    Makerere University College of Health Sciences, Kampala, Uganda.
    Andersson, Sören
    Örebro universitet, Institutionen för hälsovetenskap och medicin. Department of Laboratory Medicine, Faculty of Medicine and Health, Örebro University.
    Prevalence, genotypes and risk factors for vaccine and non-vaccine types of Human Papillomavirus (HPV) infections among Bivalent HPV-16/18 vaccinated and non-vaccinated young women in Ibanda district Uganda: 5 year follow up studyManuskript (preprint) (Övrigt vetenskapligt)
  • 9.
    Kumakech, Edward
    et al.
    Örebro universitet, Institutionen för hälsovetenskaper. Department of Pathology, School of Biomedical Sciences, Makerere University College of Health Sciences, Kampala, Uganda.
    Berggren, Vanja
    Faculty of Medicine, Lund University, Lund, Sweden; Department of Public Health (Global Health/IHCAR), Karolinska Institute, Stockholm, Sweden.
    Wabinga, Henry
    Department of Pathology, School of Biomedical Sciences, Makerere University College of Health Sciences, Kampala, Uganda.
    Lillsunde-Larsson, Gabriella
    Örebro universitet, Institutionen för medicinska vetenskaper. Department of Laboratory Medicine, Faculty of Medicine and Health, Örebro University Hospital, Örebro, Sweden.
    Helenius, Gisela
    Örebro universitet, Institutionen för medicinska vetenskaper. Department of Laboratory Medicine, Faculty of Medicine and Health, Örebro University Hospital, Örebro, Sweden.
    Kaliff, Malin
    Department of Laboratory Medicine, Faculty of Medicine and Health, Örebro University Hospital and Örebro University, Örebro, Sweden.
    Karlsson, Mats
    Örebro universitet, Institutionen för medicinska vetenskaper. Department of Laboratory Medicine, Faculty of Medicine and Health, Örebro University Hospital, Örebro, Sweden.
    Kirimunda, Samuel
    Department of Pathology, School of Biomedical Sciences, Makerere University College of Health Sciences, Kampala, Uganda.
    Musubika, Caroline
    Department of Pathology, School of Biomedical Sciences, Makerere University College of Health Sciences, Kampala, Uganda.
    Andersson, Sören
    Örebro universitet, Institutionen för medicinska vetenskaper. Department of Laboratory Medicine, Faculty of Medicine and Health, Örebro University Hospital, Örebro, Sweden.
    Significantly Reduced Genoprevalence of Vaccine-Type HPV-16/18 Infections among Vaccinated Compared to Non-Vaccinated Young Women 5.5 Years after a Bivalent HPV-16/18 Vaccine (Cervarix®) Pilot Project in Uganda2016Ingår i: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 11, nr 8, artikel-id e0160099Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The objective of this study was to determine the prevalence and some predictors for vaccine and non-vaccine types of HPV infections among bivalent HPV vaccinated and non-vaccinated young women in Uganda. This was a comparative cross sectional study 5.5 years after a bivalent HPV 16/18 vaccination (Cervarix®, GlaxoSmithKline, Belgium) pilot project in western Uganda. Cervical swabs were collected between July 2014-August 2014 and analyzed with a HPV genotyping test, CLART® HPV2 assay (Genomica, Madrid Spain) which is based on PCR followed by microarray for determination of genotype. Blood samples were also tested for HIV and syphilis infections as well as CD4 and CD8 lymphocyte levels. The age range of the participants was 15-24 years and mean age was 18.6(SD 1.4). Vaccine-type HPV-16/18 strains were significantly less prevalent among vaccinated women compared to non-vaccinated women (0.5% vs 5.6%, p 0.006, OR 95% CI 0.08(0.01-0.64). At type-specific level, significant difference was observed for HPV16 only. Other STIs (HIV/syphilis) were important risk factors for HPV infections including both vaccine types and non-vaccine types. In addition, for non-vaccine HPV types, living in an urban area, having a low BMI, low CD4 count and having had a high number of life time sexual partners were also significant risk factors. Our data concurs with the existing literature from other parts of the world regarding the effectiveness of bivalent HPV-16/18 vaccine in reducing the prevalence of HPV infections particularly vaccine HPV- 16/18 strains among vaccinated women. This study reinforces the recommendation to vaccinate young girls before sexual debut and integrate other STI particularly HIV and syphilis interventions into HPV vaccination packages.

  • 10.
    Larsson, Gabriella Lillsunde
    et al.
    Örebro universitet, Institutionen för medicinska vetenskaper. Department of Laboratory Medicine, Örebro University Hospital, Örebro, Sweden.
    Karlsson, Mats G
    Örebro universitet, Institutionen för medicinska vetenskaper. Department of Laboratory Medicine, Örebro University Hospital, Örebro, Sweden.
    Helenius, Gisela
    Örebro universitet, Institutionen för medicinska vetenskaper. Department of Laboratory Medicine, Örebro University Hospital, Örebro, Sweden.
    HPV testing of biobanked liquid-based cytology: a validation study2016Ingår i: International Journal of Biological Markers, ISSN 0393-6155, E-ISSN 1724-6008, Vol. 31, nr 2, s. E218-E223Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Introduction: The aim of the study was to investigate whether biobanked liquid-based cytology (LBC) vaginal samples could be reanalyzed for the biomarkers HPV DNA and mRNA without loss of sensitivity.

    Methods: One hundred LBC samples with ASCUS or CIN1 were tested for HPV DNA and mRNA before and after biobanking. DNA analysis targeted the viral genes E6 and E7, 12 high-risk and 2 low-risk HPV types together with the human control gene HBB, using real-time PCR. The Aptima HPV assay was used for mRNA analysis of 14 high-risk HPV types.

    Results: With Aptima there was 84% agreement between results before and after biobanking. The sensitivity and specificity were 0.79 (95% CI, 0.68-0.88) and 0.94 (95% CI, 0.80-0.99), respectively. With the DNA-based method, the agreement between results was 87%, the sensitivity 0.85 (95% CI, 0.75-0.92) and the specificity 0.95 (95% CI, 0.77-1.00). Both methods presented a significant difference between positive results before and after biobanking; McNemar test: p = 0.004, p = 0.003, Cohen's kappa: 0.67 (95% CI, 0.53-0.81), 0.68 (95% CI, 0.52-0.84). Cycle threshold values for the DNA method were higher for all genotypes after biobanking, except for HPV-59. Some loss of sensitivity was seen after biobanking but the concordance between HPV detection before and after biobanking was good for both evaluated methods.

    Conclusions: Biobanking of LBC vaginal samples offers a good platform for HPV testing and could be extended to further molecular analyses. However, in order to ensure a valid test result a larger portion needs to be analyzed from the biobanked sample.

  • 11.
    Lillsunde Larsson, Gabriella
    et al.
    Örebro universitet, Institutionen för medicinska vetenskaper. Department of Laboratory Medicine, Örebro University Hospital, Örebro, Sweden.
    Kaliff, M.
    Department of Laboratory Medicine, Faculty of Medicine and Health, Örebro University, Örebro, Sweden.
    Bergengren, Lovisa
    Department of Women's health, Faculty of Medicine and Health, Örebro University, Örebro, Sweden.
    Karlsson, Mats G.
    Örebro universitet, Institutionen för medicinska vetenskaper.
    Helenius, Gisela
    Örebro universitet, Institutionen för medicinska vetenskaper.
    HPV Genotyping from the high risk mRNA Aptima assay: a direct approach using DNA from Aptima sample tubes2016Ingår i: Journal of Virological Methods, ISSN 0166-0934, E-ISSN 1879-0984, Vol. 235, s. 80-84Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The underlying cause of cervical cancer is infection with the human papilloma virus (HPV) and HPV testing can be used for cervical cancer screening. The Aptima HPV assay from Hologic is an mRNA HPV test used to identify clinically relevant infections but the method does not discriminate between the different high risk genotypes. The aim of the current study was to evaluate if analyzed Aptima sample transfer tubes could be used as a source for HPV genotyping, using sample DNA. Study samples (n=108); were HPV-tested with mRNA Aptima assay and in parallel DNA was extracted and genotyped with Anyplex II HPV28. Analyzed mRNA Aptima tubes were thereafter used as source for a second DNA extraction and genotyping. Using mRNA Aptima result as reference, 90% of the samples (35/39) were high risk positive with the Anyplex II HPV28. Cohen's kappa 0.78 (95% CI: 0.66-0.90), sensitivity 0.90 (95% CI: 0.76-0.97) and specificity 0.90 (95% CI: 0.80-0.96). Two discordant samples carried low-risk genotypes (HPV 82 and HPV 44) and two were negative. DNA-genotyping results, in parallel to and after mRNA testing, were compared and differed significantly (McNemar test: P=0.021) possibly due to sample extraction volume difference. Cohen's kappa 0.81 (95% CI: 0.70-0.92), sensitivity 0.85 (95% CI: 0.74-0.93) and specificity 0.98 (95% CI: 0.88-1.00). In conclusion, analyzed mRNA Aptima sample tubes could be used as a source for DNA HPV genotyping. The sample volume used for extraction needs to be further explored.

  • 12.
    Lillsunde Larsson, Gabriella
    et al.
    Örebro universitet, Institutionen för hälsovetenskaper. Department of Laboratory Medicine.
    Kaliff, Malin
    Örebro universitet, Institutionen för medicinska vetenskaper. Department of Laboratory Medicine.
    Sorbe, Bengt
    Örebro universitet, Institutionen för hälsovetenskaper. Department of Oncology.
    Helenius, Gisela
    Örebro universitet, Institutionen för medicinska vetenskaper. Department of Laboratory Medicine.
    Karlsson, Mats G.
    Örebro universitet, Institutionen för medicinska vetenskaper. Department of Laboratory Medicine.
    HPV16 viral characteristics in primary, recurrent and metastatic vulvar carcinoma2018Ingår i: Papillomavirus research, ISSN 2405-8521, Vol. 6, s. 63-69Artikel i tidskrift (Refereegranskat)
    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.

  • 13.
    Lillsunde-Larsson, Gabriella
    Örebro universitet, Institutionen för hälsovetenskap och medicin.
    Characterization of HPV-induced vaginal and vulvar carcinoma2014Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)
    Delarbeten
    1. Human Papillomavirus (HPV) and HPV 16-Variant Distribution in Vulvar Squamous Cell Carcinoma in Sweden
    Öppna denna publikation i ny flik eller fönster >>Human Papillomavirus (HPV) and HPV 16-Variant Distribution in Vulvar Squamous Cell Carcinoma in Sweden
    Visa övriga...
    2012 (Engelska)Ingår i: International Journal of Gynecological Cancer, ISSN 1048-891X, E-ISSN 1525-1438, Vol. 22, nr 8, s. 1413-1419Artikel i tidskrift (Refereegranskat) Published
    Abstract [en]

    Objective: To investigate the human papillomavirus (HPV) and HPV type 16-variant distribution in a series of vulvar squamous cell carcinomas (VSCC) and to evaluate the impact of HPV and HPV 16-variant on prognosis.

    Methods: A series of 133 patients who had a diagnosis of VSCC (1983-2008) was selected for the study. Detection of 11 high-risk HPV types (16, 18, 31, 33, 39, 45, 51, 52, 56, 58, and 59) and 2 low-risk HPV types (6 and 11) was performed with real-time polymerase chain reaction. Samples positive for HPV 16 were further analyzed for variant determination of 7 positions in the E6 gene with polymerase chain reaction and pyrosequencing.

    Results: Forty (30.8%) of 130 tumors were found to be HPV positive. Human papillomavirus type 16 was found in 31 cases, HPV 18 was found in 2 cases, HPV 33 was found in 5 cases, and HPV 56 and HPV 59 were found in one case each. All but one tumor harboring HPV 16 were of European linage, and the 3 most common variants were E-p (n = 13), E-G350 (n = 7), and E-G131 (n = 5). HPV positivity was associated with the basaloid tumor type and occurred in significantly younger patients. Overall and recurrence-free survival rates were better in HPV-positive cases, but after correction for age and tumor size, HPV status was no longer an independent and significant prognostic factor. The survival rates of the various HPV 16 variants were not significantly different, but there was a trend of worse outcome for the E-G131-variant group.

    Conclusions: Human papillomavirus positivity of 30.8% is similar to other reports on VSCC. To our knowledge, this first variant determination of HPV 16 in vulvar carcinoma in a Swedish cohort indicated that the variant E-G131 may have an increased oncogenic potential in patients with VSCC.

    Nyckelord
    Vulvar carcinoma, Human papillomavirus, HPV 16 variants
    Nationell ämneskategori
    Reproduktionsmedicin och gynekologi
    Identifikatorer
    urn:nbn:se:oru:diva-43018 (URN)10.1097/IGC.0b013e31826a0471 (DOI)000309543700023 ()23013732 (PubMedID)2-s2.0-84867268780 (Scopus ID)
    Tillgänglig från: 2015-02-27 Skapad: 2015-02-27 Senast uppdaterad: 2018-05-14Bibliografiskt granskad
    2. Prognostic impact of human papilloma virus (HPV) genotyping and HPV-16 subtyping in vaginal carcinoma
    Öppna denna publikation i ny flik eller fönster >>Prognostic impact of human papilloma virus (HPV) genotyping and HPV-16 subtyping in vaginal carcinoma
    Visa övriga...
    2013 (Engelska)Ingår i: Gynecologic Oncology, ISSN 0090-8258, E-ISSN 1095-6859, Vol. 129, nr 2, s. 406-411Artikel i tidskrift (Refereegranskat) Published
    Abstract [en]

    Objective

    The objectives of this study are to investigate the human papilloma virus (HPV) distribution in vaginal cancer and to evaluate HPV-genotype as well as HPV16-variant impact on prognosis.

    Methods

    Sixty-nine patients diagnosed with primary vaginal carcinoma (1975-2002) were included in the study. Detection of twelve high-risk HPV (hr HPV) and two low-risk HPV (lr HPV) was performed with realtime-PCR. Samples positive for HPV-16 were analyzed for variants in the E6-gene with PCR and pyrosequencing.

    Results

    53.6% (37/69) of the tumors were found to be HPV-positive, mostly for HPV-16 (N=26). Other HPV-types were HPV-18 (N=2), HPV-31 (N=2), HPV-33 (N=2), HPV-45 (N=1), HPV-52 (N=2), HPV-56 (N=1) and HPV-58 (N=1). Only European subtypes of HPV-16 were represented and the two most common HPV-16-variants were E-p (N=13) and E-G350 (N=11). Patients with HPV-positive tumors (N=37) had a significantly (log-rank test=3341; p = 0.0008) superior 5-year overall survival rate as well as cancer-specific survival rate and progression-free survival rate (p = 0.0002; p = 0.0004), compared with patients with HPV-negative tumors (N=32). Interestingly, patients with HPV-16-positive tumors had a superior overall survival compared with patients with tumors containing other HPV-genotypes. In a Cox proportional multivariate analysis age, tumor size, and HPV-status were independent and significant prognostic factors with regard to overall survival rate.

    Conclusions

    HPV-status is of prognostic importance in vaginal carcinoma and varies with viral genotype. In this era of HPV-vaccination, genotypes other than those included in the vaccination program could still lead to vaginal carcinoma with unfavorable prognosis.

    Nyckelord
    Vaginal carcinoma, Human papilloma virus, HPV-16-variants, Prognosis
    Nationell ämneskategori
    Reproduktionsmedicin och gynekologi
    Forskningsämne
    Biomedicin
    Identifikatorer
    urn:nbn:se:oru:diva-29270 (URN)10.1016/j.ygyno.2013.02.004 (DOI)000318058600024 ()23402906 (PubMedID)2-s2.0-84876292443 (Scopus ID)
    Tillgänglig från: 2013-05-31 Skapad: 2013-05-31 Senast uppdaterad: 2018-05-18Bibliografiskt granskad
    3. Viral Load, Integration and Methylation of E2BS3 and 4 in Human Papilloma Virus (HPV) 16-Positive Vaginal and Vulvar Carcinomas
    Öppna denna publikation i ny flik eller fönster >>Viral Load, Integration and Methylation of E2BS3 and 4 in Human Papilloma Virus (HPV) 16-Positive Vaginal and Vulvar Carcinomas
    2014 (Engelska)Ingår i: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 9, nr 11, artikel-id e112839Artikel i tidskrift (Refereegranskat) Published
    Abstract [en]

    Objective: To investigate if viral load, integration and methylation of E2BS3 and 4 represent different ways of tumor transformation in vaginal and vulvar carcinoma and to elucidate its clinical impact.

    Methods: Fifty-seven samples, positive for HPV16, were selected for the study. Detection of viral load was made with realtime-PCR using copy numbers of E6 and integration was calculated from comparing E2 to E6-copies. Methylation of E2BS3 and 4 was analysed using bisulphite treatment of tumor DNA, followed by PCR and pyrosequencing.

    Results: Vaginal tumors were found to have a higher viral load (p=0.024) compared to vulvar tumors but a high copy number (> median value, 15 000) as well as high methylation (> 50%) was significantly (p=0.010 and p=0.045) associated with a worse cancer-specific survival rate in vulvar carcinoma, but not in vaginal carcinoma. Four groups could be defined for the complete series using a Cluster Two step analysis; (1) tumors holding episomal viral DNA, viral load below 150 000 copies not highly methylated (n=25, 46.3%); (2) tumors harboring episomal viral DNA and being highly methylated (>50%; n=6, 11.1%); (3) tumors with viral DNA fully integrated (n=11, 20.4%), and (4) tumors harboring episomal viral DNA and being medium-or unmethylated (< 50%) and having a high viral load (> total mean value 150 000; n=12, 22.2%). The completely integrated tumors were found to be distinct group, whilst some overlap between the groups with high methylation and high viral load was observed.

    Conclusion: HPV16-related integration, methylation in E2BS3 and 4 and viral load may represent different viral characteristics driving vaginal and vulvar carcinogenesis. HPV16-related parameters were found to be of clinical importance in the vulvar series only.

    Ort, förlag, år, upplaga, sidor
    Public Library Science, 2014
    Nationell ämneskategori
    Cancer och onkologi
    Identifikatorer
    urn:nbn:se:oru:diva-42542 (URN)10.1371/journal.pone.0112839 (DOI)000347709300111 ()2-s2.0-84911948854 (Scopus ID)
    Anmärkning

    Funding Agency:

    Örebro County Council Research Committee OLL-324811 OLL-259341

    Tillgänglig från: 2015-02-09 Skapad: 2015-02-09 Senast uppdaterad: 2018-06-15Bibliografiskt granskad
    4. HPV genotyping assays for archival clinical samples: an evaluation study
    Öppna denna publikation i ny flik eller fönster >>HPV genotyping assays for archival clinical samples: an evaluation study
    (Engelska)Manuskript (preprint) (Övrigt vetenskapligt)
    Nationell ämneskategori
    Reproduktionsmedicin och gynekologi
    Identifikatorer
    urn:nbn:se:oru:diva-43020 (URN)
    Tillgänglig från: 2015-02-27 Skapad: 2015-02-27 Senast uppdaterad: 2017-10-17Bibliografiskt granskad
  • 14.
    Lillsunde-Larsson, Gabriella
    et al.
    Region Örebro län. Department of Laboratory Medicine, Örebro University Hospital, Örebro, Sweden.
    Carlsson, Jessica
    Region Örebro län. Department of Urology, Örebro University Hospital, Örebro, Sweden.
    Karlsson, Mats G.
    Region Örebro län. Department of Laboratory Medicine, Örebro University Hospital, Örebro, Sweden.
    Helenius, Gisela
    Region Örebro län. Department of Laboratory Medicine, Örebro University Hospital, Örebro, Sweden.
    Evaluation of HPV Genotyping Assays for Archival Clinical Samples2015Ingår i: Journal of Molecular Diagnostics, ISSN 1525-1578, E-ISSN 1943-7811, Vol. 17, nr 3, s. 293-301Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Human papillomavirus (HPV) testing and genotyping of FFPE tissue samples is important in epidemiological investigations. Here, we compare four different HPV genotyping methods for use in FFPE clinical samples. Comparative testing was performed on 99 samples with a clinical suspicion of HPV. Specimens were analyzed with Anyplex II HPV28 detecting 28 genotypes using real-time PCR and melting curve analysis, CLART HPV2 detecting 35 genotypes using PCR and microarray detection, and MGP5+/6+ consensus primer system together with pyrosequencing. Results were compared to a real-time PCR reference protocol detecting 14 genotypes. In total, 68% of the samples were positive for an HPV genotype using the reference protocol and MGP5+/6+ primer system. Anyplex II HPV28 analysis and CLART HPV2 had 82% and 72% positive samples, respectively. All four methods showed good agreement when comparing the 14 genotypes included in the reference protocol. When evaluating all genotypes, the Anyplex II HPV28 assay and the CLART assay changed the status of the sample (individually or together) from negative with respect to the reference protocol to positive for either a Group 1 (n = 4) or Group 2 (n = 6) genotype. We conclude from this study that for an extended genotyping approach with a high sensitivity for FFPE specimens, both the Anyplex II HPV28 and CLART HPV2 assays are suitable alternatives despite minor intra-assay differences.

  • 15.
    Lillsunde-Larsson, Gabriella
    et al.
    Örebro universitet, Institutionen för hälsovetenskap och medicin.
    Carlsson, Jessica
    Karlsson, Mats G.
    Örebro universitet, Institutionen för hälsovetenskap och medicin. Örebro University Hospital.
    Helenius, Gisela
    Örebro universitet, Institutionen för läkarutbildning. Örebro University Hospital.
    HPV genotyping assays for archival clinical samples: an evaluation studyManuskript (preprint) (Övrigt vetenskapligt)
  • 16.
    Lillsunde-Larsson, Gabriella
    et al.
    Örebro universitet, Institutionen för medicinska vetenskaper. Region Örebro län. Department of Laboratory Medicine, Örebro University Hospital, Örebro, Sweden.
    Helenius, Gisela
    Örebro universitet, Institutionen för medicinska vetenskaper. Region Örebro län. Department of Laboratory Medicine, Örebro University Hospital, Örebro, Sweden.
    Digital droplet PCR (ddPCR) for the detection and quantification of HPV 16, 18, 33 and 45: a short report2017Ingår i: Cellular Oncology, ISSN 2211-3428, E-ISSN 2211-3436, Vol. 40, nr 5, s. 521-527Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Human papilloma virus (HPV) infection is associated with several anogenital malignancies. Here, we set out to evaluate digital droplet PCR (ddPCR) as a tool for HPV 16, 18, 33 and 45 viral load quantification and, in addition, to compare the efficacy of the ddPCR assay for HPV 16 detection with that of quantitative real-time PCR (qPCR).

    Clinical samples, positive for HPV genotypes 16, 18, 33 and 45 were analyzed for viral load using ddPCR. Sample DNA was cleaved before droplet generation and PCR. Droplets positive for VIC and FAM fluorescence were read in a QX200 Droplet reader (TM) (BIO-RAD) after which the viral load was calculated using Quantasoft software.

    We found that DNAs extracted from formalin fixed paraffin embedded (FFPE) tissue samples yielded lower amplification signals compared to those obtained from liquid based cytology (LBC) samples, but they were clearly distinguishable from negative background signals. The viral limit of detection was 1.6 copies of HPV 16, 2.8 copies of HPV 18, 4.6 copies of HPV 33 and 1.6 copies of HPV 45. The mean inter-assay coefficients of variability (CV) for the assays ranged from 3.4 to 7.0%, and the mean intra-assay CV from 2.6 to 8.2%. The viral load in the different cohorts of tumor samples ranged from 154 to 340,200 copies for HPV 16, 244 to 31,300 copies for HPV 18 and 738 to 69,100 copies for HPV 33. One sample positive for HPV 45 contained 1331 viral copies. When comparing qPCR data with ddPCR copy number data, the qPCR values were found to be 1 to 31 times higher.

    Separation of fragments in nanodroplets may facilitate the amplification of fragmented human and viral DNA. The method of digital droplet PCR may, thus, provide a new and promising tool for evaluating the HPV viral load in clinical samples.

  • 17.
    Lillsunde-Larsson, Gabriella
    et al.
    Örebro universitet, Institutionen för hälsovetenskap och medicin. Örebro University Hospital, Örebro, Sweden.
    Helenius, Gisela
    Örebro universitet, Institutionen för läkarutbildning. Örebro University Hospital, Örebro, Sweden.
    Andersson, Sören
    Örebro University Hospital, Örebro, Sweden.
    Elgh, Fredrik
    Umeå University Hospital, Umeå, Sweden.
    Sorbe, Bengt
    Örebro universitet, Hälsoakademin. Örebro University Hospital, Örebro, Sweden.
    Karlsson, Mats G.
    Örebro University Hospital, Örebro, Sweden.
    Human Papillomavirus (HPV) and HPV 16-Variant Distribution in Vulvar Squamous Cell Carcinoma in Sweden2012Ingår i: International Journal of Gynecological Cancer, ISSN 1048-891X, E-ISSN 1525-1438, Vol. 22, nr 8, s. 1413-1419Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Objective: To investigate the human papillomavirus (HPV) and HPV type 16-variant distribution in a series of vulvar squamous cell carcinomas (VSCC) and to evaluate the impact of HPV and HPV 16-variant on prognosis.

    Methods: A series of 133 patients who had a diagnosis of VSCC (1983-2008) was selected for the study. Detection of 11 high-risk HPV types (16, 18, 31, 33, 39, 45, 51, 52, 56, 58, and 59) and 2 low-risk HPV types (6 and 11) was performed with real-time polymerase chain reaction. Samples positive for HPV 16 were further analyzed for variant determination of 7 positions in the E6 gene with polymerase chain reaction and pyrosequencing.

    Results: Forty (30.8%) of 130 tumors were found to be HPV positive. Human papillomavirus type 16 was found in 31 cases, HPV 18 was found in 2 cases, HPV 33 was found in 5 cases, and HPV 56 and HPV 59 were found in one case each. All but one tumor harboring HPV 16 were of European linage, and the 3 most common variants were E-p (n = 13), E-G350 (n = 7), and E-G131 (n = 5). HPV positivity was associated with the basaloid tumor type and occurred in significantly younger patients. Overall and recurrence-free survival rates were better in HPV-positive cases, but after correction for age and tumor size, HPV status was no longer an independent and significant prognostic factor. The survival rates of the various HPV 16 variants were not significantly different, but there was a trend of worse outcome for the E-G131-variant group.

    Conclusions: Human papillomavirus positivity of 30.8% is similar to other reports on VSCC. To our knowledge, this first variant determination of HPV 16 in vulvar carcinoma in a Swedish cohort indicated that the variant E-G131 may have an increased oncogenic potential in patients with VSCC.

  • 18.
    Lillsunde-Larsson, Gabriella
    et al.
    Örebro universitet, Institutionen för hälsovetenskap och medicin. Region Örebro län.
    Helenius, Gisela
    Örebro universitet, Institutionen för läkarutbildning. Örebro University Hospital, Region Örebro County, Örebro, Sweden.
    Andersson, Sören
    Örebro University Hospital, Region Örebro County, Örebro, Sweden.
    Sorbe, Bengt
    Örebro University Hospital, Region Örebro County, Örebro, Sweden.
    Karlsson, Mats G.
    Region Örebro län. Örebro universitet, Institutionen för hälsovetenskap och medicin. Örebro University Hospital, Region Örebro County, Örebro, Sweden.
    Prognostic impact of human papilloma virus (HPV) genotyping and HPV-16 subtyping in vaginal carcinoma2013Ingår i: Gynecologic Oncology, ISSN 0090-8258, E-ISSN 1095-6859, Vol. 129, nr 2, s. 406-411Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Objective

    The objectives of this study are to investigate the human papilloma virus (HPV) distribution in vaginal cancer and to evaluate HPV-genotype as well as HPV16-variant impact on prognosis.

    Methods

    Sixty-nine patients diagnosed with primary vaginal carcinoma (1975-2002) were included in the study. Detection of twelve high-risk HPV (hr HPV) and two low-risk HPV (lr HPV) was performed with realtime-PCR. Samples positive for HPV-16 were analyzed for variants in the E6-gene with PCR and pyrosequencing.

    Results

    53.6% (37/69) of the tumors were found to be HPV-positive, mostly for HPV-16 (N=26). Other HPV-types were HPV-18 (N=2), HPV-31 (N=2), HPV-33 (N=2), HPV-45 (N=1), HPV-52 (N=2), HPV-56 (N=1) and HPV-58 (N=1). Only European subtypes of HPV-16 were represented and the two most common HPV-16-variants were E-p (N=13) and E-G350 (N=11). Patients with HPV-positive tumors (N=37) had a significantly (log-rank test=3341; p = 0.0008) superior 5-year overall survival rate as well as cancer-specific survival rate and progression-free survival rate (p = 0.0002; p = 0.0004), compared with patients with HPV-negative tumors (N=32). Interestingly, patients with HPV-16-positive tumors had a superior overall survival compared with patients with tumors containing other HPV-genotypes. In a Cox proportional multivariate analysis age, tumor size, and HPV-status were independent and significant prognostic factors with regard to overall survival rate.

    Conclusions

    HPV-status is of prognostic importance in vaginal carcinoma and varies with viral genotype. In this era of HPV-vaccination, genotypes other than those included in the vaccination program could still lead to vaginal carcinoma with unfavorable prognosis.

  • 19.
    Lillsunde-Larsson, Gabriella
    et al.
    Örebro universitet, Institutionen för hälsovetenskap och medicin. Region Örebro län. Department of Laboratory Medicine, Örebro University Hospital, Örebro, Sweden.
    Helenius, Gisela
    Örebro universitet, Institutionen för läkarutbildning. Region Örebro län. Department of Laboratory Medicine, Örebro University Hospital, Örebro, Sweden.
    Sorbe, Bengt
    Örebro universitet, Institutionen för hälsovetenskap och medicin. Region Örebro län. Department of Oncology, Örebro University Hospital, Örebro, Sweden.
    Karlsson, Mats G.
    Örebro universitet, Institutionen för hälsovetenskap och medicin. Region Örebro län. Department of Laboratory Medicine, Örebro University Hospital, Örebro, Sweden.
    Viral Load, Integration and Methylation of E2BS3 and 4 in Human Papilloma Virus (HPV) 16-Positive Vaginal and Vulvar Carcinomas2014Ingår i: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 9, nr 11, artikel-id e112839Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Objective: To investigate if viral load, integration and methylation of E2BS3 and 4 represent different ways of tumor transformation in vaginal and vulvar carcinoma and to elucidate its clinical impact.

    Methods: Fifty-seven samples, positive for HPV16, were selected for the study. Detection of viral load was made with realtime-PCR using copy numbers of E6 and integration was calculated from comparing E2 to E6-copies. Methylation of E2BS3 and 4 was analysed using bisulphite treatment of tumor DNA, followed by PCR and pyrosequencing.

    Results: Vaginal tumors were found to have a higher viral load (p=0.024) compared to vulvar tumors but a high copy number (> median value, 15 000) as well as high methylation (> 50%) was significantly (p=0.010 and p=0.045) associated with a worse cancer-specific survival rate in vulvar carcinoma, but not in vaginal carcinoma. Four groups could be defined for the complete series using a Cluster Two step analysis; (1) tumors holding episomal viral DNA, viral load below 150 000 copies not highly methylated (n=25, 46.3%); (2) tumors harboring episomal viral DNA and being highly methylated (>50%; n=6, 11.1%); (3) tumors with viral DNA fully integrated (n=11, 20.4%), and (4) tumors harboring episomal viral DNA and being medium-or unmethylated (< 50%) and having a high viral load (> total mean value 150 000; n=12, 22.2%). The completely integrated tumors were found to be distinct group, whilst some overlap between the groups with high methylation and high viral load was observed.

    Conclusion: HPV16-related integration, methylation in E2BS3 and 4 and viral load may represent different viral characteristics driving vaginal and vulvar carcinogenesis. HPV16-related parameters were found to be of clinical importance in the vulvar series only.

  • 20.
    Lillsunde-Larsson, Gabriella
    et al.
    Örebro universitet, Institutionen för hälsovetenskaper. Region Örebro län. Department of Laboratory Medicine, Örebro University Hospital, Örebro, Sweden.
    Kaliff, Malin
    Örebro universitet, Institutionen för medicinska vetenskaper. Department of Laboratory Medicine, Faculty of Health and Medical Sciences, Örebro University, Örebro, Sweden.
    Hansen, Marit
    Helenius, Gisela
    Örebro universitet, Institutionen för medicinska vetenskaper. Department of Laboratory Medicine, Faculty of Health and Medical Sciences, Örebro University, Örebro, Sweden.
    Comparison of mRNA and DNA HPV levels in HRHPV-positive primary screening samples using digital droplet PCR2017Konferensbidrag (Refereegranskat)
  • 21.
    Lillsunde-Larsson, Gabriella
    et al.
    Örebro universitet, Institutionen för hälsovetenskaper.
    Kaliff, Malin
    Örebro universitet, Institutionen för medicinska vetenskaper.
    Ottestig, Elin
    Helenius, Gisela
    Örebro universitet, Institutionen för medicinska vetenskaper.
    HPV genotyping of HPV primary screening positive samples in Örebro, Sweden2018Konferensbidrag (Övrigt vetenskapligt)
  • 22.
    Lillsunde-Larsson, Gabriella
    et al.
    Örebro universitet, Institutionen för hälsovetenskaper. Dep. of Laboratory Medicine.
    Kaliff, Malin
    Örebro universitet, Institutionen för medicinska vetenskaper. Dep. of Laboratory Medicine.
    Sorbe, Bengt
    2Faculty of Medicine and Health- Örebro University, Dep. Of Oncology, Örebro, Sweden.
    Helenius, Gisela
    Örebro universitet, Institutionen för medicinska vetenskaper. Dep. of Laboratory Medicine.
    Karlsson, Mats
    Örebro universitet, Institutionen för medicinska vetenskaper. Dep. of Laboratory Medicine.
    HPV16 VIRAL CHARACTERISTICS IN PRIMARY AND RECURRENT VULVAR CARCINOMA2018Konferensbidrag (Övrigt vetenskapligt)
  • 23.
    Qvick, Alvida
    et al.
    Örebro universitet, Institutionen för medicinska vetenskaper. Department of Laboratory Medicine.
    Sorbe, Bengt
    Region Örebro län. Örebro universitet, Institutionen för hälsovetenskaper. Department of Oncology.
    Helenius, Gisela
    Örebro universitet, Institutionen för medicinska vetenskaper. Region Örebro län. Department of Laboratory Medicine.
    Karlsson, Mats G.
    Örebro universitet, Institutionen för medicinska vetenskaper. Region Örebro län. Department of Laboratory Medicine.
    Lillsunde Larsson, Gabriella
    Örebro universitet, Institutionen för medicinska vetenskaper. Region Örebro län. Department of Laboratory Medicine.
    Does p53 codon 72 polymorphism have a prognostic value in carcinoma of the vulva and vagina?2017Ingår i: Medical Oncology, ISSN 1357-0560, E-ISSN 1559-131X, Vol. 34, nr 3, artikel-id 36Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Human papilloma virus (HPV) is considered to be responsible for a large part of vaginal and vulvar carcinomas, and the p53 codon 72 polymorphism has been implicated in susceptibility to cancer induced by this virus, but with contradicting results. In this study, we have investigated the prognostic value of the codon 72 polymorphism by real-time PCR (qPCR) in two cohorts of vaginal (n = 66) and vulvar (n = 123) carcinomas. In vaginal carcinoma, arginine homozygous patients were significantly associated with a higher primary cure rate (p = 0.023) but also associated with a higher recurrence rate (p = 0.073), significant at distant locations (p = 0.009). No significant differences were found in overall survival rate (p = 0.499) or cancer-specific survival rate (p = 0.222). A higher frequency of arginine homozygosity was noted in HPV-positive tumors (p = 0.190) in comparison with HPV-negative tumors. In vulvar carcinoma, the genotype homozygous for arginine was significantly associated with a larger tumor size at diagnosis in the entire cohort (p = 0.015) and a lower cancer-specific survival rate (p = 0.024) compared with heterozygous (arginine/proline) in HPV-negative tumors. Our results indicate that the relation between HPV and the p53 codon 72 polymorphism is complex and the significance and mechanisms responsible for this relationship need to be further elucidated.

  • 24.
    Ranhem, Cecilia
    et al.
    Department of Women’s and Children ’s Health, Karolinska Institutet, Stockholm, Sweden; Centre for Clinical Research, Hospital of Västmanland Västerås, Uppsala University, Västerås, Sweden; Region Västmanland, Västerås, Sweden.
    Lillsunde-Larsson, Gabriella
    Örebro universitet, Institutionen för medicinska vetenskaper. Region Örebro län. Department of Laboratory Medicine, Örebro University Hospital, Örebro, Sweden.
    Hedman, Håkan
    Department of Radiation Sciences, Umeå University, Umeå , Sweden.
    Lindquist, David
    Department of Radiation Sciences, Umeå University, Umeå , Sweden.
    Karlsson, Mats G.
    Örebro universitet, Institutionen för medicinska vetenskaper. Department of Laboratory Medicine, Faculty of Health and Medical Sciences, Örebro University, Örebro, Sweden.
    Hellström, Ann-Cathrin
    Department of Women’s and Children’s Health, Karolinska Institutet, Stockholm, Sweden.
    Östensson, Ellinor
    Department of Women’s and Children’s Health, Karolinska Institutet, Stockholm, Sweden; Department of Medical Epidem iology and Biostatistics, Karolinsk a Institutet, Stockholm, Sweden.
    Sorbe, Bengt
    Department of Oncology, Faculty of Health and Medical Sciences, Örebro University, Örebro, Sweden.
    Hellman, Kristina
    Department of Oncology-Pathology, Karolinska Institutet, Stockholm, Sweden.
    Andersson, Sonia
    Department of Women’s and Children’s Health, Karolinska Institutet, Stockholm, Sweden.
    Expression of LRIG proteins as possible prognostic factors in primary vaginal carcinoma2017Ingår i: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 12, nr 8, artikel-id e0183816Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Background: Primary vaginal carcinoma (PVC) is a rare malignancy. Established prognostic factors include tumour stage and age at diagnosis. The leucine-rich repeats and immunoglobuline-like domains (LRIG)-1 protein functions as a tumour suppressor, but less is known about the functions of LRIG2 and LRIG3. The present study aimed to evaluate the expression of LRIG proteins and analyse their possible associations with clinical characteristics and survival in a cohort of PVC patients.

    Methods: We used immunohistochemistry to investigate LRIG1, LRIG2, and LRIG3 expression in tumour samples from a consecutive cohort of 70 PVC patients. The association between LRIG protein expression and clinical characteristics and cancer-specific survival was investigated using univariate and multivariate analyses.

    Results: The majority of PVC patients (72%) had > 50% LRIG1-and LRIG2-positive cells, and no or low LRIG3-positive cells. HPV status was significantly correlated with LRIG1 expression (p = 0.0047). Having high LRIG1 expression was significantly correlated with superior cancer-specific survival in univariate and multivariate analyses. LRIG2 and LRIG3 expression did not significantly correlate with clinical characteristics or survival.

    Conclusion: LRIG1 expression might be of interest as a prognostic marker in PVC patients, whereas the role of LRIG2 and LRIG3 expression remains to be clarified.

  • 25.
    Viegas, Edna Omar
    et al.
    Instituto Nacional de Saúde, Maputo, Mozambique; Division of Clinical Microbiology, Department of Laboratory Medicine, Karolinska Institutet, Huddinge, Sweden; Eduardo Mondlane University, Maputo, Mozambique; .
    Augusto, Orvalho
    Eduardo Mondlane University, Maputo, Mozambique.
    Ismael, Nália
    Instituto Nacional de Saúde, Maputo, Mozambique.
    Kaliff, Malin
    Örebro universitet, Institutionen för medicinska vetenskaper. Department of Laboratory Medicine, Faculty of Health and Medical Sciences, Örebro University, Örebro, Sweden.
    Lillsunde-Larsson, Gabriella
    Örebro universitet, Institutionen för medicinska vetenskaper. Region Örebro län. Department of Laboratory Medicine, Örebro University Hospital, Örebro, Sweden.
    Ramqvist, Torbjörn
    Department of Oncology-Pathology, Karolinska Institutet, Stockholm, Sweden.
    Nilsson, Charlotta
    Division of Clinical Microbiology, Department of Laboratory Medicine, Karolinska Institutet, Huddinge, Sweden; Department of Microbiology, Public Health Agency of Sweden, Stockholm, Sweden; Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, Stockholm, Sweden.
    Falk, Kerstin
    Department of Microbiology, Public Health Agency of Sweden, Stockholm, Sweden; Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, Stockholm, Sweden.
    Osman, Nafissa
    Eduardo Mondlane University, Maputo, Mozambique; Hospital Central de Maputo, Maputo, Mozambique.
    Jani, Ilesh Vindorai
    Instituto Nacional de Saúde, Maputo, Mozambique.
    Andersson, Sören
    Örebro universitet, Institutionen för medicinska vetenskaper. Department of Laboratory Medicine.
    Human papillomavirus prevalence and genotype distribution among young women and men in Maputo city, Mozambique2017Ingår i: BMJ Open, ISSN 2044-6055, E-ISSN 2044-6055, Vol. 7, nr 7, artikel-id e015653Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    OBJECTIVES: Human papillomavirus (HPV) is a well-known cause of cervical cancer, the second most frequent cancer in female African populations. This study aimed at determining the prevalence of HPV infections and the genotype distribution in young adults aged 18-24, in Maputo city, Mozambique, and to assess the suitability of commercially available HPV vaccines.

    METHODS: This cross-sectional study was conducted between 2009 and 2011 at a youth clinic in Maputo Central Hospital. Cervical and urethral samples were obtained from 236 women and 176 men, respectively. Demographic and behavioural data were collected using structured questionnaires. HPV genotyping was performed for 35 different high, probably or possibly high-risk and low-risk HPV types using the CLART Human Papillomavirus 2.

    RESULTS: HPV prevalence was 168/412 (40.8%; 95% CI 36.0 to 45.5) and was significantly higher in women than in men (63.6%vs10.2%). HPV52 was the most frequent type found in women, followed by HPV35, -16,-53, -58,-6 and -51. In men, HPV51 ranked the highest, followed by HPV6, -11,-52, -59 and -70. HIV infection and sexual debut before 18 years of age were associated with multiple HPV infections (OR 3.03; 95% CI 1.49 to 6.25 and OR 6.03; 95% CI 1.73 to 21.02, respectively). Women had a significantly higher HPV infection prevalence than men (p<0.001). The 9-valent HPV vaccine would cover 36.8% of the high-risk genotypes circulating in women in this study, compared with 26.3% and 15.8% coverage by the bivalent and quadrivalent vaccines, respectively.

    CONCLUSION: This study confirmed the high burden of HPV infections in young women in Maputo city, Mozambique. The HPV prevalence was associated with high-risk sexual behaviour. Sex education and sexually transmitted infection prevention interventions should be intensified in Mozambique. Only a proportion of the high-risk HPV genotypes (37%) were covered by currently available vaccines.

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