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  • 1. Berggrund, Malin
    et al.
    Enroth, Stefan
    Lundberg, Martin
    Assarsson, Erika
    Stålberg, Karin
    Lindquist, David
    Umeå University, Faculty of Medicine, Department of Radiation Sciences.
    Hallmans, Göran
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Nutritional Research.
    Grankvist, Kjell
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Clinical chemistry.
    Olovsson, Matts
    Gyllensten, Ulf
    Identification of candidate plasma protein biomarkers for cervical cancer using the multiplex proximity extension assay2019In: Molecular & Cellular Proteomics, ISSN 1535-9476, E-ISSN 1535-9484, Vol. 18, no 4, p. 735-743, article id RA118.001208Article in journal (Refereed)
    Abstract [en]

    Human papillomavirus (HPV) is recommended as the primary test in cervical cancer screening, with co-testing by cytology for HPV-positive women to identify cervical lesions. Cytology has low sensitivity and there is a need to identify biomarkers that could identify dysplasia that are likely to progress to cancer. We searched for plasma proteins that could identify women with cervical cancer using the multiplex proximity extension assay (PEA). The abundance of 100 proteins were measured in plasma collected at the time of diagnosis of patients with invasive cervical cancer and in population controls using the Olink Multiplex panels CVD II, INF I, and ONC II. Eighty proteins showed increased levels in cases compared to controls. We identified a signature of 11 proteins (PTX3, ITGB1BP2, AXIN1, STAMPB, SRC, SIRT2, 4E-BP1, PAPPA, HB-EGF, NEMO and IL27) that distinguished cases and controls with a sensitivity of 0.96 at a specificity of 1.0. This signature was evaluated in a prospective replication cohort with samples collected before, at or after diagnosis and achieved a sensitivity of 0.78 and a specificity 0.56 separating samples collected at the time of diagnosis of invasive cancer from samples collected prior to diagnosis. No difference in abundance was seen between samples collected prior to diagnosis or after treatment as compared to population controls, indicating that this protein signature is mainly informative close to time of diagnosis. Further studies are needed to determine the optimal window in time prior to diagnosis for these biomarker candidates.

  • 2. Castellsagué, Xavier
    et al.
    Pawlita, Michael
    Roura, Esther
    Margall, Núria
    Waterboer, Tim
    Bosch, F Xavier
    de Sanjosé, Silvia
    Gonzalez, Carlos Alberto
    Dillner, Joakim
    Gram, Inger T
    Tjønneland, Anne
    Munk, Christian
    Pala, Valeria
    Palli, Domenico
    Khaw, Kay-Tee
    Barnabas, Ruanne V
    Overvad, Kim
    Clavel-Chapelon, Françoise
    Boutron-Ruault, Marie-Christine
    Fagherazzi, Guy
    Kaaks, Rudolf
    Lukanova, Annekatrin
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Steffen, Annika
    Trichopoulou, Antonia
    Trichopoulos, Dimitrios
    Klinaki, Eleni
    Tumino, Rosario
    Sacerdote, Carlotta
    Mattiello, Amalia
    Bueno-de-Mesquita, H Bas
    Peeters, Petra H
    Lund, Eiliv
    Weiderpass, Elisabete
    Quirós, J Ramón
    Sánchez, María-José
    Navarro, Carmen
    Barricarte, Aurelio
    Larrañaga, Nerea
    Ekström, Johanna
    Hortlund, Maria
    Lindquist, David
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Wareham, Nick
    Travis, Ruth C
    Rinaldi, Sabina
    Tommasino, Massimo
    Franceschi, Silvia
    Riboli, Elio
    Prospective seroepidemiologic study on the role of Human Papillomavirus and other infections in cervical carcinogenesis: Evidence from the EPIC cohort2014In: International Journal of Cancer, ISSN 0020-7136, E-ISSN 1097-0215, Vol. 135, no 2, p. 440-452Article in journal (Refereed)
    Abstract [en]

    To evaluate prospectively the association between serological markers of selected infections, including HPV, and risk of developing cervical cancer (CC) and pre-cancer, we performed a nested case-control study within the European Prospective Investigation into Cancer and Nutrition (EPIC) study that included 184 cases of invasive CC (ICC), 425 cases of cervical intraepithelial neoplasia (CIN) grade 3 or carcinoma in situ (CIS), and 1,218 matched control women. At enrollment participants completed lifestyle questionnaires and provided sera. Subjects were followed-up for a median of 9 years. Immunoassays were used to detect serum antibodies to Human Herpes Virus 2 (HHV-2), Chlamydia trachomatis (CT), Chlamydia pneumoniae, L1 proteins of mucosal and cutaneous HPV types, E6/E7 proteins of HPV16/18, as well as to four polyomaviruses. Adjusted odds ratios (OR) (and 95% confidence intervals (CI)) for CIN3/CIS and ICC risk were, respectively: 1.6 (1.2-2.0) and 1.8 (1.1-2.7) for L1 seropositivity to any mucosal HPV type, 1.0 (0.4-2.4) and 7.4 (2.8-19.7) for E6 seropositivity to HPV16/18, 1.3 (0.9-1.9) and 2.3 (1.3-4.1) for CT seropositivity, and 1.4 (1.0-2.0) and 1.5 (0.9-2.6) for HHV-2 seropositivity. The highest OR for ICC was observed for HPV16 E6 seropositivity (OR=10.2 (3.3-31.1)). Increasing number of sexually transmitted infections (STIs) was associated with increasing risk. Non-STIs were not associated with CC risk. In conclusion, this large prospective study confirms the important role of HPV and a possible contribution of CT and HHV-2 in cervical carcinogenesis. It further identifies HPV16 E6 seropositivity as the strongest marker to predict ICC well before disease development.

  • 3. Chen, Dan
    et al.
    Hammer, Joanna
    Lindquist, David
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Idahl, Annika
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology.
    Gyllensten, Ulf
    A variant upstream of HLA-DRB1 and multiple variants in MICA influence susceptibility to cervical cancer in a Swedish population2014In: Cancer Medicine, ISSN 2045-7634, E-ISSN 2045-7634, Vol. 3, no 1, p. 190-198Article in journal (Refereed)
    Abstract [en]

    In a genome-wide association study, we have previously identified and performed the initial replication of three novel susceptibility loci for cervical cancer: rs9272143 upstream of HLA-DRB1, rs2516448 adjacent to MHC class I polypeptide-related sequence A gene (MICA), and rs3117027 at HLA-DPB2. The risk allele T of rs2516448 is in perfect linkage disequilibrium with a frameshift mutation (A5.1) in MICA exon 5, which results in a truncated protein. To validate these associations in an independent study and extend our prior work to MICA exon 5, we genotyped the single-nucleotide polymorphisms at rs9272143, rs2516448, rs3117027 and the MICA exon 5 microsatellite in a nested case–control study of 961 cervical cancer patients (827 carcinoma in situ and 134 invasive carcinoma) and 1725 controls from northern Sweden. The C allele of rs9272143 conferred protection against cervical cancer (odds ratio [OR] = 0.73, 95% confidence interval [CI] = 0.65–0.82; P = 1.6 × 10−7), which is associated with higher expression level of HLA-DRB1, whereas the T allele of rs2516448 increased the susceptibility to cervical cancer (OR = 1.33, 95% CI = 1.19–1.49; P = 5.8 × 10−7), with the same association shown with MICA-A5.1. The direction and the magnitude of these associations were consistent with our previous findings. We also identified protective effects of the MICA-A4 (OR = 0.80, 95% CI = 0.68–0.94; P = 6.7 × 10−3) and MICA-A5 (OR = 0.60, 95% CI = 0.50–0.72; P = 3.0 × 10−8) alleles. The associations with these variants are unlikely to be driven by the nearby human leukocyte antigen (HLA) alleles. No association was observed between rs3117027 and risk of cervical cancer. Our results support the role of HLA-DRB1 and MICA in the pathogenesis of cervical cancer.

  • 4. Cui, Tao
    et al.
    Enroth, Stefan
    Ameur, Adam
    Gustavsson, Inger
    Lindquist, David
    Umeå University, Faculty of Medicine, Department of Radiation Sciences.
    Gyllensten, Ulf
    Invasive cervical tumors with high and low HPV titer represent molecular subgroups with different disease etiology2019In: Carcinogenesis, ISSN 0143-3334, E-ISSN 1460-2180, Vol. 40, no 2, p. 269-278Article in journal (Refereed)
    Abstract [en]

    Invasive cervical cancer (ICC) with very low titer of high-risk human papillomavirus (HPV) has worse clinical outcome than cases with high titer, indicating a difference in molecular etiology. Fresh-frozen ICC tumors (n=49) were classified into high and low HPV titer cases using real-time PCR-based HPV genotyping. The mutation spectra were studied using the AmpliSeq Comprehensive Cancer Panel and the expression profiles using total RNA-sequencing, and the results validated using the AmpliSeq Transcriptome assay. HPV DNA genotyping and RNA sequencing showed that 16.6% of ICC tumors contained very low levels of HPV DNA and HPV transcripts. Tumors with low HPV levels had more mutations with a high allele frequency and fewer mutations with low allele frequency relative to tumors with high HPV titer. A number of genes showed significant expression differences between HPV titer groups, including genes with somatic mutations. Gene ontology and pathway analyses implicated the enrichment of genes involved in DNA replication, cell cycle control and extracellular matrix in tumors with low HPV titer. The results indicate that in low titer tumors, HPV act as trigger of cancer development while somatic mutations are clonally selected and become drivers of the tumor development process. In contrast, in tumors with high HPV titer the expression of HPV oncoproteins play a major role in tumor development and the many low frequency somatic mutations represent passengers. This putative subdivision of invasive cervical tumors may explain the higher radiosensitivity of ICC tumors with high HPV titer and thereby have consequences for clinical management.

  • 5. Dahlgren, Liselotte
    et al.
    Dahlstrand, Hanna Mellin
    Lindquist, David
    Karolinska Instituet, Institutionen för Onkologi-Patologi.
    Högmo, Anders
    Björnestål, Linda
    Lindholm, Johan
    Lundberg, Bertil
    Dalianis, Tina
    Munck-Wikland, Eva
    Human papillomavirus is more common in base of tongue than in mobile tongue cancer and is a favorable prognostic factor in base of tongue cancer patients.2004In: International Journal of Cancer, ISSN 0020-7136, E-ISSN 1097-0215, Vol. 112, no 6, p. 1015-9Article in journal (Refereed)
    Abstract [en]

    The frequency of human papilloma virus (HPV) and its influence on clinical outcome was analyzed retrospectively in pre-treatment paraffin embedded biopsies from 110 patients with tongue cancer. The presence of HPV DNA was examined in 85 mobile tongue tumors and 25 base of tongue tumors by a polymerase chain reaction (PCR) with 2 general primer pairs, GP5+/6+ and CPI/IIG. When HPV-DNA was found, HPV-type specific primers and direct sequencing were used for HPV sub-type verification. Twelve of 110 (10.9%) samples were HPV-positive; 9 for HPV-16, 1 for HPV-33, 1 for HPV-35 and 1 could not be analyzed because of shortage of DNA. HPV was significantly more common in base of tongue tumors (10/25, 40.0%) compared to tumors of the mobile tongue (2/85, 2.3%). The influence of HPV on clinical outcome in mobile tongue cancer could not be studied, due to that HPV was present in too few cases. Of the 19 patients with base of tongue cancer that were included in the survival analysis, however, 7 patients with HPV-positive base of tongue cancer had a significantly favorable 5-year survival rate compared to the 12 HPV-negative patients. In conclusion, HPV is significantly more common in base of tongue cancer than in mobile tongue cancer, and has a positive impact on disease-specific survival in patients with base of tongue cancer.

  • 6. Dahlgren, Liselotte
    et al.
    Erlandsson, Fredrik
    Lindquist, David
    Karolinska Instituet, Institutionen för Onkologi-Patologi.
    Silfverswärd, Claes
    Hellström, Ann-Cathrin
    Dalianis, Tina
    Differences in human papillomavirus type may influence clinical outcome in early stage cervical cancer.2006In: Anticancer Research, ISSN 0250-7005, E-ISSN 1791-7530, Vol. 26, no 2A, p. 829-32Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: The presence of human papillomavirus (HPV), the HPV type and viral load in early stage cervical carcinoma were investigated in order to elucidate whether any of these factors were important for clinical outcome.

    PATIENTS AND METHODS: Twelve patients who were disease-free 5 years after diagnosis were matched and compared with 12 patients who died within 2 years. The presence of HPV, HPV type and viral load in their tumours was examined by PCR.

    RESULTS: The distribution and load of HPV was similar in the 2 patient groups. HPV-16 was, however, significantly more common in tumours of the surviving patients than in those of patients who died (88.9% and 18.2%, respectively, p = 0.0152).

    CONCLUSION: HPV-16 was significantly more common in early stage carcinomas of patients surviving more than 5 years in comparison to early stage carcinomas of patients with a poor prognosis.

  • 7. Dahlstrand, Hanna
    et al.
    Dahlgren, Liselotte
    Lindquist, David
    Karolinska Instituet, Institutionen för Onkologi-Patologi.
    Munck-Wikland, Eva
    Dalianis, Tina
    Presence of human papillomavirus in tonsillar cancer is a favourable prognostic factor for clinical outcome.2004In: Anticancer Research, ISSN 0250-7005, E-ISSN 1791-7530, Vol. 24, no 3b, p. 1829-35Article in journal (Refereed)
    Abstract [en]

    The purpose of this article is to review the current knowledge on the status and significance of human papillomavirus (HPV) in tonsillar cancer. Current data in scientific reports and data from the Karolinska Hospital and Karolinska Institute, Sweden, demonstrate that approximately half of all tonsillar cancer is HPV-positive. Moreover, patients with HPV-positive cancer have a lower risk of relapse and longer survival compared to patients with HPV-negative tonsillar cancer. The favourable outcome for patients harbouring HPV-positive tonsillar cancer cannot be attributed to increased radiosensitivity, since there is no significant difference in sensitivity to radiotherapy between HPV-positive and -negative tonsillar cancer. However, HPV-positive cancer exhibits less genetic instability i.e. shows a lower degree of aneuploidy and a tendency to have fewer chromosomal aberrations, when compared to HPV-negative tonsillar cancer.

  • 8. Dahlstrand, Hanna
    et al.
    Näsman, Anders
    Romanitan, Mircea
    Lindquist, David
    Karolinska Instituet, Institutionen för Onkologi-Patologi.
    Ramqvist, Torbjörn
    Dalianis, Tina
    Human papillomavirus accounts both for increased incidence and better prognosis in tonsillar cancer.2008In: Anticancer Research, ISSN 0250-7005, E-ISSN 1791-7530, Vol. 28, no 2B, p. 1133-8Article in journal (Refereed)
    Abstract [en]

    The aim of this review is to present the current knowledge on the status and significance of human papillomavirus (HPV) in tonsillar cancer. An increase in the incidence of tonsillar cancer has been reported and recent data suggest that this increase is due to an increased proportion of HPV in these tumours. Furthermore, patients with HPV positive cancer have been shown to have a lower risk of relapse and longer survival compared to patients with HPV-negative tonsillar cancer. Tailoring individual treatment in tonsillar cancer may be of importance in order to reduce patient suffering as well as to increase patient survival. Finally, the fact that the presence of HPV-type 16 E6 and E7 mRNA has been ascertained in tonsillar cancer suggests that HPV-16 indeed is an aetiological factor associated with the disease and that preventive vaccination for this patient group should be discussed.

  • 9. Hammarstedt, Lalle
    et al.
    Dahlstrand, Hanna
    Lindquist, David
    Karolinska Instituet, Institutionen för Onkologi-Patologi.
    Onelöv, Liselotte
    Ryott, Michael
    Luo, Juhua
    Dalianis, Tina
    Ye, Weimin
    Munck-Wikland, Eva
    The incidence of tonsillar cancer in Sweden is increasing.2007In: Acta Oto-Laryngologica, ISSN 0001-6489, E-ISSN 1651-2251, Vol. 127, no 9, p. 988-92Article in journal (Refereed)
    Abstract [en]

    CONCLUSIONS: The incidence of tonsillar cancer in Sweden is increasing, particularly among men. Risk factors other than smoking may have contributed to the observed secular trend in men. In women, however, smoking can be a part of the explanation. Further studies to look at changes in other environmental factors, such as human papilloma virus (HPV) infection, are clearly warranted.

    OBJECTIVES: Head and neck cancer is related to smoking habits and smoking has decreased substantially during the last 30 years in Sweden. However, there is suspicion that the incidence of tonsillar cancer has increased in the last 30 years as it has in the USA and Finland, in spite of reduced prevalence of known risk factors. The time trends of oral and oropharygeal cancer have been studied in Sweden, but not tonsillar cancer specifically.

    SUBJECTS AND METHODS: We used the Swedish Cancer Registry to assess the secular trend of incidence of tonsillar cancer in Sweden since 1960. For comparison we investigated the incidence of other oral cancers and lung cancer, which are also smoking-related. The prevalence of smoking was investigated for reference. Age-standardized incidence rates were calculated and linear regression was used to evaluate secular trends.

    RESULTS: The incidence of tonsillar cancer increased by 2.6% per year in men and 1.1% in women. No similar increase was seen in the other oral cancers. For lung cancer there was a decrease in the incidence in men, but in women the incidence is still increasing.

  • 10.
    Hammarstedt, Lalle
    et al.
    Karolinska Institutet.
    Lindquist, David
    Karolinska Instituet, Institutionen för Onkologi-Patologi.
    Dahlstrand, Hanna
    Karolinska Institutet.
    Romanitan, Mircea
    Karolinska Institutet.
    Onelöv, Liselotte
    Karolinska Institutet.
    Joneberg, Jeanna
    Karolinska Institutet.
    Creson, Nomi
    Karolinska Institutet.
    Lindholm, Johan
    Karolinska Institutet.
    Ye, Weimin
    Karolinska Institutet.
    Dalianis, Tina
    Karolinska Institutet.
    Munck-Wikland, Eva
    Karolinska Institutet.
    Human papillomavirus as a risk factor for the increase in incidence of tonsillar cancer.2006In: International Journal of Cancer, ISSN 0020-7136, E-ISSN 1097-0215, Vol. 119, no 11, p. 2620-2623Article in journal (Refereed)
    Abstract [en]

    Smoking and alcohol are well-known etiological factors in tonsillar cancer. However, as in cervical cancer, human papillomavirus (HPV) is currently found in a sizable proportion of tonsillar cancer. Recent reports from the U.S. and Finland show an increase in the incidence of tonsillar cancer, without a parallel rise in smoking and alcohol consumption. This study investigates whether the incidence of tonsillar cancer has also changed in Sweden and whether a possible explanation of the increase is a higher proportion of HPV-positive tonsillar cancer. The incidence of tonsillar cancer between 1970 and 2002 in the Stockholm area was obtained from the Swedish Cancer Registry. In parallel, 203 pretreatment paraffin-embedded tonsillar cancer biopsies taken during 1970-2002 from patients in the Stockholm area were tested for presence of HPV DNA by PCR. The incidence of tonsillar cancer increased 2.8-fold (2.6 in men and 3.5 in women) from 1970 to 2002. During the same period, a significant increase in the proportion of HPV-positive tonsillar cancer cases was observed, as it increased 2.9-fold (p < 0.001). The distribution of HPV-positive cases was 7/30 (23.3%) in the 1970s, 12/42 (29%) in the 1980s, 48/84 (57%) in the 1990s and 32/47 (68%) during 2000-2002. We have demonstrated a highly significant and parallel increase both in the incidence of tonsillar cancer and the proportion of HPV-positive tumors. Hence, HPV may play an important role for the increased incidence of tonsillar cancer. This should definitely influence future preventive strategies as well as treatment for this type of cancer.

  • 11. Hellman, K
    et al.
    Lindquist, David
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology. Oncology Research Laboratory, Department of Radiation Sciences, Umeå University.
    Ranhem, C
    Wilander, E
    Andersson, S
    Human papillomavirus, p16(INK4A), and Ki-67 in relation to clinicopathological variables and survival in primary carcinoma of the vagina2014In: British Journal of Cancer, ISSN 0007-0920, E-ISSN 1532-1827, Vol. 110, no 6, p. 1561-1570Article in journal (Refereed)
    Abstract [en]

    Background:This study aimed to determine human papillomavirus (HPV) status and to investigate p16(INK4A) and Ki-67 expression and their correlation with clinical parameters and survival in women with primary carcinoma of the vagina (PCV).Methods:The presence of HPV DNA was evaluated by PCR. Genotyping was performed by Luminex in 68 short-term (2 years) and long-term (8 years) PCV survivors. p16(INK4A) and Ki-67 expression was evaluated by immunohistochemistry.Results:Human papillomavirus DNA was detected in 43% of patients, the majority (63%) of whom were HPV16 positive. High p16(INK4A) expression was significantly correlated with low histopathological grade (P=0.004), HPV positivity (P=0.032), and long-term survival (P=0.045). High Ki-67 expression was negatively correlated with histopathological grade (P<0.001) and tumour size (P=0.047). There was an association between HPV positivity and low histopathological grade, but not between HPV positivity and survival.Conclusion:High p16(INK4A) expression was associated with long-term survival, but the only independent predictors for survival were tumour size and histopathological grade. Our results indicate that p16(INK4A) and Ki-67 expression might be useful in tumour grading, and that it might be possible to use p16(INK4A) expression as a marker for HPV positivity, but this has to be further elucidated.

  • 12.
    Kvarnbrink, Samuel
    et al.
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Karlsson, Terese
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Edlund, Karolina
    Botling, Johan
    Lindquist, David
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Jirström, Karin
    Micke, Patrick
    Henriksson, Roger
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Johansson, Mikael
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Hedman, Håkan
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    LRIG1 is a prognostic biomarker in non-small cell lung cancer2015In: Acta Oncologica, ISSN 0284-186X, E-ISSN 1651-226X, Vol. 54, no 8, p. 1113-1119Article in journal (Refereed)
    Abstract [en]

    Background: The leucine-rich repeats and immunoglobulin-like domains (LRIG) family of transmembrane proteins are involved in the regulation of cellular signal transduction. LRIG1 is an endogenous inhibitor of receptor tyrosine kinases (RTKs) and an emerging tumor suppressor. In the lung epithelium, the expression of LRIG1 is downregulated by tobacco smoking, and further downregulated in lung squamous cell carcinoma. Material and methods: The expression of LRIG proteins were analyzed in 347 cases of non-small cell lung cancer (NSCLC) by immunohistochemistry, and LRIG1 mRNA expression was evaluated in 807 lung cancer samples in silico in the Oncomine database. Potential associations between the expression data and the clinical parameters, including patient survival, were investigated. Results: Expression of the LRIG1 protein was found to be an independent prognostic factor in NSCLC, whereas expression of LRIG2 or LRIG3 did not correlate with patient survival. The levels of LRIG1 mRNA also correlated with the survival of NSCLC patients. Conclusion: These findings demonstrate that LRIG1 is an independent prognostic factor in patients with NSCLC that could be important in future decision-making algorithms for adjuvant lung cancer treatment.

  • 13.
    Kvarnbrink, Samuel
    et al.
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Karlsson, Terese
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Forssell, Joakim
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Infectious Diseases.
    Edlund, Karin
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology.
    Holmlund, Camilla
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Faraz, Mahmood
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Botling, J
    Feng, Mao
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Lindquist, David
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Micke, P
    Henriksson, Roger
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Johansson, Mikael
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Hedman, Håkan
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    LRIG1 is a prognostic biomarker and tumor suppressor in non-small cell lung cancerManuscript (preprint) (Other academic)
  • 14. La Russa, M
    et al.
    Zapardiel, I
    Halaska, M J
    Zalewski, K
    Laky, R
    Dursun, P
    Lindquist, David
    Umeå University, Faculty of Medicine, Department of Radiation Sciences.
    Sukhin, V
    Polterauer, S
    Biliatis, I
    Conservative management of endometrial cancer: a survey amongst European clinicians2018In: Archives of Gynecology and Obstetrics, ISSN 0932-0067, E-ISSN 1432-0711, Vol. 298, p. 373-380Article in journal (Refereed)
    Abstract [en]

    OBJECTIVE: To investigate differences and similarities in the clinical approach of young clinicians managing women with endometrial cancer (EC) conservatively.

    METHODS: A web-based survey was carried out. A platform of the European Network of Young Gynaecological Oncologists (ENYGO) database was used. A 38-item multiple-choice questionnaire was used to evaluate current practice in fertility-sparing management of EC. The survey covered investigations, treatment options, follow-up and management of recurrence and future family planning. Descriptive statistics were used.

    RESULTS: Overall, 116 out of 650 (17.84%) ENYGO members responded to the survey. In 92 (79.3%) centres, the caseload of early stage EC treated conservatively was less than 10 per year. One hundred and seven responders (93.8%) believe that treatment with progestins could be offered in grade 1 EC without myometrial invasion, but a minority would recommend it even for grade 2 tumours with no myometrial invasion or grade 1 with superficial invasion. The diagnostic tool for establishing grade of tumour was hysteroscopy with dilatation and curettage in 64 (55%) centres. Medroxyprogesterone acetate represents the most commonly prescribed progestogen (55, 47.4%). In 78 (67.2%) centres, a repeat endometrial biopsy was offered after 3 months of treatment commencement. Recurrences are treated mostly with hysterectomy (81, 69.9%) with only a small number of responders recommending to repeat progestin treatment. Lynch syndrome is a contraindication for conservative management in half of the responders (57, 49.1%). Most clinicians agree that patients should be referred promptly for assisted reproductive techniques once complete response has been achieved (68, 58.6%).

    CONCLUSIONS: Our study shows that conservative management is increasingly offered to women affected by early stage EC wishing to preserve their fertility. Further studies and joint registries are required to evaluate safety and effectiveness of this approach in this probably growing number of patients.

  • 15. Lindemann, Kristina
    et al.
    Zalewski, Kamil
    Halaska, Michael J.
    Lindquist, David
    Umeå University.
    Life - Literature for ENYGO2016In: International Journal of Gynecological Cancer, ISSN 1048-891X, E-ISSN 1525-1438, Vol. 26, p. 2-73Article in journal (Refereed)
    Abstract [en]

    Reviews covering publications from February 15, 2016 – September 15, 2016

  • 16.
    Lindquist, David
    Umeå University.
    Medical (chemo and radiotherapy) treatment of primary uterine cancer2016In: International Journal of Gynecological Cancer, ISSN 1048-891X, E-ISSN 1525-1438, Vol. 26, p. 28-28Article in journal (Refereed)
  • 17.
    Lindquist, David
    Institutionen för onkologi-patologi, Karolinska Institutet.
    Studies on the occurrence and effects of human papillomavirus in tumors of the head and neck2008Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    The presence of human papillomavirus (HPV) in squamous cell carcinoma of the head and neck (HNSCC) was first reported in 1985. Since then, this association has been studied intensively and today there is substantial evidence for HPV as a causative agent and positive prognostic factor for clinical outcome in tonsillar cancer, but the association to other HNSCC is still unclear. The aim of this thesis was first to examine the presence of HPV in tongue cancer and to study its possible influence on disease outcome. Thereafter, the association between HPV and cdk inhibitor p16INK4a expression and a possible correlation to response to radiotherapy (RT) and survival was studied. A third aim of this thesis was to investigate if HPV is a potential risk factor for the increase in incidence of tonsillar cancer that has been observed in Sweden. Furthermore, presence of HPV, viral load and expression of the viral oncogenes E6 and E7 in tonsillar cancer was investigated and correlated to clinical outcome. In tongue cancer, HPV DNA detected by PCR was more commonly found in base of tongue cancer (40%) as compared to mobile tongue cancer (2.4%), and was a positive prognostic factor for survival in patients with base of tongue cancer. This finding indicates that HPV might not only be involved in tonsillar cancer, but also in base of tongue cancer, which has a similar histology and is also a part of oropharynx. In tonsillar cancer there was a strong correlation between a high expression of p16INK4a detected by immunohistochemistry (IHC) and presence of HPV detected by PCR. However, only high expression of p16INK4a, and not the presence of HPV, was shown to be a predictive factor for complete response to RT in tonsillar cancer. Nevertheless, both p16INK4a and HPV were positive predictive factors for clinical outcome. The incidence of tonsillar cancer and presence of HPV was studied in the Stockholm area during 1970-2002. HPV was detected by PCR in 49% of the patient samples and 87% of these were positive for HPV-16. The frequency of HPV positive tonsillar cancer increased 2.9-fold from 1970 to 2002 and during the same time period a parallel 2.8-fold increase in the incidence of tonsillar cancer was observed. These results strongly support HPV as a risk factor for the increase in incidence of tonsillar cancer. In the tonsillar cancer patients above, the finding of HPV as a positive prognostic factor in tonsillar cancer for clinical outcome was confirmed. In addition, HPV viral load and expression of the viral oncogenes E6 and E7 was analyzed with real time quantitative PCR and reverse transcriptase PCR in the HPV-16 positive tonsillar cancer samples. In most HPV-16 positive tumors, expression of E6 and E7 was ascertained. However, in contrast to earlier studies a high viral load was not correlated to survival. The findings of an increase in incidence of tonsillar cancer and a parallel increase in frequency of HPV positive tumors, a better disease specific survival, and the expression of viral oncogenes strongly support previous findings that HPV positive tonsillar cancer should be considered a different disease entity. If the now available prophylactic vaccines are included in the childhood vaccination program for girls, the possible effects on HPV positive tonsillar cancer should be discussed, since most patients with HPV positive tonsillar cancer are men.

  • 18.
    Lindquist, David
    et al.
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Alsina, Fernando C.
    Herdenberg, Carl
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Larsson, Catharina
    Höppener, Jo
    Wang, Na
    Paratcha, Gustavo
    Tarján, Miklós
    Tot, Tibor
    Henriksson, Roger
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Hedman, Håkan
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    LRIG1 negatively regulates RET mutants and is downregulated in thyroid cancer2018In: International journal of oncology, ISSN 1791-2423, Vol. 52, no 4, p. 1189-1197Article in journal (Refereed)
    Abstract [en]

    Papillary thyroid carcinoma (PTC) and medullary thyroid carcinoma (MTC) are characterized by genomic rearrangements and point mutations in the proto-oncogene RET. Leucine-rich repeats and immunoglobulin-like domains 1 (LRIG1) is a suppressor of various receptor tyrosine kinases, including RET. LRIG1 expression levels are associated with patient survival in many cancer types. In the present study, we investigated whether the oncogenic RET mutants RET2A (C634R) and RET2B (M918T) were regulated by LRIG1, and the possible effects of LRIG1 expression in thyroid cancer were investigated in three different clinical cohorts and in a RET2B-driven mouse model of MTC. LRIG1 was shown to physically interact with both RET2A and RET2B and to restrict their ligand-independent activation. LRIG1 mRNA levels were downregulated in PTC and MTC compared to normal thyroid gland tissue. There was no apparent association between LRIG1 RNA or protein expression levels and patient survival in the studied cohorts. The transgenic RET2B mice developed pre-cancerous medullary thyroid lesions at a high frequency (36%); however, no overt cancers were observed. There was no significant difference in the incidence of pre-cancerous lesions between Lrig1 wild-type and Lrig1-deficient RET2B mice. In conclusion, the findings that LRIG1 is a negative regulator of RET2A and RET2B and is also downregulated in PTC and MTC may suggest that LRIG1 functions as a thyroid tumor suppressor.

  • 19.
    Lindquist, David
    et al.
    Department of Pathology and Clinical Cytology, Central Hospital Falun, Falun.
    Hellberg, Dan
    Tot, Tibor
    Disease Extent ≥4 cm Is a Prognostic Marker of Local Recurrence in T1-2 Breast Cancer.2011In: Pathology research international, ISSN 2042-003X, Vol. 2011, p. 860584-Article in journal (Refereed)
    Abstract [en]

    Despite improvements of the therapy for breast cancer, a proportion of the patients still get local recurrence. The status of the surgical margins is the most often used parameter for decision regarding additional treatment. However, a negative margin is not a guarantee that there is not residual cancer left in the breast; additional parameters are needed to better predict the risk of local recurrence. The disease extent was evaluated in the surgical specimen from 313 women after breast-conserving therapy using large-section histology and was correlated to the incidence of local recurrence. A disease extent ≥4 cm was shown to be an independent marker for local recurrence; the cumulative 10-year local relapse rate for the group with a disease extent ≥4 cm was 20.5%, and for the rest 6.7%. We conclude that disease extent ≥4 cm seems to be an important factor when evaluating the risk for local recurrence.

  • 20.
    Lindquist, David
    et al.
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Henriksson, Roger
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Hedman, Hakan
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Expression of the human LRIG genes and proteins as prognostic markers in human cancer2012In: International Journal of Molecular Medicine, ISSN 1107-3756, E-ISSN 1791-244X, Vol. 30, no Suppl 1, p. S42-S42Article in journal (Other academic)
  • 21.
    Lindquist, David
    et al.
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Kvarnbrink, Samuel
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Henriksson, Roger
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Hedman, Håkan
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    LRIG and cancer prognosis2014In: Acta Oncologica, ISSN 0284-186X, E-ISSN 1651-226X, Vol. 53, no 9, p. 1135-1142Article, review/survey (Refereed)
    Abstract [en]

    BACKGROUND: Optimal treatment decisions for cancer patients require reliable prognostic and predictive information. However, this information is inadequate in many cases. Several recent studies suggest that the leucine-rich repeats and immunoglobulin-like domains (LRIG) genes, transcripts, and proteins have prognostic implications in various cancer types. MATERIAL AND METHODS: Relevant literature was identified on PubMed using the key words lrig1, lrig2, and lrig3. LRIG mRNA expression in cancer versus normal tissues was investigated using the Oncomine database. RESULTS: The three human LRIG genes, LRIG1, LRIG2, and LRIG3, encode single-pass transmembrane proteins. LRIG1 is a negative regulator of growth factor signaling that has been shown to function as a tumor suppressor in vitro and in vivo in mice. The functions of LRIG2 and LRIG3 are less well defined. LRIG gene and protein expression are commonly dysregulated in human cancer. In early stage breast cancer, LRIG1 copy number was recently shown to predict early and late relapse in addition to overall survival; in nasopharyngeal carcinoma, loss of LRIG1 is also associated with poor survival. LRIG gene and protein expression have prognostic value in breast cancer, uterine cervical cancer, head-and-neck cancer, glioma, non-small cell lung cancer, prostate cancer, and cutaneous squamous cell carcinoma. In general, expression of LRIG1 and LRIG3 is associated with good survival, whereas expression of LRIG2 is associated with poor survival. Additionally, LRIG1 regulates cellular sensitivity to anti-cancer drugs, which indicates a possible role as a predictive marker. CONCLUSIONS: LRIG gene statuses and mRNA and protein expression are clinically relevant prognostic indicators in several types of human cancer. We propose that LRIG analyses could become important when making informed and individualized clinical decisions regarding the management of cancer patients.

  • 22.
    Lindquist, David
    et al.
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Näsman, A.
    Department of Oncology-Pathology, Karolinska Institute, SE-171 76, Stockholm, Sweden.
    Tarján, M.
    Department of Pathology and Clinical Cytology, Central Hospital Falun, SE-791 29, Falun, Sweden.
    Henriksson, Roger
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Tot, T.
    Department of Pathology and Clinical Cytology, Central Hospital Falun, SE-791 29, Falun, Sweden.
    Dalianis, T.
    Department of Oncology-Pathology, Karolinska Institute, SE-171 76, Stockholm, Sweden.
    Hedman, Håkan
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Expression of LRIG1 is associated with good prognosis and human papillomavirus status in oropharyngeal cancer2014In: British Journal of Cancer, ISSN 0007-0920, E-ISSN 1532-1827, Vol. 110, no 7, p. 1793-1800Article in journal (Refereed)
    Abstract [en]

    Background:The incidence of human papillomavirus (HPV)-associated oropharyngeal cancer has increased rapidly during the past decades. HPV is typically associated with a favourable outcome; however, a need exists for new and more effective prognostic and predictive markers for this disease. Leucine-rich repeats and immunoglobulin-like domains (LRIG)-1 is a tumour suppressor protein that belongs to the LRIG family. LRIG1 expression has prognostic significance in various human cancers, including cervical cancer, where HPV is a key aetiological agent.Methods:The prognostic value of LRIG1 and LRIG2 immunoreactivity was investigated in tumour specimens from a Swedish cohort of patients with tonsillar and base of tongue oropharyngeal cancers, including 278 patients.Results:LRIG1 immunoreactivity correlated with disease-free survival and overall survival in univariate and multivariate analyses. Notably, patients with HPV-positive tumours with high LRIG1 staining intensity or a high percentage of LRIG1-positive cells showed a very good prognosis. Furthermore, LRIG1 expression correlated with HPV status, whereas LRIG2 expression inversely correlated with HPV status.Conclusions:Taken together, the results suggest that LRIG1 immunoreactivity could be a clinically important prognostic marker in HPV-associated oropharyngeal cancer.

  • 23.
    Lindquist, David
    et al.
    Umeå University, Faculty of Medicine, Department of Radiation Sciences.
    Ranhem, C.
    Stefansson, Kristina
    Hellman, K.
    Andersson, S.
    PREVALENCE OF HPV-POSITIVE VAGINAL AND VULVAR CANCER OVER TIME IN TWO SWEDISH COHORTS2014In: International Journal of Gynecological Cancer, ISSN 1048-891X, E-ISSN 1525-1438, Vol. 24, no 9 suppl 4, p. 892-892Article in journal (Other academic)
  • 24.
    Lindquist, David
    et al.
    Karolinska Instituet, Institutionen för Onkologi-Patologi.
    Romanitan, Mircea
    Hammarstedt, Lalle
    Näsman, Anders
    Dahlstrand, Hanna
    Lindholm, Johan
    Onelöv, Liselotte
    Ramqvist, Torbjörn
    Ye, Weimin
    Munck-Wikland, Eva
    Dalianis, Tina
    Human papillomavirus is a favourable prognostic factor in tonsillar cancer and its oncogenic role is supported by the expression of E6 and E7.2007In: Molecular oncology, ISSN 1878-0261, Vol. 1, no 3, p. 350-5Article in journal (Refereed)
    Abstract [en]

    From 1970 to 2002 in the Stockholm area, we revealed a parallel three-fold increase in the incidence of tonsillar cancer and the proportion of human papillomavirus (HPV) positive tonsillar cancer cases, indicating a possible role of HPV infection in this disease. We have now examined whether HPV and viral load in pre-treatment tonsillar cancer biopsies correlates to disease prognosis, and whether the presence of HPV-16 E6 and E7 mRNA could be ascertained. The presence of HPV-16, but not viral load, in tonsillar cancer was shown to be a favourable prognostic factor for clinical outcome. Moreover, E6 and/or E7 were expressed in almost all assessable HPV-16 positive cases, supporting an oncogenic role of HPV-16 in tonsillar cancer.

  • 25.
    Lindquist, David
    et al.
    Center for Clinical Research Dalarna, Falun, Sweden .
    Ährlund-Richter, Andreas
    Tarján, Miklós
    Tot, Tibor
    Dalianis, Tina
    Intense CD44 expression is a negative prognostic factor in tonsillar and base of tongue cancer2012In: Anticancer Research, ISSN 0250-7005, E-ISSN 1791-7530, Vol. 32, no 1, p. 153-161Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Patients with tonsillar and base of tongue cancer, which are human papillomavirus (HPV) positive, have a better clinical outcome than those with HPV-negative tumors. The identification of additional predictive markers for response to therapy could still be of great use.

    MATERIALS AND METHODS: Tumor markers CD44, p16, epidermal growth factor receptor (EGFR), vascular endothelial growth factor (VEGF), E-cadherin, cyclooxygenase-2 (COX 2), Ki-67, and p27 were analyzed by immunochemistry, and HPV status was tested by polymerase chain reaction (PCR) in tumors from 73 patients and correlated to survival.

    RESULTS: High intensity CD44 staining (p=0.006) and high EGFR expression (p=0.026) were indicators of poor prognosis, while high p16 expression (p=0.021) and younger age (p=0.002) were positive prognostic markers for disease-specific survival. Furthermore, staining of CD44 (p=0.026) and age (p=0.002) were shown to be strong prognostic markers in multivariate analysis, which should be evaluated further for possible use in clinical practice.

  • 26.
    Lindquist, David
    et al.
    Umeå University, Faculty of Medicine, Department of Radiation Sciences.
    Öfverman, Charlotte
    Umeå University, Faculty of Medicine, Department of Radiation Sciences.
    Stefansson, Kristina
    Umeå University, Faculty of Medicine, Department of Radiation Sciences.
    Aglund, Kristina
    Umeå University, Faculty of Medicine, Department of Radiation Sciences.
    Survival-data for endometrial cancer patients in northern Sweden 2010-20112015In: International Journal of Gynecological Cancer, ISSN 1048-891X, E-ISSN 1525-1438, Vol. 25, no 9, p. 1100-1100Article in journal (Other academic)
  • 27.
    Loizou, Christos
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Otorhinolaryngology.
    Laurell, Göran
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Otorhinolaryngology.
    Arvidsson, Andreas
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Otorhinolaryngology.
    Lindquist, David
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Nylander, Karin
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Olofsson, Katarina
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Otorhinolaryngology.
    Recurrent respiratory papillomatosis in northern Sweden: Clinical characteristics and practical guidance2015In: Acta Oto-Laryngologica, ISSN 0001-6489, E-ISSN 1651-2251, Vol. 135, no 10, p. 1058-1064Article in journal (Refereed)
    Abstract [en]

    Conclusion: Recurrent respiratory papillomatosis (RRP) patients with high surgical treatment frequency (>= 1/year, HF) were significantly younger and had a more widespread laryngeal disease compared to a low frequency treated group (< 1 treatment/year, LF). This study confirms the existence of a clinical RRP group, not primarily related to HPV sub-type, but more care-intensive and in need of more vigilant follow-up. Objectives: RRP is associated with high morbidity due to its influence on breathing and voice. The purpose of this study was to characterize RRP patients in northern Sweden and investigate possible predictor factors affecting therapeutic needs. Method: Patients from the regional referral area (northern Sweden) were categorized for age, disease duration, juvenile or adult onset, profile of disease development, number of surgical sessions in relation to disease duration, laryngeal deposition of papilloma, gender, and HPV sub-types, in order to identify patients with increased need for frequent surgical treatment. Results: The median age of the RRP patients (n = 48) was 44.5 years; 34 (71%) were males and 14 (29%) females, most were infected with HPV 6. Patients with high surgical treatment frequency/year were significantly younger and showed more widespread papillomatous vegetation in the larynx, compared to the low frequency treated group.

  • 28.
    Loizou, Christos
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Otorhinolaryngology.
    Laurell, Göran
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Otorhinolaryngology. Department of Surgical Sciences, Division of Otorhinolaryngology, Uppsala University.
    Lindquist, David
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Olofsson, Katarina
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Otorhinolaryngology.
    Voice and quality of life in patients with recurrent respiratory papillomatosis in a northern Sweden cohort2014In: Acta Oto-Laryngologica, ISSN 0001-6489, E-ISSN 1651-2251, ISSN 1651-2251 (online), Vol. 134, no 4, p. 401-406Article in journal (Refereed)
    Abstract [en]

    Abstract Conclusion:

    The frequency of operations, age at onset, gender and subtype of the human papilloma virus (HPV) may be used as factors to predict voice disability.

    Objectives:

    Patients with recurrent respiratory papillomatosis (RRP) are characterized by morbid consequences due to a lifelong repetitive influence on voice and breathing ability and the need for recurrent surgical treatments. The aim of the study was to measure the quality of voice and life using evaluated and validated questionnaires in a northern Sweden RRP population.

    Methods:

    A total of 27 consecutive patients with RRP (age 21-71 years, median 47 years) were evaluated 3 months postoperatively (CO2 laser treatment) using the voice handicap index (VHI) and SF-36 questionnaires to assess the impact on life and voice in an RRP population. The values were compared to historical normative data, VHI ≤ 20.

    Results:

    Patients that underwent more than one operation per year were younger (p = 0.028) than those treated less frequently. The mean VHItotal score in patients with RRP was 39.3, indicating a statistically significant impairment of voice quality (p < 0.001) as compared with normal subjects. Voice dysfunction was observed in 21 patients (78%). Significantly lower values than the normal population regarding the quality of life in patients with RRP were obtained in the domain of social functioning (p = 0.029). Females, patients with frequent surgical treatment sessions and patients with the high-risk HPV types scored significantly lower in several domains of the quality of life assessment as compared with normal subjects. The results should be interpreted with caution due to the limited number of subjects.

  • 29.
    Loizou, Christos
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Otorhinolaryngology.
    Laurell, Göran
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Otorhinolaryngology. Department of Surgical Sciences, Division of Otorhinolaryngology, Uppsala University.
    Lindquist, David
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Öfverman, Charlotte
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Stefansson, Kristina
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Nylander, Karin
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Olofsson, Katarina
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Otorhinolaryngology.
    Incidence of tonsillar cancer in northern Sweden: Impact of human papilloma virus2015In: Oncology Letters, ISSN 1792-1074, E-ISSN 1792-1082, Vol. 10, no 6, p. 3565-3572Article in journal (Refereed)
    Abstract [en]

    The incidence rate of tonsillar cancer is increasing worldwide. The current study identifies a parallel increase in the incidence of tonsillar cancer, human papilloma virus (HPV) and p16 expression among a population from northern Sweden, a sparsely populated area, confirming the strong association between p16 and HPV infection in tonsillar tissue. Data from the Swedish Cancer Registry was assessed to identify cases of tonsillar cancer in the northern territorial area of Sweden. HPV DNA was extracted from paraffin embedded diagnostic biopsies and detected by polymerase chain reaction using general primers Gp5+/6+ and CpI/IIG. Expression of p16 was identified by immunochemistry. Patients were grouped into urban or rural residence categories. A total of 214 cases were identified, comprising 155 (72.4%) men and 59 (27.6%) women, and 65 of these patients, who presented between 2000 and 2012, were analyzed. The overall median age for the analyzed patients was 58 years; 48 (74%) were males (median age, 57.5 years) and 17 (26%) were females (median age, 65 years). Of the 65 specimens, 59 (91%) were positive for HPV, and 62 (95%) expressed p16. The incidence of tonsillar cancer in the cohort demonstrated a 2-fold increase between 1990 and 2013; specifically, a 2.7-fold increase was observed in men whilst the female group exhibited only a small increase. These findings demonstrate a strong association between p16 expression and HPV infection in tonsillar malignancies. The incidence of HPV-positive tonsillar cancer has increased in recent years, even in sparsely populated regions, as demonstrated in northern Sweden.

  • 30. Mellin Dahlstrand, Hanna
    et al.
    Lindquist, David
    Karolinska Instituet, Institutionen för Onkologi-Patologi.
    Björnestål, Linda
    Ohlsson, Ann
    Dalianis, Tina
    Munck-Wikland, Eva
    Elmberger, Göran
    P16(INK4a) correlates to human papillomavirus presence, response to radiotherapy and clinical outcome in tonsillar carcinoma.2005In: Anticancer Research, ISSN 0250-7005, E-ISSN 1791-7530, Vol. 25, no 6C, p. 4375-83Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Human papillomavirus (HPV) in tonsillar carcinoma is correlated with favourable clinical outcome. Here, p16(INK4A), in situ HPV DNA hybridisation (ISH) and HPVL1 capsid detection were evaluated in tonsillar carcinoma to predict the response to radiotherapy (RT) and prognosis.

    MATERIALS AND METHODS: Fifty-one pre-treatment paraffin-embedded tonsillar cancer biopsies were analysed. Immunohistochemistry (IHC) was used for p16(INK4A) and HPVL1 capsid analysis and PCR and ISH for HPV detection.

    RESULTS: High-risk HPV DNA was detected by PCR in 49% of the tumours. P16(INK4a) staining was correlated to HPV In the high-grade p16(INK4a) staining group, 94% had a complete RT response. High p16(INK4a) staining as well as the HPV PCR-positive cases had a favourable prognosis. HPV DNA ISH and L1 IHC could not predict RT response or clinical outcome.

    CONCLUSION: P16(INK4a) overexpression was correlated to HPV in tonsillar carcinoma and is useful for predicting RT response and prognosis in tonsillar carcinoma patients.

  • 31. Muller, Susanne
    et al.
    Lindquist, David
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Kanter, Lena
    Flores-Staino, Carmen
    Henriksson, Roger
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Hedman, Håkan
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Andersson, Sonia
    Expression of LRIG1 and LRIG3 correlates with human papillomavirus status and patient survival in cervical adenocarcinoma2013In: International Journal of Oncology, ISSN 1019-6439, Vol. 42, no 1, p. 247-252Article in journal (Refereed)
    Abstract [en]

    The incidence of cervical adenocarcinoma, which accounts for 10-20% of all cervical cancers, has increased continuously in developed countries during the last two decades, unlike squamous cell cervical carcinoma. This increasing trend, noted particularly among women under the age of 40 years, has occurred despite extensive cytological Pap smear screening. A deeper understanding of the etiology of cervical adenocarcinoma, better preventive measures and reliable prognostic markers are urgently needed. The human leucine-rich repeats and immunoglobulin-like domains (LRIG) gene family includes: LRIG1, LRIG2 and LRIG3. LRIG expression has proven to be of prognostic value in different types of human cancers, including breast cancer, early stage invasive squamous cervical cancer, cutaneous squamous cell carcinoma, oligodendroglioma and astrocytoma. LRIG1 functions as a tumor suppressor, while less is known about the functions of LRIG2 and LRIG3. This study evaluated the expression of the three LRIG proteins in tumor specimens from 86 women with pure cervical adenocarcinoma by immunohistochemistry. Possible correlations between LRIG expression and known prognostic factors, including human papillomavirus (HPV) status, FIGO stage and histology were investigated. Patient survival data were collected retrospectively and the possible prognostic value of LRIG protein expression was investigated. High staining intensity of LRIG1 and high fraction of LRIG3-positive cells were significantly associated with patient survival, and positive correlations were found between LRIG1 and LRIG3 staining intensity and HPV status. Thus, the LRIG proteins may be important determinants of cervical adenocarcinoma progression and their diagnostic and prognostic potential should be studied further.

  • 32. Munck-Wikland, Eva
    et al.
    Hammarstedt, Lalle
    Lindquist, David
    Karolinska Instituet, Institutionen för Onkologi-Patologi.
    Romanitan, Mircea
    Dahlstrand, Hanna
    Dalianis, Tina
    [Human papillomavirus important factor in the increased incidence of tonsillar cancer].2006In: Läkartidningen, ISSN 0023-7205, E-ISSN 1652-7518, Vol. 103, no 44, p. 3366-8Article in journal (Refereed)
  • 33. Nasman, A.
    et al.
    Nordfors, C.
    Tertipis, N.
    Grun, N.
    Du, J.
    Ahrlund-Richter, A.
    Haeggblom, L.
    Sivars, L.
    Vlastos, A.
    Lindquist, David
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Nordvall, L. Hammarstedt
    Marklund, L.
    Munck-Wikland, E.
    Ramqvist, T.
    Dalianis, T.
    HUMAN PAPILLOMAVIRUS (HPV) AND OTHER BIOMARKERS FOR PREDICTION OF CLINICAL OUTCOME IN OROPHARYNGEAL SQUAMOUS CELL CARCINOMA (OPSCC)2014In: Anticancer Research, ISSN 0250-7005, E-ISSN 1791-7530, Vol. 34, no 10, p. 5872-5873Article in journal (Other academic)
  • 34. Näsman, Anders
    et al.
    Attner, Per
    Hammarstedt, Lalle
    Du, Juan
    Eriksson, Mathilda
    Giraud, Geraldine
    Ahrlund-Richter, Sofie
    Marklund, Linda
    Romanitan, Mircea
    Lindquist, David
    Karolinska Instituet, Institutionen för Onkologi-Patologi.
    Ramqvist, Torbjörn
    Lindholm, Johan
    Sparén, Pär
    Ye, Weimin
    Dahlstrand, Hanna
    Munck-Wikland, Eva
    Dalianis, Tina
    Incidence of human papillomavirus (HPV) positive tonsillar carcinoma in Stockholm, Sweden: an epidemic of viral-induced carcinoma?2009In: International Journal of Cancer, ISSN 0020-7136, E-ISSN 1097-0215, Vol. 125, no 2, p. 362-6Article in journal (Refereed)
    Abstract [en]

    In the county of Stockholm, between 1970 and 2002, we have previously reported a 3-fold parallel increase in the incidence of tonsillar squamous cell carcinoma (SCC) and the proportion of human papillomavirus (HPV) positive tonsillar SCC. Here, we have followed the above parameters in all patients (n = 120) diagnosed with tonsillar SCC during 2003-2007 in the same area, and also in correlation to our previous data. Ninety-eight pretreatment biopsies were available and presence of HPV DNA and HPV-16 E6 and E7 RNA were tested by polymerase chain reaction (PCR) and RT-PCR. Incidence data were obtained from the Swedish Cancer Registry. Data reported from 1970 to 2002 were also obtained for comparison. HPV DNA was present in 83 of 98 (85%) of the tonsillar SCC biopsies from 2003 to 2007 and 77 of these were HPV-16 positive. HPV-16 E6 and E7 RNA were found in 98% of 52 analyzed HPV-16 positive cases. The proportion of HPV-positive cancers had significantly increased both from 1970 to 2007 (p < 0.0001) as well from 2000 to 2007 (p < 0.01), with 68% (95% confidence interval (CI), 53-81) 2000-2002; 77% (95% CI, 63-87) 2003-2005; and 93% (95% CI, 82-99) 2006-2007. The incidence rate of HPV-positive tumors almost doubled each decade between 1970 and 2007, in parallel with a decline of HPV-negative tumors. In conclusion, the incidence of HPV-positive cancers is still increasing in the County of Stockholm, suggesting an epidemic of a virus-induced carcinoma, with soon practically all tonsillar SCC being HPV positive, as in cervical cancer.

  • 35. Näsman, Anders
    et al.
    Bersani, Cinzia
    Lindquist, David
    Umeå University, Faculty of Medicine, Department of Radiation Sciences.
    Du, Juan
    Ramqvist, Torbjörn
    Dalianis, Tina
    Human Papillomavirus and Potentially Relevant Biomarkers in Tonsillar and Base of Tongue Squamous Cell Carcinoma2017In: Anticancer Research, ISSN 0250-7005, E-ISSN 1791-7530, Vol. 37, no 10, p. 5319-5328Article, review/survey (Refereed)
    Abstract [en]

    Human papillomavirus (HPV)-positive tonsillar- and base of tongue cancer is increasing epidemically and has much better outcome than corresponding HPV-negative cancer and most other head and neck cancers with around 80% 3-year disease free survival with conventional radiotherapy and surgery. Consequently, most HPV-positive cancer patients may not require the intensified chemoradiotherapy given to many head and neck cancer patients and would, with tapered treatment, avoid several severe side-effects. Moreover, intensified therapy has not improved survival and treatment alternatives are needed. To identify patients eligible for tapered or targeted therapy, additional biomarkers are required. Several studies have, therefore, focused on finding predictive markers, some of which are also potentially targetable. To conclude, better-tailored therapy, either as tapered or targeted, is important for increasing numbers of patients with HPV-positive tonsillar- and base of tongue cancer. This review deals with some of these issues and presents some promising markers.

  • 36.
    Näsman, Anders
    et al.
    Karolinska Institutet.
    Nordfors, Cecilia
    Karolinska Institutet.
    Grün, Nathalie
    Karolinska Institutet.
    Munck-Wikland, Eva
    Karolinska Institutet.
    Ramqvist, Torbjörn
    Karolinska Institutet.
    Marklund, Linda
    Karolinska Institutet.
    Lindquist, David
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Dalianis, Tina
    Karolinska Institutet.
    Absent/weak CD44 intensity and positive human papillomavirus (HPV) status in oropharyngeal squamous cell carcinoma indicates a very high survival2013In: Cancer Medicine, ISSN 2045-7634, E-ISSN 2045-7634, Vol. 2, no 4, p. 507-18Article in journal (Refereed)
    Abstract [en]

    Patients with human papillomavirus DNA positive (HPVDNA+) oropharyngeal squamous cell carcinoma (OSCC) have better clinical outcome than those with HPV DNA negative (HPVDNA-) OSCC upon intensive oncological treatment. All HPVDNA+ OSCC patients may not require intensive treatment, however, but before potentially deintensifying treatment, additional predictive markers are needed. Here, we examined HPV, p16(INK4a), and CD44 in OSCC in correlation to clinical outcome. Pretreatment tumors from 290 OSCC patients, the majority not receiving chemotherapy, were analyzed for HPV DNA by Luminex and for p16(INK4a) and CD44 by immunohistochemistry. 225/290 (78%) tumors were HPVDNA+ and 211/290 (73%) overexpressed p16(INK4a), which correlated to presence of HPV (P < 0.0001). Presence of HPV DNA, absent/weak CD44 intensity staining correlated to favorable 3-year disease-free survival (DFS) and overall survival (OS) by univariate and multivariate analysis, and likewise for p16(INK4a) by univariate analysis. Upon stratification for HPV, HPVDNA+ OSCC with absent/weak CD44 intensity presented the significantly best 3-year DFS and OS, with >95% 3-year DFS and OS. Furthermore, in HPVDNA+ OSCC, p16(INK4a)+ overexpression correlated to a favorable 3-year OS. In conclusion, patients with HPVDNA+ and absent/weak CD44 intensity OSCC presented the best survival and this marker combination could possibly be used for selecting patients for tailored deintensified treatment in prospective clinical trials. Absence of/weak CD44 or presence of human papillomavirus (HPV) DNA was shown as a favorable prognostic factors in tonsillar and tongue base cancer. Moreover, patients with the combination of absence of/weak CD44 and presence of HPV DNA presented a very favorable outcome. Therefore, we suggest that this marker combination could potentially be used to single out patients with a high survival that could benefit from a de-escalated oncological treatment.

  • 37.
    Ofverman, Charlotte
    et al.
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Stefansson, Kristina
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Ottander, Ulrika
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynecology.
    Lindquist, David
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    CASE SERIES OF PATIENTS WITH LEIOMYOSARCOMA OF THE UTERUS TREATED WITH TRABECTEDIN IN NORTHERN SWEDEN2016In: International Journal of Gynecological Cancer, ISSN 1048-891X, E-ISSN 1525-1438, Vol. 26, no Supplement 3, p. 1046-1046, article id IGCS-0142Article in journal (Refereed)
  • 38. Ranhem, Cecilia
    et al.
    Larsson, Gabriella Lillsunde
    Hedman, Håkan
    Umeå University, Faculty of Medicine, Department of Radiation Sciences.
    Lindquist, David
    Umeå University, Faculty of Medicine, Department of Radiation Sciences.
    Karlsson, Mats G.
    Hellstrom, Ann-Cathrin
    Ostensson, Ellinor
    Sorbe, Bengt
    Hellman, Kristina
    Andersson, Sonia
    Expression of LRIG proteins as possible prognostic factors in primary vaginal carcinoma2017In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 12, no 8, article id e0183816Article in journal (Refereed)
    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.

  • 39. Roura, Esther
    et al.
    Castellsagué, Xavier
    Pawlita, Michael
    Travier, Noémie
    Waterboer, Tim
    Margall, Núria
    Bosch, F Xavier
    de Sanjosé, Silvia
    Dillner, Joakim
    Gram, Inger T
    Tjønneland, Anne
    Munk, Christian
    Pala, Valeria
    Palli, Domenico
    Khaw, Kay-Tee
    Barnabas, Ruanne V
    Overvad, Kim
    Clavel-Chapelon, Françoise
    Boutron-Ruault, Marie-Christine
    Fagherazzi, Guy
    Kaaks, Rudolf
    Lukanova, Annekatrin
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Steffen, Annika
    Trichopoulou, Antonia
    Trichopoulos, Dimitrios
    Klinaki, Eleni
    Tumino, Rosario
    Sacerdote, Carlotta
    Panico, Salvatore
    Bueno-de-Mesquita, H Bas
    Peeters, Petra H
    Lund, Eiliv
    Weiderpass, Elisabete
    Redondo, M Luisa
    Sánchez, María-José
    Tormo, Maria-José
    Barricarte, Aurelio
    Larrañaga, Nerea
    Ekström, Johanna
    Hortlund, Maria
    Lindquist, David
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Wareham, Nick
    Travis, Ruth C
    Rinaldi, Sabina
    Tommasino, Massimo
    Franceschi, Silvia
    Riboli, Elio
    Smoking as a major risk factor for cervical cancer and pre-cancer: results from the EPIC cohort2014In: International Journal of Cancer, ISSN 0020-7136, E-ISSN 1097-0215, Vol. 135, no 2, p. 453-466Article in journal (Refereed)
    Abstract [en]

    A total of 308,036 women were selected from the European Prospective Investigation into Cancer and Nutrition (EPIC) to evaluate the association between tobacco smoking and the risk of cervical intraepithelial neoplasia grade 3 (CIN3)/carcinoma in situ (CIS) and invasive cervical cancer (ICC). At baseline, participants completed a questionnaire and provided blood samples. During a mean follow-up time of 9 years, 261 ICC cases and 804 CIN3/CIS cases were reported. In a nested case-control study, the baseline sera from 609 cases and 1,218 matched controls were tested for L1 antibodies against HPV types 11,16,18,31,33,35,45,52,58, and antibodies against Chlamydia trachomatis (CT), and Human Herpes Virus 2 (HHV-2). Cervical samples were not available for HPV-DNA analysis in this study. Multivariate analyses were used to estimate associations between smoking and risk of CIN3/CIS and ICC in the cohort and the case-control studies. In the cohort analyses smoking status, duration and intensity showed a 2-fold increased risk of CIN3/CIS and ICC, while time since quitting was associated with a 2-fold reduced risk. In the nested case-control study, consistent associations were observed after adjustment for HPV, CT and HHV-2 serostatus, in both HPV seronegative and seropositive women. Results from this large prospective study confirm the role of tobacco smoking as an important risk factor for both CIN3/CIS and ICC, even after taking into account HPV exposure as determined by HPV serology. The strong beneficial effect of quitting smoking is an important finding that will further support public health policies for smoking cessation.

  • 40. Roura, Esther
    et al.
    Travier, Noémie
    Waterboer, Tim
    de Sanjosé, Silvia
    Bosch, F Xavier
    Pawlita, Michael
    Pala, Valeria
    Weiderpass, Elisabete
    Margall, Núria
    Dillner, Joakim
    Gram, Inger T
    Tjønneland, Anne
    Munk, Christian
    Palli, Domenico
    Khaw, Kay-Tee
    Overvad, Kim
    Clavel-Chapelon, Françoise
    Mesrine, Sylvie
    Fournier, Agnès
    Fortner, Renée T
    Ose, Jennifer
    Steffen, Annika
    Trichopoulou, Antonia
    Lagiou, Pagona
    Orfanos, Philippos
    Masala, Giovanna
    Tumino, Rosario
    Sacerdote, Carlotta
    Polidoro, Silvia
    Mattiello, Amalia
    Lund, Eiliv
    Peeters, Petra H
    Bueno-de-Mesquita, H B(as)
    Quirós, J Ramón
    Sánchez, María-José
    Navarro, Carmen
    Barricarte, Aurelio
    Larrañaga, Nerea
    Ekström, Johanna
    Lindquist, David
    Umeå University, Faculty of Medicine, Department of Radiation Sciences.
    Idahl, Annika
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology.
    Travis, Ruth C
    Merritt, Melissa A
    Gunter, Marc J
    Rinaldi, Sabina
    Tommasino, Massimo
    Franceschi, Silvia
    Riboli, Elio
    Castellsagué, Xavier
    The Influence of Hormonal Factors on the Risk of Developing Cervical Cancer and Pre-Cancer: Results from the EPIC Cohort2016In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 11, no 1, article id e0147029Article in journal (Refereed)
    Abstract [en]

    Background: In addition to HPV, high parity and hormonal contraceptives have been associated with cervical cancer (CC). However, most of the evidence comes from retrospective case-control studies. The aim of this study is to prospectively evaluate associations between hormonal factors and risk of developing cervical intraepithelial neoplasia grade 3 (CIN3)/carcinoma in situ (CIS) and invasive cervical cancer (ICC). Methods and Findings: We followed a cohort of 308,036 women recruited in the European Prospective Investigation into Cancer and Nutrition (EPIC) Study. At enrollment, participants completed a questionnaire and provided serum. After a 9-year median follow-up, 261 ICC and 804 CIN3/CIS cases were reported. In a nested case-control study, the sera from 609 cases and 1,218 matched controls were tested for L1 antibodies against HPV types 11,16,18,31,33,35,45, 52,58, and antibodies against Chlamydia trachomatis and Human herpesvirus 2. Multivariate analyses were performed to estimate hazard ratios (HR), odds ratios (OR) and corresponding 95% confidence intervals (CI). The cohort analysis showed that number of fullterm pregnancies was positively associated with CIN3/CIS risk (p-trend = 0.03). Duration of oral contraceptives use was associated with a significantly increased risk of both CIN3/CIS and ICC (HR = 1.6 and HR = 1.8 respectively for >= 15 years versus never use). Ever use of menopausal hormone therapy was associated with a reduced risk of ICC (HR = 0.5, 95% CI: 0.4-0.8). A non-significant reduced risk of ICC with ever use of intrauterine devices (IUD) was found in the nested case-control analysis (OR = 0.6). Analyses restricted to all cases and HPV seropositive controls yielded similar results, revealing a significant inverse association with IUD for combined CIN3/CIS and ICC (OR = 0.7). Conclusions: Even though HPV is the necessary cause of CC, our results suggest that several hormonal factors are risk factors for cervical carcinogenesis. Adherence to current cervical cancer screening guidelines should minimize the increased risk of CC associated with these hormonal risk factors.

  • 41.
    Stefansson, Kristina
    et al.
    Umeå University, Faculty of Medicine, Department of Radiation Sciences.
    Oda, Husam
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Öfverman, Charlotte
    Umeå University, Faculty of Medicine, Department of Radiation Sciences.
    Lundin, Eva
    Umeå University, Faculty of Medicine, Department of Medical Biosciences.
    Hedman, Håkan
    Umeå University, Faculty of Medicine, Department of Radiation Sciences.
    Lindquist, David
    Umeå University, Faculty of Medicine, Department of Radiation Sciences.
    LRIG protein expression and HPV prevalence in vulvar cancer patients in northern Sweden2015In: International Journal of Gynecological Cancer, ISSN 1048-891X, E-ISSN 1525-1438, Vol. 25, no 9, p. 684-684Article in journal (Other academic)
  • 42.
    Stefansson, Kristina
    et al.
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Oda, Husam
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Öfverman, Charlotte
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Lundin, Eva
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Hedman, Håkan
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Lindquist, David
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    LRIG1‑2 and LMO7 immunoreactivity in vulvar squamous cell carcinoma: association with prognosis in relation to HPV‑DNA and p16INK4a status2019In: Oncology Reports, ISSN 1021-335X, E-ISSN 1791-2431, Vol. 42, no 1, p. 142-150Article in journal (Refereed)
    Abstract [en]

    The present study was conducted to investigate the possible prognostic value of molecular markers LRIG1‑2 and LIM domain 7 protein (LMO7) in vulvar squamous cell carcinoma (VSCC) and their possible correlation to human papilloma virus (HPV)‑ and p16INK4a‑status of the tumors. Patients diagnosed with VSCC at the University Hospital of Umeå, Sweden, during the years 1990‑2013 were selected. Tumor blocks were retrieved from tissue archives and clinical data were collected from the records of patients. HPV‑PCR analysis, HPV genotyping and immunohistochemistry were performed. In total, 112 patients were included. Forty percent of the tumors were HPV‑positive, 27% were p16INK4a‑positive and 23% were positive for both HPV and p16INK4a (considered HPV‑driven). HPV‑positivity and p16INK4a‑positivity were associated with prolonged disease‑free survival (DFS) in Kaplan‑Meier survival analysis. Leucine‑rich repeats and immunoglobulin‑like domains 1 (LRIG1) immunoreactivity was not significantly associated with survival. High leucine‑rich repeats and immunoglobulin‑like domains 2 (LRIG2) immunoreactivity was associated with a prolonged overall survival (OS) (P=0.001). By analyzing HPV‑negative cases only, it was determined that high LRIG2 immunoreactivity was associated with both favorable OS (P=0.008) and DFS (P=0.031). LRIG2 immunoreactivity was also an independent prognostic factor in multivariate analysis of OS (P=0.002, HR=0.41; 95% CI, 0.24‑0.71). High immunoreactivity with LMO7‑1250 antibody was associated with survival benefits in the whole cohort (OS; P=0.011) although DFS was only prolonged in HPV‑negative and not HPV‑driven tumors (P=0.038 and 0.042, respectively). The present study indicated that LRIG2 and LMO7 may be useful prognostic markers in VSCC, particularly for patients without HPV‑driven tumors or with advanced tumors at diagnosis. In contrast to earlier observations regarding other types of squamous cell carcinoma, LRIG1 was not a significant prognostic factor in VSCC.

  • 43. Sukhin, V. S.
    et al.
    Danyliuk, S. V.
    Sukhina, O. M.
    Sadniprjaniy, O. V.
    Lindquist, David
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Hermelin, H.
    Tarján, M.
    Expression of mmp-9 as a prognostic factor of uterine sarcoma2018In: Reports of morphology, ISSN 1818-1295, Vol. 24, no 1, p. 21-27Article in journal (Refereed)
    Abstract [en]

    Uterine sarcoma is a highly aggressive mesenchymal neoplasm with an extremely unfavorable prognosis. Up today there are still relevant issues concerning search for clinical-morphological and biomolecular criteria for prognosis relapse-free survival of uterine sarcoma patients. It is well-known, the increase of the expression level of MMP-9 in primary tumor or metastatic foci correlates with a low differentiation of tumor cells, high ability for invasiveness, high metastatic activity, and shortened life expectancy. It’s still unknown, whether it is possible to consider the expression of MMP-9 in uterine sarcoma cells as a convincing prognostic factor. For many types of epithelial malignant neoplasms, high metastatic rate is associated with an increase level of MMP-9 both in plasma and in tumor tissue. The purpose of this study is to investigate the features of MMP-9 expression in uterine sarcoma cells for development of the model for individual prediction of the disease course. The study of the surgical material of selected 54 cases of uterine sarcoma of stage I-II (according to FIGO criteria) with a known prognosis of the disease, which were distributed depending on the morphological type done: leiomyosarcoma (LMS) – 18 cases, endometrial stromal sarcoma (ESS) - 22 cases, undifferentiated sarcoma (US) – 14 (according to the classification of tumors of the uterus of the WHO). For histological examination, pieces of tissue were cut from different parts of the tumor nodes – central, peripheral, parts of the adjacent intact tissue of myometrium (total of 6-8 bits). The tumor cell phenotype was determined using low molecular weight cytokeratins (Cytokeratin PAN, AE1 / AE3), smooth muscle actin (Smooth Muscle Actin, 1A4), myogenin (Myogenin (F5D)), CD 10 and vimentin (Vimentin, V9). The histochemical label was evaluated in two parameters: the degree of prevalence and intensity of coloration. To assess the color intensity, a qualitative scale was used: 0 – no reaction, 1+ – weak cytoplasmic coloration to 30.0% of tumor cells, 2+ – moderate reaction, 30.0 to 60.0% of stained cells, 3+ – pronounced cytoplasmic reaction in 60,0-100,0% of tumor cells. Statistical processing of the data was performed using the “STATISTICA 10.0” program package. The conducted study has showed, the negative (0) and weak (1+) expression of matrix metalloproteinase-9 were observed in the most part of ESS and only partially in US. Despite the stage of the disease, with such a status of MMP-9, there was observed no signs of relapsed disease. The moderate (2+) and high (3+) expression of MMP-9 was detected in 44.5 % of uterine sarcoma, in the most part in LMS patients. However, if in LMS cases the progressive disease was observed only in one third of them (4 of 12 cases), in case of ESS and US, in all the patients with such tumors status there was observed relapsed disease. Such a reaction may be indicative for invasive and metastatic potential of ESS and US and cause of the hematogenous metastases.

  • 44. Sukhin, V. S.
    et al.
    Danyliuk, S. V.
    Sukhina, O. N.
    Zadnepryanniy, A. V.
    Lindquist, David
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Hermelin, H.
    Tarján, M.
    The investigation of PD-L1 expression as a prognostic marker for uterine sarcoma2018In: Морфологія, ISSN 1997-9665, Vol. 12, no 2, p. 62-71Article in journal (Refereed)
    Abstract [en]

    Background: The uterine sarcoma is a rare tumor with the unpredictable, aggressive clinical behavior. Medical science relies on the development of reliable tumor markers, on the basis of which the optimal treatment program can be chosen, and will be also possible to make a prognosis. The hyperexpression of PD-L1 in many cases correlates with unfavorable prognosis of the disease and is an important prognostic biomarker for some types of tumors: melanoma, kidney cancer, non-small cell lung cancer. The role of PD-L1 expression, as a tumor marker in sarcoma, remains unclear. Objective. The investigation of PD-L1 expression as a prognostic tumor marker for uterine sarcoma.

    Methods: There have been selected 30 uterine sarcoma patients stage I-II (T1-2NxM0), for immunohistochemistry analyze of PD-L1 expression. Depending on the morphological tumor types all the patients were distributed: leiomyosarcoma (LMS) - 20.0%, endometrial stromal sarcoma (ESS) - 46.7%, undifferentiated sarcoma (HC) - 33.3%.

    Results: Our results showed that 73.3 % of patients with uterine sarcoma exhibited low expression level of PD-L1. The moderate level and overexpression of PD-L1 were observed in undifferentiated and endometrial stromal sarcoma - 13.3 and 6.7 %, respectively. At further follow-up of patients with PD-L1 expression, the relapse of the disease was detected in 50.0 % of cases.

    Conclusion: The PD-L1 expression in tumor tissue, regardless of its level, is considered to be an unfavorable prognostic factor for uterine sarcoma patients. In case of moderate expression level of PD-L1, so as at its overexpression, the tumor progression was detected in 83.3% of uterine sarcoma patients.

  • 45. Tot, Tibor
    et al.
    Gere, Mária
    Pekár, Gyula
    Tarján, Miklós
    Hofmeyer, Syster
    Hellberg, Dan
    Lindquist, David
    Central Hospital Falun, Department of Pathology and Clinical Cytology, Falun.
    Chen, Tony Hsiu-His
    Yen, Amy Ming-Fang
    Chiu, Sherry Yueh-Hsia
    Tabár, László
    Breast cancer multifocality, disease extent, and survival2011In: Human Pathology, ISSN 0046-8177, E-ISSN 1532-8392, Vol. 42, no 11, p. 1761-1769Article in journal (Refereed)
    Abstract [en]

    The prognostic information implied in subgross morphologic parameters such as lesion distribution (unifocal, multifocal, or diffuse) and disease extent in breast cancer has remained largely unexplored in the literature. We aimed to test whether these parameters influence survival in breast carcinoma. The parameters were assessed in a series of 574 cases, all documented in large-format histology sections. We used Cox proportional hazards regression accompanied by Kaplan-Meyer survival curves, with P < .05 regarded as significant. The invasive component was unifocal in 62% (311/499), multifocal in 24% (122/499), and diffuse in 5% (26/499) of the cases. Combining the in situ and invasive tumor components resulted in 48% (274/574) unifocal, 25% (141/574) multifocal, and 20% (117/574) diffuse tumors. Sixty percent (347/574) of the tumors were categorized as having limited extent (occupying an area <40 mm in largest dimension) and 29% (164/574) as extensive. Highly significant (P < .0001) differences were observed in 10-year disease-specific cumulative survival among the cases with unifocal, multifocal, and diffuse invasive (89.6%, 76.0%, and 63.6%, respectively) and combined (92.3%, 82.3%, and 75.7%, respectively) lesion distribution. Patients with extensive tumors exhibited a significantly lower cumulative survival (P < .0001) compared with those with limited extent (91.6% and 75.5%) and a statistically significantly 1.89-fold (95% confidence interval, 1.07-3.37; P = .03) risk for breast cancer death after controlling for tumor attributes, type of surgery, and adjuvant therapy. The hazard ratio for breast cancer death for mutifocal and/or diffuse tumors versus unifocal ones was 1.96 (95%; 1.11-3.48; P = .02) after controlling for the same factors. Lesion distribution and disease extent represent important independent survival-related prognostic parameters in breast carcinoma.

  • 46. Tot, Tibor
    et al.
    Pekár, Gyula
    Hofmeyer, Syster
    Gere, Maria
    Tarján, Miklós
    Hellberg, Dan
    Lindquist, David
    Department of Pathology and Clinical Cytology, Central Hospital Falun, Falun.
    Molecular phenotypes of unifocal, multifocal, and diffuse invasive breast carcinomas.2011In: Pathology research international, ISSN 2042-003X, Vol. 2011, p. 480960-Article in journal (Refereed)
    Abstract [en]

    We analyzed the subgross distribution of the invasive component in 875 consecutive cases of breast carcinomas using large-format histology sections and compared the immunophenotype (estrogen and progesterone receptor expression, HER2 overexpression and expression of basal-like markers, CK5/6, CK14, and epidermal growth factor receptor) in unifocal, multifocal, and diffuse tumors. Histology grade and lymph node status were also analyzed. Unifocal invasive carcinomas comprised 58.6% (513/875), multifocal invasive carcinomas 36.5% (319/875), and diffuse invasive carcinomas 4.9% (43/875) of the cases. The proportion of lymph node-positive cases was significantly higher in multifocal and diffuse carcinomas compared to unifocal cancers, but no other statistically significant differences could be verified between these tumor categories. Histological multifocality and diffuse distribution of the invasive tumor component seem to be negative morphologic prognostic parameters in breast carcinomas, independent of the molecular phenotype.

  • 47. Zalewski, K.
    et al.
    Lindemann, K.
    Halaska, M.
    Zapardiel, I.
    Laky, R.
    Chereau, E.
    Lindquist, David
    Umeå University, Faculty of Medicine, Department of Radiation Sciences.
    Polterauer, S.
    Suhin, V.
    Dursun, P.
    A CALL FOR NEW COMMUNICATION CHANNELS FOR EUROPEAN GYNAECOLOGICAL ONCOLOGY TRAINEES: A SURVEY AMONG MEMBERS OF THE EUROPEAN NETWORK OF YOUNG GYNAECOLOGICAL ONCOLOGISTS2016In: International Journal of Gynecological Cancer, ISSN 1048-891X, E-ISSN 1525-1438, Vol. 26, p. 598-599Article in journal (Refereed)
  • 48. Zalewski, Kamil
    et al.
    Lindemann, Kristina
    Halaska, Michael J
    Zapardiel, Ignacio
    Laky, Rene
    Chereau, Elisabeth
    Lindquist, David
    Umeå University, Faculty of Medicine, Department of Radiation Sciences.
    Polterauer, Stephan
    Sukhin, Vladislav
    Dursun, Polat
    A call for new communication channels for gynecological oncology trainees: a survey on social media use and educational needs by the European network of young gynecological oncologists2017In: International Journal of Gynecological Cancer, ISSN 1048-891X, E-ISSN 1525-1438, Vol. 27, no 3, p. 620-626Article in journal (Refereed)
    Abstract [en]

    OBJECTIVE: The aim of the study was to assess patterns in the use of social media (SM) platforms and to identify the training needs among European gynecologic oncology trainees.

    METHODS: In 2014, a web-based survey was sent to 633 trainees from the European Network of Young Gynaecological Oncologists (ENYGO) database. The 14-item questionnaire (partially using a 1- to 5-point Likert scale) assessed respondents' use of SM and preference for workshop content and organization. Descriptive analysis was used to describe the mean scores reported for different items, and the internal reliability of the questionnaire was assessed by Cronbach α.

    RESULTS: In total, 170 ENYGO members (27%) responded to the survey. Of those, 91% said that they use SM platforms, mostly for private purposes. Twenty-three percent used SM professionally and 43% indicated that they would consider SM to be a clinical discussion forum. The respondents said that they would like updates on conferences and professional activities to be shared on SM platforms. Complication management, surgical anatomy, and state of the art in gynecologic oncology were identified as preferred workshops topics. The most frequently indicated hands-on workshops were laparoscopic techniques and surgical anatomy. Consultants attached a higher level of importance to palliative care education and communication training than trainees. The mean duration of the workshop preferred was 2 days.

    CONCLUSIONS: This report highlights the significance of ENYGO trainees' attachment to SM platforms. Most respondents expect ENYGO to use these online channels for promoting educational activities and other updates. Using SM for clinical discussion will require specific guidelines to secure professional and also consumer integrity. This survey confirms surgical management and the state of the art as important knowledge gaps, and ENYGO has tailored its activities according to these results. Future activities will further direct attention and resources to education in palliative care and molecular tumor biology.

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