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  • 1. Berggrund, Malin
    et al.
    Enroth, Stefan
    Lundberg, Martin
    Assarsson, Erika
    Stålberg, Karin
    Lindquist, David
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    Hallmans, Göran
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Näringsforskning.
    Grankvist, Kjell
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Klinisk kemi.
    Olovsson, Matts
    Gyllensten, Ulf
    Identification of candidate plasma protein biomarkers for cervical cancer using the multiplex proximity extension assay2019Ingår i: Molecular & Cellular Proteomics, ISSN 1535-9476, E-ISSN 1535-9484, Vol. 18, nr 4, s. 735-743, artikel-id RA118.001208Artikel i tidskrift (Refereegranskat)
    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 universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    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 universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    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 cohort2014Ingår i: International Journal of Cancer, ISSN 0020-7136, E-ISSN 1097-0215, Vol. 135, nr 2, s. 440-452Artikel i tidskrift (Refereegranskat)
    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 universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    Idahl, Annika
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk vetenskap, Obstetrik och gynekologi.
    Gyllensten, Ulf
    A variant upstream of HLA-DRB1 and multiple variants in MICA influence susceptibility to cervical cancer in a Swedish population2014Ingår i: Cancer Medicine, E-ISSN 2045-7634, Vol. 3, nr 1, s. 190-198Artikel i tidskrift (Refereegranskat)
    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.

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  • 4. Cui, Tao
    et al.
    Enroth, Stefan
    Ameur, Adam
    Gustavsson, Inger
    Lindquist, David
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    Gyllensten, Ulf
    Invasive cervical tumors with high and low HPV titer represent molecular subgroups with different disease etiology2019Ingår i: Carcinogenesis, ISSN 0143-3334, E-ISSN 1460-2180, Vol. 40, nr 2, s. 269-278Artikel i tidskrift (Refereegranskat)
    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.2004Ingår i: International Journal of Cancer, ISSN 0020-7136, E-ISSN 1097-0215, Vol. 112, nr 6, s. 1015-9Artikel i tidskrift (Refereegranskat)
    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.2006Ingår i: Anticancer Research, ISSN 0250-7005, E-ISSN 1791-7530, Vol. 26, nr 2A, s. 829-32Artikel i tidskrift (Refereegranskat)
    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.2004Ingår i: Anticancer Research, ISSN 0250-7005, E-ISSN 1791-7530, Vol. 24, nr 3b, s. 1829-35Artikel i tidskrift (Refereegranskat)
    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.2008Ingår i: Anticancer Research, ISSN 0250-7005, E-ISSN 1791-7530, Vol. 28, nr 2B, s. 1133-8Artikel i tidskrift (Refereegranskat)
    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.
    Danielsson, Johanna
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk vetenskap, Professionell utveckling.
    Hadding, Cecilia
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk vetenskap, Professionell utveckling.
    Martin, Fahlström
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk vetenskap, Professionell utveckling.
    Ottander, Ulrika
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk vetenskap, Obstetrik och gynekologi.
    Lindquist, David
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk vetenskap, Professionell utveckling.
    Medical students’ experiences in learning to perform pelvic examinations: a mixed-methods study2021Ingår i: International Journal of Medical Education, E-ISSN 2042-6372, Vol. 12, s. 233-242Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Objectives: We aimed to explore learning experiences among medical students learning to perform pelvic examinations and to identify factors that facilitate their training.

    Methods: A mixed-methods study including a web-based survey and focus group discussions (FGDs) was conducted among medical students who had completed their obstetrics and gynaecology (ObGyn) clerkship. The FGDs were recorded, transcribed and analysed using qualitative content analysis with systematic text condensation. Survey factors were compared using the χ2 test or Fisher's exact test.

    Results: 160 students (97 female, 61 male, two other) at six universities in Sweden responded to the survey. Two mixed FGDs were conducted. The majority (87%) of the students experienced confidence in performing pelvic examinations, stating that sufficient, repeated training opportunities and support from a clinical tutor were crucial components of the learning experience. Prior to the ObGyn clerkship, negative expectations were more common among male students. The male participants experienced having a disadvantage because of their gender, while female students considered their gender an advantage (p<0.001, N=121, Fisher's Exact Test). The clinical tutor and the use of professional patients (PPs) had a fundamental role in providing learning opportunities by including the student in patient care activities.

    Conclusions: The importance of the clinical tutor, as well as the use of PPs, are important factors when planning education in pelvic examinations, and this knowledge could be used when educating other intimate examinations during medical school. In addition, similar investigations on students' experience in training other intimate examinations could be considered.

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  • 10.
    Green, Caroline
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk vetenskap, Professionell utveckling.
    Mettävainio, Martin Isaksson
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Kjellman, Christina
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk vetenskap, Professionell utveckling.
    Ramqvist, Torbjörn
    Department of Oncology‑Pathology, Karolinska Institute, Stockholm, Sweden.
    Dalianis, Tina
    Department of Oncology‑Pathology, Karolinska Institute, Stockholm, Sweden.
    Israelsson, Pernilla
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    Lindquist, David
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk vetenskap, Professionell utveckling.
    Combined treatment with radiotherapy, chemotherapy and avelumab results in regression of metastatic Merkel cell carcinoma and improvement of associated Lambert‑Eaton myasthenic syndrome: a case report2022Ingår i: Oncology Letters, ISSN 1792-1074, E-ISSN 1792-1082, Vol. 24, nr 5, artikel-id 393Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Merkel cell carcinoma (MCC) is a rare and highly aggressive neuroendocrine malignancy arising from mecha‑ noreceptors in the basal epidermis. Due to a pronounced risk of spread and a high propensity for recurrence after treatment, immediate treatment is of utmost importance. Lambert‑Eaton myasthenic syndrome (LEMS) is a paraneoplastic phenom‑ enon affecting the muscles with autoimmune pathophysiology, and >50% of known cases are associated with an underlying malignancy. In the present report, the case of a 67‑year‑old man presenting with progressive proximal muscle weakness, auto‑ nomic dysfunction and involuntary weight loss is described. Symptoms and detection of voltage‑gated calcium channel antibodies were consistent with LEMS. Distant metastases were found in the inguinal and iliac lymph nodes, and these were immunohistochemically confirmed to be of epithelial and neuroendocrine origin, consistent with MCC. Local radio‑ therapy and chemotherapy improved the symptoms; however, a change of treatment was required due to the side effects of the chemotherapy. Avelumab, an immune checkpoint inhibitor, was therefore introduced, and within a year the patient did not only experience tumor remission but also exhibited marked improvements in muscle strength and mobility. At present, 2 years later, the MCC is still in remission. To the best of our knowledge, the present report is the first to describe MCC with associated LEMS, which was successfully treated with avelumab after previous radiotherapy and chemotherapy, with both improved functional motor recovery and tumor reduc‑ tion. In conclusion, the present case report demonstrated that the present treatment strategy is a potential treatment option and could thus be considered in similar cases.

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  • 11. 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.2007Ingår i: Acta Oto-Laryngologica, ISSN 0001-6489, E-ISSN 1651-2251, Vol. 127, nr 9, s. 988-92Artikel i tidskrift (Refereegranskat)
    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.

  • 12.
    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.2006Ingår i: International Journal of Cancer, ISSN 0020-7136, E-ISSN 1097-0215, Vol. 119, nr 11, s. 2620-2623Artikel i tidskrift (Refereegranskat)
    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.

  • 13. Hellman, K
    et al.
    Lindquist, David
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi. 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 vagina2014Ingår i: British Journal of Cancer, ISSN 0007-0920, E-ISSN 1532-1827, Vol. 110, nr 6, s. 1561-1570Artikel i tidskrift (Refereegranskat)
    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.

  • 14.
    Israelsson, Pernilla
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper.
    Oda, Husam
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Öfverman, Charlotte
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper.
    Stefansson, Kristina
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Klinisk kemi.
    Lindquist, David
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk vetenskap.
    High LMO-7 expression is a positive prognostic factor in oropharyngeal squamous cell carcinomaManuskript (preprint) (Övrigt vetenskapligt)
  • 15. Kacperczyk-Bartnik, J.
    et al.
    Nowosielski, K.
    Lindquist, David
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    Lanner, M.
    Nikolova, T.
    Vlachos, D.
    Selcuk, I.
    Pletnev, A.
    Zalewski, K.
    Attitudes towards sexual counselling of patients with gynaecological malignancies: preliminary results of the survey examining enygo members perspective2019Ingår i: International Journal of Gynecological Cancer, ISSN 1048-891X, E-ISSN 1525-1438, Vol. 29, s. A174-A174Artikel i tidskrift (Övrigt vetenskapligt)
    Abstract [en]

    Introduction/Background Both the location of primary disease and treatment side effects may have an impact on sexual function in the population of oncogynaecological patients. Sexual health is a major compound of the quality of life, yet due to its intimate nature tends to be underserved in the routine medical care. The aim of the study was to examine prevalence, strategies, barriers and ideas for improvement of sexual counselling among specialists managing patients with gynaecological malignancies.

    Methodology A self-prepared questionnaire concerning sexual counselling in gynaecological oncology practice (attitudes, behaviours, confronted difficulties and ideas for possible systemic improvements) was used in this cross-sectional study. Paper and online versions were distributed among participants of ESGO-ENYGO-ESO Masterclass. Link to the questionnaire was also shared among ENYGO members via the mailing system, ESGO social media channels, and ENYGO National Representatives. Ongoing data collection was initiated in June 2019. A total number of 99 answers from 39 countries were obtained.

    Results Collecting information concerning sexual function of the majority of managed patients was reported by 36% of respondents, whereas 20% discuss the topic rarely or never. 74% stated that the subject is important or very important. However, 70% are asked by less than half of managed patients about the impact of proposed therapies on sexual function.

    Most frequently mentioned barriers included time deficiency (74%), insufficient specialist knowledge (53%), patient's embarrassment (46%), and lack of educational materials for patients (35%). According to respondents more widespread sexual counselling in oncological care could be achieved by preparation of educational materials for patients (80%) and healthcare providers (74%) as well as organization of workshops for professionals (64%) and patients (50%).

    Conclusion The patients' needs regarding sexual counselling could be addressed better. Providing access to specialist educational programmes for both patients and healthcare providers may serve as adequate method for achieving this goal.

  • 16. Kacperczyk-Bartnik, Joanna
    et al.
    Nowosielski, Krzysztof
    Razumova, Zoia
    Bizzarri, Nicolò
    Pletnev, Andrei
    Lindquist, David
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk vetenskap, Professionell utveckling.
    Lanner, Maximilian
    Nikolova, Tanja
    Theofanakis, Charlampos
    Strojna, Aleksandra Natalia
    Bartnik, Paweł
    Gómez-Hidalgo, Natalia R.
    Vlachos, Dimitrios-Efthymios
    Selcuk, Ilker
    Zalewski, Kamil
    Clinician attitude towards sexual counseling in women with gynecologic malignancies: European Network of Young Gynaecological Oncologists (ENYGO) survey2022Ingår i: International Journal of Gynecological Cancer, ISSN 1048-891X, E-ISSN 1525-1438, Vol. 32, nr 10, s. 1309-1315Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    OBJECTIVE: Both the location of primary disease and treatment side effects may have an impact on sexual function in oncogynecological patients. The aim of this study was to examine the prevalence, strategies, difficulties, and ideas for improvement in sexual counseling among specialists managing patients with gynecologic malignancies.

    METHODS: This was a cross-sectional survey study performed among healthcare professionals treating patients with gynecologic malignancies. A self-prepared questionnaire included 61 questions concerning general demographic information and different aspects of sexual counseling in the gynecologic oncology practice. Analysis included attitudes, behaviors, management strategies, difficulties, and ideas for possible systemic improvements. Statistical analysis involved descriptive statistics, two-sided chi-square test, and Fisher's exact test.

    RESULTS: A total of 150 respondents from 46 countries answered the survey. The majority of survey participants stated that sexual counseling of oncological patients is very important (n=73, 49%) or important (n=46, 31%). One hundred and two (68%) respondents agreed that sexual counseling of gynecologic oncology patients should be routinely provided by the specialist managing the primary disease. However, collecting information concerning sexual function is performed often or always by only 21% of respondents and 19% discuss the topic rarely or never. The most frequently indicated barriers leading to difficulties in sexual counseling include lack of time (74%), lack of specialist knowledge (55%), and patient embarrassment (48%). One hundred and seven (71%) respondents expressed interest in participating in sexual counseling workshops organized by the European Society of Gynaecological Oncology (ESGO)/European Network of Young Gynaecological Oncologists (ENYGO), 74 (49%) would like to access webinars on the topic, and 120 (80%) would be interested in materials in the ESGO online educational resources.

    CONCLUSION: One of the proposed solutions to insufficient access to sexual care for women with gynecologic malignancies is providing access to specialist educational programs for both patients and healthcare specialists.

  • 17.
    Kvarnbrink, Samuel
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    Karlsson, Terese
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    Edlund, Karolina
    Botling, Johan
    Lindquist, David
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    Jirström, Karin
    Micke, Patrick
    Henriksson, Roger
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    Johansson, Mikael
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    Hedman, Håkan
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    LRIG1 is a prognostic biomarker in non-small cell lung cancer2015Ingår i: Acta Oncologica, ISSN 0284-186X, E-ISSN 1651-226X, Vol. 54, nr 8, s. 1113-1119Artikel i tidskrift (Refereegranskat)
    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.

  • 18.
    Kvarnbrink, Samuel
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    Karlsson, Terese
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    Forssell, Joakim
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi, Infektionssjukdomar.
    Edlund, Karin
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi, Virologi.
    Holmlund, Camilla
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    Faraz, Mahmood
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    Botling, J
    Feng, Mao
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    Lindquist, David
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    Micke, P
    Henriksson, Roger
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    Johansson, Mikael
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    Hedman, Håkan
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    LRIG1 is a prognostic biomarker and tumor suppressor in non-small cell lung cancerManuskript (preprint) (Övrigt vetenskapligt)
  • 19. La Russa, M
    et al.
    Zapardiel, I
    Halaska, M J
    Zalewski, K
    Laky, R
    Dursun, P
    Lindquist, David
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    Sukhin, V
    Polterauer, S
    Biliatis, I
    Conservative management of endometrial cancer: a survey amongst European clinicians2018Ingår i: Archives of Gynecology and Obstetrics, ISSN 0932-0067, E-ISSN 1432-0711, Vol. 298, s. 373-380Artikel i tidskrift (Refereegranskat)
    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.

  • 20. La Russa, Mariaclelia
    et al.
    Zapardiel, Ignacio
    Zalewski, Kamil
    Laky, Rene
    Dursun, Polat
    Sukhin, Vladyslav
    Lindquist, David
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk vetenskap, Professionell utveckling.
    Lindemann, Kristina
    Assessment of palliative care training in gynaecological oncology: a survey among European Network of Young Gynae-Oncologists (ENYGO) members2020Ingår i: BMJ Supportive & Palliative Care, ISSN 2045-435X, E-ISSN 2045-4368Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    INTRODUCTION: Palliative care is an important aspect of gynaecological oncology practice. In order to successfully integrate end-of-life (EOL) care in the disease trajectory, it is crucial to incorporate systematic training in subspecialty programmes in gynaecological oncology. We aimed to evaluate the quality of training in palliative care across gynaecological oncology fellows in Europe and to provide a framework to facilitate learning opportunities.

    METHODS: A web-based questionnaire was sent to members of the European Network of Young Gynae-Oncologists (ENYGO). The survey consisted of 36 items covering six domains: respondents' characteristics, quality and quantity of teaching, curriculum achievements, observation and feedback, EOL clinical practice and attitudes about palliative care.

    RESULTS: Of the 703 clinicians enrolled in the study, 142 responded (20.2%). Although the majority worked in university hospitals, only half of them (47%) were in a formal subspecialty programme. The majority of respondents (60%) were trained without a mandatory rotation in palliative care units and considered the quality of EOL care teaching as 'very poor' or 'poor' (57.7%). The majority of respondents (71.6%) did not receive any supervision or feedback at the time of their first consultation on changing the goals of care.

    CONCLUSION: Our study underlines lack of structured teaching and supervision in palliative care contents among European fellows in gynaecological oncology. Broad education of healthcare providers is a key factor to achieve the integration of palliative care in gynaecological oncology practice. Stakeholders like European Society of Gynaecological Oncology/ENYGO play an important role to facilitate educational activities and training programmes targeting to EOL care.

  • 21. Lindemann, K.
    et al.
    Martinsson, Lisa
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    Kaasa, S.
    Lindquist, David
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    Elderly gynaecological cancer patients at risk for poor end of life care: a population-based study from the Swedish Register of Palliative Care2020Ingår i: Acta Oncologica, ISSN 0284-186X, E-ISSN 1651-226X, Vol. 59, nr 6, s. 636-643Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Introduction: Poorer end-of-life (EOL) care for elderly cancer patients has been reported. We assessed the impact of age on 13 indicators for the quality of EOL care as well as adherence to 6 national quality indicators in gynaecological cancer patients.

    Methods: Age-dependent differences in 13 palliative care quality indicators were studied in gynaecological cancer patients registered in the population-based Swedish Register of Palliative Care. Association between the patient's age and each quality indicator was analyzed by logistic regression, adjusted for place of death where appropriate. Adherence to six national quality indicators determined by the Swedish National Board of Health and Welfare was estimated in all patients.

    Results: We included 3940 patients with the following age distribution: 1.6% were 18-39 years of age, 12.3% 40-59 years, 37.2% 60-74 years, 28.9% 75-84 years and 20% were ≥85 years. Age-dependent differences in implementation rate were present for some of the 13 quality indicators. Compared to elderly cancer patients, younger patients were more likely to be cared for by a specialized palliative care service, more often informed about imminent death as well as assessed for pain. For most national quality indicators, the goal level was not met. Only for the 'on demand prescription for pain', the goal level was reached.

    Conclusions: EOL care did not meet national quality indicators in this population-based data from Sweden, in particular in the elderly population. Elderly gynaecological cancer patients are at high risk of poorer EOL care without the involvement of specialized palliative care services. Palliative care services need to be implemented across all institutions of EOL care to ensure good and equal care.

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  • 22. Lindemann, Kristina
    et al.
    Zalewski, Kamil
    Halaska, Michael J.
    Lindquist, David
    Umeå universitet.
    Life - Literature for ENYGO2016Ingår i: International Journal of Gynecological Cancer, ISSN 1048-891X, E-ISSN 1525-1438, Vol. 26, s. 2-73Artikel i tidskrift (Refereegranskat)
    Abstract [en]

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

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  • 23.
    Lindquist, David
    Umeå universitet.
    Medical (chemo and radiotherapy) treatment of primary uterine cancer2016Ingår i: International Journal of Gynecological Cancer, ISSN 1048-891X, E-ISSN 1525-1438, Vol. 26, s. 28-28Artikel i tidskrift (Refereegranskat)
  • 24.
    Lindquist, David
    Institutionen för onkologi-patologi, Karolinska Institutet.
    Studies on the occurrence and effects of human papillomavirus in tumors of the head and neck2008Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)
    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.

  • 25.
    Lindquist, David
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    Alsina, Fernando C.
    Herdenberg, Carl
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    Larsson, Catharina
    Höppener, Jo
    Wang, Na
    Paratcha, Gustavo
    Tarján, Miklós
    Tot, Tibor
    Henriksson, Roger
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    Hedman, Håkan
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    LRIG1 negatively regulates RET mutants and is downregulated in thyroid cancer2018Ingår i: International journal of oncology, ISSN 1791-2423, Vol. 52, nr 4, s. 1189-1197Artikel i tidskrift (Refereegranskat)
    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.

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  • 26.
    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.2011Ingår i: Pathology research international, ISSN 2042-003X, Vol. 2011, s. 860584-Artikel i tidskrift (Refereegranskat)
    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.

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  • 27.
    Lindquist, David
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    Henriksson, Roger
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    Hedman, Hakan
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    Expression of the human LRIG genes and proteins as prognostic markers in human cancer2012Ingår i: International Journal of Molecular Medicine, ISSN 1107-3756, E-ISSN 1791-244X, Vol. 30, nr Suppl 1, s. S42-S42Artikel i tidskrift (Övrigt vetenskapligt)
  • 28.
    Lindquist, David
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    Kvarnbrink, Samuel
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    Henriksson, Roger
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    Hedman, Håkan
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    LRIG and cancer prognosis2014Ingår i: Acta Oncologica, ISSN 0284-186X, E-ISSN 1651-226X, Vol. 53, nr 9, s. 1135-1142Artikel, forskningsöversikt (Refereegranskat)
    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.

  • 29.
    Lindquist, David
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    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 universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    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 universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    Expression of LRIG1 is associated with good prognosis and human papillomavirus status in oropharyngeal cancer2014Ingår i: British Journal of Cancer, ISSN 0007-0920, E-ISSN 1532-1827, Vol. 110, nr 7, s. 1793-1800Artikel i tidskrift (Refereegranskat)
    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.

  • 30.
    Lindquist, David
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper.
    Ranhem, C.
    Stefansson, Kristina
    Hellman, K.
    Andersson, S.
    PREVALENCE OF HPV-POSITIVE VAGINAL AND VULVAR CANCER OVER TIME IN TWO SWEDISH COHORTS2014Ingår i: International Journal of Gynecological Cancer, ISSN 1048-891X, E-ISSN 1525-1438, Vol. 24, nr 9 suppl 4, s. 892-892Artikel i tidskrift (Övrigt vetenskapligt)
  • 31.
    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 E7.2007Ingår i: Molecular oncology, ISSN 1878-0261, Vol. 1, nr 3, s. 350-5Artikel i tidskrift (Refereegranskat)
    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.

  • 32.
    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 cancer2012Ingår i: Anticancer Research, ISSN 0250-7005, E-ISSN 1791-7530, Vol. 32, nr 1, s. 153-161Artikel i tidskrift (Refereegranskat)
    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.

  • 33.
    Lindquist, David
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper.
    Öfverman, Charlotte
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper.
    Stefansson, Kristina
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper.
    Aglund, Kristina
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper.
    Survival-data for endometrial cancer patients in northern Sweden 2010-20112015Ingår i: International Journal of Gynecological Cancer, ISSN 1048-891X, E-ISSN 1525-1438, Vol. 25, nr 9, s. 1100-1100Artikel i tidskrift (Övrigt vetenskapligt)
  • 34.
    Loizou, Christos
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk vetenskap, Öron- näs- och halssjukdomar.
    Laurell, Göran
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk vetenskap, Öron- näs- och halssjukdomar.
    Arvidsson, Andreas
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk vetenskap, Öron- näs- och halssjukdomar.
    Lindquist, David
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    Nylander, Karin
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Olofsson, Katarina
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk vetenskap, Öron- näs- och halssjukdomar.
    Recurrent respiratory papillomatosis in northern Sweden: Clinical characteristics and practical guidance2015Ingår i: Acta Oto-Laryngologica, ISSN 0001-6489, E-ISSN 1651-2251, Vol. 135, nr 10, s. 1058-1064Artikel i tidskrift (Refereegranskat)
    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.

  • 35.
    Loizou, Christos
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk vetenskap, Öron- näs- och halssjukdomar.
    Laurell, Göran
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk vetenskap, Öron- näs- och halssjukdomar. Department of Surgical Sciences, Division of Otorhinolaryngology, Uppsala University.
    Lindquist, David
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    Olofsson, Katarina
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk vetenskap, Öron- näs- och halssjukdomar.
    Voice and quality of life in patients with recurrent respiratory papillomatosis in a northern Sweden cohort2014Ingår i: Acta Oto-Laryngologica, ISSN 0001-6489, E-ISSN 1651-2251, ISSN 1651-2251 (online), Vol. 134, nr 4, s. 401-406Artikel i tidskrift (Refereegranskat)
    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.

  • 36.
    Loizou, Christos
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk vetenskap, Öron- näs- och halssjukdomar.
    Laurell, Göran
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk vetenskap, Öron- näs- och halssjukdomar. Department of Surgical Sciences, Division of Otorhinolaryngology, Uppsala University.
    Lindquist, David
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    Öfverman, Charlotte
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    Stefansson, Kristina
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    Nylander, Karin
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Olofsson, Katarina
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk vetenskap, Öron- näs- och halssjukdomar.
    Incidence of tonsillar cancer in northern Sweden: Impact of human papilloma virus2015Ingår i: Oncology Letters, ISSN 1792-1074, E-ISSN 1792-1082, Vol. 10, nr 6, s. 3565-3572Artikel i tidskrift (Refereegranskat)
    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.

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  • 37.
    Lorenzzi Löfgren de Melo, Alexandra
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    Linder, Anna
    Sahlgrenska Center for Cancer research, Department of Gynecology and Obstetrics, Institute of clinical Sciences, Sahlgrenska Academy at University of Gothenburg, Gothenburg, Sweden.
    Sundfeldt, Karin
    Sahlgrenska Center for Cancer research, Department of Gynecology and Obstetrics, Institute of clinical Sciences, Sahlgrenska Academy at University of Gothenburg, Gothenburg, Sweden.
    Lindquist, David
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    Hedman, Håkan
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    Single-molecule array assay reveals the prognostic impact of plasma LRIG1 in ovarian carcinoma2022Ingår i: Acta Oncologica, ISSN 0284-186X, E-ISSN 1651-226X, Vol. 61, nr 11, s. 1425-1433Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Background: Ovarian carcinoma is the eighth most common cause of cancer death in women worldwide. The disease is predominantly diagnosed at a late stage. This contributes to high recurrence rates, eventually leading to the development of treatment-resistant disease. Leucine-rich repeats and immunoglobulin-like domains protein 1 (LRIG1) is a transmembrane protein that functions as a tumor suppressor and regulator of growth factor signaling. LRIG1 levels have not been investigated in human plasma previously.

    Materials and methods: A quantitative LRIG1-specific single molecule array assay was developed and validated. LRIG1 levels were quantified in plasma samples from 486 patients with suspicious ovarian masses.

    Results: Among women with ovarian carcinoma, LRIG1 levels were significantly elevated compared to women with benign or borderline type tumors. High LRIG1 plasma levels were associated with worse overall survival and shorter disease-free survival both in the group of all malignant cases and among the stage 3 cases only. LRIG1 was an independent prognostic factor in patients with stage 3 ovarian carcinoma.

    Conclusion: LRIG1 plasma levels were elevated in patients with ovarian carcinoma, and high levels were associated with poor prognosis, suggesting that LRIG1 might be an etiologic factor and a potentially useful biomarker in ovarian carcinoma.

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  • 38. 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.2005Ingår i: Anticancer Research, ISSN 0250-7005, E-ISSN 1791-7530, Vol. 25, nr 6C, s. 4375-83Artikel i tidskrift (Refereegranskat)
    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.

  • 39. Muller, Susanne
    et al.
    Lindquist, David
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    Kanter, Lena
    Flores-Staino, Carmen
    Henriksson, Roger
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    Hedman, Håkan
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    Andersson, Sonia
    Expression of LRIG1 and LRIG3 correlates with human papillomavirus status and patient survival in cervical adenocarcinoma2013Ingår i: International Journal of Oncology, ISSN 1019-6439, E-ISSN 1791-2423, Vol. 42, nr 1, s. 247-252Artikel i tidskrift (Refereegranskat)
    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.

  • 40. 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].2006Ingår i: Läkartidningen, ISSN 0023-7205, E-ISSN 1652-7518, Vol. 103, nr 44, s. 3366-8Artikel i tidskrift (Refereegranskat)
  • 41. Nagel, Gabriele
    et al.
    Bjørge, Tone
    Jaensch, Andrea
    Peter, Raphael S.
    Häggström, Christel
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Näringsforskning. Department of Surgical Sciences, Uppsala University, Uppsala, Sweden.
    Lang, Alois
    Engeland, Anders
    Teleka, Stanley
    Jirström, Karin
    Lindquist, David
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk vetenskap, Professionell utveckling.
    Stattin, Pär
    Ulmer, Hanno
    Concin, Hans
    Stocks, Tanja
    Metabolic factors and the risk of small intestine cancers: pooled study of 800 000 individuals in the Metabolic syndrome and Cancer project2021Ingår i: International Journal of Cancer, ISSN 0020-7136, E-ISSN 1097-0215, Vol. 149, nr 1, s. 66-74Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    To explore the largely unknown etiology of small intestine cancer, we examined metabolic factors and risk of small intestine cancer overall and by subtypes. Amongst 404 220 women and 403 265 men in six European cohorts, we applied Cox regression with adjustment for smoking and body mass index (BMI), to calculate sex-specific hazard ratios (HR) of small intestine cancer by levels of BMI, mean arterial pressure (MAP), and plasma total cholesterol, triglycerides and glucose. We also calculated HRs for these factors combined (metabolic score; MetS) and used Wald test statistics to investigate pairwise interactions between metabolic factors on risk. We also performed analyses separately per subtype (neuroendocrine tumors (NETs) and adenocarcinomas). During a median follow-up of 16.9 years, 144 women and 195 men were diagnosed with small intestine cancer, including 184 NETs and 99 adenocarcinomas. Among men, no main associations or interactions between metabolic factors were observed in relation to the risk of small intestine cancer. Among women, triglycerides were positively and linearly associated with risk (HR per standard deviation [SD]: 1.23, 95% CI 1.04 to 1.46), and a positive association was also observed for the MetS (HR per SD: 1.25, 95% CI 1.02 to 1.52). Positive interactions were observed among women between triglycerides and cholesterol (p=0.0005), and between MAP and glucose (p=0.009), on risk. Glucose was positively associated with adenocarcinomas among women. This large, prospective study suggests that elevated triglycerides, and metabolic factors in interaction, confer an increased risk of small intestine cancer among women, but not among men.

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  • 42. Nasman, A.
    et al.
    Nordfors, C.
    Tertipis, N.
    Grun, N.
    Du, J.
    Ahrlund-Richter, A.
    Haeggblom, L.
    Sivars, L.
    Vlastos, A.
    Lindquist, David
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    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)2014Ingår i: Anticancer Research, ISSN 0250-7005, E-ISSN 1791-7530, Vol. 34, nr 10, s. 5872-5873Artikel i tidskrift (Övrigt vetenskapligt)
  • 43. 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?2009Ingår i: International Journal of Cancer, ISSN 0020-7136, E-ISSN 1097-0215, Vol. 125, nr 2, s. 362-6Artikel i tidskrift (Refereegranskat)
    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.

  • 44. Näsman, Anders
    et al.
    Bersani, Cinzia
    Lindquist, David
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper.
    Du, Juan
    Ramqvist, Torbjörn
    Dalianis, Tina
    Human Papillomavirus and Potentially Relevant Biomarkers in Tonsillar and Base of Tongue Squamous Cell Carcinoma2017Ingår i: Anticancer Research, ISSN 0250-7005, E-ISSN 1791-7530, Vol. 37, nr 10, s. 5319-5328Artikel, forskningsöversikt (Refereegranskat)
    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.

  • 45.
    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 universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    Dalianis, Tina
    Karolinska Institutet.
    Absent/weak CD44 intensity and positive human papillomavirus (HPV) status in oropharyngeal squamous cell carcinoma indicates a very high survival2013Ingår i: Cancer Medicine, E-ISSN 2045-7634, Vol. 2, nr 4, s. 507-18Artikel i tidskrift (Refereegranskat)
    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.

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  • 46.
    Oda, Husam
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Öfverman, Charlotte
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper.
    Lundin, Eva
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Ottander, Ulrika
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk vetenskap.
    Lindquist, David
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk vetenskap.
    Stefansson, Kristina
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Klinisk kemi.
    CD8, CD44, Ki-67, and p53 immunoreactivity in vulvar squamous cell carcinoma: correlation with prognosis in relation to HPV-DNA and p16ink4a statusManuskript (preprint) (Övrigt vetenskapligt)
  • 47.
    Ofverman, Charlotte
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    Stefansson, Kristina
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    Ottander, Ulrika
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk vetenskap, Obstetrik och gynekologi.
    Lindquist, David
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    CASE SERIES OF PATIENTS WITH LEIOMYOSARCOMA OF THE UTERUS TREATED WITH TRABECTEDIN IN NORTHERN SWEDEN2016Ingår i: International Journal of Gynecological Cancer, ISSN 1048-891X, E-ISSN 1525-1438, Vol. 26, nr Supplement 3, s. 1046-1046, artikel-id IGCS-0142Artikel i tidskrift (Refereegranskat)
  • 48.
    Patthey, Annika
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Boman, Karin
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    Tavelin, Björn
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    Lindquist, David
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk vetenskap, Professionell utveckling.
    Lundin, Eva
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Hultdin, Magnus
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Combination of aneuploidy and high S-phase fraction indicates increased risk of relapse in stage I endometrioid endometrial carcinoma2021Ingår i: Acta Oncologica, ISSN 0284-186X, E-ISSN 1651-226X, Vol. 60, nr 9, s. 1218-1224Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    INTRODUCTION: Endometrioid endometrial carcinoma is a cancer type with generally excellent prognosis when diagnosed at an early stage, but there is a subset of patients with relapsing disease in spite of early diagnosis and surgical treatment. There is a need to find prognostic markers to identify these patients with increased risk of relapse. Depth of myometrial invasion, histological grade, and presence of lymphovascular invasion are known risk factors. DNA content (ploidy) and proliferation measured as S-phase fraction (SPF) have been discussed as prognostic markers but need additional evaluation.

    MATERIAL AND METHODS: We evaluated relapse-free survival (RFS) with respect to ploidy and SPF, which was analyzed by flow cytometry on fresh tumor tissue, in a cohort of 1001 women treated for stage I endometrioid endometrial carcinoma in northern Sweden during the period of 1993-2010, with a median follow up time of 12.0 years. Data were obtained from historical records.

    RESULTS: In simple analysis, both aneuploidy and high SPF were associated to increased risk of relapse with hazard ratios (HR) 2.37 (95% CI 1.52-3.70) and 1.94 (95% CI 1.24-3.02), respectively. Our data also confirmed stage, tumor grade, and ploidy as independent prognostic markers in an age adjusted cox regression multivariable analysis but we did not find SPF to contribute to prognosis. However, the combination of aneuploidy and high SPF identified a group of patients with increased risk of relapse, HR 2.02 (95% CI 1.19-3.44).

    CONCLUSION: In this study, which is the largest study of ploidy and SPF in stage I endometrioid endometrial carcinoma using fresh frozen tissue, aneuploidy was shown to be an independent prognostic marker. Furthermore, the combination of aneuploidy and high SPF could be used to identify patients with increased risk of relapse.

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  • 49. Ranhem, Cecilia
    et al.
    Larsson, Gabriella Lillsunde
    Hedman, Håkan
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper.
    Lindquist, David
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper.
    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 carcinoma2017Ingår i: PLOS ONE, 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.

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  • 50.
    Ranhem, Cecilia
    et al.
    Department of Women's and Children's Health, Karolinska Institutet, Stockholm, Sweden; Centre for Clinical Research Region Västmanland, Uppsala University, Västmanlands Hospital Västerås, Vasteras, Sweden.
    Larsson, Gabriella Lillsunde
    School of Health and Medical Sciences, Örebro University, Campus USÖ, Örebro, Sweden; Department of Laboratory Medicine, Örebro University Hospital, Örebro, Sweden.
    Lindqvist, David
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    Sorbe, Bengt
    Department of Oncology, Örebro University Hospital, Sweden.
    Karlsson, Mats G.
    School of Medical Sciences, Örebro University, Örebro, Sweden.
    Farnebo, Marianne
    Department of Bioscience and Nutrition, Karolinska Institutet, Stockholm, Sweden; Department of Cell and Molecular Biology, Karolinska Institutet, Stockholm, Sweden.
    Hellman, Kristina
    Department of Oncology-Pathology, Karolinska Institutet, Stockholm, Sweden.
    Kovaleska, Larysa
    R.E. Kavetsky Institute of Experimental Pathology, Oncology and Radiobiology, National Academy of Sciences of Ukraine, Kiev, Ukraine.
    Kashuba, Elena
    R.E. Kavetsky Institute of Experimental Pathology, Oncology and Radiobiology, National Academy of Sciences of Ukraine, Kiev, Ukraine; Department of Microbiology, Tumour and Cell Biology, Karolinska Institutet, Stockholm, Sweden.
    Andersson, Sonia
    Department of Women's and Children's Health, Karolinska Institutet, Stockholm, Sweden.
    Evaluation of dyskerin expression and the Cajal body protein WRAP53β as potential prognostic markers for patients with primary vaginal carcinoma2022Ingår i: Oncology Letters, ISSN 1792-1074, E-ISSN 1792-1082, Vol. 23, nr 1, artikel-id 30Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Primary vaginal cancer (PVC) is a rare gynae- cological malignancy, which, at present, lacks appropriate biomarkers for prognosis. The proteins dyskerin and WD repeat containing antisense to TP53 (WRAP53β), both of which exert their functions in the telomerase holoenzyme complex, have been shown to be upregulated in different cancer types. These proteins have also been proposed as prognostic markers in some types of cancer. The aim of the present study was to examine the expression patterns of dyskerin and WRAP53β in patients with PVC. Moreover, as part of a search for effective biomarkers to evaluate prog- nosis in PVC, the expression of these two proteins and their potential association with clinical variables and survival were also evaluated. The expression of dyskerin and WRAP53β was assessed in PVC tumour samples from 68 patients using immunohistochemistry. The majority of tumour samples showed low and moderate expression levels of dyskerin. Upregulation of dyskerin in tumour samples was signifi- cantly associated with a shorter survival time and a poorer cancer-specific survival rate. WRAP53β was also expressed in most of the cells but was not significantly associated with clinical variables or survival. This study demonstrates that upregulation of dyskerin is significantly associated with poor prognosis. Thus, dyskerin may serve as a promising prognostic marker and a potential putative therapeutic target in PVC.

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