Publications by authors named "Tina Dalianis"

139 Publications

Long-Term Survival and Recurrence in Oropharyngeal Squamous Cell Carcinoma in Relation to Subsites, HPV, and p16-Status.

Cancers (Basel) 2021 May 23;13(11). Epub 2021 May 23.

Department of Clinical Science, Intervention and Technology-CLINTEC Division of Ear, Nose and Throat Diseases, Karolinska Institutet, Karolinska University Hospital, 171 64 Stockholm, Sweden.

Long-term survival data in relation to sub-sites, human papillomavirus (HPV), and p16 (p16) for patients with oropharyngeal squamous cell carcinoma (OPSCC) is still sparse. Furthermore, reports have indicated atypical and late recurrences for patients with HPV and p16 positive OPSCC. Therefore, we assessed long-term survival and recurrence in relation to oropharyngeal subsite and HPV/p16 status. A total of 529 patients with OPSCC, diagnosed in the period 2000-2010, with known HPVDNA and p16-status, were included. HPV/p16 status and sub-sites were correlated to disease-free and overall survival (DFS and OS respectively). The overexpression of p16 (p16) is associated with significantly better long-term OS and DFS in tonsillar and base of tongue carcinomas (TSCC/BOTSCC), but not in patients with other OPSCC. Patients with HPVDNA/p16 TSCC/BOTSCC presented better OS and DFS compared to those with HPVDNA/p16 tumors, while those with HPVDNA/p16 cancer had an intermediate survival. Late recurrences were rare, and significantly more frequent in patients with p16 tumors, while the prognosis after relapse was poor independent of HPVDNA/p16 status. In conclusion, patients with p16 OPSCC do not have more late recurrences than p16, and a clear prognostic value of p16 was only observed in TSCC/BOTSCC. Finally, the combination of HPVDNA and p16 provided superior prognostic information compared to p16 alone in TSCC/BOTSCC.
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http://dx.doi.org/10.3390/cancers13112553DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8196945PMC
May 2021

Prognostic Markers and Driver Genes and Options for Targeted Therapy in Human-Papillomavirus-Positive Tonsillar and Base-of-Tongue Squamous Cell Carcinoma.

Viruses 2021 05 14;13(5). Epub 2021 May 14.

Department of Oncology-Pathology, Karolinska Institutet, Bioclinicum J6:20, Karolinska University Hospital, 171 64 Stockholm, Sweden.

The incidence of Human-papillomavirus-positive (HPV) tonsillar and base-of-tongue squamous cell carcinoma (TSCC and BOTSCC, respectively) is increasing epidemically, but they have better prognosis than equivalent HPV-negative (HPV) cancers, with roughly 80% vs. 50% 3-year disease-free survival, respectively. The majority of HPV TSCC and BOTSCC patients therefore most likely do not require the intensified chemoradiotherapy given today to head and neck cancer patients and would with de-escalated therapy avoid several severe side effects. Moreover, for those with poor prognosis, survival has not improved, so better-tailored alternatives are urgently needed. In line with refined personalized medicine, recent studies have focused on identifying predictive markers and driver cancer genes useful for better stratifying patient treatment as well as for targeted therapy. This review presents some of these endeavors and briefly describes some recent experimental progress and some clinical trials with targeted therapy.
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http://dx.doi.org/10.3390/v13050910DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8156012PMC
May 2021

Targeted Therapy With PI3K and FGFR Inhibitors on Human Papillomavirus Positive and Negative Tonsillar and Base of Tongue Cancer Lines With and Without Corresponding Mutations.

Front Oncol 2021 11;11:640490. Epub 2021 May 11.

Department of Oncology-Pathology, Karolinska Institutet, Stockholm, Sweden.

Objectives: Human papillomavirus positive (HPV) tonsillar and base of tongue squamous cell carcinoma (TSCC/BOTSCC), the major subsites of oropharyngeal squamous cell carcinoma (OPSCC) have favorable outcome, but upon relapse, outcome is poor and new therapies needed. Since, phosphatidyl-inositol-4,5-bisphosphate 3-kinase, catalytic subunit alpha (PIK3CA) and fibroblast-growth-factor-receptor-3 (FGFR3) mutations often occur in such tumors, here, we tested targeted therapy directed to such genes in TSCC/BOTSCC cell lines. We also combined the two types of inhibitors with each other, and cisplatin or docetaxel that are used clinically.

Methods: The HPV CU-OP-2, -3, -20, UPCI-SCC-154, and HPV CU-OP-17 and UT-SCC-60A cell lines were first tested for common PIK3CA/FGFR3 mutations by competitive-allele-specific TaqMan-PCR. They were then treated with the food and drug administration (FDA) approved drugs, alpelisib (BYL719) and erdafitinib (JNJ-42756493) alone and in combination with cisplatin or docetaxel. Viability, proliferation, apoptosis and cytotoxicity responses were thereafter followed by WST-1 assays and the IncuCyte S3 Live Cell Analysis System.

Results: HPV CU-OP-2 had a pS249C-FGFR3, and like CU-OP-20, a pE545K-PIK3CA mutation, while no other lines had such mutations. Irrespectively, dose dependent responses to all PI3K/FGFR inhibitors were obtained, and upon combining the inhibitors, positive effects were observed. Cisplatin and docetaxel also induced dose dependent responses, and upon combination with the inhibitors, both positive and neutral effects were found.

Conclusions: The data suggest that FDA approved drugs alpelisib and erdafitinib efficiently inhibit TSCC/BOTSCC cell line growth, especially when combined irrespective of presence of corresponding mutations and should be further explored, for use upon recurrent disease.
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http://dx.doi.org/10.3389/fonc.2021.640490DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8144504PMC
May 2021

New Approaches in Targeted Therapy for Medulloblastoma in Children.

Anticancer Res 2021 Apr;41(4):1715-1726

Department of Oncology-Pathology, Karolinska Institutet, Stockholm, Sweden

Medulloblastoma (MB) is the most frequent malignant brain tumor in children. Treatment of MB is based on histopathological and molecular stratification, and includes surgical intervention, often with craniospinal irradiation and adjuvant chemotherapy. Unfortunately, however, this treatment leads to a high morbidity rate, and it does not cure all patients either, with around 30% succumbing to their disease. With improved cancer genomics and better molecular characterization, MB has been classified into four major subgroups, wingless-activated, sonic hedgehog-activated, Group 3, and Group 4, with each group consisting of additional subtypes. Recently disclosed genetic drivers of MB may in the future help improve treatment, and in this way reduce therapy-related toxicity. In this review, we describe the heterogeneity of the MB subgroups, and potential new options for targeted therapy.
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http://dx.doi.org/10.21873/anticanres.14936DOI Listing
April 2021

Psoriasin expression is associated with survival in patients with human papillomavirus-positive base of tongue squamous cell carcinoma.

Oncol Lett 2021 Apr 10;21(4):277. Epub 2021 Feb 10.

Department of Oncology-Pathology, Karolinska Institutet, 171 64 Stockholm, Sweden.

Patients with human papillomavirus-positive (HPV+) base of tongue squamous cell carcinomas (BOTSCC) have an improved survival compared with patients with HPV-negative BOTSCC and it has been suggested that treatment should be tailored. Before individualized treatment can be introduced, additional prognostic markers are required. A prognostic role of psoriasin has previously been demonstrated outside BOTSCC. Therefore, the present study aimed to examine psoriasin in BOTSCC, with focus on HPV+ BOTSCC, in relation to prognosis. A total of 72 BOTSCC samples were stained for psoriasin by immunohistochemistry, and the association between expression and clinical outcomes was analyzed. Patients with low psoriasin expression exhibited significantly improved overall survival (OS; P=0.001) and disease-free survival (DFS; P=0.007), which also was observed in patients with HPV+ BOTSCC (OS, P<0.001; DFS, P=0.02). Furthermore, psoriasin was a significant prognostic factor in univariable and multivariable analyses. In conclusion, psoriasin could be used as a prognostic marker in HPV+ BOTSCC.
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http://dx.doi.org/10.3892/ol.2021.12538DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7905654PMC
April 2021

Effects of PI3K and FGFR inhibitors alone and in combination, and with/without cytostatics in childhood neuroblastoma cell lines.

Int J Oncol 2021 02 5;58(2):211-225. Epub 2021 Jan 5.

Department of Oncology‑Pathology, Karolinska Institutet, 17164 Stockholm, Sweden.

Neuroblastoma (NB) is a heterogenous disease with treatment varying from observation for low‑risk tumors, to extensive therapy with chemotherapy, surgery, radiotherapy, and autologous bone‑marrow‑transplantation and immunotherapy. However, a high frequency of primary‑chemo‑refractory disease and recurrences urgently require novel treatment strategies. The present study therefore investigated the anti‑NB efficacy of the recently FDA‑approved phosphoinositide 3‑kinase (PI3K) and fibroblast growth factor receptor (FGFR) inhibitors, alpelisib (BYL719) and erdafitinib (JNJ‑42756493), alone and in combination with or without cisplatin, vincristine, or doxorubicin on 5 NB cell lines. For this purpose, the NB cell lines, SK‑N‑AS, SK‑N‑BE(2)‑C, SK‑N‑DZ, SK‑N‑FI and SK‑N‑SH (where SK‑N‑DZ had a deletion of PIK3C2G and none had FGFR mutations according to the Cancer Program's Dependency Map, although some were chemoresistant), were tested for their sensitivity to FDA‑approved inhibitors alone or in combination, or together with cytostatic drugs by viability, cytotoxicity, apoptosis and proliferation assays. The results revealed that monotherapy with alpelisib or erdafitinib resulted in a dose‑dependent inhibition of cell viability and proliferation. Notably, the combined use of PI3K and FGFR inhibitors resulted in an enhanced efficacy, while their combined use with the canonical cytotoxic agents, cisplatin, vincristine and doxorubicin, resulted in variable synergistic, additive and antagonistic effects. Collectively, the present study provides pre‑clinical evidence that PI3K and FGFR inhibitors exhibit promising anti‑NB activity. The data presented herein also indicate that the incorporation of these inhibitors into chemotherapeutic regimens requires careful consideration and further research in order to obtain a beneficial efficacy. Nevertheless, the addition of PI3K and FGFR inhibitors to the treatment arsenal might reduce the occurrence of refractory and relapsing disease in NB without FGFR and PI3K mutations.
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http://dx.doi.org/10.3892/ijo.2021.5167DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7864013PMC
February 2021

Tumour inflammation signature and expression of S100A12 and HLA class I improve survival in HPV-negative hypopharyngeal cancer.

Sci Rep 2021 Jan 19;11(1):1782. Epub 2021 Jan 19.

Department of Clinical Science, Intervention and Technology (CLINTEC), Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden.

Hypopharyngeal squamous cell carcinoma (HPSCC) has a very poor prognosis. Local surgery may increase survival, but is often avoided due to significant post-op co-morbidities. Since prognostic markers are lacking, the aim was to find predictive biomarkers that identify patients whose response to oncological treatment is poor and who may benefit from primary surgery to increase survival. Pretreatment biopsies from 23 HPSCC patients, 3 human papillomavirus (HPV) positive and 20 HPV-negative, were analyzed for expression of 750 mRNAs using the Nanostring nCounter IO360 panel in relation to 3-year survival. Validation was performed through immunohistochemistry (IHC) for HLA class I and S100A12 in 74 HPV-negative HPSCC samples. Clustering identified a subset of HPV-negative HPSCC with favorable prognosis and a gene expression signature overexpressing calgranulins and immune genes, distinct from that of HPV-positive HPSCC. Enrichment analysis showed immune signaling, including the tumor inflammation signature, to be enriched in surviving patients. IHC validation confirmed high S100A12 and HLA class I expression to correlate with survival in HPV-negative HPSCC. This shows that immune activity is strongly related to survival in HPV-negative HPSCC. Enrichment of the tumor inflammation signature indicates a potential benefit of immunotherapy. Low expression of both HLA class I and S100A12 could be used to select patients for local surgery.
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http://dx.doi.org/10.1038/s41598-020-80226-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7815817PMC
January 2021

Human papilloma virus (HPV) prevalence upon HPV vaccination in Swedish youth: a review based on our findings 2008-2018, and perspectives on cancer prevention.

Arch Gynecol Obstet 2021 02 27;303(2):329-335. Epub 2020 Nov 27.

Department of Oncology-Pathology, Karolinska Institutet, Stockholm, Sweden.

Purpose: Three human papillomavirus (HPV) vaccines are available against up to nine HPV types. In Sweden, from 2012, Gardasil was offered to 10-12 year old girls through the school-based vaccination program, and as catchup vaccination for women up to 26 years. To obtain a baseline, and follow HPV vaccination effects, during 2008-2018, cervical and oral HPV prevalence were followed at a youth clinic in Stockholm, and in 2013 for comparison oral HPV prevalence was examined in high-school youth in a middle-sized county in Sweden.

Methods: In this review, we discuss all our data with cervical and oral mouthwash samples that were collected and tested for 24-27 HPV types by a bead-based multiplex assay from 2008.

Results: Compared with 2008-2011, with ~ 35% HPV16 and > 60% high risk (HR) HPV cervical prevalence at the youth clinic, a decrease of vaccine HPV types was observed between 2013 and 2018, with e.g., HPV16 falling to 5% in catchup vaccinated women and 15-18% in nonvaccinated women. Most common cervical HR-HPV types were HPV39, 51, 52, 56, and 59 together accounting for ~ 10% of cervical cancer, and where only HPV52 is included in Gardasil-9. At baseline 2009-2011, oral HPV prevalence was ~ 10% in unvaccinated youth at the youth clinic, but after 2013 it dropped to < 2% at the youth clinic and high schools.

Conclusion: To conclude, Gardasil HPV types have decreased, but it is still important to follow remaining HR-HPV types and cancer development, since there is an ongoing increase in the incidence of HPV-associated tonsillar and base of tongue cancer, and cervical cancer in Sweden.
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http://dx.doi.org/10.1007/s00404-020-05879-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7858554PMC
February 2021

Survival of patients with oropharyngeal squamous cell carcinomas (OPSCC) in relation to TNM 8 - Risk of incorrect downstaging of HPV-mediated non-tonsillar, non-base of tongue carcinomas.

Eur J Cancer 2020 11 17;139:192-200. Epub 2020 Sep 17.

Department of Oncology-Pathology, Karolinska Institutet, Stockholm, Sweden; Department of Clinical Pathology, Karolinska University Hospital, Stockholm, Sweden. Electronic address:

Background: TNM-8 staging separates oropharyngeal squamous cell carcinomas (OPSCC) into human papillomavirus (HPV)-mediated and -unrelated OPSCC based on p16INK4a overexpression (p16+), as surrogate marker for HPV. However, OPSCC is histologically and clinically heterogenous including tonsillar and base of tongue squamous cell carcinomas (TSCC and BOTSCC respectively), and carcinomas of soft palate and walls (otherOPSCC). The significance of HPV is established in TSCC/BOTSCC, while its role in otherOPSCC is unclear, which is not considered in TNM-8. Here, p16+ was therefore evaluated in relation to overall survival (OS) and tumor stage per OPSCC subsite.

Patients And Methods: All 932 patients, treated with curative intent in Stockholm 2000-2016 with OPSCC, previously analyzed for p16 expression, were included. Clinical data, including stage and OS, was collected retrospectively.

Results: Patients with p16+ otherOPSCC had significantly poorer OS compared to patients with p16+ TSCC/BOTSCC (p = 0.005) and their survival was similar to that of patients with p16-otherOPSCC/TSCC/BOTSCC. Moreover, patients with TNM-8 stage I-II and p16+ otherOPSCC had a significant poorer OS compared to patients with p16+ TSCC/BOTSCC and similar stage (p = 0.02). Lastly, patients with otherOPSCC and low TNM-7 stage had a significant better OS, as compared to those with a high stage (p = 0.019) while no hazard discrimination was observed with TNM-7 in TSCC/BOTSCC.

Conclusion: Our results indicate a risk of misclassification of patients with otherOPSCC and low TNM-8 stage. We suggest that p16 should only be evaluated in TSCC/BOTSCC and that patients with otherOPSCC should all be staged as patients with HPV-unrelated (p16-) OPSCC.
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http://dx.doi.org/10.1016/j.ejca.2020.08.003DOI Listing
November 2020

The value of p16 and HPV DNA in non-tonsillar, non-base of tongue oropharyngeal cancer.

Acta Otolaryngol 2021 Jan 17;141(1):89-94. Epub 2020 Sep 17.

Department of Clinical Sciences, Intervention and Technology, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden.

Background: Oropharyngeal squamous cell carcinoma (OPSCC) is dominated by tonsillar and tongue base carcinomas (TSCC/BOTSCC), but there are carcinomas at other sites, such as uvula/soft palate/pharyngeal wall here defined as other OPSCC. Human papillomavirus (HPV) positive TSCC/BOTSCC have favorable outcome, and the TNM-classification separates OPSCC into HPV mediated (p16 overexpressing, p16+) and HPV unrelated OPSCC (p16 non-overexpressing, p16-) cancer, but the prognostic role of p16+ in other OPSCC is unclear.

Aims/objectives: This study therefore aimed to further investigate the prognostic role of p16+, presence of HPV DNA, or both combined in other OPSCC.

Material And Methods: 195 other OPSCC, from patients diagnosed 2000-2018 were tested for p16, and/or presence of HPV DNA and the data correlated to outcome.

Results: Neither overall survival, nor disease free survival correlated to presence of p16+ or HPV DNA in other OPSCC. p16+ and HPV DNA presence were correlated ( < .0001), but the sensitivity of p16 as a surrogate marker for presence of HPV DNA was low (49%).

Conclusions And Significance: The data suggest that p16+ (and p16+/HPV DNA) positive other OPSCC should be analyzed cautiously and possibly separately from the HPV mediated OPSCC staging group.
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http://dx.doi.org/10.1080/00016489.2020.1813906DOI Listing
January 2021

Immune related proteins and tumor infiltrating CD8+ lymphocytes in hypopharyngeal cancer in relation to human papillomavirus (HPV) and clinical outcome.

Head Neck 2020 11 1;42(11):3206-3217. Epub 2020 Jul 1.

Department of Clinical Science, Intervention and Technology (CLINTEC), Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden.

Background: Hypopharyngeal cancer (HPSCC) shows a poor clinical outcome, while HPSCC, caused by human papillomavirus (HPV), presents a better outcome. Here, HPCC, immune proteins, and tumor infiltrating CD8+ lymphocytes (CD8+ TILs) were evaluated in relation to HPV and outcome.

Methods: Fresh frozen tissue from four HPV-positive HPSCC, 39 HPV-negative HPSCC, and normal samples were analyzed for protein expression by the Proseek immuno-oncology immunoassay. CD8+ TIL numbers evaluated by immunohistochemistry on 144 formalin-fixed biopsies were analyzed in relation to clinical outcome.

Results: Proteins differing between HPV-positive and negative HPSCC included CD8A, PD-L1, Fas ligand, and chemokines. High CD8+ TIL numbers were correlated to improve clinical outcome in HPV-negative HPSCC.

Conclusions: High expression of immune proteins in HPV-positive HPSCC may explain the better clinical outcome. CD8+ TILs are of relevance for outcome of HPV-negative HPSCC, while tumors with high immune activity but poor patient survival suggest a role for immune therapy.
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http://dx.doi.org/10.1002/hed.26364DOI Listing
November 2020

Targeting Fibroblast Growth Factor Receptor (FGFR) and Phosphoinositide 3-kinase (PI3K) Signaling Pathways in Medulloblastoma Cell Lines.

Anticancer Res 2020 Jan;40(1):53-66

Department of Oncology-Pathology, Karolinska Institutet, Stockholm, Sweden

Background/aim: Medulloblastoma (MB) accounts for ~20% of pediatric malignant central nervous system tumors. Treatment strategies, including surgery, radiation therapy and/or chemotherapy, are effective, but recurrence and metastasis frequently occur. Therefore, novel therapies are required. Herein, the effects of fibroblast growth factor receptor (FGFR) and phosphoinositide 3-kinase (PI3K) inhibitors on MB cells lines were evaluated.

Materials And Methods: MB cell lines (UW228-3, DAOY, Med8a, D425, D283) were tested for sensitivity to FGFR (AZD4547) and PI3K (BEZ235 and BYL719) inhibitors by viability, cytotoxicity, apoptosis, and proliferation assays.

Results: Single treatments with FGFR and PI3K inhibitors decreased viability and proliferation in a dose-dependent pattern in most cell lines. Combinination of the two type of drugs, increased sensitivity, especially of the most resistant cell line UW228-3.

Conclusion: Combination treatments with FGFR and PI3K inhibitors were superior to single treatments with FGFR and PI3K inhibitors, especially with BEZ235, for MB cell lines.
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http://dx.doi.org/10.21873/anticanres.13925DOI Listing
January 2020

antitumor effects of FGFR and PI3K inhibitors on human papillomavirus positive and negative tonsillar and base of tongue cancer cell lines.

Oncol Lett 2019 Dec 9;18(6):6249-6260. Epub 2019 Oct 9.

Department of Oncology-Pathology, Karolinska Institute, Bioclinicum, Karolinska University Hospital, 171 64 Stockholm, Sweden.

Human papillomavirus positive (HPV) tonsillar and base of tongue squamous cell carcinoma (TSCC/BOTSCC) have better outcomes than corresponding HPV negative (HPV) cancer cases. Our previous study demonstrated that fibroblast growth factor receptor 3 (FGFR3) and phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit a (PIK3CA) are often mutated in HPV cancer. To investigate whether targeted therapy is an option for TSCC/BOTSCC, two HPV and one HPV TSCC/BOTSCC cell lines were tested for their sensitivity towards FGFR and PI3K inhibitors. The HPV cell lines UM-SCC-47 and UPCI-SCC-154, and the HPV cell line UT-SSC-60A were tested by competitive allele-specific TaqMan-PCR for presence/absence of frequently occurring FGFR3 and PIK3CA mutations. All cells were then treated with FGFR inhibitor AZD4547 and PI3K inhibitors BEZ235 and BKM120 alone, or with AZD4547 and BEZ235 in combination. Viability was analyzed using a WST-1 assay, cytotoxicity tested by a CellTox Green cytotoxicity assay, apoptosis analyzed by a Caspase Glo 3/7 assay and proliferation examined with the xCELLigence system. HPV UM-SCC-47 and UPCI-SCC-154 cells, and HPV UT-SSC-60A cells, did not exhibit any common FGFR3 or PIK3CA mutations, but were all sensitive to FGFR inhibitor AZD4547 and PI3K inhibitors BEZ235 and BKM120. Notably, HPV UPCI-SCC-154 cells were more sensitive than the other two cell lines. Furthermore, when AZD4547 and BEZ235 treatment was combined in HPV UPCI-SCC-154 and HPV UT-SSC-60A cells, potentiated combination effects were observed. HPV UM-SCC-47 and UPCI-SCC-154 cells, and HPV UT-SSC-60A cells had no common FGFR3 or PIK3CA mutations, but were sensitive to FGFR inhibitor AZD4547, and PI3K inhibitors BEZ235 and BKM120. Furthermore, the latter two cell lines were particularly sensitive to combinations of AZD4547 and BEZ235.
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http://dx.doi.org/10.3892/ol.2019.10973DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6865836PMC
December 2019

Analyses of FGFR3 and PIK3CA mutations in neuroblastomas and the effects of the corresponding inhibitors on neuroblastoma cell lines.

Int J Oncol 2019 Dec 7;55(6):1372-1384. Epub 2019 Oct 7.

Department of Oncology‑Pathology, Karolinska Institutet, 171 74 Stockholm, Sweden.

Fibroblast growth factor receptor (FGFR)3 and phosphatidylinositol‑4,5‑bisphosphate 3‑kinase, catalytic subunit alpha (PIK3CA) mutations are found in various types of cancer, such as urinary bladder cancer, human papillomavirus‑positive tonsillar and base of the tongue squamous cell carcinoma, breast cancer and some childhood sarcomas. Several drugs can target these genes, some of which have been used for the treatment of urinary bladder cancer. Much less is known about childhood cancer. For this reason, the present study investigated the presence of such mutations in neuroblastomas (NBs) and tested NB cell lines for sensitivity to FGFR and phosphoinositide 3‑kinase (PI3K) inhibitors. In total, 29 NBs were examined for the presence of the three most common FGFR3 and PIK3CA mutations using a competitive allele‑specific TaqMan PCR (CAST‑PCR). Furthermore, the SK‑N‑AS, SK‑N‑BE(2)‑C, SK‑N‑DZ, SK‑N‑FI and SK‑N‑SH NB cell lines (where SK‑N‑DZ had a deletion of PIK3C2G, none had FGFR mutations according to the Cancer Program's Dependency Map, but some were chemoresistant), were tested for sensitivity to FGFR (AZD4547) and PI3K (BEZ235 and BKM120) inhibitors by viability, cytotoxicity, apoptosis and proliferation assays. CAST‑PCR detected one FGFR3 mutation in 1/29 NBs. Following treatment with FGFR and PI3K inhibitors, a decrease in viability and proliferation was observed in the majority, but not all, the cell lines. Following combination treatment with both drugs, the sensitivity of all cell lines was increased. On the whole, the findings of this study demonstrate that FGFR3 and PIK3CA mutations are uncommon in patients with NB. However, certain NB cell lines are rather sensitive to both FGFR and PI3K inhibitors alone, and even more so when the different drugs are used in combination.
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http://dx.doi.org/10.3892/ijo.2019.4896DOI Listing
December 2019

Paediatric virology and human papillomaviruses: An update.

Exp Ther Med 2019 Jun 22;17(6):4337-4343. Epub 2019 Apr 22.

Department of Clinical Virology, School of Medicine, University of Crete, 71003 Heraklion, Greece.

Almost 10 years ago, in October, 2008, the scientist who reported for the first time the association between human papillomaviruses (HPV) and cervical cancer, was awarded with the Nobel prize. In the years that followed, Professor Harald zur Hausen actively supported the value of the HPV vaccination in the prevention of different types of cancer and highlighted the necessity of its introduction in both girls and boys. However, to date, in the majority of countries, HPV vaccination among male adolescents has not been implemented into the national vaccination schemes, while in several countries, including Greece, the participation rate to HPV vaccination among female adolescents still remains low. Recent data indicate that catch-up HPV vaccination among young women has been extremely useful and has exhibited a significant effect in decreasing the prevalence of HPV. While the marketed current HPV vaccines prevent anogenital HPV infection, their impact on the natural history of oral HPV and their efficacy in preventing HPV-related head and neck carcinomas need to be further investigated. Juvenile onset recurrent respiratory papillomatosis, as well as HPV-associated conjunctival papillomas continue to be observed in childhood and their clinical management involves different therapeutic approaches with controversial outcomes. This review article provides an overview of recent views and advances on HPV infections and prevention in childhood that were presented at the '4th Workshop on Paediatric Virology' on Saturday September 22, 2018 in Athens, Greece.
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http://dx.doi.org/10.3892/etm.2019.7516DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6507507PMC
June 2019

A paediatric influenza update 100 years after the Skyros island Spanish flu outbreak.

Exp Ther Med 2019 Jun 22;17(6):4327-4336. Epub 2019 Apr 22.

Department of Clinical Virology, School of Medicine, University of Crete, 71003 Heraklion, Greece.

This year marks the 100th anniversary of the 1918 Spanish flu outbreak on the Greek Aegean Sea island of Skyros, which devastated its population in less than 30 days. According to Constantinos Faltaits's annals published in 1919, the influenza attack on the island of Skyros commenced acutely 'like a thunderbolt' on the 27th of October, 1918 and was exceptionally severe and fatal. At that time, the viral cause of the influenza had not been detected, while the total number of victims of the Spanish flu outbreak has been estimated to have surpassed 50 million, worldwide. Almost one century after this Aegean Sea island's tragedy, the '4th Workshop on Paediatric Virology', organised on the 22nd of September, 2018 in Athens, Greece, was dedicated to the 100 years of the 'Spanish' flu pandemic. This review article highlights the plenary and key lectures presented at the workshop on the recent advances on the epidemiology, clinical management and prevention of influenza in childhood.
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http://dx.doi.org/10.3892/etm.2019.7515DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6507498PMC
June 2019

Management of BK-virus infection - Swedish recommendations.

Infect Dis (Lond) 2019 07 23;51(7):479-484. Epub 2019 Apr 23.

k Department of Infectious Diseases , Karolinska University Hospital , Stockholm , Sweden.

BK-virus (BKV) associated nephropathy (BKVAN) and BKV associated haemorrhagic cystitis (HC) are complications of BKV infection/reactivation in renal and allogeneic haematopoietic stem cell transplantation (HSCT) patients, respectively. The task of how to manage these diseases was given to the chair by the Swedish Reference Group for Antiviral Therapy (RAV). After individual contributions by members of the working group, consensus discussions were held in a meeting on 23 January 2018 arranged by RAV. Thereafter, the recommendations were published in Swedish on November 2018. The current translation to English has been approved by all co-authors. High BKV serum levels suggest an increased risk for BKVAN and potential graft failure. For detection of BKVAN, careful monitoring of BKV DNA levels in serum or plasma is recommended the first year after renal transplantation and when increased creatinine serum levels of unknown cause are observed. Notably, a renal biopsy is mandatory for diagnosis. To reduce the risk for progression of BKVAN, there is no specific treatment, and tailored individual decrease of immunosuppression is recommended. For BKV-HC, BKV monitoring is not recommended, since BK-viruria frequently occurs in HSCT patients and the predictive value of BKV in plasma/serum has not been determined. However, the risk for BKV-HC is higher for patients undergoing myeloablative conditioning, having an unrelated, HLA-mismatched, or a cord blood donor, and awareness of the increased risk and early intervention may benefit the patients. Also for BKV-HC, no specific therapy is available. Symptomatic treatment, e.g. forced diuresis and analgesics could be of use.
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http://dx.doi.org/10.1080/23744235.2019.1595130DOI Listing
July 2019

Changes in Cervical Human Papillomavirus (HPV) Prevalence at a Youth Clinic in Stockholm, Sweden, a Decade After the Introduction of the HPV Vaccine.

Front Cell Infect Microbiol 2019 20;9:59. Epub 2019 Mar 20.

Department of Microbiology, Tumor and Cell Biology, Centre for Translational Microbiome Research, Karolinska Institutet, Stockholm, Sweden.

This study aimed to follow the impact of human papillomavirus (HPV) catch-up and vaccination on the very high cervical HPV-prevalence in women at a youth clinic in central Stockholm during the period 2008-2018. 2008-2010, cervical HPV-prevalence (69.5%) and HPV16 prevalence (34.7%) were high in non-vaccinated women at a youth clinic in Stockholm. 2013-2015, after the introduction of the quadrivalent-Gardasil® HPV-vaccine, HPV16 and HPV6 prevalence had decreased. Here, cervical HPV-prevalence was investigated 10 years after primary sampling. 2017-2018, 178 cervical swabs, from women aged 15-23 years old, were tested for 27 HPV types by a bead-based multiplex method. HPV-prevalence data were then related to vaccination status and age and compared to HPV-prevalence in 615 samples from 2008 to 2010 and 338 samples from 2013 to 2015 from the same clinic, and to HPV types in 143 cervical cancer cases during 2003-2008 in Stockholm. The proportion of vaccinated women increased from 10.7% (2008-2010) to 82.1% (2017-2018). The prevalence of all 27 HPVs, all high-risk HPVs (HR-HPVs) and the combined presence of the quadrivalent-Gardasil® types HPV16, 18, 6, and 11, was lower in vaccinated compared to unvaccinated women (67.4 vs. 93.3%, = 0.0031, 60.1 vs. 86.7%, = 0.0057 and 5.8 vs. 26.7%, = 0.002, respectively). Furthermore, HPV16 prevalence in non-vaccinated women 2017-2018 was lower than that in 2008-2010 (16.7 and 34.7%, respectively, = 0.0471) and similar trends were observed for HPV18 and 11. In both vaccinated and non-vaccinated women, the most common non-quadrivalent-Gardasil® vaccine HR-HPV types were HPV39, 51, 52, 56, and 59. Together they accounted for around 9.8% of cervical cancer cases in Stockholm during 2003-2008, and their prevalence tended to have increased during 2017-2018 compared to 2008-2010. Quadrivalent-Gardasil® vaccination has decreased HPV-vaccine type prevalence significantly. However, non-vaccine HR-HPV types remain high in potentially high-risk women at a youth clinic in Stockholm.
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http://dx.doi.org/10.3389/fcimb.2019.00059DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6435486PMC
November 2019

TLR5 and TLR7 are differentially expressed in human papillomavirus-positive and negative base of tongue squamous cell carcinoma, and TLR7 may have an independent prognostic influence.

Acta Otolaryngol 2019 Feb 22;139(2):206-210. Epub 2019 Feb 22.

a Department of Oncology-Pathology , Karolinska Institute, CCK , Stockholm , Sweden.

Background: Human papillomavirus-positive (HPV) base of tongue squamous cell carcinoma (BOTSCC) has a better outcome than corresponding HPV cancer. TLR5 and TLR7 expression was previously shown to differ depending on HPV - status and correlate with outcome in oropharyngeal squamous cell carcinoma.

Aims/objectives: For validation, TLR5 and TLR7 were analyzed in a BOTSCC-cohort for correlation with HPV, survival, CD4 and CD8 tumor-infiltrating lymphocyte (TIL) counts, the latter being a well-documented prognostic marker.

Materials And Methods: BOTSCC biopsies, (49HPV/28HPV) were analyzed by immunohistochemistry for TLR5 and TLR7, and correlated with the above parameters.

Results: TLR5 expression was more frequently absent/weak than medium/strong in HPV compared to HPV BOTSCC (p < .001). The opposite was observed for TLR7 (p < .007). TLR5 and TLR7 expression did not correlate to survival in either the HPV or HPV cases, or to CD4 TILs. TLR5, (but not TLR7) expression was correlated to CD8 TIL counts (p = .023).

Conclusion And Significance: Absent/weak TLR5 and medium/strong TLR7 expression was validated as more frequent in HPV compared with HPV BOTSCC. A correlation between CD8 TIL counts, and TLR5 expression was disclosed, but not with TLR7. Therefore, it could be useful to investigate TLR7 further as a potential independent prognostic marker.
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http://dx.doi.org/10.1080/00016489.2018.1552014DOI Listing
February 2019

Changes in incidence and prevalence of human papillomavirus in tonsillar and base of tongue cancer during 2000-2016 in the Stockholm region and Sweden.

Head Neck 2019 06 24;41(6):1583-1590. Epub 2018 Dec 24.

Department of Oncology-Pathology, Karolinska Institutet, Stockholm, Sweden.

Background: Tonsillar and base of tongue squamous cell carcinoma (TSCC/BOTSCC) has increased. In Stockholm, the proportion of human papillomavirus (HPV)-positive cases and the incidence of TSCC rose between 1970 and 2006 then stabilized. Here, HPV-prevalence, and TSCC/BOTSCC incidence 2000-2016, in Stockholm and Sweden were followed.

Methods: Incidence data for 2000-2016 were obtained from the Swedish Cancer Registry. TSCC/BOTSCC biopsies, 2013-2016 from Stockholm, were examined for HPV DNA and p16 , or data obtained from medical reports. For cases 2000-2012, data were available from previous studies.

Results: The incidence of TSCC/BOTSCC has continued to rise in Stockholm and Sweden 2000-2016, especially after 2008. HPV DNA and p16 analysis was determined for 795 Stockholm cases from 2000 to 2016, with 72% being HPV DNA and p16 positive 2013-2016, and 70% positive 2000-2016.

Conclusion: During 2000-2016, especially after 2008, the incidence of TSCC/BOTSCC has continued to increase in Stockholm and Sweden, with an HPV-prevalence of approximately 70% in Stockholm.
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http://dx.doi.org/10.1002/hed.25585DOI Listing
June 2019

'I also want to be vaccinated!' - adolescent boys' awareness and thoughts, perceived benefits, information sources, and intention to be vaccinated against Human papillomavirus (HPV).

Hum Vaccin Immunother 2019 20;15(7-8):1794-1802. Epub 2018 Dec 20.

a Department of Women's and Children's Health, Uppsala University , Uppsala , Sweden.

This study investigates boys' awareness and thoughts about human papillomavirus (HPV) and HPV vaccination, perceived benefits of vaccinating men, information sources and intention to be vaccinated against HPV. We used a qualitative approach and interviews were conducted with 31 upper secondary school male students. Two main themes 1) and 2) emerged from the analysis. The informants believed that it was important and fair to protect boys and girls equally against HPV. If HPV vaccination could prevent both girls and boys against an HPV-related disease, there was nothing to question or to discuss. It was not a matter of sex; it was a matter of equal rights. Moreover, an important reason for vaccinating boys was to prevent the transmission of the virus. However, the boys felt unsure and stated that they needed to know more. The school nurse and the school health were considered suitable both for distributing information and for providing the vaccinations. In conclusion, the participants were in favor of introducing HPV vaccination also for boys in the national vaccination program. Sex-neutral HPV vaccinations were viewed both as a way to stop the virus transmission and a means to promote equal health for the entire population.
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http://dx.doi.org/10.1080/21645515.2018.1551670DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6746528PMC
March 2020

Overexpression of FGFR3 in HPV-positive Tonsillar and Base of Tongue Cancer Is Correlated to Outcome.

Anticancer Res 2018 Aug;38(8):4683-4690

Department of Oncology-Pathology, Karolinska Institutet, Stockholm, Sweden

Background/aim: Human papillomavirus-positive (HPV) tonsillar and base of tongue squamous cell carcinoma (TSCC/BOTSCC) have better outcome than corresponding HPV cancers. To better individualize treatment, additional predictive markers are needed. Previously, we have shown that mutated fibroblast growth factor receptor 3 protein (FGFR3) was correlated to poorer prognosis and here FGFR3 expression was further analyzed.

Patients And Methods: One-hundred-fifteen HPVTSCC/ BOTSCC biopsies were analyzed for FGFR3 by immunohistochemistry (IHC), and 109/115 were analyzed for FGFR3 mutations by Ion Proton sequencing, or by Competitive Allele-Specific Taqman PCR (CAST-PCR). Disease-free survival (DFS) was then calculated according to FGFR3 IHC expression.

Results: CAST-PCR was useful for detecting the three most common FGFR3 mutations. Focusing especially on the 98/115 patients with HPVTSCC/BOTSCC and wild-type FGFR3, high FGFR3 expression correlated to significantly better 3-year DFS, p=0.043.

Conclusion: In patients with HPVTSCC/BOTSCC and wild-type FGFR3, overexpression of FGFR3 was correlated with better DFS.
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http://dx.doi.org/10.21873/anticanres.12774DOI Listing
August 2018

MicroRNA-155, -185 and -193b as biomarkers in human papillomavirus positive and negative tonsillar and base of tongue squamous cell carcinoma.

Oral Oncol 2018 07 4;82:8-16. Epub 2018 May 4.

Dept. of Oncology-Pathology, Karolinska Institutet, 171 76 Stockholm, Sweden. Electronic address:

Objective: Three-year disease-free survival (DFS) is 80% for human papillomavirus (HPV) positive tonsillar and base of tongue cancer (TSCC/BOTSCC) treated with radiotherapy alone, and today's intensified therapy does not improve prognosis. More markers are therefore needed to more accurately identify patients with good prognosis or in need of alternative therapy. Here, microRNAs (miRs) 155, 185 and 193b were examined as potential prognostic markers in TSCC/BOTSCC.

Material And Methods: 168 TSCC/BOTSCC patients diagnosed 2000-2013, with known data on HPV-status, CD8 tumour infiltrating lymphocytes, tumour staging and survival were examined for expression of miR-155, -185 and -193b using Real-Time PCR. Associations between miR expression and patient and tumour characteristics were analysed using univariate testing and multivariate regression.

Results: Tumours compared to normal tonsils showed decreased miR-155 and increased miR-193b expression. miR-155 expression was associated with HPV-positivity, low T-stage, high CD8 TIL counts and improved survival. miR-185 expression was associated with HPV-negativity and a tendency towards decreased survival, while miR-193b expression was associated with higher T-stage, male gender and lower CD8 TIL counts, but not with outcome. Upon Cox regression, miR-185 was the only miR significantly associated with survival. Combining miR-155 and miR-185 to predict outcome in HPV patients yielded an area under curve (AUC) of 71%.

Conclusion: Increased miR-155 expression was found as a positive predictor of survival, with the effect mainly due to its association with high CD8 TIL numbers, while miR-185 independently associated with decreased survival. Addition of these miRs to previously validated prognostic biomarkers could improve patient stratification accuracy.
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http://dx.doi.org/10.1016/j.oraloncology.2018.04.021DOI Listing
July 2018

Development and external validation of nomograms in oropharyngeal cancer patients with known HPV-DNA status: a European Multicentre Study (OroGrams).

Br J Cancer 2018 06 24;118(12):1672-1681. Epub 2018 May 24.

Department of Otorhinolaryngology, Head and Neck Surgery and Audiology, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark.

Background: The proxy marker for human papillomavirus (HPV), p16, is included in the new AJCC 8th/UICC 8th staging system, but due to incongruence between p16 status and HPV infection, single biomarker evaluation could lead to misallocation of patients. We established nomograms for overall survival (OS) and progression-free survival (PFS) in patients with oropharyngeal squamous cell carcinoma (OPSCC) and known HPV-DNA and p16 status, and validated the models in cohorts from high- and low-prevalent HPV countries.

Methods: Consecutive OPSCC patients treated in Denmark, 2000-2014 formed the development cohort. The validation cohorts were from Sweden, Germany, and the United Kingdom. We developed nomograms by applying a backward-selection procedure for selection of variables, and assessed model performance.

Results: In the development cohort, 1313 patients, and in the validation cohorts, 344 German, 503 Swedish and 463 British patients were included. For the OS nomogram, age, gender, combined HPV-DNA and p16 status, smoking, T-, N-, and M-status and UICC-8 staging were selected, and for the PFS nomogram the same variables except UICC-8 staging. The nomograms performed well in discrimination and calibration.

Conclusions: Our nomograms are reliable prognostic methods in patients with OPSCC. Combining HPV DNA and p16 is essential for correct prognostication. The nomograms are available at www.orograms.org .
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http://dx.doi.org/10.1038/s41416-018-0107-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6008433PMC
June 2018

Human papillomavirus (HPV) is absent in branchial cleft cysts of the neck distinguishing them from HPV positive cystic metastasis.

Acta Otolaryngol 2018 Sep 15;138(9):855-858. Epub 2018 May 15.

b Department of Clinical Science, Intervention and Technology, Otorhinolaryngology Head and Neck Surgery , Karolinska University Hospital , Stockholm , Sweden.

Background: Distinguishing branchial cleft cysts (BCCs) from cystic metastases of a human papillomavirus (HPV) positive oropharyngeal squamous cell carcinoma (OPSCC) is challenging. Fine needle aspirates (FNAs) from cystic metastasis may be non-representative, while reactive squamous cells from BCC can be atypic. Based on cytology and with the support of HPV DNA positivity many centers treat cystic metastasis oncological and thus patients are spared neck dissection. To do so safely, one must investigate whether HPV DNA and p16 overexpression is found exclusively in cystic metastases and not in BCC.

Patients And Methods: DNA was extracted from formalin fixed paraffin embedded (FFPE) surgically resected BCCs from 112 patients diagnosed 2007-2015 at Karolinska University Hospital and amplified by PCR. A multiplex bead-based assay used to detect 27 HPV-types and p16 expression was analyzed by immunohistochemistry (IHC).

Results: All 112 BCCs were HPV DNA negative, and of 105 BCCs possible to evaluate for p16, none overexpressed p16.

Conclusions: HPV DNA and p16 overexpression were absent in BCCs. Lack of HPV DNA and p16 protein overexpression in BCCs is helpful to discriminate benign BCCs from HPV OPSCC metastasis. HPV testing definitely has a role in the diagnostics of cystic masses of the neck.
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http://dx.doi.org/10.1080/00016489.2018.1464207DOI Listing
September 2018

Human Polyomaviruses Are Not Frequently Present in Cancer of the Salivary Glands.

Anticancer Res 2018 05;38(5):2871-2874

Department of Oncology-Pathology, Karolinska Institute, Karolinska University Hospital, Stockholm, Sweden

Background/aim: Malignant tumors of the salivary glands are rare and heterogeneous, with more than 20 subtypes, and classified mainly by histopathology. Their diagnosis is often challenging and their etiology unknown. Here, the possible association between human polyomaviruses (PyVs) and one or more salivary gland tumor subtypes was examined.

Materials And Methods: Ninety-one primary tumors, including 12 subtypes and eight corresponding metastases, were analyzed for the presence of DNA of 10 different human PyV species by a bead-based multiplex assay using polymerase chain reaction and Luminex analyses.

Results: Three samples, one adenocarcinoma (not otherwise specified), one adenoid cystic carcinoma, and one mucoepidermoid carcinoma were found to be positive. However, the amount of MCPyV DNA in these tumors was estimated to be less than one genome per tumor cell.

Conclusion: The analysis of DNA from 10 human PyVs in a large number of malignant salivary gland cancers did not implicate any of these human PyVs as an important causative agent in any of the 12 subtypes studied.
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http://dx.doi.org/10.21873/anticanres.12532DOI Listing
May 2018

Protein Expression in Tonsillar and Base of Tongue Cancer and in Relation to Human Papillomavirus (HPV) and Clinical Outcome.

Int J Mol Sci 2018 Mar 25;19(4). Epub 2018 Mar 25.

Department of Clinical Science and Technology (CLINTEC), Karolinska Institutet, Karolinska University Hospital, 171 76 Stockholm, Sweden.

Human papillomavirus (HPV) is a major etiological factor for tonsillar and the base of tongue cancer (TSCC/BOTSCC). HPV-positive and HPV-negative TSCC/BOTSCC present major differences in mutations, mRNA expression and clinical outcome. Earlier protein studies on TSCC/BOTSCC have mainly analyzed individual proteins. Here, the aim was to compare a larger set of cancer and immune related proteins in HPV-positive and HPV-negative TSCC/BOTSCC in relation to normal tissue, presence of HPV, and clinical outcome. Fresh frozen tissue from 42 HPV-positive and 17 HPV-negative TSCC/BOTSCC, and corresponding normal samples, were analyzed for expression of 167 proteins using two Olink multiplex immunoassays. Major differences in protein expression between TSCC/BOTSCC and normal tissue were identified, especially in chemo- and cytokines. Moreover, 34 proteins, mainly immunoregulatory proteins and chemokines, were differently expressed in HPV-positive vs HPV-negative TSCC/BOTSCC. Several proteins were potentially related to clinical outcome for HPV-positive or HPV-negative tumors. For HPV-positive tumors, these were mostly related to angiogenesis and hypoxia. Correlation with clinical outcome of one of these, VEGFA, was validated by immunohistochemistry. Differences in immune related proteins between HPV-positive and HPV-negative TSCC/BOTSCC reflect the stronger activity of the immune defense in the former. Angiogenesis related proteins might serve as potential targets for therapy in HPV-positive TSCC/BOTSCC.
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http://dx.doi.org/10.3390/ijms19040978DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5979357PMC
March 2018

ECIL guidelines for the prevention, diagnosis and treatment of BK polyomavirus-associated haemorrhagic cystitis in haematopoietic stem cell transplant recipients.

J Antimicrob Chemother 2018 Jan;73(1):12-21

Transplantation & Clinical Virology, Department Biomedicine (Haus Petersplatz), University of Basel, Petersplatz 10; CH-4009 Basel, Switzerland.

Objectives: To define guidelines for BK polyomavirus (BKPyV)-associated haemorrhagic cystitis (BKPyV-HC) after paediatric and adult HSCT.

Methods: Review of English literature and evidence-based recommendations by expert consensus.

Results: BKPyV-HC occurs in 8%-25% of paediatric and 7%-54% of adult recipients undergoing allogeneic HSCT. Diagnosis requires the triad of cystitis, macro-haematuria and high urine BKPyV loads >7 log10 copies/mL, and exclusion of other relevant aetiologies. BKPyV viraemia is frequent and may serve as a more specific semiquantitative follow-up marker. No randomized controlled trials are available to inform antiviral prophylaxis or treatment. However, hyper-hydration and/or bladder irrigation showed limited prophylactic value. Fluoroquinolones are not effective for prophylaxis or treatment, but rather increase antibiotic resistance. Hyperbaric oxygen or fibrin glue is marginally effective based on small case series from correspondingly equipped centres. Although cidofovir has been reported to improve and/or reduce BKPyV viraemia or viruria, the current data do not support its regular use.

Conclusions: BKPyV-HC remains a disabling unmet clinical need in HSCT that requires novel approaches supported by proper clinical trials.
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http://dx.doi.org/10.1093/jac/dkx324DOI Listing
January 2018

Time to change perspectives on HPV in oropharyngeal cancer. A systematic review of HPV prevalence per oropharyngeal sub-site the last 3 years.

Papillomavirus Res 2017 12 19;4:1-11. Epub 2017 May 19.

Dept. of Oncology-Pathology, Karolinska Institutet, 171 76 Stockholm, Sweden; Dept. of Clinical Pathology, Karolinska University Hospital, 171 76 Stockholm, Sweden. Electronic address:

Objectives: Human papillomavirus (HPV) as a risk factor in oropharyngeal squamous cell carcinoma (OPSCC) is well established. However, accumulating data imply that the OPSCC concept is too unspecific with regard to HPV prevalence and clinical importance. To further study the role of HPV in OPSCC by sub-site, a systematic review and meta-analysis was performed.

Material And Method: PubMed was searched and all studies reporting HPV data (p16/HPV DNA/RNA) in both "lymphoepithelial associated" (i.e. tonsillar and base of tongue cancer; TSCC and BOTSCC respectively) and "non-lymphoepithelial" ("other" OPSCC) OPSCC were included. Pooled odds ratios by HPV detection method were analysed using a random effects model.

Results: In total, 58 unique patient cohorts were identified. Total HPV prevalence in TSCC/BOTSCC was 56%, 95%CI: 55-57% (59%, 95%CI: 58-60% for TSCC only) as compared to 19%, 95%CI: 17-20%, in "other" OPSCC. Significant association of HPV to TSCC/BOTSCC vs. "other" OPSCC was observed no matter HPV detection method used, but statistical homogeneity was only observed when studies using algorithm based HPV detection were pooled.

Conclusion: HPV prevalence differs markedly between OPSCC sub-sites and while the role of HPV in TSCC/BOTSCC is strong, the role in "other" OPSCC is more uncertain and needs further evaluation.
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http://dx.doi.org/10.1016/j.pvr.2017.05.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5883233PMC
December 2017