| 1. |
- Bersani, Cinzia, et al.
(författare)
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A model using concomitant markers for predicting outcome in human papillomavirus positive oropharyngeal cancer
- 2017
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Ingår i: Oral Oncology. - : Elsevier. - 1368-8375 .- 1879-0593. ; 68, s. 53-59
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Tidskriftsartikel (refereegranskat)abstract
- Objective: Head-neck cancer therapy has become intensified. With radiotherapy alone, 3-year disease-free survival (DFS) is 80% for HPV-positive TSCC/BOTSCC and better for patients with favorable characteristics, suggesting therapy could be tapered for some, decreasing side-effects. Therefore, we built a model to predict progression-free survival for patients with HPV-positive TSCC and BOTSCC. Material and methods: TSCC/BOTSCC patients treated curatively between 2000 and 2011, with HPV16 DNA/E7 mRNA positive tumors examined for CD8(+) TILs, HPV16 mRNA and HLA class I expression were included. Patients were split randomly 65/35 into training and validation sets, and LASSO regression was used to select a model in the training set, the performance of which was evaluated in the validation set. Results: 258 patients with HPV DNA/E7 mRNA positive tumors could be included, 168 and 90 patients in the respective sets. No treatment improved prognosis compared to radiotherapy alone. CD8(+) TIL counts and young age were the strongest predictors of survival, followed by T-stage <3 and presence of HPV16 E2 mRNA. The model had an area under curve (AUC) of 76%. A model where the presence of three of four of these markers defined good prognosis captured 56% of non-relapsing patients with a positive predictive value of 98% in the validation set. Furthermore, the model identified 35% of our cohort that was over-treated and could safely have received de-escalated therapy. Conclusion: CD8(+) TIL counts, age, T-stage and E2 expression could predict progression-free survival, identifying patients eligible for randomized trials with milder treatment, potentially reducing side effects without worsening prognosis.
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| 2. |
- Bersani, Cinzia, et al.
(författare)
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Targeted sequencing of tonsillar and base of tongue cancer and human papillomavirus positive unknown primary of the head and neck reveals prognostic effects of mutated FGFR3
- 2017
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Ingår i: Oncotarget. - : IMPACT JOURNALS LLC. - 1949-2553. ; 8:21, s. 35339-35350
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Human papillomavirus positive (HPV+) tonsillar cancer (TSCC), base of tongue cancer (BOTSCC) and unknown primary cancer of the head and neck (HNCUP) have better outcome than corresponding HPV- cancers. To find predictive markers for response to treatment, and correlations and differences in mutated oncogenes and suppressor genes between HPV+ TSCC/BOTSSCC and HPV+ HNCUP and HPV- TSCC/BOTSCC targeted next-generation sequencing was performed of frequently mutated regions in 50 cancer related genes.PATIENTS AND METHODS: DNA from 348 TSCC/BOTSCC and 20 HNCUP from patients diagnosed 2000-2011, was sequenced by the Ion Proton sequencing platform using the Ion AmpliSeq Cancer Hotspot Panel v2 to identify frequently mutated regions in 50 cancer related genes. Ion Torrent Variant Caller software was used to call variants.RESULTS: 279 HPV+ TSCC/BOTSCC, 46 HPV- TSCC/BOTSCC and 19 HPV+ HNCUP samples qualified for further analysis. Mutations/tumor were fewer in HPV+ TSCC/BOTSCC and HNCUP, compared to HPV- tumors (0.92 vs. 1.32 vs. 1.68). Differences in mutation frequency of TP53 and PIK3CA were found between HPV+ TSCC/BOTSCC and HNCUP and HPV- TSCC/BOTSCC. In HPV+ TSCC/BOTSCC presence of FGFR3 mutations correlated to worse prognosis. Other correlations to survival within the groups were not disclosed.CONCLUSIONS: In HPV+ TSCC/BOTSCC mutation of PIK3CA was most frequently observed, while TP53 mutations dominated in HPV- TSCC/BOTSCC. In HPV+ TSCC/ BOTSCC and HNCUP, mutations/tumor were similar in frequency and fewer compared to that in HPV- TSCC/BOTSCC. Notably, FGFR3 mutations in HPV+ TSCC/BOTSCC indicated worse prognosis.
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| 3. |
- Nordfors, Cecilia, et al.
(författare)
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Oral human papillomavirus prevalence in high school students of one municipality in Sweden
- 2013
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Ingår i: Scandinavian Journal of Infectious Diseases. - : Informa UK Limited. - 0036-5548 .- 1651-1980. ; 45:11, s. 878-881
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Tidskriftsartikel (refereegranskat)abstract
- The rise in human papillomavirus (HPV) infection has been suggested to be responsible for the increased incidence of oropharyngeal cancer in the Western world. This has boosted interest in oral HPV prevalence and whether HPV vaccines can prevent oral HPV infection. In a previous study we showed oral HPV prevalenceto be almost 10% in youth aged 15-23 y attending a youth clinic in Stockholm, Sweden. However, this may not be a generalizable sample within the Swedish population. Therefore, mouthwashes were used to investigate oral HPV prevalence in 335 Swedish high school students aged 17-21 y (median age 18 y), from 1municipality with 140,000 inhabitants. The presence of HPV DNA in the oral samples, as examined by a Luminex-based assay, was significantly lower in this cohort, only 1.8% (3.1% in females and 0.6% in males), as compared to our previous study.
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| 4. |
- Sivars, Lars, et al.
(författare)
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Cell-Free Human Papillomavirus DNA Is a Sensitive Biomarker for Prognosis and for Early Detection of Relapse in Locally Advanced Cervical Cancer
- 2024
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Ingår i: Clinical Cancer Research. - : American Association For Cancer Research (AACR). - 1078-0432 .- 1557-3265. ; 30:13, s. 2764-2771
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Tidskriftsartikel (refereegranskat)abstract
- Purpose: Human papillomavirus (HPV) is the cause of the majority of cervical cancer cases and has been showed to be released as cell-free tumor DNA (ctHPV DNA) into the circulation. Here, we analyze if ctHPV DNA could be used as a prognostic biomarker and/or to detect relapse earlier than traditional methods in locally advanced cervical cancer (LACC).Experimental Design: A total of 74 patients with LACC were included; 66of 74 were positive for 13 high-risk HPV types on a bead-based assay of tumor biopsy samples. HPV-type-specific droplet digital PCR assays were developed. Longitudinal plasma samples were then analyzed for the biopsy-verified HPV type for each patient. In total, 418 plasma samples were analyzed. Patients were followed for a median of 37 months. Results were correlated to tumor and clinical characteristics.Results: Of the pretreatment plasma samples, 92.4% were positive for ctHPV DNA. Persistent ctHPV DNA in end-of-treatment, early follow-up (1-2 months after end-of-treatment), or tumor evaluation (3-4 months after end-of-treatment) plasma was correlated with worse progression-free survival (P < 0.001) compared with if ctHPV DNA was not found. The positive predictive value of ctHPV status at early follow-up for predicting disease progression was 87.5%, and the negative predictive value was 89.3%. ctHPV DNA was found in plasma before relapse was diagnosed using radiology in all patients (n = 10) who experienced relapse after complete clinical response to treatment with a median 315 days lead time.Conclusions: ctHPV DNA in follow-up plasma is a promising prognostic biomarker in patients with LACC, useful for analysis of response to therapy and for early detection of relapse.
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| 5. |
- Sivars, Lars
(författare)
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Human papillomavirus and other biomarkers in neck masses of unknown origin and in head and neck cancer
- 2018
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Background. Human papillomavirus (HPV) is, in addition to smoking and alcohol, a risk factor for developing oropharyngeal squamous cell carcinoma (OPSCC), and more specifically tonsillar- and base of tongue squamous cell carcinoma (TSCC & BOTSCC respectively). Interestingly, HPV-positive (HPV+) TSCC/BOTSCC has a remarkably better clinical outcome than HPV-negative (HPV-) TSCC/BOTSCC and head and neck cancer in general. However, the role of HPV and other biomarkers in cancer of unknown primary in the head and neck region (HNCUP), i.e. where only a lymph node metastasis and no primary tumour is found, is not well understood. Moreover, the genetic landscape of HPV-positive HNCUP and the prognostic implications of certain mutations in TSCC/BOTSCC has not been studied extensively. Furthermore, using fine-needle aspiration cytology (FNAC) from neck masses for HPV-detection and potentially for predicting an HPV-positive TSCC/BOTSCC as the final diagnosis would be highly clinically useful, but has not been studied prospectively in a cohort consisting of both malignant and benign neck masses. Aims. To investigate HPV DNA and mRNA and other prognostic biomarkers (p16, p53, CD8+ tumour infiltrating lymphocytes (TILs), HLA Class I expression) in HNCUP in relation to clinical outcome. Moreover, to study mutations in HPV+ HNCUP and TSCC/BOTSCC in relation to prognosis and to analyse whether HPV-detection in FNAC from neck masses is reliable and if a finding of HPV could predict an HPV+ TSCC/BOTSCC as the final diagnosis. Results. In Paper I, we show that HPV is a favourable prognostic factor in HNCUP, and in Paper II, we validate this finding in a separate cohort (3-year overall survival 86% vs. 54% for HPV+ and HPV- HNCUP respectively, in the combined cohorts). In Paper II, we also demonstrate that HPV mRNA is expressed in the vast majority of HPV DNA+ HNCUP. Moreover, in Paper I we find that high p53-expression correlates to a poor prognosis, and in Paper II that a low number of CD8+ TILs are potentially related to a poor outcome, while HLA Class I expression does not appear to be a prognostic factor in HNCUP. In Paper III, we show that TP53, CDKN2A and PIK3CA are the most commonly mutated genes in HPV+ HNCUP, and that having a mutation in FGFR3 correlated to a poor prognosis in HPV+ TSCC/BOTSCC. In Paper IV, we demonstrate that HPV DNA detection in FNAC from neck masses of unknown origin is reliable and could be used prospectively to predict an HPV+ TSCC/BOTSCC as the final diagnosis. HPV DNA was not found in malignant conditions other than HPV+ TSCC/BOTSCC or in any benign conditions, including branchial cleft cysts. Conclusions. HPV appears to have a similar causative and prognostic role in HNCUP as in TSCC/BOTSCC. Investigation of HPV-status should therefore be part of the diagnostic work-up of an HNCUP. Examination of HPV DNA-status using FNAC is useful in the clinical investigation of patients with neck masses of unknown origins, including patients eventually diagnosed with HNCUP or TSCC/BOTSCC.
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| 6. |
- Sivars, Lars, et al.
(författare)
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Human papillomavirus DNA detection in fine-needle aspirates as indicator of human papillomavirus-positive oropharyngeal squamous cell carcinoma : A prospective study
- 2017
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Ingår i: Head and Neck. - : Wiley. - 1043-3074 .- 1097-0347. ; 39:3, s. 419-426
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Tidskriftsartikel (refereegranskat)abstract
- Background. Human papillomavirus (HPV)-positive oropharyngeal squamous cell carcinoma (SCC) has a better outcome than most head neck squamous cell carcinomas (HNSCCs) and an HPV-positive lymph node metastasis likely has an HPV-positive oropharyngeal SCC origin. Determining HPV-status in cervical lymph nodes by fine-needle aspiration cytology (FNAC) may be useful for diagnosis. Methods. FNACs from 66 patients with neck masses were prospectively examined for HPV DNA and HPV16 mRNA by a polymerase chain reaction (PCR)-based assay, and the data correlated to diagnosis and HPV-status obtained from histopathological specimens. Results. Aspirates from 17 of 66 patients, later diagnosed with HPV-positive oropharyngeal SCC, were HPV16 DNA-positive. HPV16 mRNA was detected in all cases with extractable RNA. All remaining FNACs, including 18 branchial cleft cysts, were HPV DNA-negative. HPV DNA status in the aspirates showed perfect concordance with corresponding biopsies. Conclusion. HPV16 DNA detection in fine-needle aspirations from neck masses is reliable and HPV16 DNA in a metastasis is a strong indicator of an HPV-positive oropharyngeal SCC.
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| 7. |
- Zupancic, Mark, et al.
(författare)
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Human papillomavirus (HPV) load is higher in HPVDNA/p16 positive than in HPVDNA positive/p16 negative oropharyngeal squamous cell carcinoma but does not differ significantly between various subsites or correlate to survival
- 2024
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Ingår i: Oral Oncology. - : Elsevier. - 1368-8375 .- 1879-0593. ; 151
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Tidskriftsartikel (refereegranskat)abstract
- ObjectivePatients with human papillomavirus DNA positive (HPVDNA+) and p16ink4a overexpressing (p16+) oropharyngeal squamous cell carcinoma (OPSCC), especially those with cancer in the tonsillar and base of tongue subsites as compared to other OPSCC subsites have a better outcome than those with only HPVDNA+ or only p16+ cancer. Likewise having a high viral load has been suggested to be a positive prognostic factor. We therefore hypothesized, that HPV viral load could vary depending on OPSCC subsite, as well as with regard to whether the cancer was HPVDNA+ and p16+, or only HPVDNA+, or only p16+ and that this affected outcome.Material and methodsTo address these issues HPV viral load was determined by HPV digital droplet (dd) PCR in tumor biopsies with previously known HPVDNA/p16 status from 270 OPSCC patients diagnosed 2000–2016 in Stockholm, Sweden. More specifically, of these patients 235 had HPVDNA+/p16+, 10 had HPVDNA+/p16-, 13 had HPVDNA-/p16+ and 12 had HPVDNA-/p16- cancer.ResultsWe found that HPVDNA+/p16+ OPSCC had a significantly higher viral load than HPVDNA+/p16- OPSCC. Moreover, there was a tendency for a higher viral load in the tonsillar and base of tongue OPSCC subsites compared to the other subsites and for a low viral load to correlate to a better clinical outcome but none of these tendencies reached statistical significance.ConclusionTo conclude, the mean viral load in HPVDNA+/p16+ OPSCC was higher than in HPVDNA+/p16- OPSCC, but there was no statistically significant difference in viral load depending on OPSCC subsite or on clinical outcome.
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