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  • 1
    Abstract: BACKGROUND: We conducted a large international study to estimate fractions of head and neck cancers (HNCs) attributable to human papillomavirus (HPV-AFs) using six HPV-related biomarkers of viral detection, transcription, and cellular transformation. METHODS: Formalin-fixed, paraffin-embedded cancer tissues of the oral cavity (OC), pharynx, and larynx were collected from pathology archives in 29 countries. All samples were subject to histopathological evaluation, DNA quality control, and HPV-DNA detection. Samples containing HPV-DNA were further subject to HPV E6*I mRNA detection and to p16(INK4a), pRb, p53, and Cyclin D1 immunohistochemistry. Final estimates of HPV-AFs were based on HPV-DNA, HPV E6*I mRNA, and/or p16(INK4a) results. RESULTS: A total of 3680 samples yielded valid results: 1374 pharyngeal, 1264 OC, and 1042 laryngeal cancers. HPV-AF estimates based on positivity for HPV-DNA, and for either HPV E6*I mRNA or p16(INK4a), were 22.4%, 4.4%, and 3.5% for cancers of the oropharynx, OC, and larynx, respectively, and 18.5%, 3.0%, and 1.5% when requiring simultaneous positivity for all three markers. HPV16 was largely the most common type. Estimates of HPV-AF in the oropharynx were highest in South America, Central and Eastern Europe, and Northern Europe, and lowest in Southern Europe. Women showed higher HPV-AFs than men for cancers of the oropharynx in Europe and for the larynx in Central-South America. CONCLUSIONS: HPV contribution to HNCs is substantial but highly heterogeneous by cancer site, region, and sex. This study, the largest exploring HPV attribution in HNCs, confirms the important role of HPVs in oropharyngeal cancer and drastically downplays the previously reported involvement of HPVs in the other HNCs.
    Type of Publication: Journal article published
    PubMed ID: 26823521
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  • 2
    Abstract: Patients with neck squamous cell carcinomas of unknown primary tumour (NSCCUP) present with lymph node metastasis without evidence for a primary tumour. Most patients undergo an aggressive multimodal treatment, which induces severe, potentially unnecessary toxicity. Primary tumours of NSCCUP can be hidden in the oropharynx. Human papillomavirus (HPV) is causally involved in a subgroup of oropharyngeal squamous cell carcinomas (OPSCC) associated with early lymph node metastasis and good prognosis. Detection of markers for HPV transformation in NSCCUP could allow focussing on the oropharynx in primary tumour search and could be of value for choice and extent of treatment. In a retrospective multicentre study (Germany, Italy and Spain), we analysed metastatic lymph nodes from 180 NSCCUP patients for the presence of HPV DNA, HPV E6*I mRNA and cellular p16INK4a overexpression, a surrogate marker for HPV-induced transformation. HPV status, defined as positivity for viral mRNA with at least one additional marker, was correlated with clinical parameters and survival outcome. A substantial proportion (16%) of NSCCUP were HPV-driven, mainly by HPV16 (89%). HPV prevalence increased with year of diagnosis from 9% during 1998-2004 to 23% during 2005-2014 (p = 0.007). HPV-driven NSCCUP had significantly better overall and progression-free survival rates (p 〈/= 0.008). Based on this survival benefit, it is contended that HPV RNA status should be included in NSCCUP diagnosis and in therapeutic decision-making. Deintensification of radiation in patients with HPV-driven NSCCUP, while concurrently concentrating on the oropharynx appears to be a promising therapeutic strategy, the efficacy of which should be assessed in prospective trials. To our knowledge, this is the largest study on HPV in NSCCUP.
    Type of Publication: Journal article published
    PubMed ID: 28335889
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  • 3
    Abstract: BACKGROUND: The etiologic role of human papillomaviruses (HPV) in oropharyngeal cancer (OPC) is well established. Nevertheless, information on survival differences by anatomic sub-site or treatment remains scarce, and it is still unclear the HPV-relatedness definition with best diagnostic accuracy and prognostic value. METHODS: We conducted a retrospective cohort study of all patients diagnosed with a primary OPC in four Catalonian hospitals from 1990 to 2013. Formalin-fixed, paraffin-embedded cancer tissues were subjected to histopathological evaluation, DNA quality control, HPV-DNA detection, and p16(INK4a)/pRb/p53/Cyclin-D1 immunohistochemistry. HPV-DNA positive and a random sample of HPV-DNA negative cases were subjected to HPV-E6*I mRNA detection. Demographic, tobacco/alcohol use, clinical and follow-up data were collected. Multivariate models were used to evaluate factors associated with HPV positivity as defined by four different HPV-relatedness definitions. Proportional-hazards models were used to compare the risk of death and recurrence among HPV-related and non-related OPC. RESULTS: 788 patients yielded a valid HPV-DNA result. The percentage of positive cases was 10.9%, 10.2%, 8.5% and 7.4% for p16(INK4a), HPV-DNA, HPV-DNA/HPV-E6*I mRNA, and HPV-DNA/p16(INK4a), respectively. Being non-smoker or non-drinker was consistently associated across HPV-relatedness definitions with HPV positivity. A suggestion of survival differences between anatomic sub-sites and treatments was observed. Double positivity for HPV-DNA/p16(INK4a) showed strongest diagnostic accuracy and prognostic value. CONCLUSIONS: Double positivity for HPV-DNA/p16(INK4a), a test that can be easily implemented in the clinical practice, has optimal diagnostic accuracy and prognostic value. Our results have strong clinical implications for patients' classification and handling and also suggest that not all the HPV-related OPC behave similarly.
    Type of Publication: Journal article published
    PubMed ID: 29496041
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  • 4
    ISSN: 1434-4726
    Keywords: Key words Laryngeal carcinoma ; Laryngectomy ; Organ preservation ; Chemotherapy ; Treatment costs
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Various studies report an increase in costs when induction chemotherapy is included in the treatment of advanced laryngeal cancer, but to our knowledge no studies have yet compared the economic costs of total laryngectomy versus induction chemotherapy in the treatment of advanced laryngeal cancer. We have conducted a retrospective study comparing the costs of treatment and survival in 96 patients with a T3N0-1 glottic carcinoma. Findings showed that the average cost per patient in the group of patients treated by total laryngectomy with or without postoperative radiotherapy was 5,853 Eur, while that for the group of patients who began treatment with induction chemotherapy was 6,452 Eur. The adjusted 5-year survival for patients treated with total laryngectomy with or without postoperative radiotherapy was 80%, and 72% for patients who began treatment with induction chemotherapy. Sixteen of the 35 patients (46%) receiving induction chemotherapy were spared laryngectomy. The use of induction chemotherapy in the treatment of patients with advanced laryngeal carcinomas involved an increase in cost of 600 Eur in relation to treatment with total laryngectomy and postoperative radiotherapy. However, from an economic point of view, we consider induction chemotherapy to be an important consideration in an organ-preservation strategy.
    Type of Medium: Electronic Resource
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  • 5
    ISSN: 1434-4726
    Keywords: Key words Supraglottic cancer ; Early stages ; Radiotherapy ; Partial surgery ; Laser
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract The purpose of this study was to define the treatment of choice (partial laryngectomy vs radiotherapy) in the early stage of supraglottic squamous cell cancer (ESSC). One hundred and fifteen patients with ESSC were treated with either partial laryngectomy (25 patients) or with radiotherapy(90 patients) between January 1984 and December 1996. All patients had a follow-up of over ¶29 months. Radiotherapy (RT) had a local control rate of 79%, which increased to 90% with salvage surgery, and a high larynx preservation rate (83%). Partial laryngectomy (PL) offered a better initial local control rate of 84%, which increased to 88% with salvage surgery, and functional results were also good (80%). No statistically significant differences were found between RT and PL. RT was less costly, showed better suitability for treatment, produced moderate morbidity and sequelae, and local recurrence was easier to rescue. However, it is a once-only application technique. PL showed higher immediate postoperative morbidity, higher cost and lower suitability for treatment but had fewer sequelae, offered the best initial local control and is multi-applicable. No clear oncological arguments were found in our series to define whether PL or RT is the treatment of choice for ESSC. Both are effective therapies. Secondary factors such as suitability for treatment, morbidity, cost and applicability should be individually evaluated when choosing the type of treatment. As the laser endoscopic approach decreases morbidity and costs and makes the condition more suitable for treatment, it could be the treatment of choice for ESSC, in cases where local tumoral extent and larynx exposure allow radical excision.
    Type of Medium: Electronic Resource
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  • 6
    ISSN: 1434-4726
    Keywords: Key words Metastatic neck nodes ; Induction ¶chemotherapy ; Regional treatment ; Head and neck ¶carcinoma
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Responsiveness of neck nodes to induction chemotherapy often differs from that of the primary tumour. We have conducted a retrospective study to evaluate the results of treating the neck in a cohort of 350 patients with locally advanced (T3–4) head and neck carcinomas treated with radiation therapy at the primary location of the tumour after induction chemotherapy. One hundred and thirty-nine patients (40%) did not have neck nodes on diagnosis (N0). The treatment of the neck included surgery in 65 patients. Neck dissections were carried out before radiotherapy in 37 patients and after radiotherapy in 28 patients. The frequency of neck treatment failure was 24%. There was a tendency to better neck control when treatment included neck dissection, independently of the neck stage or response to chemotherapy. This tendency was statistically significant in patients with an advanced regional tumour (N2–3) who did not achieve a complete regional response after chemotherapy. In a multivariate analysis the variables that were related to the regional failure were the relapse of the tumour at the primary site, the neck stage (N), the type of treatment used in the neck, and the grade of regional response after induction chemotherapy. Our results lead us to suggest that after induction chemotherapy neck surgery is advisable in all cases with advanced regional disease (N2–3), independently of the grade of response achieved after induction chemotherapy, and is also advisable in N1 patients in whom induction chemotherapy does not achieve a complete response.
    Type of Medium: Electronic Resource
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  • 7
    Publication Date: 2018-07-06
    Description: Background: Cortactin ( CTTN ) and the focal adhesion kinase ( FAK ) are two major candidate genes to, respectively, drive 11q13- and 8q24-associated aggressive behavior in various cancers. Recent evidence uncovered their clinical relevance in early stages of tumorigenesis as promising biomarkers for cancer risk assessment. Methods: Using a multicenter validation study, CTTN and FAK expression was evaluated by immunohistochemistry (IHC) in a cohort of 109 patients with laryngeal precancerous lesions, and correlated with clinicopathologic parameters and laryngeal cancer risk. The pathophysiologic role of CTTN and FAK was further investigated using functional studies in cellular models. Results: Positive CTTN and FAK expression (scores 2 and 3) was detected in 49 (41%) and 35 (32%) laryngeal dysplasias, respectively. Univariate Cox analysis showed that CTTN and FAK expression but not histologic grading was significantly associated with both recurrence risk and laryngeal cancer risk. Patients carrying strong CTTN- or FAK-expressing lesions (score 3) experienced the highest laryngeal cancer incidence (log-rank P 〈 0.001). In multivariate stepwise analysis, FAK expression [HR = 13.91; 95% CI, 4.82–40.15; P 〈 0.001] and alcohol consumption (HR = 2.22; 95% confidence interval, 1.17–4.20; P = 0.014) were significant independent predictors of laryngeal cancer development. Targeting FAK by either RNAi or pharmacologic inhibitors effectively blocked cell growth, colony formation, and invasion into 3D collagen matrices. Conclusions: CTTN and FAK emerge as powerful predictors of laryngeal cancer risk and recurrence risk beyond histologic grading. Impact: Our work supports the applicability of IHC CTTN and FAK as complementary markers for risk stratification in patients with laryngeal precancerous lesions. Cancer Epidemiol Biomarkers Prev; 27(7); 805–13. ©2018 AACR .
    Print ISSN: 1055-9965
    Electronic ISSN: 1538-7755
    Topics: Medicine
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