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Tongue cancers are common in the spectrum of oral malignancies. In base of tongue cancers, tumour excision might lead to injury of ipsilateral or both lingual arteries, leading to ischemia of residual, native tongue. Free radial artery forearm flap is commonly used for tongue reconstruction. It can also be used as a flow-through flap for the reconstruction of the tongue defect as well as to revascularise the cancer-free tongue remnant. We report here two cases of base of tongue excision for which free flow-through radial forearm flap was used to reconstruct the tongue defect as well as salvage the remaining part of ischemic tongue. This technique can be effectively considered in selected cases of vascular compromise due to lingual vessel sacrifice to preserve the cancer-free anterior native tongue tissue with improved functional outcomes. [ABSTRACT FROM AUTHOR]

Background: The purpose of this retrospective cohort study is to describe the association between the history of tonsillectomy and the risk of oropharyngeal squamous cell carcinoma (OPSSC), using a large cohort of patients. Materials and methods: We performed a retrospective cohort study with 3620 patients diagnosed with OPٍSCC from 2010 to 2021. We utilized the University of Florida patients' registry i2b2 system. Three subsets of OPSSC were defined, base of tongue(BOT) cancer, tonsillar cancer, and other OPSSC. Tumor demographics and history of tonsillectomy were collected. Odds ratio for OPSSC were assessed utilizing a logistic regression model with adjusting for gender, race, and age. P < 0.05 was deemed significant. Results: Of the 3620 OPSSC patients were BOT cancer (N = 964), tonsillar cancer (N = 995), and other OPSSC (N = 1661). There was a statistically significant reduction in tonsillar cancer and BOT cancer odds ratio in patients with a history of tonsillectomy vs. patients without tonsillectomy (0.086 and 0.117), respectively, with a P value <.0001. The odds ratio of OPSSC in patients with a history of tonsillectomy vs. patients without tonsillectomy is 1.031. Conclusion: This study showed that the OPSSC and previous history of tonsillectomy are associated. Our results showed a significant reduction in BOT and tonsillar cancer risk in patients with a history of tonsillectomy and an insignificant decrease in other OPSSC. This study could emphasize the importance of the development of future clinical trials to investigate the role of prophylactic tonsillectomy as a secondary preventive strategy to reduce OPSSC. [ABSTRACT FROM AUTHOR]

Background and Objectives: to describe current scientific knowledge regarding the treatment options in advanced oropharyngeal cancer. The standard care for advanced oropharyngeal cancer (OPSCC) has been chemoradiotherapy, although surgical approaches followed by adjuvant treatment have been proposed. The best therapy for each patient should be decided by an interdisciplinary tumour-board. Different strategies should be considered for the specific patient's treatment: surgery, chemotherapy and radiation therapy or combinations of them. The treatment choice is influenced by tumour variability and prognostic factors, but it also depends on cancer extension, extranodal extension, nervous invasion, human papilloma virus (HPV) presence, making the decisional algorithm not always clear. HPV-related OPSCC is strongly associated with a favourable overall survival (OS) and disease-free survival rate (DSS); by contrast, HPV-negative OPSCC often flags a worse prognosis. Consequently, the American Joint Committee on Cancer (AJCC) differentiates OPSCC treatment and prognosis based on HPV status. Methods: we carried out a review of current scientific literature to analyze the different indications and limitations of surgical treatment options in OPSCC stage III and IV. Conclusion: robotic surgery or open approaches with reconstructive flaps can be considered in advanced stages, resulting in the de-intensification of subsequent systemic therapy and fewer related side effects. Furthermore, in the event of the primary failure of systemic therapy or disease recurrence, the surgical approach constitutes an additional therapeutic option which lengthens patient survival functions. [ABSTRACT FROM AUTHOR]

Base of tongue cancer incidence and patient survival is increasing why treatment sequelae becomes exceedingly important. Osteoradionecrosis (ORN) is a late adverse effect of radiotherapy and brachytherapy (BT) could be a risk factor. Brachytherapy is used in three out of six health care regions in Sweden. Investigate if patients treated in regions using BT show an increased risk for ORN and whether brachytherapy has any impact on overall survival. We used data from the Swedish Head and Neck Cancer Register between 2008–2014. Due to the nonrandomized nature of the study and possible selection bias we compared the risk for ORN in brachy vs non-brachy regions. Fifty out of 505 patients (9.9%) developed ORN; eight of these were treated in nonbrachy regions (16%), while 42 (84%) were treated in brachy regions. Neither age, sex, TNM-classification/stage, p16, smoking, neck dissection, or chemotherapy differed between ORN and no-ORN patients. The risk for ORN was significantly higher for patients treated in brachy regions compared to non-brachy regions (HR = 2,63, p =.012), whereas overall survival did not differ (HR = 0.95, p =.782). Brachytherapy ought to be used cautiously for selected patients or within prospective randomized studies. [ABSTRACT FROM AUTHOR]

Simple Summary: Human papillomavirus positive tonsillar and base of tongue cancers are rising in incidence but chemoradiotherapy has not improved survival, so novel treatments are needed. Therefore, targeted therapy with phosphoinositide 3-kinase, poly-ADP-ribose-polymerase, and WEE1 inhibitors was pursued alone or combined with/without radiotherapy or using APR-246 and their effects were analyzed by WST-1 viability, proliferation, and cytotoxicity assays on tonsillar and base of tongue cancer cell lines. All three inhibitors induced dose dependent inhibition of viability and proliferation and their effects were enhanced by adding irradiation or by combining the inhibitors. However, adding irradiation to already synergistic inhibitor combinations did generally not induce additional inhibitory effects. Only very high APR-246 doses decreased viability, so its use was limited in this context. To conclude, the effects of the inhibitors were frequently enhanced by adding radiotherapy or by combining them, but adding radiotherapy to the latter did not generally induce further inhibition. Human papillomavirus positive (HPV+) tonsillar and base of tongue cancer (TSCC/BOTSCC) is rising in incidence, but chemoradiotherapy is not curative for all. Therefore, targeted therapy with PI3K (BYL719), PARP (BMN-673), and WEE1 (MK-1775) inhibitors alone or combined was pursued with or without 10 Gy and their effects were analyzed by viability, proliferation, and cytotoxicity assays on the TSCC/BOTSCC cell lines HPV+ UPCI-SCC-154 and HPV− UT-SCC-60A. Effective single drug/10 Gy combinations were validated on additional TSCC lines. Finally, APR-246 was assessed on several TSCC/BOTSCC cell lines. BYL719, BMN-673, and MK-1775 treatments induced dose dependent responses in HPV+ UPCI-SCC-154 and HPV− UT-SCC-60A and when combined with 10 Gy, synergistic effects were disclosed, as was also the case upon validation. Using BYL719/BMN-673, BYL719/MK-1775, or BMN-673/MK-1775 combinations on HPV+ UPCI-SCC-154 and HPV− UT-SCC-60A also induced synergy compared to single drug administrations, but adding 10 Gy to these synergistic drug combinations had no further major effects. Low APR-246 concentrations had limited usefulness. To conclude, synergistic effects were disclosed when complementing single BYL719 BMN-673 and MK-1775 administrations with 10 Gy or when combining the inhibitors, while adding 10 Gy to the latter did not further enhance their already additive/synergistic effects. APR-246 was suboptimal in the present context. [ABSTRACT FROM AUTHOR]

Human papillomavirus positive (HPV+) tonsillar and base of tongue squamous cell carcinoma (TSCC/BOTSCC) have a favorable outcome, but upon relapse, survival is poor and new therapeutical options are needed. Recently, we found synergistic effects by combining the food and drug administration approved (FDA) phosphoinositide 3-kinase (PI3K) and fibroblast-growth-factor-receptor (FGFR) inhibitors BYL719 and JNJ-42756493 on TSCC cell lines. Here this approach was extended and Cyclin-Dependent-Kinase-4/6 (CDK4/6) and Poly-ADP-ribose-polymerase (PARP) and WEE1 inhibitors PD-0332991, and MK-1775 respectively were also examined. HPV+ CU-OP-2, -3, -20, and HPV− CU-OP-17 TSCC cell lines were treated with either BYL719 and JNJ-42756493, PD-0332991 BMN-673 and MK-1775 alone or in different combinations. Viability, proliferation, and cytotoxicity were followed by WST-1 assays and the IncuCyte S3 Live® Cell Analysis System. All inhibitors presented dose-dependent inhibitory effects on tested TSCC lines. Synergy was frequently obtained when combining CDK4/6 with PI3K inhibitors, but only sometimes or rarely when combining CDK4/6 with FGFR inhibitors or PARP with WEE1 inhibitors. To conclude, using CDK4/6 with PI3K or FGFR inhibitors, especially PD-0332991 with BYL719 presented synergy and enhanced the decrease of viability considerably, while although dose dependent responses were obtained with PARP and WEE1 inhibitors (BMN-673 and MK-1775 resp.), synergy was rarely disclosed. [ABSTRACT FROM AUTHOR]

The base of tongue squamous cell carcinoma (BOTSCC) is mainly an HPV-related tumor. Radiotherapy (EBRT) ± concomitant chemotherapy (CT) is the backbone of the curatively intended treatment, with brachytherapy (BT) boost as an option. With four different treatment strategies in Sweden, a retrospective study based on the population-based Swedish Head and Neck Cancer Register (SweHNCR) was initiated. Data on tumors, treatment and outcomes in patients with BOTSCC treated between 2008 and 2014 were validated through medical records and updated as needed. Data on p16 status were updated or completed with immunohistochemical analysis of archived tumor material. Tumors were reclassified according to the UICC 8th edition. Treatment was EBRT, EBRT + CT, EBRT + BT or EBRT + CT + BT in 151, 145, 82 and 167 patients respectively (n = 545). A p16 analysis was available in 414 cases; 338 were p16+ and 76 p16−. 5-year overall survival (OS) was 68% (95% CI: 64–72%), with76% and 37% for p16+ patients and p16− patients, respectively. An increase in OS was found with the addition of CT to EBRT for patients with p16+ tumors, stages II–III, but for patients with tumor stage I, p16+ (UICC 8) none of the treatment strategies was superior to EBRT alone. In the present retrospective population-based study of BOTSCC brachytherapy was found to be of no beneficial value in curatively intended treatment. An increase in survival was found for EBRT + CT compared to EBRT alone in patients with advanced cases, stages II and III (UICC 8), but none of the regimes was significantly superior to EBRT as a single treatment modality for stage I (UICC 8), provided there was p16 positivity in the tumor. In the small group of patients with p16− tumors, a poorer prognosis was found, but the small sample size did not allow any comparisons between different treatment strategies. [ABSTRACT FROM AUTHOR]

Background and Objectives: to describe current scientific knowledge regarding the treatment options in advanced oropharyngeal cancer. The standard care for advanced oropharyngeal cancer (OPSCC) has been chemoradiotherapy, although surgical approaches followed by adjuvant treatment have been proposed. The best therapy for each patient should be decided by an interdisciplinary tumour-board. Different strategies should be considered for the specific patient’s treatment: surgery, chemotherapy and radiation therapy or combinations of them. The treatment choice is influenced by tumour variability and prognostic factors, but it also depends on cancer extension, extranodal extension, nervous invasion, human papilloma virus (HPV) presence, making the decisional algorithm not always clear. HPV-related OPSCC is strongly associated with a favourable overall survival (OS) and disease-free survival rate (DSS); by contrast, HPV-negative OPSCC often flags a worse prognosis. Consequently, the American Joint Committee on Cancer (AJCC) differentiates OPSCC treatment and prognosis based on HPV status. Methods: we carried out a review of current scientific literature to analyze the different indications and limitations of surgical treatment options in OPSCC stage III and IV. Conclusion: robotic surgery or open approaches with reconstructive flaps can be considered in advanced stages, resulting in the de-intensification of subsequent systemic therapy and fewer related side effects. Furthermore, in the event of the primary failure of systemic therapy or disease recurrence, the surgical approach constitutes an additional therapeutic option which lengthens patient survival functions.

Abstract Background Human papillomavirus (HPV) is a causative agent for tonsillar and base of tongue squamous cell carcinoma (TSCC/BOTSCC), as well as for cervical cancer. Premalignant stages in cervical cancer have been studied extensively, while little is known about premalignant stages in TSCC/BOTSCC and the role of HPV. Here we analyzed differences in gene and protein expression between high‐grade dysplasia and invasive cancer in both HPV‐positive (HPV+) and HPV‐negative (HPV−) TSCC/BOTSCC. Methods High‐grade dysplasia and invasive carcinoma were laser microdissected from HPV+ and HPV− TSCC/BOTSCC tumor sections. Differential gene expression was studied utilizing nanoString RNA‐panels and genes of interest were validated on the protein level by immunohistochemistry. Results Forty genes in the HPV+ tumors showed significantly different expression between high‐grade dysplasia and invasive cancer and 33 genes in the HPV− tumors. Five out of the nine most significant pathways showed similar increased activity in invasive cancer as compared to high‐grade dysplasia in both HPV+ and HPV− tumors. Lastly, significant differences in protein expression was confirmed for SPARC, psoriasin, type I collagen and galectin‐1 in both HPV+ and HPV− tumors. Conclusions This is to our knowledge the first study disclosing differences and similarities in gene expression between dysplastic and invasive HPV+ and HPV− TSCC/BOTSCC.

ObjectivesHuman 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.MethodsThe 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.ResultsHPV+ 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.ConclusionsThe 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.

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. [ABSTRACT FROM AUTHOR]

Background/Aims Clinical trials have not consistently supported the use of induction chemotherapy (IC) for locally advanced head and neck squamous cell cancer. Hypopharynx and base of tongue (BOT) cancer has shown relatively poor survival. We investigated the role of IC in improving outcome over current chemoradiotherapy (CRT) in patients with hypopharynx and BOT cancer. Methods Treatment-naïve patients with stage III/IV (M0) hypopharynx or BOT cancer were randomly assigned to receive CRT alone (CRT arm: cisplatin 100 mg/m2 on D1 3-weekly, two times plus radiotherapy 68.4 Gy/30 fractions on weekdays) versus two 21-day cycles of IC with TPF (docetaxel & cisplatin 75 mg/m2 on D1, and fluorouracil 75 mg/m2 on D1-4) followed by the same CRT regimen (IC arm). The primary endpoint was progression-free survival (PFS). Results This study closed early after enrollment of 36 patients (19 in the CRT arm, 17 in the IC arm). After a median follow-up of 47.2 months, there was no significant difference in PFS: the median PFS was 26.8 months for the CRT arm and was not reached for the IC arm (p = 0.13). However, the survival curves were widely separated with a plateau after 3 years, suggesting a potential survival benefit from IC: 3-year PFS rates were 45% and 68%, and 3-year overall survival rates were 56% and 86%, in the CRT and IC arms, respectively. Conclusions This study failed to demonstrate that induction TPF chemotherapy improves survival in patients with BOT and hypopharynx cancer. However, it suggested a favorable outcome with IC to this population.

Human papillomavirus positive (HPV+) tonsillar and base of tongue squamous cell carcinoma (TSCC/BOTSCC) have a favorable outcome, but upon relapse, survival is poor and new therapeutical options are needed. Recently, we found synergistic effects by combining the food and drug administration approved (FDA) phosphoinositide 3-kinase (PI3K) and fibroblast-growth-factor-receptor (FGFR) inhibitors BYL719 and JNJ-42756493 on TSCC cell lines. Here this approach was extended and Cyclin-Dependent-Kinase-4/6 (CDK4/6) and Poly-ADP-ribose-polymerase (PARP) and WEE1 inhibitors PD-0332991, and MK-1775 respectively were also examined. HPV+ CU-OP-2, -3, -20, and HPV− CU-OP-17 TSCC cell lines were treated with either BYL719 and JNJ-42756493, PD-0332991 BMN-673 and MK-1775 alone or in different combinations. Viability, proliferation, and cytotoxicity were followed by WST-1 assays and the IncuCyte S3 Live® Cell Analysis System. All inhibitors presented dose-dependent inhibitory effects on tested TSCC lines. Synergy was frequently obtained when combining CDK4/6 with PI3K inhibitors, but only sometimes or rarely when combining CDK4/6 with FGFR inhibitors or PARP with WEE1 inhibitors. To conclude, using CDK4/6 with PI3K or FGFR inhibitors, especially PD-0332991 with BYL719 presented synergy and enhanced the decrease of viability considerably, while although dose dependent responses were obtained with PARP and WEE1 inhibitors (BMN-673 and MK-1775 resp.), synergy was rarely disclosed.

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. [ABSTRACT FROM AUTHOR]

In 2007, human papillomavirus (HPV) type 16 was finally recognized as a risk factor, besides smoking and alcohol, for oropharyngeal squamous cell carcinoma (OPSCC), including tonsillar squamous cell carcinoma (TSCC), by the International Agency for Research against Cancer. Just before, in 2006, the Food and Drug Administration had approved Gardasil, the first vaccine against HPV16, 18, 6 and 11, for preventive vaccination women against cervical cancer. Concurrently, some Western countries, where smoking was decreasing, disclosed an epidemic increase in the incidence of OPSCC, especially of TSCC and base of tongue cancer (BOTSCC), together accounting for 80-90% of all OPSCCs, and mainly affecting men. The epidemic was later revealed to be due to a rise in HPV-positive cases, and scientists in the field suggested HPV vaccination also of boys. Globally, there are roughly 96 000 incident OPSCC cases/year of which 20-24% are caused by HPV, thereby accounting for around 22 000 OPSCC cases annually. Of these cases, 80-90% are due to HPV16 infection and would be prevented with the presently registered HPV vaccines. In Western countries, such as Sweden (with almost 400 TSCC and BOTSCC cases per year) and the United States, HPV prevalence in OPSCC is higher and around 70%. HPV vaccination of girls has been initiated in many countries, and the vaccines have been efficient and their side effects limited. HPV vaccination of boys has, however, been the exception, but should definitely not be delayed any further. It would benefit both girls and boys directly, and result in better and more robust herd immunity. Today, we have the possibility to eliminate several high-risk HPV types in the younger generations and avoid more than 600 000 cancer cases annually worldwide, and this possibility should be embraced by offering global pan-gender HPV vaccination. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Background: Human papillomavirus (HPV) is a causative agent for tonsillar and base of tongue squamous cell carcinoma (TSCC/BOTSCC), as well as for cervical cancer. Premalignant stages in cervical cancer have been studied extensively, while little is known about premalignant stages in TSCC/BOTSCC and the role of HPV. Here we analyzed differences in gene and protein expression between high‐grade dysplasia and invasive cancer in both HPV‐positive (HPV+) and HPV‐negative (HPV−) TSCC/BOTSCC. Methods: High‐grade dysplasia and invasive carcinoma were laser microdissected from HPV+ and HPV− TSCC/BOTSCC tumor sections. Differential gene expression was studied utilizing nanoString RNA‐panels and genes of interest were validated on the protein level by immunohistochemistry. Results: Forty genes in the HPV+ tumors showed significantly different expression between high‐grade dysplasia and invasive cancer and 33 genes in the HPV− tumors. Five out of the nine most significant pathways showed similar increased activity in invasive cancer as compared to high‐grade dysplasia in both HPV+ and HPV− tumors. Lastly, significant differences in protein expression was confirmed for SPARC, psoriasin, type I collagen and galectin‐1 in both HPV+ and HPV− tumors. Conclusions: This is to our knowledge the first study disclosing differences and similarities in gene expression between dysplastic and invasive HPV+ and HPV− TSCC/BOTSCC. [ABSTRACT FROM AUTHOR]

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 p16INK4a, 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 p16INK4a analysis was determined for 795 Stockholm cases from 2000 to 2016, with 72% being HPV DNA and p16INK4a 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. [ABSTRACT FROM AUTHOR]

Background: We performed an analysis of the National Cancer Database (NCDB) to evaluate overall survival (OS) in patients with base of tongue (BOT) cancer treated with external beam radiation therapy (EBRT) combined with brachytherapy (BT). Methods: The tongue NCDB Participant User File was used to obtain demographic and clinical patient data. The Kaplan–Meier method was used to determine OS. Significance was determined using univariable and multivariable Cox proportional hazards models. Results: At 3 years, OS was 69.6%, 77.1%, and 63.7% for patients treated with EBRT (n = 27 954), EBRT + BT (n = 209), or BT alone (n = 154), respectively (P = .01). On multivariable analysis, the instantaneous hazard of death for patients receiving EBRT + BT was 25% (Hazard ratio [HR] = 0.75, 95% CI: 0.58‐0.98) lower than patients receiving only EBRT (P = .03). Conclusions: The addition of BT to EBRT in BOT cancer has an OS benefit. [ABSTRACT FROM AUTHOR]

Objectives/hypothesis: To characterize the demographics, clinicopathologic characteristics, and treatment and reconstructive outcomes of patients who underwent total glossectomy STUDY DESIGN: Retrospective chart review at an academic tertiary-care medical center.Methods: All patients who had undergone total glossectomy (as an individual procedure or as part of a more extensive resection) between January 1, 1995 and December 31, 2014 were included in the analysis. Patient characteristics and clinical outcomes were reviewed.Results: Forty-eight patients underwent total glossectomy for oral tongue and base of tongue cancer. The mean age of the patients was 56 (range, 29-92 years). History of tobacco and heavy alcohol use was found in 76% and 11% of patients, respectively. The majority of patients had advanced cancer (91.7% at stage IV), and 60.4% had salvage therapy for recurrent disease. T4 disease comprised 81% of patients. Sixty percent had clinical or radiographic evidence of nodal metastasis. Reconstruction of the defect was performed with free flaps from the rectus abdominus (40%), fibula (25%), anterolateral thigh (23%), and other donor tissues. One- and 5-year survival rates were 42% and 26%, with locoregional and distant recurrence reported at 36% and 25%, respectively.Conclusions: Total glossectomy for oncologic control is most commonly performed in patients who have stage IV cancers. Despite high reconstructive success rates, the likelihood of locoregional and distance recurrence was high. Most patients can communicate intelligibly and achieve decannulation, but swallowing outcomes remain guarded, especially considering previous irradiation and resection of the base of tongue.Level Of Evidence: 4 Laryngoscope, 129:1087-1092, 2019. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Purpose The purpose of this study was to compare the clinical and functional outcomes in patients with primary base of tongue (BOT) cancer who received definitive radiotherapy (RT) or surgery followed by radiotherapy (SRT). Materials and Methods Between January 2002 and December 2016, 102 patients with stage I-IVB primary BOT cancer underwent either definitive RT (n=46) or SRT (n=56), and treatment outcomes were compared between two groups. The expression of p16 was also analyzed. Results The RT group had more patients with advanced T stage (T3-4) disease (58.7% vs. 35.7%, p=0.021) and who received chemotherapy (91.3% vs. 37.5%, p < 0.001) than the SRT group. At a median follow up of 36.9 months (range, 3.3 to 181.5 months), the 5-year overall survival (OS) and disease-free survival (DFS) were 75.5% and 68.7%, respectively. With respect to treatment group, the 5-year OS and DFS in the RT and SRT groups did not differ significantly (OS, 68.7% vs. 80.5%, p=0.601; DFS, 63.1% vs. 73.1%, p=0.653). In multivariate analysis, OS differed significantly according to p16 expression (p16-negative vs. p16- positive; hazard ratio [HR], 0.145; 95% confidence interval [CI], 0.025 to 0.853; p=0.033). Regarding DFS, p16 expression (p16-negative vs. p16-positive; HR, 0.164; 95% CI, 0.045 to 0.598; p=0.006) showed a significant effect in multivariate analysis. Functional defects (late grade ≥ 3 dysphagia or voice alteration) were more frequently reported in the SRT than in the RT group (16.1% vs. 2.2%, p=0.021). Conclusion Despite advanced disease, patients in the RT group showed comparable survival outcomes and better functional preservation than those in the SRT group. [ABSTRACT FROM AUTHOR]

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 p16INK4a 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 p16INK4a expression was analyzed by immunohistochemistry (IHC). Results: All 112 BCCs were HPV DNA negative, and of 105 BCCs possible to evaluate for p16INK4a, none overexpressed p16INK4a. Conclusions: HPV DNA and p16INK4a overexpression were absent in BCCs. Lack of HPV DNA and p16 protein overexpression in BCCs is helpful to discriminate benign BCCs from HPVþ OPSCC metastasis. HPV testing definitely has a role in the diagnostics of cystic masses of the neck. [ABSTRACT FROM AUTHOR]

Considering the emerging advantages related to da Vinci Xi robotic platform, the aim of this study is to compare for the first time the operative outcomes of this tool to the previous da Vinci Si during transoral robotic surgery (TORS), both performed for squamous cell carcinomas (SCC) of the base of tongue (BOT). Intra- and peri-operative outcomes of eight patients with early stage (T1-T2) of the BOT carcinoma and undergoing TORS by means of the da Vinci Xi robotic platform (Xi-TORS) are compared with the da Vinci Si group ones (Si-TORS). With respect to Si-TORS group, Xi-TORS group demonstrated a significantly shorter overall operative time, console time, and intraoperative blood loss, as well as peri-operative pain intensity and length of mean hospital stays and nasogastric tube positioning. Considering recent advantages offered by surgical robotic techniques, the da Vinci Xi Surgical System preliminary outcomes could suggest its possible future routine implementation in BOT squamous cell carcinoma procedures. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Bazex syndrome (acrokeratosis paraneoplastica) is an uncommon dermatologic condition associated with an underlying malignancy, most commonly squamous cell carcinomas of the head and neck. This article describes Bazex syndrome in a 56-year-old woman who presented with bilateral cervical lymphadenopathy and a mass at the base of her tongue. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Background: The American Joint Commission on Cancer (AJCC) recently created new staging for human papillomavirus associated oropharyngeal cancer (HPV+ OPSCC) for its 8th edition. These proposals have not yet been validated in a national registry.Methods: Review of National Cancer Database (NCDB) for surgically-treated HPV+ OPSCC for years 2010-2014 to validate the new staging system using the Kaplan Meier method to explore survival outcomes.Results: 3745 cases were analyzed. Median follow-up was 31.3months. Most patients were Caucasian males with tonsillar cancer. Distribution of stage I disease increased from 3.7% to 80.2% in AJCC 8th. pN1 disease shifted from 17.3% to 75.9%. Treatment and distribution of T-stage varied by pathologic nodal (pN) staging. Extranodal extension (ENE) was positive in 41% cases. Four-year overall survival (OS) for AJCC 8th stages I (92%), II (81%), and stage III (62%) showed excellent hazard discrimination (all pairwise p<0.001). Only 4-year OS by pN staging showed significantly different curves when comparing pN2 (79%) with others (pN0 88%; pN1 91%, p=0.01 and <0.001 respectively). Presence of ENE confers a negative effect on overall survival (92% ENE- vs. 85% ENE+, p<0.001).Conclusion: The NCDB shows improved hazard discrimination and outcome prediction in the AJCC 8th edition staging for HPV+ OPSCC. While overall staging had excellent hazard discrimination, this accounted for poorer discrimination between pN0 and pN1. The majority of patients are reclassified as overall stage I. Presence of extranodal extension demonstrated a statistically significant but modest negative effect on overall survival. CONDENSED ABSTRACT (2 SENTENCES): Using NCDB data for validation, the AJCC 8th ed. pathologic staging system offers much improved hazard discrimination and prognostication in HPV oropharyngeal cancer, with the majority of cases reclassified as pStage I. Of note, only pN2 offered hazard discrimination within nodal staging and presence of pathologic extranodal extension has a modest negative effect on survival. [ABSTRACT FROM AUTHOR]

Background The purpose of this study was to assess whether different tongue positions change the radiation doses to swallowing organs at risks: the pharyngeal constrictor, oral cavity, and larynx during intensity-modulated radiotherapy (IMRT) for base of tongue (BOT) cancer. Methods IMRT plans with Tongue-out (IMRT-TO) and tongue-in position (IMRT-TI) was compared in 3 cases. Results Distance from BOT to pharyngeal constrictor was increased to 1.8 ± 0.8 cm with IMRT-TO from 0.9 ± 0.6 cm with IMRT-TI ( P < .01). Compared to IMRT-TI, IMRT-TO significantly decreased the radiation dose to the anterior oral cavity, oral tongue, superior pharyngeal constrictor, middle pharyngeal constrictor, and supraglottic larynx (all P ≤ .04). IMRT-TO also had a smaller volume irradiated than IMRT-TI to the anterior oral cavity and the oral tongue receiving ≥30 Gy (V30) and V35, and superior pharyngeal constrictor and middle pharyngeal constrictor for V55 and V65 (all P ≤ .04). Conclusion Dosimetric advantage with IMRT-TO over IMRT-TI may potentially reduce post-IMRT swallowing dysfunction in selected patients with BOT cancer. [ABSTRACT FROM AUTHOR]

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 overtreated 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. [ABSTRACT FROM AUTHOR]

Objectives/hypothesis: Transoral surgery (TOS) is commonly performed in a supine patient with an oral retractor. Paradoxically, this strategy can create difficulty with visualizing and accessing pathology at the base of tongue, inferior pharynx, and larynx. We investigate the feasibility of TOS with the patient in the seated position.Study Design: Pilot study.Methods: TOS utilizing the da Vinci Robotic Surgical Xi and Si systems (Intuitive Surgical, Sunnyvale, CA) was performed on a fresh cadaver placed in both the traditional supine position and the seated position. Transoral robotic surgery (TORS) in the seated position was then performed on two patients for a supraglottic laryngectomy and a hypopharyngeal carcinoma resection.Results: Visualization of the entire upper aerodigestive tract was possible in the cadaver and two patients in the seated position. The Si was superior for docking, instrumentation, and assistant access. The minimum operating table height is critical for successful access. Advantages of this position included increased posterior airway/operative space by approximately 2 cm, ability to manipulate the surgical field (nonrigid retraction), and improved visualization. Surgical procedures were completed in comparable times compared with standard TORS procedures. There were no complications related to seated TORS.Conclusions: TORS in the seated position was both safe and effective in this pilot study. It allows the surgeon to optimally operate in the inferior pharynx and larynx without the limitation of line of site access and visualization. A paradigm shift in patient positioning during TOS may allow improved surgical access and even greater patient candidacy. Further clinical investigation into this technique is warranted.Level Of Evidence: NA Laryngoscope, 127:122-126, 2017. [ABSTRACT FROM AUTHOR]

Otorhinolaryngology tradition is that tonsillectomy (TE) is conducted among children and adolescents for obstructive sleep apnea secondary to adenotonsillar hypertrophy and in adults for chronic disease of the tonsils and adenoids (recurrent tonsillitis). Nevertheless, over the last 50 years, we have observed a decline in TE worldwide. As a result, there is an emerging concern of a correlated possible increased risk of tonsil cancer (TC) and other subtypes of oropharyngeal squamous cell carcinoma. Since the available data on such topics are limited and controversial, our aim was to elucidate the impact of TE on the incidence mainly of TC through a systematic review of the literature and a meta-analysis of the studies. After a thorough search, 7 retrospective studies were considered eligible for review and meta-analysis (MA). At MA, patients with a history of TE seem to show a reduced risk of TC but a higher predisposition for base of tongue (BOT) cancer (p<0.001): however, the elevated heterogeneity of the studies hampers drawing firm and convincing conclusions (statistical inconsistency >95%). In future, randomized control trials will be welcome to elucidate the prophylactic role of TE against TC and its real impact on BOT cancer., (Copyright © 2023 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Human papillomavirus (HPV) causes cervical, head, and neck cancers. We studied 483 patients at a youth clinic in Stockholm, Sweden, and found oral HPV prevalence was 9.3% and significantly higher for female youth with than without cervical HPV infection (p = 0.043). Most oral HPV types matched the co-occurring cervical types.

Purpose: To evaluate long time outcome with regard to local tumour control, side effects and quality of life of combined pulsed dose rate (PDR) boost and hyperfractionated accelerated external beam radiotherapy (EBRT) for primary base of tongue (BOT) cancers. Material and methods: Between 1994 and 2007, the number of 83 patients were treated with primary T1-T4 BOT cancers. Seven patients (8%) were T1-2N0 (AJCC stage I-II) and 76 (92%) patients were T1-2N+ or T3-4N0-2 (AJCC stage III-IV). The mean estimated primary tumour volume was 15.4 (1-75) cm3. EBRT was given with 1.7 Gy bid to 40.8 Gy to primary tumour and bilateral neck lymph nodes in 2.5 weeks. PDR boost of 35 Gy and a neck dissection in clinical node positive case was performed 2-3 weeks later. The patients were followed for a median of 54 (2-168) months. Results: The 2-, 5- and 10-years rates of actuarial local control were 91%, 89% and 85%, overall survival 85%, 65% and 44%, disease free survival 86%, 80% and 76%, respectively. The regional control rate was 95%. Six patients (7%) developed distant metastases. A dosimetric analysis showed a mean of 100% isodose volume of 58.2 (16.7-134) cm3. In a review of late complications 11 cases of minor (13%) and 5 of major soft tissue necroses (6%), as well as 6 cases of osteoradionecroses (7%) were found. The patients median subjective SOMA/LENT scoring at last follow up was as follow: grade 0 for pain and trismus, grade 1 for dysphagia and taste alteration, and grade 2 for xerostomia. Global visual- analogue-scale (VAS) scoring of quality of life was 8. Conclusion: Local and regional tumour control rate was excellent in this treatment protocol. The data shows the PDR boost as at least as effective as published continuous low dose rate (CLDR) results.