Tonsillar Squamous Cell Carcinoma Research Articles

Abstract CT259: Results from monotherapy dose escalation of MDNA11, a long-acting IL-2 superkine, in a phase 1/2 trial show evidence of single-agent activity in advanced solid tumors

Abstract Background: MDNA11 is an albumin-fused ‘beta-enhanced not-alpha’ IL-2 agonist engineered to preferentially expand and activate CD8+ T and NK cells with minimal impact on Tregs. The ABILITY-1 (A Beta-only IL-2 ImmunoTherapY) is a global Phase 1/2 study evaluating the safety, pharmacokinetics (PK), pharmacodynamics (PD), and preliminary clinical activity of MDNA11, both as single agent and in combination with a PD-1 inhibitor, in pre-treated patients with advanced solid tumors. Method: The ABILITY-1 study (NCT05086692) comprises monotherapy dose escalation/evaluation with a modified 3+3 design (enrollment complete); monotherapy dose expansion (enrolling); combination with pembrolizumab dose escalation (enrolling) followed by combination expansion. Thirty participants were enrolled in the monotherapy cohorts (3, 10, 30, 60, 90, and 120 μg/kg, IV, Q2W): 23 in dose escalation and 7 in dose evaluation. To enhance tolerability, step-up dosing with 2 or 3 priming doses was implemented starting at 60 μg/kg. Primary endpoints were incidence and severity of adverse events (AEs) and secondary endpoints included PK, PD, and tumor response (RECIST 1.1 and iRECIST). Results: As of December 22, 2023, 30 patients were enrolled in dose-escalation/evaluation, comprising 16 melanoma, 3 NSCLC, 3 PDAC, 2 RCC, 2 sarcoma, 2 ovarian cancer, 1 tonsillar squamous cell carcinoma and 1 gastro-esophageal adenocarcinoma. No dose-limiting toxicities (DLTs) were observed. Most common treatment related AEs were infusion-related reactions (53.3%), primarily grade 1-2, encompassing pyrexia (43.3%), nausea (33.3%), chills (33.3%), hypotension (30%), and fatigue (26.6%) that resolved within 48-72 hours. PK analysis showed sustained dose-dependent increase in serum concentration of MDNA11 with repeat doses. PD evaluation showed robust and durable dose-dependent increase in lymphocyte counts without eosinophilia. Immune effector cells, particularly CD8+ T cells, showed durable expansion with evidence of activation markers (CD25, ICOS and OX40) peaking at the 90 μg/kg dose. Single-agent anti-tumor activity was evident among 26 evaluable patients with confirmed partial responses (PRs) in a PDAC (MSI-H) patient (60 μg/kg cohort) and a melanoma patient (90 μg/kg cohort) as well as 8 (30.7%) stable disease (SD) including 3 melanoma patients with durable SD (>6 months, >8 months, >1.5 years). Based on the combined safety, PK, PD and preliminary anti-tumor activity, a recommended dose for expansion (RDE) of 90 μg/kg (preceded by priming doses of 30 and 60 μg/kg; Q2W) was selected for the ongoing monotherapy dose expansion of the ABILITY-1 study. Conclusions: MDNA11 was well-tolerated with no DLTs observed at all dose levels up to 120 μg/kg. With study currently ongoing, single agent clinical activity was evident with an ORR of 7.7% and Clinical Benefit Rate (CBR) of 19.2% (2 PRs + 3 SDs > 6 months) in dose escalation to date. Monotherapy dose expansion at 90 μg/kg and combination dose escalation with pembrolizumab are enrolling. Citation Format: Victoria G. Atkinson, Jesus F. Antras, Philippe Bedard, Warren Brenner, Jacqueline Brown, Charlotte R. Lemech, Peter Lloyd, Kim Margolin, Matthen Mathew, John J. Park, Sajeve Thomas, Przemyslaw Twardowski, Humphrey Gardner, Amy Prawira, Melissa Coello, Walead Ebrahimimizadeh, Minh D. To, Rosemina Merchant, Sudhir Madduri Karanam, Arash Yavari, Lillian L. Siu, Hussein A. Tawbi, Paolo A. Ascierto. Results from monotherapy dose escalation of MDNA11, a long-acting IL-2 superkine, in a phase 1/2 trial show evidence of single-agent activity in advanced solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr CT259.

Risk of malignancy in incidental oropharyngeal lesions exhibiting fluorodeoxyglucose uptake which proceed to tissue biopsy.

Utilization of positron emission tomography/computed tomography (PET/CT) with fluorodeoxyglucose is increasing in use for a variety of indications, including surveillance of cancer patients. There is a paucity of evidence pertaining to the significance of incidental PET-avid oropharyngeal lesions. This study aims to examine the clinical and radiological features of these incidental oropharyngeal lesions in patients undergoing PET for indications other than head and neck cancer. Retrospective cohort study of three Australian tertiary hospitals, from 2015 to 2021, on adult patients undergoing biopsy of incidental PET-avid oropharyngeal lesions. Primary outcome of interest was the incidence of malignancy. Patients with a previous history of, or undergoing investigations for, head and neck cancer were excluded. Thirty-one patients were included, wherein 21 patients had tonsillar uptake, and 13 patients had base of tongue uptake. Tonsillar disease was mostly asymmetrical (n = 15/21), bilateral (n = 11/21), and had median SUVmax 9.35 (n = 12, IQR 7.4-11.15). Base of tongue was mostly asymmetrical (n = 7/13, 54%), bilateral (n = 8/13, 62%), and had median SUVmax 8.2 (n = 10, IQR 6.9-12.65). Seven patients had malignancy confirmed on tissue biopsy: five biopsies confirmed the tissue diagnosis of suspected lymphoma, and two incidental findings of unexpected malignancies: one p16 positive tonsillar squamous cell carcinoma, and one metastatic breast cancer. In 31 patients undergoing tissue biopsy for incidental PET-avid oropharyngeal lesions, there were two unexpected malignancies. Our study results indicate that although unexpected malignancies are uncommon, a malignant diagnosis cannot be excluded from clinical features alone.

Mortality patterns of patients with tonsillar squamous cell carcinoma: a population-based study.

Tonsillar squamous cell carcinoma (TSCC) and second primary malignancies (SPMs) are the most common causes of mortality in patients with primary TSCC. However, the competing data on TSCC-specific death (TSD) or SPM-related death in patients with TSCC have not been evaluated. This study aimed to analyze the mortality patterns and formulate prediction models of mortality risk caused by TSCC and SPMs. Data on patients with a first diagnosis of TSCC were extracted as the training cohort from the 18 registries comprising the Surveillance, Epidemiology, and End Results (SEER) database. A competing risk approach of cumulation incidence function was used to estimate cumulative incidence curves. Fine and gray proportional sub-distributed hazard model analyses were performed to investigate the risk factors of TSD and SPMs. A nomogram was developed to predict the 5- and 10-year risk probabilities of death caused by TSCC and SPMs. Moreover, data from the 22 registries of the SEER database were also extracted to validate the nomograms. In the training cohort, we identified 14,530 patients with primary TSCC, with TSCC (46.84%) as the leading cause of death, followed by SPMs (26.86%) among all causes of death. In the proportion of SPMs, the lungs and bronchus (22.64%) were the most common sites for SPM-related deaths, followed by the larynx (9.99%), esophagus (8.46%), and Non-Melanoma skin (6.82%). Multivariate competing risk model showed that age, ethnicity, marital status, primary site, summary stage, radiotherapy, and surgery were independently associated with mortality caused by TSCC and SPMs. Such risk factors were selected to formulate prognostic nomograms. The nomograms showed preferable discrimination and calibration in both the training and validation cohorts. Patients with primary TSCC have a high mortality risk of SPMs, and the competing risk nomogram has an ideal performance for predicting TSD and SPMs-related mortality. Routine follow-up care for TSCC survivors should be expanded to monitor SPMs.

Comprehensive Transcriptome Analysis Reveals the Distinct Gene Expression Patterns of Tumor Microenvironment in HPV-Associated and HPV-Non Associated Tonsillar Squamous Cell Carcinoma

Comprehensive Transcriptome Analysis Reveals the Distinct Gene Expression Patterns of Tumor Microenvironment in HPV-Associated and HPV-Non Associated Tonsillar Squamous Cell Carcinoma

Dysregulated microRNA Expression Relevant to TERT Promoter Mutations in Tonsil Cancer-A Pilot Study.

Tonsillar squamous cell carcinomas (TSCCs) exhibit high rates of human papillomavirus (HPV) positivity. The expression profiles of microRNA (miRNA), which are small RNA molecules that play pivotal roles in biological processes, in TSCC in relation to the HPV status and cancer-related genetic mutations are not well investigated. Herein, we expanded our previous research, which was focused on established clinicopathological and genetic mutational data, to profile miRNA expression in TSCC, aiming to identify clinically relevant targets for early diagnosis and therapeutic intervention. The miRNA profiles were analyzed using the nCounter Nanostring miRNA Expression assay in 22 surgically resected TSCC tissues and their contralateral normal tonsil tissues. The TERT promoter (TERTp) gene was the only relevant candidate gene associated with differentially expressed miRNAs in TSCC. Hierarchical clustering analysis revealed high expression levels of hsa-miR-1285-5p, hsa-miR-1203, hsa-miR-663a, hsa-miR-1303, hsa-miR-33a-5p, and hsa-miR-3615 coupled with low expression levels of hsa-miR-3182, hsa-miR-219a-2-3p, and hsa-miR-767-3p, which were associated with HPV-positive TSCC (p = 0.009). Functional enrichment analysis revealed that these dysregulated miRNAs tended to be involved in protein binding (molecular function) and cellular components (biological processes). Therefore, hsa-miR-1285-5p and hsa-miR-663a may be associated with HPV-positive TERTp-mutated tumors and may serve as potential treatment targets and biomarkers for early detection.

1099 Tonsillar Carcinoma Metastasis to the Central Nervous System: Case Report and Literature Review

Abstract We present a case report of a 51-year-old left-handed male with a background of human papillomovairus 16-positive tonsil squamous cell carcinoma presenting with tonic-clonic seizures and a radiological diagnosis of secondary CNS metastatic deposits. These were initially treated with stereotactic radiosurgery and subsequently with surgery. Surgical resection was performed under general anesthesia with right-sided temporal and parietal approaches. Both the parietal and temporal deposits were removed, while the intraventricular mass was intentionally left to avoid postoperative deficits. Adjuvant radiotherapy and chemotherapy were administered postoperatively. The patient experienced a satisfactory post operative recovery. However, he was reoperated for recurrence 4 months later. He maintained a good quality of life and an excellent performance status throughout, but unfortunately, he passed away in November 2018 due to septic complications. This case history stresses the difficulty in managing oropharyngeal squamous cell carcinomas (SCC) with brain metastatic deposits. There are no current guidelines regarding the management of patients presenting with such a rare condition. Additionally, we performed a literature review and describe the limited previous cases within the literature. More data is thus desirable to better define treatment guidelines and protocols when tonsillar SCC brain metastases are present.

MicroRNA-203 inhibits migration and invasion of canine tonsillar squamous cell carcinoma cells by targeting SLUG.

Squamous cell carcinoma (SCC) occurring in the tonsils (TSCC) has a poorer prognosis than SCC occurring in other regions of the oral cavity (non-tonsillar SCC [NTSCC]) because it easily metastasizes to distant organs. This study aimed to elucidate the molecular mechanisms underlying the migration and invasion of TSCC cells in vitro. This study focused on differential microRNA (miRNA) expression using microRNA microarrays and quantitative polymerase chain reaction in canine TSCC and NTSCC tissues and cell lines. A target gene of the miRNA involved in cell migration and invasion was validated by wound healing, transwell, and luciferase assays. miR-203 expression was lower in TSCC tissues than in the normal oral mucosa and NTSCC tissues. Transfection of the miR-203 mimic resulted in the downregulation of mesenchymal marker protein expression and attenuation of cell migration and invasion in TSCC cells, but not in NTSCC cells. A dual-luciferase assay revealed that miR-203 directly targeted the mesenchymal transcription factor SLUG. SLUG overexpression enhances the migration of TSCC cells. Our study indicates that the miR-203/SLUG axis may be involved in the metastatic mechanisms of TSCC.

Comparison of narrow-band imaging with autofluorescence imaging for endoscopic detection of squamous cell carcinoma of the tonsil

PurposeEarly detection of mucosal neoplastic lesions is crucial for a patient’s prognosis. This has led to the development of effective optical endoscopic diagnostic methods such as narrow band imaging (NBI) and autofluorescence (AFI). Independent of each other, both of these methods were proven useful in the detection of mucosal neoplasias. There are limited reported data comparing both methods for oropharyngeal cancer diagnostics. The aim of the study was to compare NBI and AFI endoscopic visualization of signs in identifying tonsillar squamous cell carcinoma (SCC) and assessing its extent and to determine whether the score was related to the evaluator’s experience.MethodsPatients with tonsillar SCC underwent endoscopic pharyngeal examination using NBI and AFI. Fiftyseven video sequences of examinations of lesions proven to be SCC were evaluated by three reviewers. The accuracy of determination of lesion extent and visualization of its endoscopic signs of malignancy were evaluated.ResultsEndoscopic visualization of tumour spread was significantly better using AFI than NBI (p = 0.0003). No significant difference was found between NBI and AFI in the visualization of endoscopic malignancy determining signs (p = 0.1405). No significant difference was found among the three reviewers in the visualization of tumour spread and for identifying malignancy-determining signs in NBI endoscopy or AFI endoscopy.ConclusionsThe results show that AFI obtained better results for assessing the extent of tonsillar cancers than NBI. Both methods were proven to be equal in the visualization of endoscopic malignancy-determining signs. Both are useful even for less experienced evaluators.

Intrathyroidal metastasis of tonsillar squamous cell carcinoma masquerading as a primary thyroid tumor.

Intrathyroidal metastasis of tonsillar squamous cell carcinoma is rare. To date, only six cases have been reported in the literature. This case was unusual and presented with thyromegaly before the diagnosis of the primary tumor. A 55-year-old male patient was suspected to have a primary thyroid tumor with nodal metastasis. The thyroid gland was diffusely enlarged, with no discernible mass. Histologically, the thyroid parenchyma revealed extensive endolymphatic tumor emboli, which were positive for p40 and p16 in a background of chronic lymphocytic thyroiditis. Positron emission tomography-computed tomography revealed hypermetabolic activity in the right tonsillar region. Tonsillar biopsy revealed human papillomavirus-positive squamous cell carcinoma. The present case is the first reported case of intrathyroidal metastasis of tonsillar squamous cell carcinoma with an initial clinical presentation of thyroid enlargement before the primary tumor of tonsillar cancer was diagnosed.

Detection of the high-risk factors for synchronous bone metastasis in tonsillar squamous cell carcinoma.

To analyze the risk factors for synchronous bone metastases (BM) in patients with tonsillar squamous cell carcinomas. Tonsillar carcinomas patients were extracted from the Surveillance, Epidemiology and End Results (SEER) database between 2010 and 2013. We examined the association between risk factors and synchronous BM using Chi-squared tests. Predictors of survival rates were assessed using univariate and multivariate analyses. A total of 5752 patients were analyzed, which including 35 patients (0.6%) with synchronous BM, and 5717 patients without synchronous BM (99.4%). Multivariate logistic regression analysis showed that Caucasian, lower T or N classification were associated with a significantly lower risk of BM (P < 0.05, respectively). Elderly not married non-Caucasian patients with highly differentiated disease, higher T or N classification, multiple sites of metastases and no surgical therapy to primary tumor were more likely to reduce life expectancy. By analyzing data from a large cohort, Caucasian, lower T or N classification were associated with a significantly lower risk of BM. Elderly not married non-Caucasian patients with highly differentiated disease, higher T or N classification, multiple sites of metastases and no surgical therapy to primary tumor were more likely to reduce life expectancy. More accurate assessments of BM will be imperative for early diagnosis and treatment in non-Caucasian tonsillar carcinoma patients who harbored with higher T or N classification.

ID: 206119 Chronic Facial Pain In Patient With Tonsillar Squamous Cell Carcinoma Resolved With Pterygopalatine Fossa Block

A 64-year-old male with history of tonsillary squamous cell carcinoma with tumor invasion to the right pterygoid musculature with extension and ulceration to the lateral wall of the right oral cavity was admitted to the hospital with 10/10 right-sided neuropathic facial pain for pain control.

Low contralateral neck recurrence risk with ipsilateral neck radiotherapy in N2b tonsillar squamous cell carcinoma

ObjectivesTo characterize factors including nodal burden, pre-treatment imaging, and other patient factors which may influence the role of ipsilateral neck radiotherapy (IRT) in tonsillar squamous cell carcinoma (SCC) with multiple involved ipsilateral nodes. MethodsPatients with cT1-2N0-2bM0 (AJCC 7th edition) tonsillar SCC treated with definitive radiation therapy (RT) at Duke University Medical Center from 1/1/1990–10/1/2019 were identified. Patient, tumor, and treatment characteristics were compared between those that received bilateral neck RT (BRT) versus IRT. Recurrence-free survival (RFS) was estimated with Kaplan-Meier method. A subset analysis of patients with N2b disease was performed. Patterns of recurrence were analyzed. Results120 patients with cT1-2N0-2b tonsillar SCC were identified, including 71 with N2b disease (BRT: n = 30; IRT: n = 41). Median follow-up was 80 months (range: 7–209). No N2b patients who received IRT had > 1 cm of soft palate/base of tongue extension. N2b patients treated with IRT had a median of 3 (range 2–9) involved lymph nodes, with median largest nodal dimension of 2.8 cm (range 1.3–4.8 cm). 93 % of N2b patients who received IRT had staging by PET/CT, and 100 % received IMRT. For N2b patients treated with IRT, there were no contralateral neck recurrences, and 10 year RFS was 95 % (95 % CI 82 %–98 %). ConclusionsFor patients treated with IRT for well-lateralized N2b tonsillar SCC, we observed high rates of local control with no observed contralateral neck recurrence. These data suggest that BRT is not universally necessary for patients with multiple involved ipsilateral nodes, particularly in the setting of baseline staging with PET/CT.

Assessment of the Mutation Profile of Tonsillar Squamous Cell Carcinomas Using Targeted Next-Generation Sequencing.

Data regarding driver mutation profiles in tonsillar squamous cell carcinomas (TSCCs) remain scarce, limiting the understanding of its pathogenesis and unexpected behavior in the updated staging system. We investigated the incidence of clinically relevant mutations and their contribution in the prognosis of the condition, and their association with human papillomavirus (HPV) infection and adjuvant therapy. We subjected 43 surgically resected TSCC samples to targeted next-generation sequencing, determined their HPV status using polymerase chain reaction, and performed The Cancer Genomic Atlas and Gene Set Enrichment analyses. Thirty-five TSCC samples (81.4%) showed at least one oncogenic/likely oncogenic mutation among twenty-nine cancer-related genes. The top five mutated genes were TP53 (46.5%), PIK3CA (25.6%), PTEN (18.6%), EGFR (16.3%), and SMAD4 (14.0%). The EGFR pathway was the most frequently affected (51.2%), followed by the p53 (48.8%), PI3K (39.5%), and RTK (34.9%) pathways. The gene set enrichment analysis confirmed that the genes involved in signal transduction, such as growth factor receptors and second messengers, EGFR tyrosine kinase inhibitors, and PI3K signaling pathways, were mostly related with TSCCs. TP53 mutation was an independent prognostic factor predicting worse overall survival in the adjuvant therapy group. RTK mutations were related to survival in all patients and in the HPV-positive group, but multivariate analyses showed no significance. In conclusion, oncogenic/likely oncogenic mutations were relatively high in TSCCs, and TP53 and RTK mutations may be candidate predictors for poor prognosis in the adjuvant therapy and HPV-positive groups, respectively, under the updated staging system.

Targeted Therapy with PI3K, PARP, and WEE1 Inhibitors and Radiotherapy in HPV Positive and Negative Tonsillar Squamous Cell Carcinoma Cell Lines Reveals Synergy while Effects with APR-246 Are Limited

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.

Two-Year Patient-Reported Outcomes after Ipsilateral IMRT for T1-2 N2b Squamous Cell Carcinoma of the Tonsils

<h3>Purpose/Objective(s)</h3> Although unilateral neck irradiation is frequently implemented in patients with well-lateralized stage T1-2 HPV+ tonsillar squamous cell carcinoma (SCC) to minimize toxicity, its role in patients with N2b (AJCC-7 staging) nodal disease remains controversial. We have separately reported on contralateral nodal recurrence risk in patients with N2b disease receiving unilateral neck radiation. The quality-of-life patient reported outcomes (PRO) in these patients have not been previously reported. Our hypothesis was that patients with AJCC 7^th edition T1-2 N2b tonsillar squamous cell carcinoma treated with unilateral neck radiation had mild quality-of-life PROs. <h3>Materials/Methods</h3> The PROs of 44 AJCC-7 T1-2 N2b tonsillar squamous cell carcinoma (SCC) patients from two academic institutions treated with definitive, ipsilateral intensity modulation radiation therapy (IMRT) with or without systemic therapy were reviewed retrospectively. PROs were completed using either the MD Anderson Symptom Inventory-Head and Neck module (MDASI-HN) at the first institution, or the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Head and Neck Module 35 (EORTC QLQ-H&N35) at the second institution. The primary endpoint was the head and neck-related PROs at 2 years after completion of radiation. <h3>Results</h3> Twenty-eight of 30 and 4 of 14 patients from the first and second institutions, respectively, met the primary endpoint and were further analyzed. Of these, 34.4% received radiation alone without systemic therapy and 93.7% received ipsilateral-only neck IMRT. The most common head and neck-related PRO was dry mouth at the first and second institutions (64.2% and 100%, respectively); the least common was difficulty with voice or speech at both institutions (14% and 0%, respectively). There were also no reports of mouth pain or soreness, trouble with teeth, opening mouth, or swallowing liquid/pureed food at the second institution. The overall symptom severity for all PRO categories in both modules were in the mild range, with the highest mean score reported for dry mouth: 2.54 out of 10 on MDASI-HN for the first institution and 2.5 out of 4 on EORTC QLQ-H&N35 for the second institution. The rest of the mean scores for the first institution were < 1.5, while the remainder for the second institution were ≤ 2. The locoregional control and overall survival after a median follow-up of 4.5 years were each 100%. <h3>Conclusion</h3> We assessed the 2-year quality-of-life PROs for ipsilaterally radiated tonsillar SCC from 2 institutions using either MDASI-HN or EORTC QLQ-H&N35, and most patients reported mild symptom burden. These findings suggest that ipsilateral-only IMRT is well tolerated in patients with AJCC-7 N2b disease and can be safely employed as a de-escalation strategy.

Targeted Therapy of HPV Positive and Negative Tonsillar Squamous Cell Carcinoma Cell Lines Reveals Synergy between CDK4/6, PI3K and Sometimes FGFR Inhibitors, but Rarely between PARP and WEE1 Inhibitors.

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.

Additional parameters to improve the prognostic value of the 8th edition of the UICC classification for human papillomavirus-related oropharyngeal tumors.

BackgroundThe prognostic reliability of the UICC's TNM classification (8th edition) for human papillomavirus (HPV)‐positive tonsillar squamous cell carcinomas (TSCCs) compared to the 7th edition was explored, and its improvement by using additional anatomical and nonanatomical parameters.MethodsOne hundred and ten HPV‐positive and 225 HPV‐negative TSCCs were retrospectively analyzed. Survival was correlated with patient and tumor characteristics (7th and 8th edition UICC TNM classification).ResultsIn HPV‐positive TSCCs, the 8th edition UICC's TNM classification correlated better with prognosis than the 7th edition. Also, smoking status was a stronger prognosticator of survival than UICC staging. Non‐ or former smokers had a 5‐year overall survival of 95.1% regardless of tumor stage. Furthermore, age (>65 years), cN3, and M1 classification were significant prognostic factors.ConclusionThe prognostic value of the 8th edition UICC's TNM classification improved significantly when compared to the 7th edition. Nonetheless, further improvement is possible by adding nonanatomical factors (smoking, age >65 year) and separating N0‐N2 from N3.

A Case of Cutaneous Metastatic Tonsillar Squamous Cell Carcinoma in a Female

Cutaneous metastatic tonsillar squamous cell carcinoma (SCC) is extremely rare and indicates a poor prognosis. To our knowledge, only 8 cases of cutaneous metastatic tonsillar SCC previously have been reported in the English literature. Here, we present the third case of a female with cutaneous metastatic tonsillar SCC.

Prophylactic contralateral neck dissection has no advantage in patients with early stage HPV-positive tonsil cancer

ABSTRACT Background Patients with locally advanced HPV-positive tonsil cancer would benefit from prophylactic contralateral neck dissection (pCND). Aims/Objectives The aim of this study was to analyze rates of contralateral lymph node metastases (LNM) and their prognostic effects on locally advanced HPV-positive tonsillar squamous cell carcinoma. Materials and methods Medical records of 54 patients who underwent upfront primary surgery and pCND were retrospectively reviewed. Results Six (11.1%) patients had contralateral LNM in 54 locally advanced HPV-positive tonsil cancer. Of these, five patients had contralateral level II LNM and one patient had contralateral level II and III LNM. Contralateral LNM showed significant positive correlations with advanced T stage (p = .017) and the presence of extracapsular spread (p = .007). Contralateral lymph node metastasis had no significant association with five-year disease-specific survival. Conclusions and significance This study demonstrated no advantage in performing pCND in early stage HPV-positive tonsil cancer.

Tonsillar swabs and sputum predict SLPI- and AnxA2 expression in tonsils: A prospective study on smoking dependent SLPI- and AnxA2-expression, and tonsillar HPV infection.

Previous retrospective studies have elucidated a correlation between secretory leucocyte protease inhibitor (SLPI) and Annexin A2 (AnxA2), patient smoking status and tonsillar human papilloma virus (HPV) status. The current study assessed these parameters prospectively and to the best of our knowledge, analyzed SLPI-/AnxA2-expression for the first time in tonsillar swabs and sputum. Samples were obtained from 52 patients with tonsillar squamous cell carcinoma and 163 patients with tonsillar hyperplasia (H; n=56) and chronic or recurrent tonsillitis (CRT; n=107). HPV-DNA, SLPI and AnxA2 gene expression was analyzed in sputum, tonsillar swabs and tissue by performing reverse transcription-quantitative PCR. Results were compared with smoking status, revealing that smoking resulted in significantly increased SLPI gene expression in all biomaterials of all cases. SLPI-gene expression was significantly decreased in all HPV-DNA-positive samples (tissue/swab/sputum), while AnxA2 was significantly increased in all HPV-DNA-positive samples. Results from swabs and sputum were able to predict SLPI- and AnxA2 gene expression of the corresponding tonsil. The current prospective study confirmed previous retrospective results underlining this hypothesis: Smoking enhances SLPI-expression, preventing HPV-binding to AnxA2. HPV-binding to AnxA2 appears essential for successful cell-entry. SLPI/AnxA2-gene expression in swabs and sputum reflect their expression in tonsillar tissue. Accordingly, a positive AnxA2/SLPI-ratio in sputum/swabs could possibly be used to reduce HPV-associated carcinogenesis, by performing tonsillectomy or HPV-vaccination in patients with positive AnxA2/SLPI-ratios.