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Human papillomavirus (HPV)-driven oropharyngeal squamous cell carcinoma (OPSCC) is increasing globally. In Taiwan, HPV-positive OPSCC is obscured by tobacco, alcohol, and betel quid use. We investigated the role of high-risk HPV (hrHPV) in a large retrospective Taiwan OPSCC cohort. The cohort of 541 OPSCCs treated at Chang Gung Memorial Hospital from 1998-2016 consisted of 507 men (94%) and 34 women (6%). Most used tobacco (81%), alcohol (51%), and betel quid (65%). Formalin-fixed, paraffin-embedded tissue was used for p16 staining (a surrogate marker for HPV) and testing for HPV DNA presence and type by Multiplex HPV PCR-MassArray. HPV DNA and/or p16 staining (HPV-positive) was found in 28.4% (150/528) tumors. p16 and HPV DNA were strongly correlated (F < 0.0001). HPV16 was present in 82.8%, and HPV58 in 7.5% of HPV-positive tumors. HPV was associated with higher age (55.5 vs. 52.7 years, p = 0.004), lower T-stage (p = 0.008) better overall survival (OS) (hazard ratio [HR] 0.58 [95% CI 0.42-0.81], p = 0.001), and disease-free survival (DFS) (HR 0.54 [95% CI 0.40-0.73], p < 0.0001). Alcohol was strongly associated with recurrence and death (OS: HR 2.06 [95% CI 1.54-2.74], p < 0.0001; DFS: HR 1.72 [95% CI 1.33-2.24], p < 0.0001). OS and DFS in HPV-positive cases decreased for alcohol users (p < 0.0001). Obscured by the strong alcohol effect, predictive associations were not found for tobacco or betel quid. As with HPV-positive OPSCC globally, HPV is an increasingly important etiological factor in Taiwanese OPSCC. HPV-positive OPSCC has considerable survival benefit, but this is reduced by alcohol, tobacco, and betel quid use. hrHPV is a cancer risk factor in males and females. Vaccinating both sexes with a multivalent vaccine including HPV58, combined with alcohol and tobacco cessation policies will be effective cancer-prevention public health strategies in Taiwan.

Despite major progress in elucidating the pathobiology of head and neck squamous cell carcinoma (HNSCC), the high frequency of disease relapse correlates with unacceptably deficient patient survival. We previously showed that cancer stem-like cells (CSCs) drive tumorigenesis and progression of HNSCC. Although CSCs constitute only 2–5% of total tumor cells, CSCs contribute to tumor progression by virtue of their high tumorigenic potential and their resistance to chemo-, radio-, and immunotherapy. Not only are CSCs resistant to therapy, but cytotoxic agents actually enhance cancer stemness by activating transcription of pluripotency factors and by inducing expression of Bmi-1, a master regulator of stem cell self-renewal. We hypothesized therapeutic inhibition of interleukin-6 receptor (IL-6R) suppresses Bmi-1 to overcome intrinsic chemoresistance of CSCs. We observed that high Bmi-1 expression correlates with decreased ( p  = 0.04) recurrence-free survival time in HNSCC patients ( n  = 216). Blockade of IL-6R by lentiviral knockdown or pharmacologic inhibition with a humanized monoclonal antibody (Tocilizumab) is sufficient to inhibit Bmi-1 expression, secondary sphere formation, and to decrease the CSC fraction even in Cisplatin-resistant HNSCC cells. IL-6R inhibition with Tocilizumab abrogates Cisplatin-mediated increase in CSC fraction and induction of Bmi-1 in patient-derived xenograft (PDX) models of HNSCC. Notably, Tocilizumab inhibits Bmi-1 and suppresses growth of xenograft tumors generated with Cisplatin-resistant HNSCC cells. Altogether, these studies demonstrate that therapeutic blockade of IL-6R suppresses Bmi-1 function and inhibits cancer stemness. These results suggest therapeutic inhibition of IL-6R might be a viable strategy to overcome the CSC-mediated chemoresistance typically observed in HNSCC patients.

Objective Assess a single local application of curcumin-loaded nanoparticles as an adjunct to scaling and root planing (SRP) in nonsurgical periodontal treatment (NPT). Materials and methods Twenty healthy subjects with periodontitis received SRP+PLGA/PLA nanoparticles loaded with 50 μg of curcumin (N-Curc) or SRP+empty nanoparticles. Probing pocket depth (PPD), clinical attachment level (CAL), and bleeding on probing (BOP) were monitored at baseline, 30, 90, and 180 days. IL-1α, IL-6, TNFα, and IL-10 in the gingival crevicular fluid (GCF) were assessed by ELISA, and counts of 40 bacterial species were determined by DNA hybridization at baseline, 3, 7, and 15 days post-therapy. Results PPD, CAL, and BOP were similarly and significantly improved in both experimental groups. There was no difference in GCF cytokine levels between experimental groups, although IL-6 was decreased at 3 days only in the N-Curc group. NPT reduced counts of red complex bacterial species in both groups. Veillonella Parvula counts increased significantly only in N-Curc group at 7 days, whereas Aggregatibacter actinomycetemcomitans counts increased significantly only in the control group from day 3 to day 15. Conclusion We conclude that a single local administration of nanoencapsulated curcumin in periodontally diseased sites had no additive benefits to NPT. Clinical relevance Our results showed that a single local application of curcumin-loaded nanoparticles associated with nonsurgical periodontal therapy did not improve clinical outcomes. Hence, our findings do not support the use of curcumin as an adjunct to nonsurgical periodontal therapy.

Preclinical studies have evaluated murine double minue 2 (MDM2) inhibitors as a treatment for adenoid cystic carcinoma (ACC), but clinical trials are lacking. This phase I trial (NCT03781986) assesses the safety and antitumor activity of an oral MDM2 inhibitor, alrizomadlin (APG-115), +/- carboplatin in TP53 wild type unresectable recurrent/metastatic salivary gland cancers (R/M SGC) with a planned 1:1 randomization to carboplatin chemotherapy. The co-primary endpoints are determination of dose-limiting toxicity (DLT) and response rate (RR) for alrizomadlin monotherapy +/- carboplatin. Secondary endpoints include safety, survival, and RR by tumor histology. After enrollment of 4 patients to combination therapy, the trial was modified to a single arm study of alrizomadlin monotherapy due to excess toxicity. 1 DLT was seen in the combination arm, all patients had ≥ G3 treatment related adverse events (TRAE). 37 patients were enrolled to alrizomadlin monotherapy. 3 DLTs were encountered, 67% of patients had ≥ G3 TRAE. The RR was 15% with median progression free survival 10.5 months. These findings demonstrate encouraging tolerability of alrizomadlin monotherapy with antitumor activity in patients with TP53 wild type SGC, especially ACC. Preclinical studies have evaluated murine double minue 2 (MDM2) inhibitors as a treatment for adenoid cystic carcinoma (ACC). Here the authors present a phase I clinical trial reporting tolerability and efficacy preliminary data for the MDM2 inhibitor alrizomadlin (APG-115) in patients with TP53 wild type salivary gland cancers, especially adenoid cystic carcinoma.

SummaryBackground Palbociclib is a selective inhibitor of CDK4/6 approved in metastatic breast cancer as well as evidence of activity in malignancies with CDK4-amplifications. Extensive preclinical evidence has demonstrated synergy of CDK4/6 inhibitors with platinum chemotherapy suggesting a potential role for clinical synthetic lethality. Given the sensitivity to platinum therapy as well as the landscape of genomic alterations, concurrent treatment with platinum chemotherapy and palbociclib is of significant interest as a novel treatment approach. Patients and Methods Patients with unresectable, recurrent, or metastatic head and neck cancer (R/M HNC) were enrolled. Eligible patients were required to have no previous treatment with cytotoxic chemotherapy in the recurrent/metastatic setting. This was a multicenter phase II trial in which patients were administered carboplatin in addition to concurrent palbociclib. The primary endpoint of this trial was 12-week disease control rate (DCR). Results Twenty-one patients were enrolled and 18 were evaluable for response. Grade 3/4 treatment related toxicities were seen in 79% of patients of which the most common were related to myelosuppression. 12-week DCR was 33% (5 patients with stable disease, 1 with a partial response). Median progression free survival was 2.9 months (range: 1.2–13.3) and overall survival was 4.6 months (range: 1.4–14.8). Conclusion The combination of carboplatin and palbociclib is associated with significant treatment related toxicity and insufficient anti-tumor activity.

Background Oral squamous cell carcinoma (SCC) is associated with oral microbial dysbiosis. In this unique study, we compared pre- to post-treatment salivary microbiome in patients with SCC by 16S rRNA gene sequencing and examined how microbiome changes correlated with the expression of an anti-microbial protein. Results Treatment of SCC was associated with a reduction in overall bacterial richness and diversity. There were significant changes in the microbial community structure, including a decrease in the abundance of Porphyromonaceae and Prevotellaceae and an increase in Lactobacillaceae . There were also significant changes in the microbial community structure before and after treatment with chemoradiotherapy, but not with surgery alone. In patients treated with chemoradiotherapy alone, several bacterial populations were differentially abundant between responders and non-responders before and after therapy. Microbiome changes were associated with a change in the expression of DMBT1, an anti-microbial protein in human saliva. Additionally, we found that salivary DMBT1, which increases after treatment, could serve as a post-treatment salivary biomarker that links to microbial changes. Specifically, post-treatment increases in human salivary DMBT1 correlated with increased abundance of Gemella spp., Pasteurellaceae spp . , Lactobacillus spp., and Oribacterium spp . This is the first longitudinal study to investigate treatment-associated changes (chemoradiotherapy and surgery) in the oral microbiome in patients with SCC along with changes in expression of an anti-microbial protein in saliva. Conclusions The composition of the oral microbiota may predict treatment responses; salivary DMBT1 may have a role in modulating the oral microbiome in patients with SCC. Graphical Abstract After completion of treatment, 6 months after diagnosis, patients had a less diverse and less rich oral microbiome. Leptotrichia was a highly prevalent bacteria genus associated with disease. Expression of DMBT1 was higher after treatment and associated with microbiome changes, the most prominent genus being Gemella -6tcCpfJtMWsEpEDBUWdC3 Video Abstract

BackgroundPatients undergoing salvage laryngectomy are predisposed to radiation-induced hypothyroidism and impaired wound healing secondary to the tissue effects of prior treatment. The impact of hypothyroidism on postoperative wound healing is not established.MethodsA single-institution retrospective case series was performed. The inclusion criteria specified preoperatively euthyroid adults who underwent salvage laryngectomy with concurrent neck dissection between 1997 and 2015 for persistent or recurrent laryngeal squamous cell carcinoma after radiation or chemoradiation therapy (n = 182). The principal explanatory variable was postoperative hypothyroidism, defined as thyroid-stimulating hormone (TSH) higher than 5.5 mIU/L. The primary end points of the study were pharyngocutaneous fistulas and wounds requiring reoperation. Multivariate analysis was performed.ResultsThe fistula rate was 47% among hypothyroid patients versus 23% among euthyroid patients. In the multivariate analysis, the patients who experienced hypothyroidism in the postoperative period had a 3.6-fold greater risk of fistula [95% confidence interval (CI) 1.8–7.1; p = 0.0002]. The hypothyroid patients had an 11.4-fold greater risk for a required reoperation (24.4 vs 5.4%) than the euthyroid patients (95% CI 2.6–49.9; p = 0.001). The risk for fistula (p = 0.003) and reoperation (p = 0.001) increased with increasing TSH. This corresponds to an approximate 12.5% incremental increase in the absolute risk for fistula and a 10% increase in the absolute risk for reoperation with each doubling of the TSH.ConclusionPostoperative hypothyroidism independently predicts postoperative wound-healing complications. The association of hypothyroidism with fistula formation may yield opportunities to modulate wound healing with thyroid supplementation or to provide a biomarker of wound progression.

Background: In recent years, interest in prognostic calculators for predicting patient health outcomes has grown with the popularity of personalized medicine. These calculators, which can inform treatment decisions, employ many different methods, each of which has advantages and disadvantages. Methods: We present a comparison of a multistate model (MSM) and a random survival forest (RSF) through a case study of prognostic predictions for patients with oropharyngeal squamous cell carcinoma. The MSM is highly structured and takes into account some aspects of the clinical context and knowledge about oropharyngeal cancer, while the RSF can be thought of as a black-box non-parametric approach. Key in this comparison are the high rate of missing values within these data and the different approaches used by the MSM and RSF to handle missingness. Results: We compare the accuracy (discrimination and calibration) of survival probabilities predicted by both approaches and use simulation studies to better understand how predictive accuracy is influenced by the approach to (1) handling missing data and (2) modeling structural/disease progression information present in the data. We conclude that both approaches have similar predictive accuracy, with a slight advantage going to the MSM. Conclusions: Although the MSM shows slightly better predictive ability than the RSF, consideration of other differences are key when selecting the best approach for addressing a specific research question. These key differences include the methods’ ability to incorporate domain knowledge, and their ability to handle missing data as well as their interpretability, and ease of implementation. Ultimately, selecting the statistical method that has the most potential to aid in clinical decisions requires thoughtful consideration of the specific goals.

Background Head and neck squamous cell carcinoma (HNSCC) is an aggressive cancer with poor overall survival. New therapeutic strategies that target specific molecular lesions driving advanced disease are needed. Herein we demonstrate the utility of the chicken chorioallantoic membrane (CAM) assay for in vivo human HNSCC tumor growth and metastasis and the tumor suppressive effects of a new chemotherapeutic agent. Methods We tested anti-metastatic effects of a WNT pathway inhibitor, WNT974 (also known as LGK974), which targets porcupine (PORCN) the palmityl-transferase that is essential for secretion of Wnt proteins. CAM assays were performed with 8 HNSCC cell lines: UM-SCC-1, UM-SCC-10A, UM-SCC-10B, UM-SCC-11A, UM-SCC-14A UM-SCC-17A, UM-SCC-17B, UM-SCC-25, and UM-SCC-34. Results UM-SCC-1 (University of Michigan Squamous Cell Carcinoma cell line) CAM xenografts contain CD44+ and ALDH+ cancer stem cell (CSC) proportions similar to UM-SCC-1 mouse xenografts supporting the applicability of the CAM assay for study of CSCs. Inhibition of WNT signaling by the PORCN inhibitor WNT974 reduced metastatic spread of UM-SCC cells, especially in UM-SCCs with Notch1 deficiency. Conclusions Our data demonstrate decreased tumor growth and metastases in tumors from cell lines that showed in vitro responses to WNT974, providing evidence that this agent may have a role in future HNSCC therapy.