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A. Correlation of CSC marker expressions. B. Multivariate analyses of stem cell markers and additional prognostic factors for all patients. HR = hazard ratio; 95% CI = 95 percent confidence interval ; ECE = extracapsular extension. C. Correlation of CSC marker expression and HPV16 DNA.

Correlation of tumor hypoxia using nanoString vs PCR.

Multivariate analyses of hypoxia-gene signatures and additional prognostic factors assessed for all patients. HR = hazard ratio; 95% CI = 95 percent confidence interval; ECE = extracapsular extension.

Univariate analyses of both hypoxia gene signatures using nanoString or RT-PCR analyses. HR = hazard ratio; 95% CI = 95 percent confidence interval.

Purpose: To investigate the impact of hypoxia-induced gene expression and cancer stem cell (CSC) marker expression on outcome of postoperative cisplatin-based radiochemotherapy (PORT-C) in patients with locally advanced head and neck squamous cell carcinoma (HNSCC).Experimental Design: Expression of the CSC markers CD44, MET, and SLC3A2, and hypoxia gene signatures were analyzed in the resected primary tumors using RT-PCR and nanoString technology in a multicenter retrospective cohort of 195 patients. CD44 protein expression was further analyzed in tissue microarrays. Primary endpoint was locoregional tumor control.Results: Univariate analysis showed that hypoxia-induced gene expression was significantly associated with a high risk of locoregional recurrence using the 15-gene signature (P = 0.010) or the 26-gene signature (P = 0.002). In multivariate analyses, in patients with HPV16 DNA–negative but not with HPV16 DNA–positive tumors the effect of hypoxia-induced genes on locoregional control was apparent (15-gene signature: HR 4.54, P = 0.006; 26-gene signature: HR 10.27, P = 0.024). Furthermore, MET, SLC3A2, CD44, and CD44 protein showed an association with locoregional tumor control in multivariate analyses (MET: HR 3.71, P = 0.016; SLC3A2: HR 8.54, P = 0.037; CD44: HR 3.36, P = 0.054; CD44 protein n/a because of no event in the CD44-negative group) in the HPV16 DNA–negative subgroup.Conclusions: We have shown for the first time that high hypoxia-induced gene expression and high CSC marker expression levels correlate with tumor recurrence after PORT-C in patients with HPV16 DNA–negative HNSCC. After validation in a currently ongoing prospective trial, these parameters may help to further stratify patients for individualized treatment de-escalation or intensification strategies. Clin Cancer Res; 22(11); 2639–49. ©2016 AACR.

Univariate analyses of CSC markers. HR = hazard ratio; 95% CI = 95 percent confidence interval.

Combined multivariate analyses of HPV16 DNA, cancer stem cell markers, hypoxia and additional prognostic factors for all patients (endpoint loco-regional control). HR = hazard ratio; 95% CI = 95 percent confidence interval; ECE = extracapsular extension.

A. Correlation of hypoxia gene-signatures and HPV16 DNA. B. Correlation of CSC marker expression and HPV16 DNA.

A. Patient characteristics. B. Hypoxia gene signatures.

Objective: To investigate the impact of HPV status in patients with locally advanced head and neck squamous cell carcinoma (HNSCC), who received surgery and cisplatin-based postoperative radiochemotherapy. Materials and methods: For 221 patients with locally advanced squamous cell carcinoma of the hypopharynx, oropharynx or oral cavity treated at the 8 partner sites of the German Cancer Consortium, the impact of HPV DNA, p16 overexpression and p53 expression on outcome were retrospectively analysed. The primary endpoint was loco-regional tumour control; secondary endpoints were distant metastases and overall survival. Results: In the total patient population, univariate analyses revealed a significant impact of HPV16 DNA positivity, p16 overexpression, p53 positivity and tumour site on loco-regional tumour control. Multivariate analysis stratified for tumour site showed that positive HPV 16 DNA status correlated with loco-regional tumour control in patients with oropharyngeal carcinoma (p = 0.02) but not in the oral cavity carcinoma group. Multivariate evaluation of the secondary endpoints in the total population revealed a significant association of HPV16 DNA positivity with overall survival (p

Background Despite clear differences in clinical presentation and outcome, squamous cell carcinomas of the head and neck (SCCHN) arising from human papilloma virus (HPV) infection or heavy tobacco/alcohol consumption are treated equally. Next-generation sequencing is expected to reveal novel targets for more individualised treatment. Patients and methods Tumour specimens from 208 patients with locally advanced squamous cell carcinoma of the hypopharynx, oropharynx or oral cavity, all uniformly treated with adjuvant cisplatin-based chemoradiation, were included. A customised panel covering 211 exons from 45 genes frequently altered in SCCHN was used for detection of non-synonymous point and frameshift mutations. Mutations were correlated with HPV status and treatment outcome. Results Mutational profiles and HPV status were successfully established for 179 cases. HPV– tumours showed an increased frequency of alterations in tumour suppressor genes compared to HPV+ cases ( TP53 67% versus 4%, CDKN2A 18% versus 0%). Conversely, HPV+ carcinomas were enriched for activating mutations in driver genes compared to HPV– cases ( PIK3CA 30% versus 12%, KRAS 6% versus 1%, and NRAS 4% versus 0%). Hotspot TP53 missense mutations in HPV– carcinomas correlated with an increased risk of locoregional recurrence (hazard ratio [HR] 4.3, 95% confidence interval [CI] 1.5–12.1, P =0.006) and death (HR 2.2, 95% CI 1.1–4.4, P =0.021). In HPV+ SCCHN, driver gene mutations were associated per trend with a higher risk of death (HR 3.9, 95% CI 0.7–21.1, P =0.11). Conclusions Distinct mutation profiles in HPV– and HPV+ SCCHN identify subgroups with poor outcome after adjuvant chemoradiation. Mutant p53 and the phosphoinositide 3-kinase pathway were identified as potential druggable targets for subgroup-specific treatment optimisation.

We examined the prognostic value of tumour-infiltrating lymphocytes (TILs) in patients with squamous cell carcinoma of the head and neck (SCCHN) after surgery and postoperative cisplatin-based chemoradiotherapy. FFPE-tissue originating from the surgery of 161 patients treated in 8 DKTK partner sites was immunohistochemically stained for CD3 and CD8. Their expression was correlated with clinicopathological characteristics as well as overall survival (OS), local progression-free survival (LPFS) and distant metastases free-survival (DMFS), also in the context of the HPV16-DNA/p16 status. After a median follow-up of 48 months (range: 4100 months), OS at 4 years was 46.5% for the entire cohort. In multivariate analysis, high CD8 expression was confirmed as an independent prognostic parameter for OS (p 5 0.002), LPFS (p 5 0.004) and DMFS (p 5 0.006), while CD3 expression lacked significance. In multivariate analysis HPV16 DNA positivity was associated with improved OS (p 5 0.025) and LPFS (p 5 0.013) and p16-positive patients showed improved DMFS (p 5 0.008). Interestingly, high CD8 expression was a prognostic parameter for the clinical outcome in both HPV16 DNA-positive and HPV16 DNA-negative patients. Similar findings were observed in the multivariate analysis for the combined HPV16 DNA/p16 status. Altogether, CD81 TILs constitute an independent prognostic marker in SCCHN patients treated with adjuvant chemoradiotherapy. These data indicate that CD8-positive TILs have antitumour activity and could be used for treatment stratification. Further validation of the prognostic value of CD81 TILs as a biomarker and its role in the immune response in SCCHN patients after adjuvant chemoradiotherapy is warranted and will be performed in the prospective DKTK-ROG study. What’s new? Squamous cell carcinomas of the head and neck (SCCHN) are not a homogenous group of tumors. This means that biomarkers are urgently needed, so that prognosis and treatment can be individualised. In this study, the authors found that patients with higher levels of CD81 tumor-infiltrating lymphocytes (TILs) within their tumors had improved outcomes after treatment. These results suggest that CD8-positive TILs may have antitumor activity, and that their expression may be a useful prognostic biomarker for treatment stratification.

Purpose: To investigate the impact of hypoxia-induced gene expression and cancer stem cell (CSC) marker expression on outcome of postoperative cisplatin-based radiochemotherapy (PORT-C) in patients with locally advanced head and neck squamous cell carcinoma (HNSCC). Experimental Design: Expression of the CSC markers CD44, MET, and SLC3A2, and hypoxia gene signatures were analyzed in the resected primary tumors using RT-PCR and nanoString technology in a multicenter retrospective cohort of 195 patients. CD44 protein expression was further analyzed in tissue microarrays. Primary endpoint was locoregional tumor control. Results: Univariate analysis showed that hypoxia-induced gene expression was significantly associated with a high risk of locoregional recurrence using the 15-gene signature (P = 0.010) or the 26-gene signature (P = 0.002). In multivariate analyses, in patients with HPV16 DNA–negative but not with HPV16 DNA–positive tumors the effect of hypoxia-induced genes on locoregional control was apparent (15-gene signature: HR 4.54, P = 0.006; 26-gene signature: HR 10.27, P = 0.024). Furthermore, MET, SLC3A2, CD44, and CD44 protein showed an association with locoregional tumor control in multivariate analyses (MET: HR 3.71, P = 0.016; SLC3A2: HR 8.54, P = 0.037; CD44: HR 3.36, P = 0.054; CD44 protein n/a because of no event in the CD44-negative group) in the HPV16 DNA–negative subgroup. Conclusions: We have shown for the first time that high hypoxia-induced gene expression and high CSC marker expression levels correlate with tumor recurrence after PORT-C in patients with HPV16 DNA–negative HNSCC. After validation in a currently ongoing prospective trial, these parameters may help to further stratify patients for individualized treatment de-escalation or intensification strategies. Clin Cancer Res; 22(11); 2639–49. ©2016 AACR.

Although less invasive then SAVR, TAVI is associated with a significant rate of access site and non-access site bleeding. These complications are major determinants of therapy outcome, however, the economic consequences are not well defined. The purpose of this study was to determine the relationship between bleeding, in-hospital resource utilization and costs among patients undergoing transfemoral aortic valve implantation (TF-AVI) at a representative university hospital in Germany. Between February 2010 and December 2011, we prospectively enrolled 60 consecutive patients undergoing TAVI using a 18F transfemoral approach at our institution. The relationship between overt bleeding (OVB), defined according to the definitions provided by the Valve Academic Research Consortium, in-hospital resource utilization and in-hospital costs was investigated. The mean age was 82 (±6) years, 53 % were female and the mean EuroScore was 17.2 % (±8, 7). Thirty-eight percent (23/60) of the patients had an OVB following TF-AVI procedure. In-hospital mortality was 8.7 % in the OVB patients (2/23) and 2.7 % among patients without any OVB (1/37; NOVB), which was not statistically significant (p = 0.3). The total length of stay (LOS) of patients with and without bleeding complication were 15.0 ± 6.4 and 10.4 ± 5.1 days, respectively (p < 0.01). Time spent on ICU in the OVB group was twice as long as compared to the NOVB group (120.5 ± 98.5 min vs. 63.6 ± 26.5 min, p < 0.01). Consequently, in-hospital costs were statistically significant higher in OVB patients (40.051 ± 9.293€ vs. 33.625 ± 4.368€, p < 0.01). Bleeding is associated with increased resource use and in-hospital costs among TF-AVI patients. Our data indicates that strategies reducing bleeding risk may have the potential to generate important in-hospital costs reductions in TF-AVI patients.