***TASK*** the task is to summarize an input biomedical literature in six sentences 
    ***INPUT*** the input is a biomedical literature 
    ***OUTPUT*** the output is the summary of an input biomedical literature in six sentences 
    ***DOCUMENTATION*** 
    ***EXAMPLES*** 
    Input: PURPOSE To vali date the predictive impact of a hypoxia gene expression classifier in identifying patients with head and neck squamous cell carcinoma ( HNSCC ) having benefit from hypoxic modification of radiotherapy .  PATIENTS AND METHODS Gene expressions were quantified from formalin-fixed , paraffin-embedded tumour biopsies of 323 HNSCC patients r and omized for placebo or nimorazole in conjunction with radiotherapy in the DAHANCA 5 study . Tumours were classified as either " more " or " less " hypoxic with a classifier constituting of 15 hypoxia responsive genes . The predictive impact was evaluated by analysing the response to nimorazole vs. placebo in terms of loco-regional tumour control ( LRC ) and disease-specific survival ( DSS ) in the two classified groups . RESULTS Hundred and fourteen patients ( 35 % ) were classified as having " more " hypoxic tumours . These patients had a significant benefit of hypoxic modification with nimorazole compared with placebo in terms of LRC ( 5-year actuarial values 49 % vs. 18 % ; p=0.001 ) and DSS ( 48 % vs. 30 % ; p=0.04 ) . " Less " hypoxic tumours had no significant effect of hypoxic modification ( LRC : 50 % vs. 44 % ; p=0.39 , DSS : 57 % vs. 51 % ; p=0.49 ) and generally an outcome , which was similar to " more " hypoxic tumours treated with nimorazole . In contrast to HPV-negative tumours , HPV-positive tumours had a substantially better outcome in response to radiotherapy , which was irrespective of hypoxic modification . CONCLUSIONS A predictive 15-gene hypoxia classifier could identify patients associated with improved outcome after combining radiotherapy with hypoxic modification and underlines the relevance of such therapy . The impact of the classifier was limited to HPV-negative tumours PURPOSE Tumor hypoxia is known to be associated with resistance to chemotherapy , radiotherapy , and poorer survival . Recently , it is shown that hypoxia induces the expression of hypoxia-inducible factor-1alpha and 2alpha ( HIF-1alpha and HIF-2alpha ) , which then up-regulates the expression of downstream genes such as carbonic anhydrase IX ( CA IX ) and vascular endothelial growth factor ( VEGF ) . EXPERIMENTAL DESIGN We examined the expression of HIF-1alpha , HIF-2alpha , CA IX , and VEGF by immunohistochemistry in nasopharyngeal carcinoma ( NPC ) biopsies from 90 consecutive patients recruited between 1994 and 1997 in a r and omized controlled trial of chemoradiation in locally advanced NPC and investigated their relationship with survival . RESULTS HIF-1alpha was expressed in 52 of 90 ( 58 % ) , HIF-2alpha in 6 of 89 ( 7 % ) , CA IX in 51 of 90 ( 57 % ) , and VEGF in 54 of 90 ( 60 % ) of tumors . Tumor HIF-1alpha expression correlated significantly with that of CA IX ( P = 0.008 ) and VEGF ( P = 0.003 ) . High tumor HIF-1alpha expression was associated with a trend for poor overall survival ( P = 0.06 ) . Tumors with a positive hypoxic profile ( defined as high expression of both HIF-1alpha and CA9 ) were associated with worse progression-free survival ( P = 0.04 ) . Tumors with both hypoxic and angiogenic profile ( defined as high VEGF expression ) were associated with a worse progression-free survival ( P = 0.0095 ) . CONCLUSION Overexpression of HIF-1alpha , CA IX , and VEGF is common in NPC , which is probably related to hypoxia up-regulated expression involving a HIF-dependent pathway , and is associated with poor prognosis . Targeting the hypoxia pathway may be useful in the treatment of NPC Hypoxia , a common feature of the microenvironment in solid tumors , is associated with resistance to radiotherapy , reduced therapeutic response , and a poorer clinical outcome . In head and neck squamous cell carcinomas ( HNSCC ) , the negative effect of hypoxia on radiotherapy can be counteracted via addition of hypoxic modification to the radiotherapy . To predict which patients harbor hypoxic tumors and would therefore benefit from hypoxic modification , clinical ly applicable methods for pretherapeutic hypoxic evaluation and categorization are needed . In this study , we developed a hypoxia classifier based on gene expression . Through study of xenograft tumors from human squamous cell carcinoma cell lines , we verified the in vivo relevance of previously identified in vitro derived hypoxia-induced genes . We then evaluated a training set of 58 hypoxia-evaluated HNSCCs to generate a gene expression classifier containing 15 genes . This 15-gene hypoxia classifier was vali date d in 323 patients with HNSCC r and omized for hypoxic modification or placebo in combination with radiotherapy .  Tumors categorized as hypoxic on the basis of the classifier were associated with a significantly poorer clinical outcome than nonhypoxic tumors . This outcome was improved and equalized to the nonhypoxic tumors by addition of hypoxic modification . Thus , findings show that the classifier attained both prognostic and predictive impact , and its pretherapeutic use may provide a method to identify those patients who will benefit from hypoxic modification of radiotherapy BACKGROUND AND PURPOSE CA IX is suggested to be an endogenous marker of hypoxia in tumours like squamous cell carcinomas of the head and neck ( HNSCC ) . The aim of the present study was to investigate whether CA IX served as a prognostic factor for outcome in a large population of HNSCC and if CA IX was able to discriminate the tumours that did benefit from hypoxic modification with nimorazole . MATERIAL S AND METHODS Paraffin-embedded formalin-fixed pre-treatment tumour tissue was available from 320 of the 414 patients treated in the r and omized DAHANCA 5 protocol with primary radiotherapy+/-the hypoxic radiosensitizer nimorazole .  CA IX was measured using immunohistochemistry and results were divided into four groups of CA IX expression : < 1 % , 1 - 10 % , 10 - 30 % and > 30 % of the tumour area with positive membrane staining . Locoregional control and disease-specific survival were used as endpoints . RESULTS Expression of CA IX was not correlated to any of the tumour or patient characteristics investigated . Furthermore , CA IX did not serve as a prognostic marker in the total cohort as well as in the group of 150 patients treated without nimorazole . Finally , no relation was found between the different expression levels of CA IX and the influence of nimorazole  when locoregional control or disease-specific survival was used as endpoints . CONCLUSIONS This is to date one of the largest studies of CA IX in HNSCC . The data suggest that CA IX have no prognostic or predictive potential in patients with cancer in the head and neck treated with conventional radiotherapy and concomitant nimorazole Previously , we and others showed that hypoxia‐inducible factor‐1α ( HIF‐1α ) and transcriptionally upregulated Aurora‐A were required for disease progression in several tumors . Here , we address the clinicopathologic value of Aurora‐A and HIF‐1α in locally advanced nasopharyngeal carcinoma ( NPC ) . Aurora‐A and HIF‐1α expression was semiquantitatively evaluated by immunohistochemistry staining in 144 cases from a r and omized controlled trial . Of these patients , 69 received neoadjuvant chemotherapy plus concurrent chemoradiotherapy  , and acted as the training set , and 75 cases treated with neoadjuvant chemotherapy plus radiotherapy  were used as the testing set to vali date the prognostic effect of Aurora‐A and HIF‐1α . We found that Aurora‐A and HIF‐1α were highly expressed in NPC , but were deficient in normal adjacent epithelia . In the testing set , Aurora‐A overexpression predicted a shortened 5‐year overall survival ( 59.1 % vs 82.5 % , P = 0.024 ) , progression‐free survival ( 44.8 % vs 79.8 % , P = 0.004 ) , and distant metastasis‐free survival ( 43.0 % vs 17.3 % , P = 0.016 ) . Multivariate regression analysis confirmed that Aurora‐A was indeed an independent prognostic factor for death , recurrence , and distant metastasis both in the testing set and overall patients . Moreover , a positive correlation between Aurora‐A and HIF‐1α was detected ( P = 0.037 ) . Importantly , although HIF‐1α did not show any prognostic effect for patient outcome , the subset with Aurora‐A and HIF‐1α co‐overexpression had the poorest overall , progression‐free , and distant metastasis‐free survival ( all P < 0.05 ) . Our results confirmed that Aurora‐A was an independent prognostic factor for NPC . Aurora‐A combined with HIF‐1α refined the risk definition of the patient subset , thus potentially directing locally advanced NPC patients for more selective therapy . ( Cancer Sci , doi : 10.1111/j.1349‐7006.2012.02332.x , 2012 BACKGROUND AND PURPOSE In a phase III trial in patients with advanced stage laryngeal carcinoma comparing ARCON ( accelerated radiotherapy with carbogen breathing and nicotinamide ) to accelerated radiotherapy alone ( AR ) the prognostic and predictive value of CAIX , a hypoxia-associated protein , was investigated . MATERIAL AND METHODS 261 Paraffin embedded tumor biopsies and 79 fresh frozen biopsies from patients entered in the trial were immunohistochemically stained for CAIX . CAIX-fraction and CAIX expression pattern were related to tumor control and patient survival . RESULTS Low CAIX-fraction was prognostic for worse regional control and overall survival in patients treated with AR . Patients with a low CAIX-fraction treated with ARCON had better regional control and metastasis-free survival compared to AR ( RC 97 % vs 71 % , p < 0.01 and MFS 92 % vs 69 % , p = 0.06 ) . Patients with a perinecrotic CAIX staining pattern had a significantly worse local control , metastasis-free and overall survival compared to patients with a diffuse pattern ( 65 % vs 84 % , p = 0.01 , 70 % vs 96 % , p < 0.01 and 42 % vs 71 % , p < 0.01 respectively ) , and this could not be improved with ARCON . After multivariate analysis CAIX pattern and N-stage emerged as significant predictors for metastasis-free survival and overall survival . CONCLUSIONS ARCON improves regional control and metastasis-free survival only in patients with low CAIX expression . The different patterns of CAIX expression suggest different mechanisms of upregulation and have important prognostic value Abstract Purpose / Objective . A phase II clinical trial evaluating the feasibility and outcome of treating locally advanced head and neck squamous cell carcinoma ( HNSCC ) with accelerated radiotherapy , the hypoxic modifier nimorazole and weekly cisplatin . Material and methods . A total of 227 patients with stage III or IV HNSCC of the larynx , oropharynx , hypopharynx , or oral cavity where included between January 2007 and December 2010 . The prescribed radiotherapy ( RT ) dose was 66–68 Gy in 2 Gy fractions , 6 F/W. The hypoxic radiosensitiser nimorazole was given orally at a dose of 1200 mg/m2 before each fraction . Concomitant cisplatin ( 40 mg/m2 ) i.v . was given once a week for a maximum of six cycles . Outcome data were evaluated in terms of loco-regional tumour control ( LRC ) , event-free survival ( EFS ) and overall survival ( OS ) . Morbidity data were evaluated based on the DAHANCA routine registration . Human papillomavirus (HPV)-status was estimated by immunohistochemical staining of p16 . Results . Included were 178 ( 78 % ) men and 49 ( 22 % ) women with a median age of 57 years . All except five patients received RT as prescribed . At least five series of cisplatin was given to 164 ( 72 % ) of the patients , and 149 patients ( 66 % ) received the full dose of nimorazole .  The five-year actuarial LRC , EFS and OS rates were 80 % , 67 % and 72 % , respectively . The LRC rates according to site were : oropharynx : 88 % , larynx : 77 % , hypopharynx 72 % and oral cavity 49 % , respectively . HPV/p16 staining was obtained in 141 of the 150 oropharyngeal cancers . Of these , 112 ( 79 % ) were p16 pos and 29 ( 21 % ) were p16 neg . LRC for the p16 neg oropharyngeal cancers was poorer than for the p16 pos ( 74 % vs. 
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Positive expression was often correlated with adverse clinical characteristics , including disease stage and differentiation grade .
In summary , EMH expression was common in HNSCC patients and negatively influenced their prognosis .