***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 
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    ***EXAMPLES*** 
    Input: Purpose : Hypoxia in breast cancer is associated with poor prognosis and down-regulation of the estrogen receptor . Carbonic anhydrase IX ( CA IX ) is a hypoxia-inducible gene that has been associated with poor outcome in many epithelial cancers . Previous studies of CA IX in breast cancer have been carried out on mixed cohorts of premenopausal and postmenopausal patients with locally advanced disease and varying treatment regimens . We examined the potential prognostic and predictive role of CA IX in premenopausal breast cancer patients . Experimental Design : Using tissue microarrays , we analyzed CA IX expression in 400 stage II breast cancers from premenopausal women . The patients had previously participated in a r and omized control trial comparing 2 years of  tamoxifen to no systemic adjuvant treatment .  Median follow-up was 13.9 years . Results : CA IX expression correlated positively with tumor size , grade , hypoxia-inducible factor 1α , Ki-67 , cyclin E , and cyclin A2 expression . CA IX expression correlated negatively with cyclin D1 , estrogen receptor , and progesterone receptor . CA IX expression was associated with a reduced relapse-free survival ( P = 0.032 ) , overall survival ( P = 0.022 ) , and breast cancer – specific survival ( P = 0.005 ) . Multivariate analysis revealed that CA IX was an independent prognostic marker in untreated patients with one to three positive lymph nodes ( hazard ratio , 3.2 ; 95 % confidence interval , 1.15 - 9.13 ; P = 0.027 ) . Conclusion : CA IX is marker of poor prognosis in premenopausal breast cancer patients and it is an independent predictor of survival in patients with one to three positive lymph nodes . As all these patients received locoregional radiation therapy , CA IX may be associated with resistance to radiotherapy BACKGROUND Chemokine receptor 4 ( CXCR4 ) has been demonstrated to have a critical role in the early metastatic process . The aim of this study was to evaluate the prognostic value of CXCR4 expression in primary breast tumors and describe correlations with the occurrence of metastasis in organs expressing the CXCR4 lig and stromal cell-derived factor 1 ( i.e. , liver , lung , brain , and bone ) . PATIENTS AND METHODS CXCR4 expression in primary breast tumors was evaluated by immunohistochemistry  in 823 patients included in two prospect i ve clinical trials .  CXCR4 expression was considered positive when > 1 % of tumor cells were stained . The prognostic value of CXCR4 expression was assessed by a Cox regression model adjusted for clinical characteristics . We assessed the association of CXCR4 expression with the rate of distant metastasis to specific organ sites . RESULTS CXCR4 was expressed in 92 of 794 primary tumors ( 12 % ) . CXCR4 expression was not associated with clinical characteristics . CXCR4 was not prognostic for overall survival and showed a nonsignificant trend toward a higher risk for distant metastasis . CXCR4(+ ) tumors showed a significantly higher risk for bone metastasis . The 10-year incidences of bone metastases were 23 % ( 13.6%-32.6 % ) and 12 % ( 9.7%-15 % ) in CXCR4(+ ) and CXCR4(- ) tumors , respectively . CONCLUSION This study suggests that expression of CXCR4 in primary breast tumors is associated with a higher likelihood of developing bone metastases . This finding could open new avenues for the development of novel adjuvant strategies , including bone-targeting agents Introduction Primary breast cancer involving four or more axillary lymph nodes carries a poor prognosis . We hypothesized that use of an immunohistochemical biomarker scoring system could allow for identification of variable risk subgroups . Methods Patients with four or more positive axillary nodes were identified from a clinical ly annotated tissue microarray of formalin-fixed paraffin-embedded primary breast cancers and r and omized into a ' test set ' and a ' validation set ' . A prospect ively defined prognostic scoring model was developed in the test set and was further assessed in the validation set combining expression for eight biomarkers by immunohistochemistry , including estrogen receptor , human epidermal growth factor receptors 1 and 2 , carbonic anhydrase IX , cytokeratin 5/6 , progesterone receptor , p53 and Ki-67 . Survival outcomes were analyzed by the Kaplan – Meier method , log rank tests and Cox proportional-hazards models . Results A total of 313 eligible patients were identified in the test set for whom 10-year relapse-free survival was 38.3 % ( SEM 2.9 % ) , with complete immunohistochemical data available for 227 . Tumor size , percentage of positive axillary nodes and expression status for the progesterone receptor , Ki-67 and carbonic anhydrase IX demonstrated independent prognostic significance with respect to relapse-free survival . Our combined biomarker scoring system defined three subgroups in the test set with mean 10-year relapse-free survivals of 75.4 % ( SEM 7.0 % ) , 35.3 % ( SEM 4.1 % ) and 19.3 % ( SEM 7.0 % ) . In the validation set , differences in relapse-free survival for these subgroups remained statistically significant but less marked . Conclusion Biomarkers assessed here carry independent prognostic value for breast cancer with four or more positive axillary nodes and identified clinical ly relevant prognostic subgroups . This approach requires refinement and validation of methodology Introduction A significant survival improvement after postmastectomy radiotherapy was identified in the Danish Breast Cancer Cooperative Group ( DBCG82 ) b and c studies and in the British Columbia R and omized Radiation Trial . Recently , potential predictive value regarding response to postmastectomy radiotherapy was reported for carbonic anhydrase ( CA ) IX in a study ( reported in abstract form ) that included 160 patients . The purpose of the present study was to examine the importance of CA IX to response to postmastectomy radiotherapy in the larger scaled DBCG82 b and c studies . Methods The DBCG82 b and c studies included 3,083 high-risk Danish breast cancer patients . The women were r and omly assigned to postmastectomy radiotherapy plus systemic therapy ( cyclophosfamide , methotrexate and fluorouracil in premenopausal women ; and tamoxifen in postmenopausal women ) or to systemic therapy alone . Cores from invasive tumour-containing paraffin blocks from 1,000 patients ( more than seven nodes surgically removed ) were transferred to tissue microarrays . Tissue microarray sections were stained immunohistochemically for CA IX ( M75 ) . The median follow up for patients remaining alive was 17 years . Clinical end-points were loco-regional recurrence , distant metastases , disease-specific survival and overall survival . Statistical analyses included κ statistics , χ2 or exact tests , Kaplan-Meier probability plots , Log-rank test and Cox regression analyses . Results CA IX was assessable in 945 cores . The percentage of tumours positive for CA IX was 16 % ( ≥ 10 % invasive tumour staining ) . CA IX was not an independent prognostic marker for survival , distant metastases , or locoregional recurrence in the subgroup of 945 patients or within either of the two r and omization arms . In subgroup analyses , however , CA IX was an independent prognostic marker for overall survival among postmenopausal women ( P = 0.001 ) , women with one to three positive nodes ( P = 0.02 ) and hormone receptor positive women ( P = 0.001 ) . Fifteen-year probabilities of overall survival were improved by 9 % and 7 % after postmastectomy radiotherapy for the subgroups of CA IX negative and CA IX positive patients , respectively . Conclusion Within this series of 945 high-risk premenopausal and postmenopausal women , positivity for CA IX was not overall an independent prognostic marker for survival ; only in subgroup analyses was it found to have prognostic value . The improvement in 15-year survival  after postmastectomy radiotherapy was of similar magnitude in the two subgroups of CA IX positive and CA IX negative patients R AND OM association of VL and VH repertoires contributes considerably to antibody diversity1 . The diversity and the affinity are then increased by hypermutation in B cells located in germinal centres2 . Except in the case of ' heavy chain ' disease3 , naturally occurring heavy-chain antibodies have not been described , although antigen binding has been demonstrated for separated heavy chains4 or cloned VH domains5 . Here we investigate the presence of considerable amounts of IgG-like material of Mr 100 K in the serum of the camel ( Camelus dromedarius)6 . These molecules are composed of heavy-chain dimers and are devoid of light chains , but nevertheless have an extensive antigen-binding repertoire , a finding that calls into question the role of light chains in the camel . Camel heavy-chain IgGs lack CH1 , which in one IgG class might be structurally replaced by an extended hinge . Heavy-chain IgGs are a feature of all camelids . These findings open new perspectives in the engineering of antibodies Tumour hypoxia is a microenvironmental factor related to poor response to radiation , chemotherapy , genetic instability , selection for resistance to apoptosis , and increased risk of invasion and metastasis . Hypoxia-regulated carbonic anhydrase IX ( CA IX ) has been studied in various tumour sites and its expression has been correlated with the clinical outcome . The purpose of this study was to investigate the correlation of CA IX expression with outcome in patients with invasive breast cancer . We conducted a retrospective study examining the effects of carbonic anhydrase IX ( CA IX ) on survival in patients with breast cancer . To facilitate the screening of multiple tissue blocks from each patient , tissue microarrays were prepared containing between two and five representative sample s of tumour per patient . Immunohistochemistry was used to examine expression of CA IX in patients with breast cancer . The study includes a cohort of 144 unselected patients with early invasive breast cancer who underwent surgery , and had CA IX expression and follow-up data available for analysis . At the time of analysis , there were 28 deaths and median follow-up of 48 months with 96 % of patients having at least 2 years of follow-up . CA IX was negative for 107 patients ( 17 deaths ) and positive for 37 patients ( 11 deaths ) . Kaplan – Meier survival curves show that survival was superior in the CA IX-negative group with a 2-year survival of 97 % for negatives and 83 % for positives ( log-rank test P=0.01 ) . Allowing for potential prognostic variables in a Cox regression analysis , CA IX remained a significant independent predictor of survival ( P=0.035 ) . This study showed in both univariate and multivariate analysis that survival is significantly inferior in patients with tumour expressing CA IX . Prospect i ve studies are underway to investigate this correlation in clinical trial setting The purpose of this study is to investigate the role of carbonic anhydrase IX ( CAIX ) expression in predicting the response to epirubicin  and disease-free survival ( DFS ) in breast cancer patients enrolled in a single institution trial of primary anthracycline and tamoxifen therapy .  CAIX expression was assessed in 183 patients with T2 - 4 N0 - 1 breast cancer enrolled in a r and omized trial comparing four cycles of single agent epirubicin versus epirubicin+tamoxifen as primary systemic treatment . All patients received postoperatively four cycles of the four weekly i.v . cyclophosphamide , methotrexate , 5-fluorouracil regimen .  Patients with estrogen receptor (ER)-positive primary tumors received 5 years of adjuvant tamoxifen . Pretreatment , p53 ( P=0.007 ) , c-erbB2 ( P<0.01 ) , and Ki67 ( P=0.02 ) were directly associated with CAIX expression , while bcl2 ( P<0.000 ) and ER ( P=0.000 ) and progesterone receptor ( PgR ; P<0.01 ) were inversely correlated . In multivariate analysis , only high p53 and low bcl2 were independently associated with CAIX positivity . CAIX immunostaining was significantly associated with poor outcome for DFS ( P<0.002 ) and overall survival ( P=0.001 ) . In multivariate analysis , a significant interaction was found between CAIX and markers of hormone sensitivity , bcl2 ( P=0.01 ) , ER ( P=0.02 ) , PgR ( P=0.02 ) , and lymph node involvement ( P=0.04 ) , in predicting DFS . Presently , there are few clinical markers of resistance to tamoxifen treatment in ER-positive tumors . CAIX expression in breast cancer patients shows a negative predictive role of treatment efficacy in ER-positive patients on the adjuvant tamoxifen after primary chemo-endocrine therapy . Studies investigating the effects of pH on tamoxifen uptake and the effects of therapy with CA inhibitors are planned Introduction The purpose of the present study was to investigate the relationship of expression of hypoxia inducible factor (HIF)-1α-modifying enzymes prolyl hydroxylase (PHD)1 , PHD2 and PHD3 to response of tumours and survival in breast cancer patients enrolled in a phase II trial of neoadjuvant anthracycline and tamoxifen therapy .  Methods The expression 
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Conclusions Our results support the potential of hypoxia-related markers as breast cancer molecular imaging targets .
Although specificity is promising , combining targets would be necessary for optimal sensitivity .