***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: The need to identify biomarkers for bevacizumab-based treatment in advanced colorectal cancer is imperative . The aim of this study was to investigate the prognostic role of circulating VEGF , PDGF , SDF-1 , osteopontin and CEA in patients r and omly assigned to three bevacizumab-based regimens . Plasma sample s from 50 patients treated at a single Institution were analysed using the multiplex assay BioPlex ™ 2200 ( Bio-Rad Laboratories , Inc , Berkeley , CA , USA ) at baseline , before first three cycles and subsequently every three cycles until disease progression . Prognostic analyses of baseline values were performed using multivariable Cox models , including disease extension > 10 cm or ≤10 cm ( measured as the sum of the diameters for all target lesions ) as adjustment factor . The association between progression-free and overall survival and biomarkers modulation during treatment was studied using multivariable Cox models , which included summary statistics synthesizing during-treatment modulation together with disease extension . The biomarkers significantly associated with disease extension were baseline CEA ( p = 0.012 ) and SDF-1 ( p = 0.030 ) . High values of VEGF and SDF-1 tended to be associated with worse prognosis , especially in terms of overall survival . The negative prognostic trend was more marked for baseline CEA as compared to other biomarkers ; increasing values during treatment was significantly related to worse prognosis independently of disease extension ( p = 0.007 and 0.016 for progression-free and overall survival , respectively ) . VEGF is related to bevacizumab pharmacodynamics and is associated to other angiogenic cytokines ; some of the proposed biomarkers such as SDF-1 and CEA should be further vali date d for prognosis assessment and monitoring of bevacizumab-based treatment of advanced colorectal cancer Introduction : We previously reported the prognostic significance of the lung adenocarcinoma immune microenvironment . In this study , we preformed comprehensive analysis of immune markers and their associations with prognosis in patients with lung squamous cell carcinoma . Methods : We review ed surgically resected , solitary lung squamous cell carcinoma patients ( n = 485 ; 1999–2009 ) who were r and omly split into a training cohort ( n = 331 ) and validation cohort ( n = 154 ) . We constructed tissue microarrays and performed immunostaining for CD3 , CD45RO , CD8 , CD4 , FoxP3 , CD20 , CD68 , CXCL12 , CXCR4 , CCR7 , interleukin-7 receptor , and interleukin-12 receptor & bgr;2 . Overall survival ( OS ) was analyzed using the log-rank test and the Cox proportional hazards model . Results : Analysis of single immune cell infiltration revealed that high tumor-infiltrating CD10 + neutrophils were associated with worse prognoses in the training cohort ( p = 0.021 ) . Analysis of biologically relevant immune cell combinations identified that patients with high CD10 + neutrophil and low CD20 + lymphocyte had a significantly worse OS ( 5-year OS , 42 % ) than those with other combinations of CD10 and CD20 ( 5-year OS , 62 % ; p < 0.001 ) ; this was confirmed in the validation cohort ( p = 0.032 ) . For the multivariate analysis , high CD10/low CD20 immune cell infiltration was an independent predictor of OS in both the training cohort ( hazard ratio = 1.61 , p = 0.006 ) and the validation cohort ( hazard ratio = 1.75 ; p = 0.043 ) . Conclusion : High CD10+/low CD20 + immune cell infiltration ratio is a significant prognostic factor of lung squamous cell carcinoma . Immunomodulatory therapy of tumor-specific neutrophil and B-lymphocyte responses may have applicability in the treatment of lung squamous cell carcinoma PURPOSE To evaluate the safety , efficacy and biomarkers of short-course proton beam radiation and capecitabine , followed by pancreaticoduodenectomy in a phase 1/2 study in pancreatic ductal adenocarcinoma ( PDAC ) patients . METHODS AND MATERIAL S Patients with radiographically resectable , biopsy-proven PDAC were treated with neoadjuvant short-course ( 2-week ) proton-based radiation with capecitabine , followed by surgery and adjuvant gemcitabine . The primary objective was to demonstrate a rate of toxicity grade ≥ 3 of < 20 % . Exploratory biomarker studies were performed using surgical specimen tissues and peripheral blood . RESULTS The phase 2 dose was established at 5 daily doses of 5 GyE. Fifty patients were enrolled , of whom 35 patients were treated in the phase 2 portion . There were no grade 4 or 5 toxicities , and only 2 of 35 patients ( 4.1 % ) experienced a grade 3 toxicity event ( chest wall pain grade 1 , colitis grade 1 ) . Of 48 patients eligible for analysis , 37 underwent pancreaticoduodenectomy . Thirty of 37 ( 81 % ) had positive nodes . Locoregional failure occurred in 6 of 37 resected patients ( 16.2 % ) , and distant recurrence occurred in 35 of 48 patients ( 72.9 % ) . With median follow-up of 38 months , the median progression-free survival for the entire group was 10 months , and overall survival was 17 months . Biomarker studies showed significant associations between worse survival outcomes and the KRAS point mutation change from glycine to aspartic acid at position 12 , stromal CXCR7 expression , and circulating biomarkers CEA , CA19 - 9 , and HGF ( all , P<.05 ) . CONCLUSIONS This study met the primary endpoint by showing a rate of 4.1 % grade 3 toxicity for neoadjuvant short-course proton-based chemoradiation . Treatment was associated with favorable local control . In exploratory analyses , KRAS(G12D ) status and high CXCR7 expression and circulating CEA , CA19 - 9 , and HGF levels were associated with poor survival Background CXCL12 has been widely reported to play a biologically relevant role in tumor growth and spread . In epithelial ovarian cancer ( EOC ) , CXCL12 enhances tumor angiogenesis and contributes to the immunosuppressive network . However , its prognostic significance remains unclear . We thus compared CXCL12 status in healthy and malignant ovaries , to assess its prognostic value . Methods Immunohistochemistry was used to analyze CXCL12 expression in the reproductive tracts , including the ovaries and fallopian tubes , of healthy women , in benign and borderline epithelial tumors , and in a series of 183 tumor specimens from patients with advanced primary EOC enrolled in a multicenter prospect i ve clinical trial of paclitaxel/carboplatin/gemcitabine-based chemotherapy ( GINECO study ) . Univariate COX model analysis was performed to assess the prognostic value of clinical and biological variables . Kaplan-Meier methods were used to generate progression-free and overall survival curves . Results Epithelial cells from the surface of the ovary and the fallopian tubes stained positive for CXCL12 , whereas the follicles within the ovary did not . Epithelial cells in benign , borderline and malignant tumors also expressed CXCL12 . In EOC specimens , CXCL12 immunoreactivity was observed mostly in epithelial tumor cells . The intensity of the signal obtained ranged from strong in 86 cases ( 47 % ) to absent in 18 cases ( < 10 % ) . This uneven distribution of CXCL12 did not reflect the morphological heterogeneity of EOC . CXCL12 expression levels were not correlated with any of the clinical parameters currently used to determine EOC prognosis or with HER2 status . They also had no impact on progression-free or overall survival . Conclusion Our findings highlight the previously unappreciated constitutive expression of CXCL12 on healthy epithelia of the ovary surface and fallopian tubes , indicating that EOC may originate from either of these epithelia . We reveal that CXCL12 production by malignant epithelial cells precedes tumorigenesis and we confirm in a large cohort of patients with advanced EOC that CXCL12 expression level in EOC is not a valuable prognostic factor in itself . Trial Registration Clinical Trials.gov : The development of tumor biomarkers ready for clinical use is complex . We propose a refined system for biomarker study design , conduct , analysis , and evaluation that incorporates a hierarchal level of evidence scale for tumor marker studies , including those using archived specimens . Although fully prospect i ve r and omized clinical trials to evaluate the medical utility of a prognostic or predictive biomarker are the gold st and ard , such trials are costly , so we discuss more efficient indirect " prospect ive-retrospective " design s using archived specimens . In particular , we propose new guidelines that stipulate that 1 ) adequate amounts of archived tissue must be available from enough patients from a prospect i ve trial ( which for predictive factors should generally be a r and omized design ) for analyses to have adequate statistical power and for the patients included in the evaluation to be clearly representative of the patients in the trial ; 2 ) the test should be analytically and preanalytically vali date d for use with archived tissue ; 3 ) the plan for biomarker evaluation should be completely specified in writing before the performance of biomarker assays on archived tissue and should be focused on evaluation of a single completely defined classifier ; and 4 ) the results from archived specimens should be vali date d using specimens from one or more similar , but separate , studies 
    Output:
    
Conclusions : Determination of CXCL12 expression has the potential to be of use as a cancer biomarker and adds prognostic information in various cancer types .