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Purpose: To develop an immune-based gene expression risk score to identify patients with cervical cancer at increased risk of distant metastases (DM)., Experimental Design: Tumor biopsies were obtained from 81 patients prior to chemoradiotherapy. Whole-transcriptome RNA sequencing was performed (Illumina NextSeq500). Beginning with 4,723 immune-related genes, a 55-gene risk score for DM was derived using Cox modeling and principal component analysis. It was validated in independent cohorts of 274 patients treated at the Norwegian Radium Hospital (NRH) and 206 patients from The Cancer Genome Atlas (TCGA)., Results: The risk score was predictive of DM (HR, 2.7; P < 0.0001) and lower cause-specific survival (CSS) by univariate analysis (HR, 2.0; P = 0.0003) and multivariate analysis adjusted for clinical factors (DM HR, 3.0; P < 0.0001; CSS HR, 2.2; P = 0.0004). The risk score predicted DM (HR, 1.4; P = 0.05) and CSS (HR, 1.48; P = 0.013) in the NRH cohort and CSS (HR, 1.4; P = 0.03) in TCGA cohort. Higher risk scores were associated with lower CIBERSORT estimates of tumor-infiltrating immune cells, including CD8 T cells and M1 and M2 macrophages (all P < 0.001). Higher risk scores were associated with lower expression (all P < 0.001) of important chemokines (CXCL12, CXCR4), IFN-regulated genes (IRF1, STAT1, IDO1), and immune checkpoint regulators (PD-1, PD-L1, CTLA-4)., Conclusions: The immune metastatic risk score addresses important challenges in the treatment of cervical cancer-identifying patients at high risk of DM after radiotherapy. The findings of this study indicate that high tumor mutational burden and a "cold," immune-excluded tumor microenvironment influence distant metastatic recurrence. Further validation of the risk score is needed., (©2024 American Association for Cancer Research.)

Background: Standard treatment for locally advanced cervical cancer is chemoradiotherapy, but many patients relapse and die of metastatic disease. We aimed to determine the effects on survival of adjuvant chemotherapy after chemoradiotherapy., Methods: The OUTBACK trial was a multicentre, open-label, randomised, phase 3 trial done in 157 hospitals in Australia, China, Canada, New Zealand, Saudi Arabia, Singapore, and the USA. Eligible participants were aged 18 year or older with histologically confirmed squamous cell carcinoma, adenosquamous cell carcinoma, or adenocarcinoma of the cervix (FIGO 2008 stage IB1 disease with nodal involvement, or stage IB2, II, IIIB, or IVA disease), Eastern Cooperative Oncology Group performance status 0-2, and adequate bone marrow and organ function. Participants were randomly assigned centrally (1:1) using a minimisation approach and stratified by pelvic or common iliac nodal involvement, requirement for extended-field radiotherapy, FIGO 2008 stage, age, and site to receive standard cisplatin-based chemoradiotherapy (40 mg/m 2 cisplatin intravenously once-a-week for 5 weeks, during radiotherapy with 45·0-50·4 Gy external beam radiotherapy delivered in fractions of 1·8 Gy to the whole pelvis plus brachytherapy; chemoradiotherapy only group) or standard cisplatin-based chemoradiotherapy followed by adjuvant chemotherapy with four cycles of carboplatin (area under the receiver operator curve 5) and paclitaxel (155 mg/m 2 ) given intravenously on day 1 of a 21 day cycle (adjuvant chemotherapy group). The primary endpoint was overall survival at 5 years, analysed in the intention-to-treat population (ie, all eligible patients who were randomly assigned). Safety was assessed in all patients in the chemoradiotherapy only group who started chemoradiotherapy and all patients in the adjuvant chemotherapy group who received at least one dose of adjuvant chemotherapy. The OUTBACK trial is registered with ClinicalTrials.gov, NCT01414608, and the Australia New Zealand Clinical Trial Registry, ACTRN12610000732088., Findings: Between April 15, 2011, and June 26, 2017, 926 patients were enrolled and randomly assigned to the chemoradiotherapy only group (n=461) or the adjuvant chemotherapy group (n=465), of whom 919 were eligible (456 in the chemoradiotherapy only group and 463 in the adjuvant chemotherapy group; median age 46 years [IQR 37 to 55]; 663 [72%] were White, 121 [13%] were Black or African American, 53 [6%] were Asian, 24 [3%] were Aboriginal or Pacific islander, and 57 [6%] were other races) and included in the analysis. As of data cutoff (April 12, 2021), median follow-up was 60 months (IQR 45 to 65). 5-year overall survival was 72% (95% CI 67 to 76) in the adjuvant chemotherapy group (105 deaths) and 71% (66 to 75) in the chemoradiotherapy only group (116 deaths; difference 1% [95% CI -6 to 7]; hazard ratio 0·90 [95% CI 0·70 to 1·17]; p=0·81). In the safety population, the most common clinically significant grade 3-4 adverse events were decreased neutrophils (71 [20%] in the adjuvant chemotherapy group vs 34 [8%] in the chemoradiotherapy only group), and anaemia (66 [18%] vs 34 [8%]). Serious adverse events occurred in 107 (30%) in the adjuvant chemotherapy group versus 98 (22%) in the chemoradiotherapy only group, most commonly due to infectious complications. There were no treatment-related deaths., Interpretation: Adjuvant carboplatin and paclitaxel chemotherapy given after standard cisplatin-based chemoradiotherapy for unselected locally advanced cervical cancer increased short-term toxicity and did not improve overall survival; therefore, it should not be given in this setting., Funding: National Health and Medical Research Council and National Cancer Institute., Competing Interests: Declaration of interests LRM reports grant from National Health and Medical Research Council (NHMRC) Australia for support for the present manuscript. KNM reports research funding to institution outside of submitted work from PTC Therapeutics, Lilly, Merck, and GSK/Tesaro; participation on an Advisory Board for AstraZeneca, Aravive, Alkemeres, Addi, Blueprint Medicines, Eisai, EMD Serono, Elevar Therapeutics, GSK/Tesaro, Genentench/Roche, Hengrui, Immunogen, INXmed, IMab, Lilly, Mereo, Mersana Therapeutics, Merck, Myriad, Novartis, Novocure, OncXerna, Onconova Therapeutics, Tarveda Therapeutics, VBL Therapeutics, and Verastem Oncology; and leadership role as Associate Director of Gynecological Oncology Group Partners and on the Board of Directors for GOG Foundation. WSJ reports honoraria for invited talks from Carl Zeiss; payments made for participation on a data and safety monitoring board from Novocure; and Co-Chair of Gynaecological Committee until June 2020 with NRG Oncology. DKG reports grants and contracts from Elekta; payment or honoraria from ANZGOG, payment for expert testimony from in a Montana court case, participating on a DSMB or Advisory Board for Merck; and leadership role in NRG Oncology as Co-Chair of the Gyn Committee. PK reports funding outside of this submitted work from ANZGOG Fund for New Research and Medical Research Future Fund Reproductive Cancers Grant; is the Deputy Chair of Treatment Pillar for the National Cervical Cancer Elimination Strategy; is on the Board Director for ANZGOG and AMA Victoria. WKH reports consulting fee payments from AstraZeneca and SeaGen and payment for participation on a DSMB from Syneos and Inovio. CAM reports support for the present manuscript from National Cancer Institute, and funding to their institution from Syros, Deciphera, Astellas Pharma GlaxoSmithKline/Tesaro, Seagen, Genmab, EMD Serono, Merck, Regeneron, Moderna, Astra Zeneca, and Genentech, outside of the submitted work. TEL reports support for the present manuscript from the National Cancer Institute Community Research Program and support for attending meetings and travel from SHCC MU NCORP Grant. CHH reports support for the present manuscript from GOG and NRG, and leadership role in the Executive Board, Western Association of Gynecologic Oncology, and the 2023 Program Committee Chair, Western Association of Gynecologic Oncology. MQ reports personal payment as Chair of an independent data and safety monitoring committee for the Garnet Study and Tesaro Study from GSK, and Chair of DSMB for the COMPASS Study. DR reports trial funding all to institution outside of submitted work from MSD, GSK, Regeneron, Roche, Bristol Myers Squibb, Kura, ALX Oncology and participation on a DSMB for MSD, Regeneron, Sanofi. BJM reports consulting fees from Acrivon, Adaptimune, Agenus, Akeso Bio, Amgen, Aravive, AstraZeneca, Bayer, Clovis, Easai, Elevar, EMD Merck, Genmab/Seagen, GOG Foundation, Gradalis, Heng Rui, ImmunoGen, Karyopharm, Iovance, Laekna, Macrogenics, Merck, Mersana, Myriad, Novartis, Novocure, OncoC4, Panavance, Pieris, Pfizer, Puma, Regeneron, Roche/Genentech, Sorrento, TESARO/GSK, US Oncology Research, and VBL Therapeutics, Verastem, Zentalis and payment or honoraria from AstraZeneca, Merck, Myriad, TESARO/GSK, Roche/Genentech, Clovis, and Easai. MRS reports grant to institution from NHMRC Australia for support for the present manuscript, and grants to their institution from Amgen, Astellas, AstraZeneca, Bayer, BeiGene, Bristol Myers Squibb, Celgene, Medivation, Merck Sharp & Dohme, Novartis, Pfizer, Roche, Sanofi, and Tilray. All other authors declare no competing interests., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Purpose: Accurate target definition is critical for the appropriate application of radiation therapy. In 2008, the Radiation Therapy Oncology Group (RTOG) published an international collaborative atlas to define the clinical target volume (CTV) for intensity modulated pelvic radiation therapy in the postoperative treatment of endometrial and cervical cancer. The current project is an updated consensus of CTV definitions, with removal of all references to bony landmarks and inclusion of the para-aortic and inferior obturator nodal regions., Methods and Materials: An international consensus guideline working group discussed modifications of the current atlas and areas of controversy. A document was prepared to assist in contouring definitions. A sample case abdominopelvic computed tomographic image was made available, on which experts contoured targets. Targets were analyzed for consistency of delineation using an expectation-maximization algorithm for simultaneous truth and performance level estimation with kappa statistics as a measure of agreement between observers., Results: Sixteen participants provided 13 sets of contours. Participants were asked to provide separate contours of the following areas: vaginal cuff, obturator, internal iliac, external iliac, presacral, common iliac, and para-aortic regions. There was substantial agreement for the common iliac region (sensitivity 0.71, specificity 0.981, kappa 0.64), moderate agreement in the external iliac, para-aortic, internal iliac and vaginal cuff regions (sensitivity 0.66, 0.74, 0.62, 0.59; specificity 0.989, 0.966, 0.986, 0.976; kappa 0.60, 0.58, 0.52, 0.47, respectively), and fair agreement in the presacral and obturator regions (sensitivity 0.55, 0.35; specificity 0.986, 0.988; kappa 0.36, 0.21, respectively). A 95% agreement contour was smoothed and a final contour atlas was produced according to consensus., Conclusions: Agreement among the participants was most consistent in the common iliac region and least in the presacral and obturator nodal regions. The consensus volumes formed the basis of the updated NRG/RTOG Oncology postoperative atlas. Continued patterns of recurrence research are encouraged to refine these volumes., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Importance: In women with locally advanced cancer of the cervix (LACC), staging defines disease extent and guides therapy. Currently, undetected disease outside the radiation field can result in undertreatment or, if disease is disseminated, overtreatment., Objective: To determine whether adding fludeoxyglucose F 18 positron emission tomography-computed tomography (PET-CT) to conventional staging with CT of the abdomen and pelvis affects therapy received in women with LACC., Design, Setting, and Participants: A randomized clinical trial was conducted. Women with newly diagnosed histologically confirmed International Federation of Gynecology and Obstetrics stage IB to IVA carcinoma of the cervix who were candidates for chemotherapy and radiation therapy (CRT) were allocated 2:1 to PET-CT plus CT of the abdomen and pelvis or CT alone. Enrollment occurred between April 2010 and June 2014 at 6 regional cancer centers in Ontario, Canada. The PET-CT scanners were at 6 associated academic institutions. The median follow-up at the time of the analysis was 3 years. The analysis was conducted on March 30, 2017., Interventions: Patients received either PET-CT plus CT of the abdomen and pelvis or CT of the abdomen and pelvis., Main Outcomes and Measures: Treatment delivered, defined as standard pelvic CRT vs more extensive CRT, ie, extended field radiotherapy or therapy with palliative intent., Results: One hundred seventy-one patients were allocated to PET-CT (n = 113) or CT (n = 58). The trial stopped early before the planned target of 288 was reached because of low recruitment. Mean (SD) age was 48.1 (11.2) years in the PET-CT group vs 48.9 (12.7) years in the CT group. In the 112 patients who received PET-CT, 68 (60.7%) received standard pelvic CRT, 38 (33.9%) more extensive CRT, and 6 (5.4%) palliative treatment. The corresponding data for the 56 patients who received CT alone were 42 (75.0%), 11 (19.6%), and 3 (5.4%). Overall, 44 patients (39.3%) in the PET-CT group received more extensive CRT or palliative treatment compared with 14 patients (25.0%) in the CT group (odds ratio, 2.05; 95% CI, 0.96-4.37; P = .06). Twenty-four patients in the PET-CT group (21.4%) received extended field radiotherapy to para-aortic nodes and 14 (12.5%) to common iliac nodes compared with 8 (14.3%) and 3 (5.4%), respectively, in the CT group (odds ratio, 1.64; 95% CI, 0.68-3.92; P = .27)., Conclusions and Relevance: There was a trend for more extensive CRT with PET-CT, but the difference was not significant because the trial was underpowered. This trial provides information on the utility of PET-CT for staging in LACC., Trial Registration: ClinicalTrials.gov Identifier: NCT00895349.

Background: To examine the association between metformin use and mortality in patients with diabetes and cervical cancer., Methods: Using Ontario health databases, a retrospective, population-based cohort study was conducted in women with diabetes ≥ age 66 years diagnosed with cervical cancer between 1997 and 2010. The association between metformin exposure and cervical cancer-specific mortality was examined using Fine-Gray regression models, with noncancer death as a competing risk and cumulative metformin use as a time-varying exposure. The association with overall mortality was examined using Cox regression models., Results: Among the 181 women with diabetes and cervical cancer, there were 129 deaths, including 61 cervical cancer-specific deaths. The median follow-up was 5.8 years (interquartile range 4.2-9.6 years) for surviving patients. Cumulative dose of metformin after cervical cancer diagnosis was independently associated with a decreased risk of cervical cancer-specific mortality and overall mortality in a dose-dependent fashion [HR 0.79; 95% confidence interval (CI), 0.63-0.98; and HR 0.95; 95% CI, 0.90-0.996 per each additional 365 g of metformin use, respectively]. There was no significant association between cumulative use of other antidiabetic drugs and cervical cancer-specific mortality., Conclusion: This study suggests an association between cumulative metformin use after cervical cancer diagnosis and lower cervical cancer-specific and overall mortality among older women with diabetes., Impact: Cumulative dose of metformin use after cervical cancer diagnosis among older women with diabetes may be associated with a significant decrease in mortality. This finding has important implications if validated prospectively, as metformin is inexpensive and can be easily combined with standard treatment for cervical cancer., (©2015 American Association for Cancer Research.)

Radiotherapy (RT) with concurrent cisplatin (CRT) is standard treatment for locally advanced cervical cancer. However, not all patients benefit from the addition of cisplatin to RT alone. This study explored the value of pretreatment tumor interstitial fluid pressure (IFP) and hypoxia measurements as predictors of cisplatin response in 291 patients who were treated with RT (1994-1998) or RT plus concurrent cisplatin (1999-2009). Clinical characteristics were similar between the two groups, apart from a greater proportion of patients with pelvic lymph node metastases and hypoxic tumors in the CRT cohort. Patients were followed for a median duration of 5.6 years. Information about recurrence and survival was recorded prospectively. The addition of cisplatin to RT improved survival compared to treatment with RT alone (HR 0.61, p = 0.0097). This improvement was confined to patients with high-IFP tumors at diagnosis (HR 0.40, p = 0.00091). There was no benefit of adding cisplatin in those with low-IFP tumors (HR 1.05, p = 0.87). There was no difference in the effectiveness of cisplatin in patients with more or less hypoxic tumors. In conclusion, patients with locally advanced cervical cancer and high tumor IFP at diagnosis have greater benefit from the addition of cisplatin to RT than those with low IFP. This may reflect high tumor cell proliferation, which is known to influence IFP, local tumor control and patient survival., (© 2013 UICC.)

Purpose: ERCC1 (excision repair cross-complementation group 1) expression has been shown to be a molecular marker of cisplatin resistance in many tumor sites, but has not been well studied in cervical cancer patients. The purpose of this study was to measure tumoral ERCC1 in patients with locally advanced cervical cancer treated with chemoradiation therapy (CRT) in a large multicenter cohort, and to correlate expression with clinical outcome parameters., Methods and Materials: A total of 264 patients with locally advanced cervical cancer, treated with curative-intent radical CRT from 3 major Canadian cancer centers were evaluated. Pretreatment formalin-fixed, paraffin-embedded tumor specimens were retrieved, and tissue microarrays were constructed. Tumoral ERCC1 (FL297 antibody) was measured using AQUA (R) technology. Statistical analysis was performed to determine the significance of clinical factors and ERCC1 status with progression-free survival (PFS) and overall survival (OS) at 5 years., Results: The majority of patients had International Federation of Gynecology and Obstetrics (FIGO) stage II disease (n=119, 45%); median tumor size was 5 cm. OS was associated with tumor size (HR 1.16, P=.018), pretreatment hemoglobin status (HR 2.33, P=.00027), and FIGO stage. In addition, tumoral ERCC1 status (nuclear to cytoplasmic ratio) was associated with PFS (HR 2.33 [1.05-5.18], P=.038) and OS (HR 3.13 [1.27-7.71], P=.013). ERCC1 status was not significant on multivariate analysis when the model was adjusted for the clinical factors: for PFS (HR 1.49 [0.61-3.6], P=.38); for OS (HR 2.42 [0.94-6.24] P=.067)., Conclusions: In this large multicenter cohort of locally advanced cervical cancer patients treated with radical CRT, stage, tumor size, and pretreatment hemoglobin status were significantly associated with PFS and OS. ERCC1 status appears to have prognostic impact on univariate analysis in these patients, but was not independently associated with outcome on multivariate analysis., (Copyright © 2013. Published by Elsevier Inc.)

Background: Hedgehog (Hh) signaling was assessed in patients with primary cervical carcinoma who were receiving chemoradiation. Because the up-regulation of Hh has been reported in response to hypoxia, the authors examined associations between Hh gene expression and measurements of HP5 (the percentage of oxygen pressure readings in each tumor <5 mm Hg) and interstitial fluid pressure (IFP)., Methods: Sonic hedgehog (SHH), Indian hedgehog (IHH), patched 1 and 2 (PTCH1 and PTCH2), smoothened (SMO), and glioma-associated oncogene family zinc finger 1 (Gli1) expression levels were determined using quantitative reverse transcriptase-polymerase chain reaction analysis on 85 frozen samples of primary cervical carcinoma and on 16 normal cervical samples. Clinicopathologic data were collected prospectively. Possible correlations between Hh expression and tumor hypoxia (HP5 and IFP) measured at the time of biopsy, the time to local recurrence, and disease-free survival (DFS) were examined., Results: At least 1 member of the Hh pathway was elevated in all but 1 tumor compared with normal tissue (P < .0001). Hh gene expression was heterogeneous with SHH, IHH, and GLI exhibiting bimodal distribution. Elevation of SHH expression (P = .04) and low SMO expression (P = .0007) were associated with HP5. The risk of local recurrence was associated with the up-regulation of SMO (hazard ratio [HR], 2.41; 95% confidence interval [CI], 1.00-5.82; P = .044), the up-regulation of >3 Hh genes (HR, 2.56; 95% CI, 1.09-6.00; P = .026), tumor size (HR, 1.41; 95% CI, 1.14-1.74; P = .0015), and lymph node-positive disease (HR, 2.82; 95% CI, 1.16-6.86; P = .022)., Conclusions: The proportion of tumors that expressed Hh genes in cervical cancer was very high. The current data support a role for the Hh pathway in repopulation after chemoradiation and suggest that SMO may be a valid therapeutic target. The authors concluded that further investigation into this pathway after radiation and Hh inhibition are warranted., (Copyright © 2011 American Cancer Society.)

Objective: To determine the optimal recommended program for the follow-up of patients who are disease free after completed primary therapy for cervical cancer., Methods: Systematic search of MEDLINE, EMBASE and the Cochrane Library databases (1980-November 2007)., Results: Seventeen retrospective trials were identified. Most studies reported similar intervals for follow-up and ranged from a low of 9 visits to a high of 28 visits over 5 years. Follow-up visits typically occurred once every 3-4 months for the first 2 years, every 6 months for the next 3 years and then annually until year 10. All 17 trials reported that a physical exam was performed at each visit. Vaginal vault cytology was analyzed in 13 trials. Other routine surveillance tests included chest x-ray, ultrasound, CT scans, MRI, intravenous pyelography and tumour markers. Median time to recurrence ranged from 7-36 months after primary treatment. Rates of recurrence ranged from 8-26% with 14-57% of patients recurring in the pelvis, and 15-61% of patients recurring at distant or multiple sites. Of the 8-26% of patients who experienced disease recurrence, the vast majority, 89-99%, had recurred by year 5. Upon recurrence, median survival was 7-17 months. Asymptomatic recurrent disease was detected using physical exam in 29-71%, chest x-ray in 20-47%, CT in 0-34% and vaginal vault cytology in 0-17% of patients, respectively., Conclusion: There is modest low quality evidence to inform the most appropriate follow-up strategy for patients with cervical cancer who are clinically disease free after receiving primary treatment. Follow-up visits should include a complete physical examination whereas, frequent vaginal vault cytology does not add significantly to the detection of early disease recurrence. Patients should return to annual population-based screening after 5 years of recurrence-free follow-up.

Immunohistochemistry (IHC) is used extensively to assess markers for prognosis and sensitivity to novel anticancer agents, as well as in the routine clinical assessment of cancers. Yet, although it is well known that tumors are highly heterogeneous, the resulting sampling error in the measurement of histological markers is often ignored, particularly in basic scientific studies. In this paper, we tested the hypothesis that the optimization of tissue sampling to compensate for heterogeneity improves the correlation between histological measurements of the intrinsic hypoxia marker carbonic anhydrase IX (CAIX) and global tumor oxygenation status. The study was based on a group of 24 patients with invasive cervical carcinoma from whom multiple biopsies were obtained at the time of direct pO2 assessment within the tumor, done as part of a research study. Measurements were made by image analysis of multiple deep sections cut through these biopsies, labeled for CAIX using both immunofluorescence and immunohistochemical techniques, and included tissue microarray (TMA) simulations. Variance and correlation analysis showed that the size of the tissue sample (biopsy or TMA core) was the major factor affecting accuracy of measurement in the sample. Sampling of multiple biopsies/cores also improved the global tumor assessment, provided that these were sufficiently separated in space. Optimization of sampling resulted in an improved correlation of CAIX staining with tumor pO2 measurements, consistent with the hypothesis. However, CAIX was inferior to pO2 measurements as a tool for patient stratification. Improved analytical methods to account for intratumoral heterogeneity are needed to provide reliable measurements of molecular markers.

Purpose: To define the minimal number of pO(2) measurements, with 90% sensitivity and 90% specificity, needed to categorize cervical tumors as either hypoxic or oxic., Methods and Materials: Using Eppendorf oxygen probe data from our ongoing prospective trial, we simulated the measurement of tumor oxygenation with a smaller number of data points in 135 patients with cervical cancer. The hypoxic proportion, defined as the percentage of pO(2) values <5 mm Hg (HP5), was calculated for each tumor. Hypoxic tumors were defined as those with a median HP5 >50%, and tumors with normal oxygen levels as those with a median HP5 < or =50%. A small number of pO(2) measurements were randomly selected from the Eppendorf measurements in each tumor, or per Eppendorf track, and used to define the tumor as hypoxic or oxic. The sensitivity and specificity were calculated, considering the classification as given by the complete set of Eppendorf measurements as the reference standard., Results: The probability of falsely classifying the tumor decreased as the selected number of pO(2) measurements per tumor increased, and at 16 measurements was approximately 10%. Adding additional measurements per tumor beyond 24 improved the ability to classify the tumor accurately only slightly. The probability of falsely classifying the tumor decreased as the pO(2) measurements per track increased. At five measurements per track, the probability of falsely classifying the tumor was approximately 9%., Conclusion: Approximately 20 measurements per tumor, or five measurements per track, using the Eppendorf pO(2) histograph, are sufficient to categorize cervical tumors as hypoxic or oxic. The results of this study will serve as a guide for research clinicians in the use of this and other systems in the assessment of tumor oxygenation in humans.

Purpose: To investigate the relations between hypoxia-inducible factor-1 (HIF-1), tumor oxygenation, and clinical correlates in patients with locally advanced carcinoma of the uterine cervix., Methods and Materials: Biopsies from 42 patients with invasive cervical carcinoma and previous polarographic O2 measurements were assessed for the expression of HIF-1alpha using digitized microscopic imaging and analysis., Results: The HIF-1alpha expression levels ranged from <0.1% to 10.7% of the total tumor area; the positive staining was localized exclusively to the nuclei. Three distinct arrangement patterns of HIF-1alpha-positive cells in relation to blood vessels were identified using spatial image mapping: (1) most HIF-1alpha-positive cells were located within the typical oxygen diffusion distance in tissue (< or =150 microm to the nearest blood vessel); (2) most HIF-1alpha-positive cells were located in the vicinity (< or =60 microm) of the blood vessels; and (3) no apparent spatial relationship was found between HIF-1alpha-positive cells and blood vessels. A statistically significant association was found between HIF-1alpha expression and tumor oxygenation (Spearman correlation coefficient = 0.4, p <0.01), as determined with the Eppendorf pO2 histograph. No correlation was found between the level of HIF-1alpha expression and patient outcome, using disease-free survival as the end point., Conclusion: Our results suggest that HIF-1alpha expression may represent a useful biologic marker for hypoxia in uterine cervical cancer.