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Pelvic Lymph Node FDG Uptake as a Prognostic Biomarker in Newly Diagnosed Locally-advanced Cervical Cancer
Proceedings of the 51st Annual ASTRO Meeting \14 cc cohort had Grade 3 images. In the $62 cc cohort, HR-GTV and PET MTV had a mean volume overlap of 70.7% (mean HR-GTV 124.1 cc, mean PET MTV 117.2 cc.) This overlap fell to 51.2% (33.2, 34.5 cc) for the 14–62 cc cohort, and 30.1% (8.6, 8.8 cc) for the \14 cc cohort. These overlap differences between cohorts were statistically significant on ANOVA testing (p \ 0.001). Conclusions: Tumors of all sizes were well-visualized on FDG-PET/CT. MRI provided better measurements for larger tumors compared with smaller tumors. This led to a higher volume of FDG-avid disease excluded from the HR-GTV for smaller tumors. The FDG-PET/CT simulation for 3D treatment planning visualizes GTVs that are otherwise missed by MRI, especially in tumors \14 cc. Author Disclosure: D.J. Ma, None; J. Zhu, None; P.W. Grigsby, None.
1054
Evaluation of Nodal Coverage for Cervical Cancer by In Vivo Localization of Sentinel Lymph Nodes
A. K. Bhatt, G. M. Cannon, D. M. Kushner, M. A. Wilson, K. A. Bradley University of Wisconsin Hospitals & Clinics, Madison, WI Purpose/Objective(s): To assess coverage of sentinel nodes, as determined by hybrid SPECT/CT scan followed by sentinel lymph node (SLN) dissection, in carcinoma of the cervix by 2D conventional, CT-based 3D conformal (3D-CRT) and intensity modulated radiation therapy (IMRT) pelvic treatment fields. Materials/Methods: Twenty patients previously enrolled on a prospective trial assessing the role of SPECT/CT scan and SLN dissection in cervical cancer were evaluated. Operative notes, pathology reports, and SPECT/CT scans were used to locate the SLNs. Identified SLNs were then contoured on a representative patient. The initial nodal area was contoured as a 1 cm circle on an axial slice and then volumetrically expanded 0.5 cm axially and 0.75 cm cranio-caudally to create a sentinel node PTV (snPTV). These contours were hidden and 2D conventional (based on bony landmarks: sup. border, L5-S1 interspace; inf. border, obturator foramina; lat. border, 2 cm lateral to pelvic brim; ant. border, symphysis pubis; post. border, behind sacrum), 3D-CRT (based on vessels contours), and IMRT (per RTOG 0418) treatment fields were designed. Adequacy of the treatment fields was determined by whether the treatment field encompassed the snPTV. Results: Of the 20 patients originally enrolled, 18 had evaluable SPECT/CT images. Forty-four SLN (19 right and 25 left) were identified and evaluated. There were 15 external iliac, 11 obturator, 8 internal iliac, 6 common iliac, 3 presacral, and 1 para-aortic SNL identified. Conventional 2D fields inadequately covered the snPTV in 6 patients (33%), representing 6 of 44 (13.6%) of the SLNs. Specifically, 3 common iliac, 2 internal iliac and 1 para-aortic snPTV regions extended outside the treatment portal. In 3 patients (16.6 %), the snPTV extended beyond the superior border of the AP/PA and LAT fields. In 3 patients (16.6%), the snPTV extended laterally outside the AP/PA treatment portal. With 3D-CRT and IMRT, 2 patients (11.1%) had inadequate coverage, representing 4.5% (2 of 44) of the identified sentinel nodes. Of the two inadequately covered snPTV, one was a high common iliac node that extended 2 mm beyond the treatment field superiorly and the second was a para-aortic node located at the L4 vertebral body level and was entirely outside the treatment field. Conclusions: Overall, the majority of SLNs identified were covered by radiation pelvic fields. However, conventional treatment fields were more likely to leave SLNs uncovered compared to 3D-CRT or IMRT treatment plans, with greater than 95% of snPTV regions adequately covered using 3D-CRT and IMRT volumes. In 2 cases involving high common iliac and para-aortic nodes, the expanded superior border in the IMRT and 3D-CRT plans still placed the snPTV outside of the treated volume. Author Disclosure: A.K. Bhatt, None; G.M. Cannon, None; D.M. Kushner, None; M.A. Wilson, None; K.A. Bradley, None.
1055
Pelvic Lymph Node FDG Uptake as a Prognostic Biomarker in Newly Diagnosed Locally-advanced Cervical Cancer
P. W. Grigsby, E. A. Kidd, F. Dehdashti, B. A. Siegel Washington University Medical Center, St. Louis, MO Purpose/Objective(s): The goal of this study was to evaluate the prognostic significance of the maximal standardized uptake value (SUVmax) for F-18 fluorodeoxyglucose (FDG) measured by positron emission tomography (PET) in pelvic lymph nodes of cervical cancer patients. Materials/Methods: The study included cervical cancer patients with pelvic lymph node metastasis, as evidenced on FDG-PET, treated between November 2003 and October 2008. Treatment included pelvic external beam radiation, intracavitary brachytherapy, and concurrent chemotherapy. Maximal diameter and SUVmax for the largest pelvic lymph node (SUVPLN) and primary cervix tumor SUVmax (SUVcervix) were recorded from the FDG-PET/CT. The SUVPLN was analyzed for its association with treatment response, pelvic recurrence, disease-specific survival, and overall survival. Results: The population consisted of 83 women with FIGO Stages Ib1–IIIb cervical cancer. The mean age was 51 years (range, 25–88 years) and 88% of tumors were squamous cell histology. The mean SUVPLN was 6.9 (range, 2.1–33.0), while the average SUVcervix was 14.0 (range, 3.2–38.4). The SUVcervix and SUVPLN were weakly correlated, R2 = 0.301. The average pelvic lymph node size was 2.1 cm (range, 0.6–7.9 cm), and also was only weakly associated with SUVPLN, R2 = 0.225. The SUVPLN correlated with the risk of having any persistent disease after treatment (p = 0.0025), specifically in the pelvic lymph node region (p = 0.0003). SUVPLN predicted for increased risk of ever having a pelvic recurrence (p = 0.0035). Patients with higher SUVPLN had significantly worse disease-free (p = 0.0313) and overall survival (p = 0.0474), by Kaplan-Meier evaluation. The Cox Proportional Hazards model for risk of pelvic recurrence was performed including: SUVPLN, maximum pelvic lymph node size, patient age, and tumor stage, and found only increased SUVPLN as an independent predictor.
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I. J. Radiation Oncology d Biology d Physics
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Volume 75, Number 3, Supplement, 2009
Conclusions: The SUVPLN is not strongly related to pelvic lymph node size or SUVcervix, but predicts for treatment response, pelvic recurrence risk, and disease-free survival. The SUVPLN is more predictive of pelvic recurrence risk than young patient age or advanced cervical cancer stage. Author Disclosure: P.W. Grigsby, None; E.A. Kidd, None; F. Dehdashti, None; B.A. Siegel, None.
1056
Topography of Perfusion within the Tumor: Impact of the Differential Distribution of Perfusion on Metastatic Failure in Cervical Cancer
D. Zhang, N. A. Mayr, W. T. C. Yuh, S. S. Lo, J. C. Grecula, Z. Huang, J. Z. Wang The Ohio State University, Columbus, OH Purpose/Objective(s): Poor tumor perfusion, indicative of hypoxia, has been associated with poor local control and survival in cervical cancer. Assessments of tumor perfusion with dynamic contrast-enhanced (DCE) MRI have focused on the overall degree of low DCE in tumors and on imaging timing, without considering the characteristic geographic distribution of the perfusion pattern within the tumor. The purpose of the study was to investigate the topographic and temporal perfusion patterns of cervical cancer and correlate them with treatment failure. Materials/Methods: One hundred one Stage IB2-IVA cervical cancer patients were treated with external beam radiation therapy (RT), concurrent chemotherapy, and brachytherapy. The patients underwent serial DCE-MRI prior to RT start, in early-RT (at 20– 25 Gy), and in mid-RT (at 45–50 Gy). In each MRI, the tumor was delineated as region of interest (ROI) based on the T2-weighted images, and ROIs were transferred to the DCE images. Each tumor contour was separated into a central zone (subcontour at half radius of ROI) and a peripheral zone (beyond outer 10% of radius). The mean signal intensity (mSI) of the peripheral zone (mSIP) and central zone (mSIC) from each serial DCE-MRI were compared and correlated with local control and distant metastasis. Follow-up was 1.2–12.3 (mean, 6.8) years. Results: At pre-RT, mSIP was significantly higher than mSIC (p = 0.001). From pre-RT to early-RT, both increased and mSIP remained significantly higher (p = 0.037). All but one distant metastasis occurred in patients with higher peripheral than central perfusion (mSIP.mSIC) in the early-RT MRI. In this group, the 8-year actuarial metastasis rate was 23% vs. 2% for patients with mSIP# mSIC (p = 0.006). Patients with metastasis had a mean mSIP/mSIC ratio of 1.20 vs. 1.05 for patients without metastasis. There was no difference in local recurrence rate based on differential distribution of perfusion (19% vs. 20%). Differential perfusion in pre-RT and mid-RT MRIs did not correlate with outcome. Conclusions: This preliminary data suggests that relative topographic and temporal variations of tumor perfusion pattern influence metastatic failure, and relatively higher perfusion in the tumor periphery confers a higher risk of developing hematogenous metastases. The mechanism of this is unknown and remains to be determined by future studies. Our findings may suggest that a higher degree of central tumor hypoxia, combined with higher peripheral blood flow may promote tumor cell invasion and metastasis. This additional new DCE-MRI information may augment patients’ risk profiling for metastatic failure, and has the potential to impact therapy selection and treatment outcome. Supported in part by NIH R01 CA 71906. Author Disclosure: D. Zhang, None; N.A. Mayr, NIH R01 CA 71906, B. Research Grant; W.T.C. Yuh, NIH R01 CA 71906, B. Research Grant; S.S. Lo, None; J.C. Grecula, None; Z. Huang, None; J.Z. Wang, None.
1057
Low COX-2 Expression, But Not CD34, Predicts for Worse Overall Survival in Patients with Locallyadvanced Cervical Cancer Treated with Chemoradiotherapy and Celecoxib: A Comparative Immunohistochemical Analysis of RTOG 0128
C. M. Doll1, K. Winter2, D. K. Gaffney3, J. K. Ryu4, A. Jhingran5, A. P. Dicker6, J. B. Weidhaas7, B. E. Miller8, R. Diaz9, A. M. Magliocco10 1 Department of Oncology, Tom Baker Cancer Centre, Calgary, AB, Canada, 2Statistical Department, Radiation Therapy Oncology Group, Philadelphia, PA, 3Department of Radiation Oncology, Huntsman Cancer Hospital, Salt Lake City, UT, 4 Department of Radiation Oncology, University of CA Davis Cancer Center, Sacramento, CA, 5Department of Radiation Oncology, MD Anderson Cancer Center, Houston, TX, 6Department of Radiation Oncology, Thomas Jefferson University, Philadelphia, PA, 7Department of Therapeutic Radiology, Yale University School of Medicine, New Haven, CT, 8Department of Obstetrics/Gynecology, Wake Forest University, Winston Salem, NC, 9Department of Pathology, Tom Baker Cancer Centre, Calgary, AB, Canada, 10Departments of Oncology and Pathology Tom Baker Cancer Centre, Calgary, AB, Canada
Purpose/Objective(s): To measure expression of COX-2 and CD34 in pretreatment tumor biopsies in patients with advanced cervical cancer enrolled on the RTOG 0128 Phase I/II study, and to correlate expression, using multiple technologies, with clinical outcome parameters. Materials/Methods: Patients were treated with concurrent 5-FU and cisplatinum chemotherapy, pelvic radiotherapy, and brachytherapy. Celecoxib was prescribed at 400 mg twice daily, beginning on Day 1, for 1 year. Pretreatment biopsies were placed into tissue microarrays. The COX-2 expression was measured with two different quantitative techniques: automated quantitative image analysis (AQUA), and Chromavision. The CD34 was measured with conventional IHC scoring and AQUA. Cytoplasmic intensity of COX-2, and cytoplasmic percentage area of CD34 were collected. Protein expression data for AQUA scoring was recorded as a continuous variable. Cox regression models and Fisher’s exact test were used to explore associations between expression of the protein markers and clinical endpoints (local-regional failure, disease-free survival, or overall survival). Results: A total of 84 patients were accrued to RTOG 0128 between 2001 and 2004, of which 78 were eligible and analyzable. Median follow-up (range) for patients with COX-2 and CD34 data was 44.5 months (30–66). The COX-2 expression was determined for 37 (47%) and 38 (48%) of patients using AQUA and Chromavision, respectively. The CD34 expression was determined for 42 (54%) and 34 (44%) of patients, using conventional IHC and AQUA, respectively. Median AQUA pretreatment scores COX-2 were 694.2 (AQUA) and 0.93 (Chromavision); median CD34 scores were 3.9 (AQUA) and 3 (conventional IHC). In
1054
Evaluation of Nodal Coverage for Cervical Cancer by In Vivo Localization of Sentinel Lymph Nodes
A. K. Bhatt, G. M. Cannon, D. M. Kushner, M. A. Wilson, K. A. Bradley University of Wisconsin Hospitals & Clinics, Madison, WI Purpose/Objective(s): To assess coverage of sentinel nodes, as determined by hybrid SPECT/CT scan followed by sentinel lymph node (SLN) dissection, in carcinoma of the cervix by 2D conventional, CT-based 3D conformal (3D-CRT) and intensity modulated radiation therapy (IMRT) pelvic treatment fields. Materials/Methods: Twenty patients previously enrolled on a prospective trial assessing the role of SPECT/CT scan and SLN dissection in cervical cancer were evaluated. Operative notes, pathology reports, and SPECT/CT scans were used to locate the SLNs. Identified SLNs were then contoured on a representative patient. The initial nodal area was contoured as a 1 cm circle on an axial slice and then volumetrically expanded 0.5 cm axially and 0.75 cm cranio-caudally to create a sentinel node PTV (snPTV). These contours were hidden and 2D conventional (based on bony landmarks: sup. border, L5-S1 interspace; inf. border, obturator foramina; lat. border, 2 cm lateral to pelvic brim; ant. border, symphysis pubis; post. border, behind sacrum), 3D-CRT (based on vessels contours), and IMRT (per RTOG 0418) treatment fields were designed. Adequacy of the treatment fields was determined by whether the treatment field encompassed the snPTV. Results: Of the 20 patients originally enrolled, 18 had evaluable SPECT/CT images. Forty-four SLN (19 right and 25 left) were identified and evaluated. There were 15 external iliac, 11 obturator, 8 internal iliac, 6 common iliac, 3 presacral, and 1 para-aortic SNL identified. Conventional 2D fields inadequately covered the snPTV in 6 patients (33%), representing 6 of 44 (13.6%) of the SLNs. Specifically, 3 common iliac, 2 internal iliac and 1 para-aortic snPTV regions extended outside the treatment portal. In 3 patients (16.6 %), the snPTV extended beyond the superior border of the AP/PA and LAT fields. In 3 patients (16.6%), the snPTV extended laterally outside the AP/PA treatment portal. With 3D-CRT and IMRT, 2 patients (11.1%) had inadequate coverage, representing 4.5% (2 of 44) of the identified sentinel nodes. Of the two inadequately covered snPTV, one was a high common iliac node that extended 2 mm beyond the treatment field superiorly and the second was a para-aortic node located at the L4 vertebral body level and was entirely outside the treatment field. Conclusions: Overall, the majority of SLNs identified were covered by radiation pelvic fields. However, conventional treatment fields were more likely to leave SLNs uncovered compared to 3D-CRT or IMRT treatment plans, with greater than 95% of snPTV regions adequately covered using 3D-CRT and IMRT volumes. In 2 cases involving high common iliac and para-aortic nodes, the expanded superior border in the IMRT and 3D-CRT plans still placed the snPTV outside of the treated volume. Author Disclosure: A.K. Bhatt, None; G.M. Cannon, None; D.M. Kushner, None; M.A. Wilson, None; K.A. Bradley, None.
1055
Pelvic Lymph Node FDG Uptake as a Prognostic Biomarker in Newly Diagnosed Locally-advanced Cervical Cancer
P. W. Grigsby, E. A. Kidd, F. Dehdashti, B. A. Siegel Washington University Medical Center, St. Louis, MO Purpose/Objective(s): The goal of this study was to evaluate the prognostic significance of the maximal standardized uptake value (SUVmax) for F-18 fluorodeoxyglucose (FDG) measured by positron emission tomography (PET) in pelvic lymph nodes of cervical cancer patients. Materials/Methods: The study included cervical cancer patients with pelvic lymph node metastasis, as evidenced on FDG-PET, treated between November 2003 and October 2008. Treatment included pelvic external beam radiation, intracavitary brachytherapy, and concurrent chemotherapy. Maximal diameter and SUVmax for the largest pelvic lymph node (SUVPLN) and primary cervix tumor SUVmax (SUVcervix) were recorded from the FDG-PET/CT. The SUVPLN was analyzed for its association with treatment response, pelvic recurrence, disease-specific survival, and overall survival. Results: The population consisted of 83 women with FIGO Stages Ib1–IIIb cervical cancer. The mean age was 51 years (range, 25–88 years) and 88% of tumors were squamous cell histology. The mean SUVPLN was 6.9 (range, 2.1–33.0), while the average SUVcervix was 14.0 (range, 3.2–38.4). The SUVcervix and SUVPLN were weakly correlated, R2 = 0.301. The average pelvic lymph node size was 2.1 cm (range, 0.6–7.9 cm), and also was only weakly associated with SUVPLN, R2 = 0.225. The SUVPLN correlated with the risk of having any persistent disease after treatment (p = 0.0025), specifically in the pelvic lymph node region (p = 0.0003). SUVPLN predicted for increased risk of ever having a pelvic recurrence (p = 0.0035). Patients with higher SUVPLN had significantly worse disease-free (p = 0.0313) and overall survival (p = 0.0474), by Kaplan-Meier evaluation. The Cox Proportional Hazards model for risk of pelvic recurrence was performed including: SUVPLN, maximum pelvic lymph node size, patient age, and tumor stage, and found only increased SUVPLN as an independent predictor.
S149
I. J. Radiation Oncology d Biology d Physics
S150
Volume 75, Number 3, Supplement, 2009
Conclusions: The SUVPLN is not strongly related to pelvic lymph node size or SUVcervix, but predicts for treatment response, pelvic recurrence risk, and disease-free survival. The SUVPLN is more predictive of pelvic recurrence risk than young patient age or advanced cervical cancer stage. Author Disclosure: P.W. Grigsby, None; E.A. Kidd, None; F. Dehdashti, None; B.A. Siegel, None.
1056
Topography of Perfusion within the Tumor: Impact of the Differential Distribution of Perfusion on Metastatic Failure in Cervical Cancer
D. Zhang, N. A. Mayr, W. T. C. Yuh, S. S. Lo, J. C. Grecula, Z. Huang, J. Z. Wang The Ohio State University, Columbus, OH Purpose/Objective(s): Poor tumor perfusion, indicative of hypoxia, has been associated with poor local control and survival in cervical cancer. Assessments of tumor perfusion with dynamic contrast-enhanced (DCE) MRI have focused on the overall degree of low DCE in tumors and on imaging timing, without considering the characteristic geographic distribution of the perfusion pattern within the tumor. The purpose of the study was to investigate the topographic and temporal perfusion patterns of cervical cancer and correlate them with treatment failure. Materials/Methods: One hundred one Stage IB2-IVA cervical cancer patients were treated with external beam radiation therapy (RT), concurrent chemotherapy, and brachytherapy. The patients underwent serial DCE-MRI prior to RT start, in early-RT (at 20– 25 Gy), and in mid-RT (at 45–50 Gy). In each MRI, the tumor was delineated as region of interest (ROI) based on the T2-weighted images, and ROIs were transferred to the DCE images. Each tumor contour was separated into a central zone (subcontour at half radius of ROI) and a peripheral zone (beyond outer 10% of radius). The mean signal intensity (mSI) of the peripheral zone (mSIP) and central zone (mSIC) from each serial DCE-MRI were compared and correlated with local control and distant metastasis. Follow-up was 1.2–12.3 (mean, 6.8) years. Results: At pre-RT, mSIP was significantly higher than mSIC (p = 0.001). From pre-RT to early-RT, both increased and mSIP remained significantly higher (p = 0.037). All but one distant metastasis occurred in patients with higher peripheral than central perfusion (mSIP.mSIC) in the early-RT MRI. In this group, the 8-year actuarial metastasis rate was 23% vs. 2% for patients with mSIP# mSIC (p = 0.006). Patients with metastasis had a mean mSIP/mSIC ratio of 1.20 vs. 1.05 for patients without metastasis. There was no difference in local recurrence rate based on differential distribution of perfusion (19% vs. 20%). Differential perfusion in pre-RT and mid-RT MRIs did not correlate with outcome. Conclusions: This preliminary data suggests that relative topographic and temporal variations of tumor perfusion pattern influence metastatic failure, and relatively higher perfusion in the tumor periphery confers a higher risk of developing hematogenous metastases. The mechanism of this is unknown and remains to be determined by future studies. Our findings may suggest that a higher degree of central tumor hypoxia, combined with higher peripheral blood flow may promote tumor cell invasion and metastasis. This additional new DCE-MRI information may augment patients’ risk profiling for metastatic failure, and has the potential to impact therapy selection and treatment outcome. Supported in part by NIH R01 CA 71906. Author Disclosure: D. Zhang, None; N.A. Mayr, NIH R01 CA 71906, B. Research Grant; W.T.C. Yuh, NIH R01 CA 71906, B. Research Grant; S.S. Lo, None; J.C. Grecula, None; Z. Huang, None; J.Z. Wang, None.
1057
Low COX-2 Expression, But Not CD34, Predicts for Worse Overall Survival in Patients with Locallyadvanced Cervical Cancer Treated with Chemoradiotherapy and Celecoxib: A Comparative Immunohistochemical Analysis of RTOG 0128
C. M. Doll1, K. Winter2, D. K. Gaffney3, J. K. Ryu4, A. Jhingran5, A. P. Dicker6, J. B. Weidhaas7, B. E. Miller8, R. Diaz9, A. M. Magliocco10 1 Department of Oncology, Tom Baker Cancer Centre, Calgary, AB, Canada, 2Statistical Department, Radiation Therapy Oncology Group, Philadelphia, PA, 3Department of Radiation Oncology, Huntsman Cancer Hospital, Salt Lake City, UT, 4 Department of Radiation Oncology, University of CA Davis Cancer Center, Sacramento, CA, 5Department of Radiation Oncology, MD Anderson Cancer Center, Houston, TX, 6Department of Radiation Oncology, Thomas Jefferson University, Philadelphia, PA, 7Department of Therapeutic Radiology, Yale University School of Medicine, New Haven, CT, 8Department of Obstetrics/Gynecology, Wake Forest University, Winston Salem, NC, 9Department of Pathology, Tom Baker Cancer Centre, Calgary, AB, Canada, 10Departments of Oncology and Pathology Tom Baker Cancer Centre, Calgary, AB, Canada
Purpose/Objective(s): To measure expression of COX-2 and CD34 in pretreatment tumor biopsies in patients with advanced cervical cancer enrolled on the RTOG 0128 Phase I/II study, and to correlate expression, using multiple technologies, with clinical outcome parameters. Materials/Methods: Patients were treated with concurrent 5-FU and cisplatinum chemotherapy, pelvic radiotherapy, and brachytherapy. Celecoxib was prescribed at 400 mg twice daily, beginning on Day 1, for 1 year. Pretreatment biopsies were placed into tissue microarrays. The COX-2 expression was measured with two different quantitative techniques: automated quantitative image analysis (AQUA), and Chromavision. The CD34 was measured with conventional IHC scoring and AQUA. Cytoplasmic intensity of COX-2, and cytoplasmic percentage area of CD34 were collected. Protein expression data for AQUA scoring was recorded as a continuous variable. Cox regression models and Fisher’s exact test were used to explore associations between expression of the protein markers and clinical endpoints (local-regional failure, disease-free survival, or overall survival). Results: A total of 84 patients were accrued to RTOG 0128 between 2001 and 2004, of which 78 were eligible and analyzable. Median follow-up (range) for patients with COX-2 and CD34 data was 44.5 months (30–66). The COX-2 expression was determined for 37 (47%) and 38 (48%) of patients using AQUA and Chromavision, respectively. The CD34 expression was determined for 42 (54%) and 34 (44%) of patients, using conventional IHC and AQUA, respectively. Median AQUA pretreatment scores COX-2 were 694.2 (AQUA) and 0.93 (Chromavision); median CD34 scores were 3.9 (AQUA) and 3 (conventional IHC). In